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Von Recklinghausen Neurofibromatosis

Synonyms: 

Discussion:

Neurofibromatosis(NF) is an autosomal dominant disease characterized by disordered growth of ectodermal tissues, and is part of a group of disorders called Phakomatoses (neurocutaneous syndrome). (1)

There are three types of neurofibromatosis, although some researchers have proposed as many as eight categories. The two main types of neurofibromatosis are neurofibromatosis 1 (NF1), which affects about 85% of patients diagnosed with neurofibromatosis, and neurofibromatosis 2 (NF2), which accounts for another 10% of patients. NF1 affects approximately 1 in 2,000 to 1 in 5,000 births worldwide. NF2 affects 1 in 35,000 to 1 in 40,000 births worldwide. Recently, schwannomatosis has been recognized as a rare form of NF. Since NF is the most common neurological disorder, NF is more prevalent than the number of people affected by cystic fibrosis, hereditary muscular dystrophy, Huntington's disease, and Tay-Sachs disease combined. In addition to skin and nervous system tumors and skin freckling, NF can lead to disfigurement, blindness, deafness, skeletal abnormalities, loss of limbs, malignancies, and learning disabilities. The degree a person is affected with a form of neurofibromatosis may vary greatly between patients. (2)

NF-1 may also be characterized by unusual largeness of the head (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs, and improper development of certain bones. In individuals with NF-1, associated symptoms and findings may vary greatly in range and severity from case to case. Most people with NF-1 have normal intelligence but learning disabilities appear in about 50% of children with NF-1.

NF-1 is caused by changes (mutations) of a relatively large gene on the long arm (q) of chromosome 17 (17q11.2). The gene regulates the production of a protein known as neurofibromin, which is thought to function as a tumor suppressor. In about 50 percent of individuals with NF-1, the disorder results from spontaneous (sporadic) mutations of the gene that occur for unknown reasons. In others with the disorder, NF-1 is inherited as an autosomal dominant trait.

The name "neurofibromatosis" is sometimes used generally to describe NF-1 as well as a second, distinct form of NF known as neurofibromatosis Type II (NF-2). Also an autosomal dominant disorder, NF-2 is primarily characterized by benign tumors of both acoustic nerves, leading to progressive hearing loss. The auditory nerves (eight cranial nerves) transmit nerve impulses from the inner ear to the brain. (3)

Heredity: The reponsible gene is located on the long arm of chromosome 17 - neurofibromin gene.

Gene map locus 17q11.2

Epidemiology: Its incidence is 1 per 3.000 births and present in about 30 persons per 10.000 population. It is inherited as an autosomal dominant trait, but about 50 percent of cases arise as mutations. (1)

Sypmtoms: NF1

Additional symptoms may include speech impairment, learning disabiltiies, attention deficit disorder.  Siezures, cancers such as brin tumors, leukemia, muscle cancers (rhabdomyosarcoma), adrenal glands (peochromocytome), kidneys, edema/lymphedema.

Diagnosis:

NF1 (Neurofibromatosis 1(Von Recklinghausen's disease) 

Diagnostic criteria - A patient meeting two or more of the following criteria
can be diagnosed as suffering from NF 1

1 - Neurofibromas - Two or more, or one plexiform neurofibroma
2 - Café-au-lait macules - Six or more measuring 1,5 cm in their greatest dimension
3 - Freckling - In the axillary or inguinal areas
4 - Optic glioma
5 - Iris hamartomas(Lisch nodules) - Two or more
6 - Sphenoid dysplasia or thinning of the cortex of the long bones
7 - First-degree relative (1)

Treatment:

There is no treatment for the disease, so any treatment would be symptomatic. Such as surgical removal of neurofibromas if painful or if they present complications.

The lymphedema treatment program would include: Manual lymphatic drainage; compression wraps or compression bandages (using short stretch bandages), compression garments, compression sleeves.

Prognosis:

In most cases, symptoms of NF1 are mild, and patients live normal and productive lives. In some cases, however, NF1 can be severely debilitating. In some cases of NF2, the damage to nearby vital structures, such as other cranial nerves and the brainstem, can be life-threatening.

Pat O'Connor

June 17, 2008

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NEUROFIBROMATOSIS, TYPE I; NF1

Alternative titles; symbols

NEUROFIBROMATOSIS
VON RECKLINGHAUSEN DISEASE
NEUROFIBROMIN, INCLUDED
NF1 MICRODELETION SYNDROME, INCLUDED
NF1 MICRODUPLICATION SYNDROME, INCLUDED

Gene map locus 17q11.2

TEXT

Neurofibromatosis type I (NF1) is caused by mutation in the neurofibromin gene.

DESCRIPTION

Neurofibromatosis is an autosomal dominant disorder characterized particularly by cafe-au-lait spots and fibromatous tumors of the skin. Other features are variably present.

Trovo-Marqui and Tajara (2006) provided a detailed review of neurofibromin and its role in neurofibromatosis.

Some patients with homozygous or compound heterozygous mutations in mismatch repair genes (see, e.g., MLH1; 120436 and MSH2; 609309) have a phenotype characterized by early onset malignancies and mild features of NF1, especially cafe-au-lait spots: see the mismatch repair cancer syndrome (276300), sometimes referred to as brain tumor-polyposis syndrome 1 or Turcot syndrome. These patients typically do not have germline mutations in the NF1 gene, although a study by Wang et al. (2003) suggested that biallelic mutations in mismatch repair genes may cause somatic mutations in the NF1 gene, perhaps resulting in isolated features resembling NF1. 

CLINICAL FEATURES

Crowe et al. (1956) suggested that the presence of 6 spots, each more than 1.5 cm in diameter, is necessary for the diagnosis of neurofibromatosis. Crowe (1964) considered axillary freckling to be an especially useful diagnostic clue. Occasional features include scoliosis, pseudarthrosis of the tibia, pheochromocytoma, meningioma, glioma, acoustic neuroma, optic neuroma, mental retardation, hypertension, and hypoglycemia. Central neurofibromatosis (101000), characterized by bilateral acoustic neuroma and meningioma but few skin lesions or neurofibromas, is a distinct nosologic entity which has come to be known as neurofibromatosis type II. 

The patients described by Hashemian (1952, 1953) apparently had von Recklinghausen neurofibromatosis, although the skin changes were not as striking as in some patients. They had intestinal fibromatosis. Hayes et al. (1961) reported hypoglycemia associated with massive intraperitoneal tumor of mesodermal origin in a patient with typical cutaneous lesions. Neurofibromata of the intestine are a recognized though rare feature of von Recklinghausen neurofibromatosis. Neurofibromata of the bowel leading to gastrointestinal bleeding were described by Manley and Skyring (1961) in a patient with striking skin changes. Chu et al. (1999) described a 10-year-old girl with a 9-month history of anemia and low gastrointestinal bleeding. Imaging studies confirmed by surgery demonstrated a jejunal leiomyoma. 

Fibromas may occur in the iris, and glaucoma occurs in rare instances (Grant and Walton, 1968). Lisch nodules in the iris, a frequent finding in adults, are true tumors, not merely hyperpigmented patches. Zehavi et al. (1986) found Lisch nodules in 73% of 30 cases. They concluded that their presence correlated directly with the severity of skin manifestations. 

Otsuka et al. (2001) performed serial opthalmologic exams on 70 patients of various ages with NF1. Lisch nodules were found in 80% of patients of all ages and in two-thirds of patients younger than 10 years. Only 2 of 45 individuals older than age 10 years did not have Lisch nodules. Lisch nodules were more frequent in familial cases than in sporadic cases, which is likely to be significant as the average age of the first exam was younger for familial cases in this study. Cutaneous neurofibromas developed at the average +/- SD age of 15.1 +/- 3.6 years in patients who had more than 10 Lisch nodules and at 21.8 +/- 3.9 years in those who had fewer than 10 Lisch nodules. The former group was significantly younger than the latter. 

Unusual clinical manifestations were described by Diekmann et al. (1967): hypertension due to renal artery stenosis, and hypertrophy of the clitoris. Sutphen et al. (1995) described clitoromegaly in 4 patients with NF1 and reviewed the literature documenting 26 NF1 patients with clitoral involvement. Involvement of the heart in neurofibromatosis was described and reviewed by Rosenquist et al. (1970), who also reviewed involvement of the abdominal aorta and renal, carotid and other arteries. 

Crowe et al. (1956) found 6 secondary malignant lesions in 168 patients with neurofibromatosis. D'Agostino et al. (1963) discovered 21 cases of secondary neoplasms in his study of 678 cases of neurofibromatosis.

Neurofibromatosis is associated with a tendency to malignant degeneration of the neurofibromas in an estimated 3 to 15% of cases. Knight et al. (1973) reviewed 69 patients with single and 45 patients with multiple neurofibromas. Five patients in the group were found to have a total of 11 secondary malignant lesions including 3 fibrosarcomas, 3 squamous cell carcinomas, and 1 neurofibrosarcoma, among other forms. Some earlier studies have reported mainly sarcomas associated with neurofibromatosis. Hunerbein et al. (1996) described a 56-year-old man with NF1 who had had a 6-month history of recurrent epigastric pain and was found to have a multifocal malignant schwannoma of the duodenum causing biliary obstruction. 

Adornato and Berg (1977) observed the diencephalic syndrome in 2 infants who had neurofibromatosis and hypothalamic tumors.

Although neurofibromatosis type I had been called peripheral neurofibromatosis, it has been associated with tumors of the central nervous system, which include astrocytomas of the visual pathways, ependymomas, meningiomas, and some primitive neuroectodermal tumors. The most common neuroimaging abnormality in neurofibromatosis type I has been a high signal intensity lesion in the basal ganglia, thalamus, brainstem, cerebellum, or subcortical white matter referred to as an 'unidentified bright object' (UBO). These UBOs are thought to represent sites of vacuolar change. Parazzini et al. (1995) documented spontaneous regression of optic pathway lesions in 4 patients with neurofibromatosis type I. They cautioned against diagnosis of optic nerve glioma without evidence of progression. Molloy et al. (1995) studied 17 NF1 patients with brainstem tumors, which also presented increased T2 signal abnormality on MRI scanning. Fifteen of these 17 patients had neurologic signs and symptoms indicative of brainstem dysfunction and 35% of them had evidence of radiographic tumor progression. In the 2 patients that had partial surgical resection, pathology demonstrated either a fibrillary or anaplastic astrocytoma. As 15 of these 17 patients remained alive after a 52-month follow-up, this suggested that these are much less aggressive than typical pontine tumors which should be distinguished from the UBOs seen elsewhere in the brains of neurofibromatosis patients. 

Balcer et al. (2001) examined the neuroophthalmologic records and brain/orbital MRI scans from 43 consecutive pediatric patients with neurofibromatosis type I and optic pathway gliomas. Involvement of the optic tracts and other postchiasmal structures was associated with a significantly higher probability of visual acuity loss. Visual loss was noted in 47% of patients at a median age of 4 years. However, 7% of patients developed initial visual loss during adolescence. The authors recommended close follow-up beyond the early childhood years, particularly for those children with postchiasmal tumor. 

In 54 patients with NF1, Thiagalingam et al. (2004) reviewed the natural history of optic pathway gliomas. The mean age at the time of diagnosis was 5.2 years, with 32 patients having signs or symptoms at the time of diagnosis. Seventeen patients were diagnosed after the age of 6 years. Twenty-two patients had tumor progression within 1 year of diagnosis and 6 patients showed progression after 1 year. Most patients' conditions were managed conservatively (68.5%). At follow-up, 17 patients (31.5%) had severe visual impairment in their worse eye and 16.7% had bilateral moderate to severe visual impairment. Contrary to previous reports (e.g., Balcer et al., 2001), these results showed that optic pathway gliomas in patients with NF1 often presented in older children and might progress some time after diagnosis. Given the potential for serious visual consequences, the authors stressed the need for regular ophthalmologic monitoring of patients with NF1 for a long duration. 

Robertson (1979) reported a patient with neurofibromatosis and grotesque, massive overgrowth of one leg. Benedict et al. (1968) studied the pigmentary anomaly of neurofibromatosis in relation to that of Albright polyostotic fibrous dysplasia. Gross appearance of the pigmented areas was not always reliable. However, special microscopic studies showed giant pigment granules in malpighian cells or melanocytes of normal skin and of neurofibromatosis spots but rarely in Albright syndrome. 

Erickson et al. (1980) described 2 sisters with neurofibromatosis and intracranial arterial occlusive disease leading to the moyamoya pattern of collateral circulation (252350). Four other members of their sibship of 8, and members of 2 previous generations, including the mother, had neurofibromatosis. Yamauchi et al. (2000) stated that more than 50 cases of the association of NF1 and moyamoya disease (607151) had been described, including the cases reported Woody et al. (1992) and Barrall and Summers (1996)

Zonana and Weleber (1984) illustrated a patient who had multiple cafe-au-lait spots of von Recklinghausen type only on the right side of the body. Iris hamartomata (Lisch nodules) were present in the right eye only.

Clark and Hutter (1982) reported an apparent association between the rare entity juvenile chronic myelogenous leukemia and neurofibromatosis. They suggested that other types of nonlymphocytic leukemia have an increased frequency, but Riccardi (1982) raised the question as to whether these are families with only cafe-au-lait spots. Voutsinas and Wynne-Davies (1983) suggested that the risk of malignant change in NF has been exaggerated and that the true value is 2.0% (or 4.2% of those over 21 years). 

Crawford (1986) reported on a study of 116 patients under 12 years of age and reviewed the literature. Among the unusual presentations was rhabdomyosarcoma projecting from the urethra in a girl who also had congenital pseudarthrosis of the tibia. Crawford (1986) stated that 'most of the rhabdomyosarcomas associated with neurofibromatosis involve the genitourinary tract.' 

Oguzkan et al. (2006) described 2 cases of NF1 with rhabdomyosarcoma. The first was that of an infant with overlapping phenotypic features of NF1 and Noonan syndrome who presented with rhabdomyosarcoma of the bladder. The second infant likewise exhibited NF1 features and was also associated with bladder rhabdomyosarcoma. Loss of heterozygosity (LOH) analysis of the NF1 gene using 7 intragenic markers and 1 extragenic polymorphic marker detected a deletion in the NF1 gene in the NF1-Noonan syndrome (NF-NS) case associated with bladder rhabdomyosarcoma. 

Sorensen et al. (1986) conducted a highly valuable follow-up study of natural history in a nationwide cohort of 212 cases (and their families) identified in Denmark by Borberg (1951). Follow-up information was obtained in 99%. All 76 probands had been ascertained through hospitals and were more severely affected than their incidentally identified relatives. Relatives had poorer survival rates than persons in the general population. The worst prognosis was shown by female probands. Malignant neoplasms or benign CNS tumors occurred in 45% of the probands, giving a relative risk of 4.0 compared with expected numbers. Pheochromocytoma occurred in 3 of 212 patients. 

Senveli et al. (1989) reported 6 patients with NF1 who had aqueductal stenosis and hydrocephalus requiring surgical intervention. Ages varied from 14 to 24. Twenty-two similar cases were found in the literature. Westerhof et al. (1983) found hypertelorism in 24% of patients with neurofibromatosis. 

Benatar (1994) described a 27-year-old man with neurofibromatosis who presented with 3 intracranial fusiform aneurysms. He referred to 3 previous descriptions of large intracranial fusiform aneurysms in patients with neurofibromatosis type I, which he considered to be considerably less common than renal and gastrointestinal vascular lesions in this disorder. 

Nopajaroonsri and Lurie (1996) described venous aneurysm, arterial dysplasia, and near-fatal hemorrhages in a 62-year-old who was said to have familial neurofibromatosis (no family history was given). The patient presented with an aneurysm of the internal jugular vein which was associated with dysplasia of cervical arteries. Neurofibromatous tissue was found in the wall of the aneurysm as well as in small veins. During and after surgical excision of the aneurysm, the patient developed massive hemorrhages that required reexploration and evacuation of cervical hematomas. During surgery, bleeding was difficult to control because of excessive friability of blood vessels. Despite the vascular invasion by a tumor, there was no evidence of malignancy or malignant transformation in the patient after a 10-year follow-up. 

Uren et al. (1988) found a congenital left atrial wall aneurysm in a patient with neurofibromatosis; the association may be coincidence. Fitzpatrick and Emanuel (1988) observed the association of typical autosomal dominant neurofibromatosis with hypertrophic cardiomyopathy in a brother and sister. Kousseff and Gilbert-Barness (1989) reported what they referred to as 'vascular neurofibromatosis' in 2 patients who as infants developed idiopathic gangrene with vascular changes resembling those of NF1. An additional review of 105 patients uncovered a 27-month-old boy with NF1 and extensive vascular changes with renal hypertension. They discussed the possible relationship to fibromuscular dysplasia. Stanley (1975) found that 5 of 25 children with fibromuscular dysplasia had NF1 as well. Massaro and Katz (1966) established the association of interstitial pulmonary fibrosis (fibrosing alveolitis) with von Recklinghausen neurofibromatosis on the basis of studies of 76 patients. Porterfield et al. (1986) described pulmonary hypertension secondary to interstitial pulmonary fibrosis. 

Among 18 cases of neurofibromatosis with hypertension, Kalff et al. (1982) found pheochromocytoma in 10. Age at diagnosis ranged from 15 to 62 years. The clinical characteristics of the neurofibromatosis did not predict the presence of pheochromocytoma. Younger patients tended to have causes of hypertension other than pheochromocytoma. Several causes of hypertension may coexist. The pheochromocytomas secreted epinephrine as well as norepinephrine and resided in or next to the adrenal gland. Control of hypertension was less successful in the patients without surgically resected pheochromocytoma. One patient without pheochromocytoma had coarctation of the aorta and 1 had renal artery stenosis; this patient was described as having the Turner phenotype. At least 2 of the pheochromocytoma patients had renal artery stenosis. Three had small-bowel and/or stomach neurofibromata. One patient with pheochromocytoma also had hypernephroma with metastases and another had disseminated metastases from an undifferentiated leiomyosarcoma thought to originate from her upper gastrointestinal tract. Horwich et al. (1983) presented evidence that aqueductal stenosis occurs in neurofibromatosis. Sayed et al. (1987) described malignant schwannoma in 3 brothers who had inherited neurofibromatosis from their mother. Two of the brothers had been reported by Herrmann (1950). Sakaguchi et al. (1996) described a 48-year-old man with NF1 and paroxysmal hypertension in progressive respiratory insufficiency. Clinical investigation displayed calcified tumors in the anterior mediastinum and perirenal region. Histologic examination at autopsy revealed composite tumors consisting of pheochromocytoma and malignant peripheral nerve sheath tumor at 2 sites: the left adrenal gland and the region surrounding the inferior vena cava, probably corresponding to the right adrenal gland. In addition, the gastrointestinal tract was involved with mesenchymal tumors showing neurogenic differentiation. 

In 9 cases of neurofibromatosis with a carcinoid tumor studied by Griffiths et al. (1987), all carcinoid tumors were in the duodenum, were distinctive histologically, and had widespread somatostatin immunoreactivity. Furthermore, the duodenum was the primary site in 18 of 20 published cases of carcinoid tumor and neurofibromatosis. Pheochromocytoma was also present in 6 of the 27 cases with neurofibromatosis and duodenal carcinoid tumor. In cases of von Hippel-Lindau syndrome (193300), with which pheochromocytoma also occurs, Griffiths et al. (1987) found no carcinoid tumors, but did find islet cell tumor in association with pheochromocytoma. Swinburn et al. (1988) reported 2 patients with neurofibromatosis and duodenal carcinoid tumor, bringing the total number of cases of this association to 18. Their 2 cases as well as 5 others were positively identified as somatostatinomas. The histologic finding of psammoma bodies is important in the diagnosis of duodenal somatostatinomas. One patient also had a parathyroid adenoma which was found at postmortem. 

Konishi et al. (1991) described the case of a 40-year-old woman with NF1 and typical hypophosphatemic osteomalacia. Bone pain, multiple pseudofractures, marked increase in osteoid by bone biopsy, and hypophosphatemia with renal phosphate wasting were features. Treatment with oral phosphate and vitamin D was effective. They found reports of 34 similar cases and pointed out that of the 67 patients collected by Dent (1952), 2 had neurofibromatosis. 

In a father and 3 children by 2 different women, Schotland et al. (1992) described cosegregation of NF1 and osseous fibrous dysplasia. In the 4 individuals with NF1, cafe-au-lait spots and neurofibromata were present in all 4, Lisch nodules and macrocrania in 3, and scoliosis and curvature of the long bones in 2. Schotland et al. (1992) found at least 8 reports of NF1 and osseous fibrous dysplasia associated in individuals but no previous description of a familial association. The osseous dysplasia consisted of multiple lesions at the distal ends of the shafts of the femurs and in the tibias and fibulas, with bowing of the fibulas. 

Friedman et al. (1993) described a central database designed to collect information on NF1 from 16 centers around the world. The aspects of the disorder for which information was being collected included renal artery stenosis and cerebral artery stenosis.

Ragge et al. (1993) provided a comprehensive discussion of Lisch nodules accompanied by colored photographs in irides of different colors. They pointed out that iris nodules were reported by several workers in the decade before the paper by Lisch (1937). In particular, Sakurai (1935) published a beautifully illustrated paper linking characteristic iris nodules with von Recklinghausen neurofibromatosis. They suggested that the lesions be renamed Sakurai-Lisch nodules in her honor. Kurotaki et al. (1993) described the case of a 13-year-old Japanese boy who was found to have small nodules in the lung on chest radiography. He was asymptomatic. Although there was no family history of NF1, he had multiple cafe-au-lait spots over the whole body since birth, and soft subcutaneous tumors of the forehead and back were noticed from the age of 7 years. On biopsy the lung lesions were found to be papillary adenomas of type II pneumocytes. The patient had remained asymptomatic for 6 years thereafter. 

Easton et al. (1993) studied variation in expression of 3 quantitative traits (number of cafe-au-lait patches, number of cutaneous neurofibromas, and head circumference) and 5 binary traits (presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education). For cafe-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The higher correlation between MZ twins suggested a strong genetic component in variation of expression, but the low correlation between distant relatives suggested that the type of mutation at the NF1 locus itself plays only a minor role. All 5 binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of NF1 mutations. There was no evidence of any association between different traits in affected individuals. Easton et al. (1993) concluded that the phenotypic expression of NF1 is to a large extent determined by the genotype at other 'modifying' loci and that these modifying genes are trait specific. 

Parsa et al. (2001) found that large, clinically symptomatic optic gliomas may undergo spontaneous regression. Regression was seen in 13 patients, 5 with and 8 without NF1. All regressions were documented with serial neuroimaging. Regression manifested as an overall shrinkage in tumor size or as a signal change on MRI. A variable degree of improvement in visual function accompanied regression. The authors concluded that the possibility of spontaneous regression of an optic glioma should be considered in planning the treatment of patients with these tumors. 

All the lesions of NF1, the benign and malignant tumors, the cafe-au-lait spots, the Lisch iris nodules, etc., are presumably the result of 2 mutations, the inherited mutation and a second mutation on the normal homolog. Collins (1993) suggested that the wide variability of clinical manifestations in members of the same family is related to the element of chance in determining what cells are involved by the second mutation and at what stage of development. The progressive nature of the disorder is also indicated. 

Hofman et al. (1994) conducted a study to determine whether the presence of the NF1 gene results in a global cognitive deficit, as measured by lowering of IQ, or in a more specific cognitive deficit or learning disability. In addition, they sought to establish whether learning disabilities could be correlated with brain MRI scan findings. Families were informed concerning the study by NF centers and organizations. Of those expressing interest, 12 families with the appropriate structure were chosen. Each comprised 1 child with NF1, an unaffected sib, and both natural parents. NF children with known intracranial problems were excluded, but family members with known learning disabilities or hyperactivity disorders were not, making some of the results difficult to interpret. Full scale IQs ranged from 70 to 130 among children with NF1 and from 99 to 139 among unaffected sibs. Scores of parents with NF1 ranged from 85 to 114 compared to 80 to 134 in unaffected parents. Children with NF1 showed significant deficits in language and reading abilities compared to sibs, but not in mathematics. They also had impaired visuospatial and neuromotor skills. In 11 of 12 NF1 children but in none of the unaffected sibs, foci of high signal intensity on T2-weighted MRI scan images were observed. A statistically significant correlation was found between lowering of IQ and visuospatial deficits and the number of foci seen on scan. 

Legius et al. (1994) studied the neuropsychologic profiles of 46 children with NF1. They found a reduction in total IQ, but a significantly better verbal rating than performance rating in all age groups. Concentration problems were especially significant in children with a higher IQ. Legius et al. (1994) suggested that these children may benefit from the use of Ritalin. 

T2 'unidentified bright objects' are seen in 50 to 75% of children with neurofibromatosis type I, most frequently in the basal ganglia, corpus cerebellum, and brainstem. Legius et al. (1995) found no difference in the mean intelligence of 18 children with such lesions and 10 neurofibromatosis children who did not show such lesions. 

Winter (1991) described dural ectasia in neurofibromatosis causing bony erosion that was sufficiently severe to destroy spinal stability. Eichhorn et al. (1995) described dural ectasia in a 20-year-old woman with NF1 who presented with back and leg pain. Increasingly severe back pain led to investigations which showed multiple fractures of the pedicles of L1 to L4 with dural ectasia penetrating the body of L2. The transverse diameter of the dura was twice that of the vertebral body at that level, reaching and lifting the psoas. 

Dugoff and Sujansky (1996) reported outcome data of 247 pregnancies in 105 women with NF1. The 247 pregnancies resulted in 44 first trimester spontaneous abortions. The cesarean section rate (36%) was greater than in the general population (9.1 to 23.5%). In 7 of the patients, cesarean section was required because of maternal complications of NF1 including pelvic neurofibromas, pelvic bony abnormality with or without kyphoscoliosis, pheochromocytoma, and spinal cord neurofibroma. Dugoff and Sujansky (1996) reported that 80% of the women in their study experienced either the appearance of new neurofibromas, growth of existing neurofibromas, or both. Thirty-three percent of these women noted a decrease in the size of their neurofibromas in the postpartum period. Eighteen percent of the women reported no changes in neurofibromas and no appearance of new neurofibromas during pregnancy. 

Precocious puberty in NF1 occurs, as a generalization, in children with tumors of the optic chiasm. A longitudinal study of 219 patients with NF1 reported that clinical precocious puberty developed in 7 children, all of whom had optic chiasmal tumors (198,199:Listernick et al., 1994, 1995). On the other hand, Zacharin (1997) described precocious puberty in a 5-year-old girl and 8-year-old boy with NF1 in whom magnetic resonance imaging on 2 occasions failed to demonstrate any abnormality of the optic tracts or optic chiasm. Previous studies have indicated that optic tract lesions develop at a mean age of 3.6 years, and longitudinal studies have failed to demonstrate symptomatic optic tract tumors occurring after age 6 years. The 2 patients of Zacharin (1997) were aged 11 and 14.7 years at the time of the report. Thus, the possibility of new lesions developing in these patients is unlikely. 

Pheochromocytoma is not the only cause of hypertension in patients with NF1; renal artery stenosis due to 'vascular neurofibromatosis' is a relatively common cause. Salyer and Salyer (1974) found peculiar arterial lesions in 7 of 18 autopsy cases of neurofibromatosis at the Johns Hopkins Hospital. They proposed that the pathogenesis of the arterial lesions was proliferation of Schwann cells within arteries with secondary degenerative changes, e.g., fibrosis, resulting in lesions with various appearances. Among 40 pediatric patients (16 girls and 24 boys), aged 22 months to 17 years, undergoing operation for renovascular hypertension, Stanley and Fry (1981) found that 10 had neurofibromatosis, including 3 with abdominal aortic anomalies. Abdominal aortic coarctation affected 5 other children. Cure of the hypertension was achieved in 34 patients (85%); the condition was improved in 5; and one case was classified as a therapeutic failure. Single cases of renovascular hypertension in neurofibromatosis were reported by Allan and Davies (1970), Finley and Dabbs (1988), and others. Craddock et al. (1988) reported a case of neurofibromatosis in a 24-year-old white woman with renovascular hypertension resulting from a proximal renal artery stenosis and poststenotic aneurysmal degeneration. Her sister, aged 38 years, presented similarly but without clinical evidence of neurofibromatosis. Intracranial arterial occlusive disease has also been reported with NF1 (Tomsick et al., 1976). 

Zochodne (1984) reported the case of a 16-year-old female with aneurysm of the superior mesenteric artery complicating renovascular hypertension associated with coarctation of the abdominal aorta from above the celiac trunk to above the origin of the inferior mesenteric artery. The coarctation was associated with stenosis of the renal, celiac and superior mesenteric arteries. The patient had typical skin signs of neurofibromatosis and had had a right below-knee amputation at age 5 for nonunion of a tibial fracture. The mother and 2 sibs were affected. A very similar patient with neurofibromatosis vasculopathy, or vascular neurofibromatosis, was reported by Lehrnbecher et al. (1994). The 4-year-old boy presented with congenital pseudarthrosis of the right tibia (suggesting the vascular origin of this well-known complication of NF1), multiple cafe-au-lait spots, short stature, and mild systemic arterial hypertension. The mother and grandmother had NF1. Subsequent complications of the vasculopathy were hypertension, septic infection of an aneurysm in the deltoid muscle, infarction of a segment of colon, sudden appearance of multiple arterial aneurysms, and venous thrombosis. Histologic examination of the bowel specimen confirmed the clinical diagnosis of vascular NF1. The vascular changes were not secondary to the initially mild arterial hypertension lasting less than 4 months. Reubi (1945) first described vascular NF1. The pathogenesis of the vascular lesions has been subject to controversy. In the case of Lehrnbecher et al. (1994), the proliferating cells seemed to have originated from myoblasts or myofibroblasts and not, as has been speculated, from Schwann cells. Brunner et al. (1974) described a case of chronic mesenteric arterial insufficiency caused by vascular neurofibromatosis in a 50-year-old man with a 30-year history of chronic malabsorption and chronic small intestinal paralysis. He was said to have no signs of systemic disease or cafe-au-lait spots. Pigmentation of the perioral area and lips of the patient were attributed to longstanding malabsorption syndrome. 

Because neurofibromin is expressed in blood vessel endothelial and smooth muscle cells, Hamilton and Friedman (2000) suggested that NF1 vasculopathy may result from an alteration of neurofibromin function in these cells. They reviewed the descriptions of NF1 pathology. Riccardi (2000) supported the view that endothelial injury and its repair, which appear to be important in the pathogenesis of atherosclerosis, may also play a role in NF1 vasculopathy. He recommended a regimen of aggressive antihypertensive treatment of children with NF1 in whom either episodic or persistent systemic hypertension is documented. The goal would be to decrease intravascular trauma, based on the supposition that such trauma is directly related to the evolution of the vascular disease in patients with NF1. Hamilton et al. (2001) reported a previously healthy 33-year-old man with NF1 who died suddenly. Autopsy revealed multiple cardiac abnormalities, including evidence of an intramyocardial vasculopathy characteristic of the vascular pathology found in NF1. Other cardiac findings included nonspecific cardiomyopathic changes, myocardial fibrosis, and a floppy mitral valve. The authors emphasized the importance of recognition of vascular lesions in patients with NF1 so that appropriate management can be provided. 

Stevenson et al. (1999) reported a descriptive analysis of tibial pseudarthrosis in a large series of NF1 patients. A male predominance was observed among patients with pseudarthrosis, leading the authors to suggest that male gender may be a susceptibility factor. Examination of the natural history of pseudarthrosis showed that half of the patients who had a fracture sustained it before age 2 years, and that approximately 16% of the pseudarthrosis patients had an amputation. 

McGaughran et al. (1999) reported a study of 523 individuals from 304 families with NF1. More than 6 cafe-au-lait patches were seen in 383 of 442 (86.7%); 310 of 370 (83.8%) had axillary freckling; 151 of 357 (42.3%) had inguinal freckling; and 157 of 249 (63%) had Lisch nodules. Cutaneous neurofibromas were seen in 217 of 365 (59.4%) and 150 of 330 (45.5%) had subcutaneous tumors. A positive family history of NF1 was found in 327 of 459 (71.2%). Learning disabilities of varying severity were seen in 186 of 300 (62%), and 49 (9.4%) of patients had CNS tumors, 25 of which were optic gliomas. Scoliosis was seen in 11.7%; 1.9% had pseudoarthrosis; 4.3% had epilepsy; and 2.1% had spinal neurofibromas. 

Macrocephaly and short stature have been reported in several clinical studies of NF1. Clementi et al. (1999) studied growth in 528 NF1 patients obtained from a population-based registry in northeast Italy. In their study, macrocephaly was a consistent and common finding in NF1. However, the authors found that short stature was less prominent and less frequent than previously reported. No differences in height were apparent between NF1 and normal subjects up to 7 years of age in girls and 12 years of age in boys. Clementi et al. (1999) presented growth charts for use by physicians following NF1 patients to assist in the identification of the effects of secondary growth disorders, for growth prognosis, and for evaluation of the effects of therapy. 

Szudek et al. (2000) presented growth charts derived from study of 569 white North American children with NF1. They found that stature and occipitofrontal circumference (OFC) measurements were shifted and unimodal, with 13% of children being at or more than 2 SD below mean and 24% having OFC at or more than 2 SD above mean. 

Mukonoweshuro et al. (1999) reviewed the central nervous system manifestations and neuroradiologic findings in NF1.

DeBella et al. (2000) studied 1,893 NF1 patients under 21 years of age from the National Neurofibromatosis Foundation International Database to determine the age at which the features included in the NIH Diagnostic Criteria appear. Approximately 46% of sporadic NF1 cases failed to meet the NIH Diagnostic Criteria by 1 year of age. Nearly all (97%; 95% CI: 94 to 98) NF1 patients meet the criteria for diagnosis by 8 years of age, and all do so by 20 years of age. The usual order of appearance of the clinical features listed as NIH criteria is cafe-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas. Symptomatic optic glioma is usually diagnosed by 3 years old, and characteristic osseous lesions are usually apparent within the first year of life. 

One of the most clinically aggressive cancers associated with NF1 is malignant peripheral nerve sheath tumor (MPNST). To determine the incidence and relative risk of these tumors in individuals with NF1, King et al. (2000) reviewed 1,475 individuals with NF1 from a cohort of patients examined by a single investigator, Vincent M. Riccardi, between 1977 and 1996. MPNST was identified in 34 individuals (2%). The relative risk of MPNST was increased with an relative risk value of 113. Lesions occurred in the limbs in 18 patients (53%), and those with limb lesions survived longer than those with nonlimb MPNSTs. Pain associated with a mass was the strongest suggestion of MPNST development. 

Cross-sectional studies had shown that 1 to 2% of patients with NF1 develop MPNSTs. Evans et al. (2002) ascertained NF1 patients with MPNST in an attempt to assess lifetime risk. They found 21 NF1 patients who developed MPNST, equivalent to an annual incidence of 1.6 per 1,000 and a lifetime risk of 8 to 13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST. In Kaplan-Meier analyses, the 5-year survival after diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases. One NF1 patient developed 2 separate MPNSTs in the radiation field of a previous optic glioma. 

McCaughan et al. (2007) surveyed Scottish medical records across a 10-year period and identified 14 NF1 patients with coexistent diagnosis of MPNST. They calculated that the lifetime risk of developing MPNST was 5.9 to 10.3%, and the mean age at diagnosis of the tumors was 42.1 years. Five-year survival after diagnosis of MPNST was significantly lower in NF1 patients compared to patients without NF1 (0% vs 54%, p less than 0.01). 

Waggoner et al. (2000) conducted a retrospective review of NF1 patients seen in a tertiary care referral center. Sixty-eight of 405 (16.8%) patients with NF1 had plexiform neurofibromas. About 43% of plexiform neurofibromas were located on the trunk, 42% were in the head and neck region, and 15% were on the extremities. About 44% of these tumors were detected by 5 years of age. Presenting symptoms were most often related to the increasing size of the tumor, a loss of function (usually weakness), or pain. Only 2 patients (3%) developed malignant peripheral nerve sheath tumors in their preexisting plexiform neurofibromas. No specific NF1 features were associated with plexiform tumors. 

Yasunari et al. (2000) studied 33 eyes of 17 consecutive patients diagnosed with NF1 by conventional ophthalmoscopy and by noninvasive infrared monochromatic light with confocal scanning laser ophthalmoscopy (SLO). Seventy-six eyes of 39 age-matched controls were examined similarly by confocal SLO. Twenty-one digital fluorescein and indocyanine-green angiographies were obtained from 11 adult patients, and 77 angiograms were obtained from age-matched controls. Infrared monochromatic light examination by confocal SLO showed multiple bright patchy regions at and around the entire posterior pole of all 33 eyes examined from NF1 patients. All bright patchy regions seen in adult patients corresponded to hypofluorescent areas on their indocyanine-green angiograms; however, no abnormalities were noted in any patient at corresponding areas under conventional ophthalmoscopic examination or fluorescein angiography. Control patients and their angiograms showed no choroidal abnormalities. Iris nodules were noted in 25 eyes (76%) of 14 patients (82%) and eyelid neurofibroma in 5 patients (29%). Since choroidal abnormalities were detected in 100% of NF1 patients examined, Yasunari et al. (2000) suggested that this abnormality be included in the diagnostic criteria for NF1. 

Lin et al. (2000) reviewed cases of NF1 and cardiovascular malformations among 2,322 patient records in the National Neurofibromatosis Foundation International Database, collected between 1991 and 1998. Cardiovascular malformations were reported in 54 (2.3%) of the NF1 patients, 4 of whom had Watson syndrome (193520) or NF1-Noonan syndrome (NFNS; 601321). Of the 54 patients, 25 had pulmonic stenosis, and 5 had coarctation of the aorta, representing a higher proportion of all cardiovascular malformations than expected. The authors recommended that all individuals with NF1 have careful cardiac auscultation and blood pressure monitoring as part of every NF-related examination. 

Singhal et al. (2002) compared the natural history of sporadic and NF1-associated optic gliomas in a series of 52 patients from northwest Britain. Ages at presentation were similar, but those associated with NF1 were less likely to present with impaired vision. Although NF1 optic gliomas were less aggressive, there was little difference in 5- and 10-year mortality rates between the 2 tumor groups. NF1 optic glioma cases were also at risk of a second primary central nervous system tumor; in 2 of 5 cases this occurred following radiotherapy, suggesting an etiologic link. 

Leroy et al. (2001) performed a retrospective study of malignant peripheral nerve sheath tumors in a cohort of 395 patients with NF1 followed for 11 years in a teaching hospital setting. Seventeen patients (4.3%) developed tumors, with a mean age at diagnosis of 32 years (SD = 14 years). Twelve patients had high-grade tumors; all tumors except 1 developed on preexisting nodular or plexiform neurofibromas. Pain and enlarging mass were the first and predominant signs. None of the benign tumors displayed significant p53 staining or p53 mutations. Six of 12 malignant tumors significantly overexpressed p53, and 4 of 6 harbored p53 missense mutations. Median survival was 18 months overall, 53 months in peripheral locations, and 21 months in axial locations. Leroy et al. (2001) concluded that investigations and deep biopsy of painful and enlarging nodular or plexiform neurofibromas should be considered in patients with NF1, and that late appearance of p53 mutations and overexpression precludes their use as predictive markers of malignant transformation. 

Friedman et al. (2002) reviewed cardiovascular disease in NF1. The NF1 Cardiovascular Task Force suggested that all patients with NF1, especially those with Watson or NF1-Noonan phenotypes, have a careful cardiac examination with auscultation and blood pressure measurement.

Schrimsher et al. (2003) studied visuospatial performance deficits and attention deficit-hyperactivity disorder (ADHD; 143465) in NF1.

Lee et al. (2004) classified the periorbital deformities of adult orbitotemporal NF, reported previously undescribed clinical findings, and recommended guidelines for surgical treatment as well as management of surgical complications. They proposed a new classification for periorbital deformities: (1) brow ptosis; (2) upper eyelid infiltration with ptosis; (3) lower eyelid infiltration; (4) lateral canthal disinsertion; and (5) conjunctival and lacrimal gland infiltration. Of 33 patients over age 16 years with orbitotemporal NF, 2 (6%) had bilateral involvement whereas 31 (94%) had unilateral orbitotemporal NF. Previously undescribed findings included severe brow infiltration, lacrimal gland involvement, and functional nasolacrimal duct obstruction. 

Optic pathway gliomas (pilocytic astrocytomas) typically involve some combination of the optic nerves, chiasm, or optic tracts. Involvement of the optic radiations is rare. Liu et al. (2004) described the clinical and radiologic features of 7 children with NF1 with gliomas involving the pregeniculate optic pathway in addition to the optic radiations. Two of the patients had expanding mass lesions within the white matter of the temporal or parietal lobes, which were histopathologically demonstrated to be pilocytic astrocytomas; the other 5 had radiographic involvement of the optic radiations but did not undergo biopsy. In 3 of the cases, the visual acuity was 20/200 or worse in each eye. Liu et al. (2004) found that optic pathway gliomas in NF1 rarely involved the optic radiations and that optic radiation involvement might signal a more aggressive optic pathway glioma in patients with NF1. 

To obtain information concerning mortality in neurofibromatosis 1, Rasmussen et al. (2001) used Multiple-Cause Mortality Files, compiled from U.S. death certificates by the National Center for Health Statistics, for 1983-1997. They identified 3,770 cases among 32,722,122 deaths in the United States, a frequency of 1 in 8,700, which is one-third to one-half the estimated prevalence. Mean and median ages at death for persons with NF1 were 54.4 and 59 years, respectively, compared with 70.1 and 74 years in the general population. Results of proportionate mortality ratio (PMR) analyses showed that persons with NF1 were 34 times more likely to have a malignant connective or other soft-tissue neoplasm listed on their death certificates than were persons without NF1. Overall, persons with NF1 were 1.2 times more likely than expected to have a malignant neoplasm listed on their death certificates, but the PMR was 6.07 for persons who died at 10 to 19 years of age and was 4.93 for those who died at 20 to 29 years of age. Similarly, vascular disease was recorded more often than expected on death certificates of persons with NF1 who died before 30 years of age, but not in older persons. 

Szudek et al. (2003) studied statistical associations among 13 of the most common or significant clinical features of NF1 in data from 4 large sets of NF1 patients. The results suggested grouping 9 of the clinical features into 3 sets: (1) cafe-au-lait spots, intertriginous freckling, and Lisch nodules; (2) cutaneous, subcutaneous, and plexiform neurofibromas; (3) macrocephaly, optic glioma, and other neoplasms. In addition, 3-way interactions among cafe-au-lait spots, intertriginous freckling, and subcutaneous neurofibromas indicated that the first 2 groups are not independent. 

To identify the main clinical features of NF1 associated with mortality, Khosrotehrani et al. (2003) performed a cohort study among 378 NF1 patients receiving more than 1 year of follow-up care at an NF1 referral center in France. Clinical features, especially dermatologic, were evaluated as potential factors associated with mortality. Factors associated independently with mortality were the presence of subcutaneous neurofibromas (odds ratio, 10.8; 95% confidence interval, 2.1-56.7; P less than 0.001), the absence of cutaneous neurofibromas (odds ratio, 5.3; 95% confidence interval, 1.2-25.0; P = 0.03), and facial asymmetry (odds ratio, 11.4; 95% confidence interval, 2.6-50.2; P less than 0.01). The absence of cutaneous neurofibromas in adulthood associated with high mortality may correspond to a subtype of NF1, familial spinal neurofibromatosis (162210). Khosrotehrani et al. (2003) concluded that features that can be found by a routine clinical examination are associated with mortality in patients with NF1 and that clinical follow-up should be focused on patients with subcutaneous neurofibromas, absence of cutaneous neurofibromas, and/or facial asymmetry. In a parallel study of a cohort of 703 NF1 patients in North America, Khosrotehrani et al. (2005) validated the observation that subcutaneous neurofibromas were associated with mortality. 

Vandenbroucke et al. (2004) described a patient with NF1 manifestations throughout the body, but leaving a few sharply delineated segments of the skin unaffected, suggestive of revertant mosaicism. A large intragenic deletion was found by mutational analysis using long-range RT-PCR. The intra-exonic breakpoints were identified in exon 13 and exon 28, resulting in a deletion of 99,571 bp at the genome level. Analysis of several tissues demonstrated the presence of 2 genetically distinct cell populations, confirming mosaicism for this NF1 mutation. Revertant mosaicism was excluded by demonstrating heterozygosity for markers residing in the deletion region. 

Coffin et al. (2004) reviewed information indicating that children and young adults with NF1 have a higher risk for non-neurogenic sarcomas than the general population, in addition to an increased risk for malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas occur in early childhood, a subsequent malignant peripheral nerve sheath tumor can occur as a second malignant neoplasm, especially after alkylating agent chemotherapy and irradiation. Coffin et al. (2004) presented 4 patients. In 1, embryonal rhabdomyosarcoma was diagnosed at the age of 2 years, and was treated by surgery, radiation, and chemotherapy. A malignant peripheral nerve sheath tumor was detected at the age of 13 years. A second patient likewise had the diagnosis of embryonal rhabdomyosarcoma at the age of 2 years and had the same therapy followed by T-cell lymphoblastic lymphoma at the age of 7 years. 

The primary skeletal abnormalities associated with NF1 include long bone dysplasia, sphenoid wing dysplasia, and scoliosis. Long bone dysplasia, seen in 5% of patients with NF1, typically involves the tibia and frequently presents with anterolateral bowing that may progress to fracture and nonunion. Tibial dysplasia is most often unilateral, evident in the first year of life, and usually not associated with a neurofibroma at the site. The unilateral nature suggests a random molecular event. In neurofibromas, there is biallelic inactivation of NF1; Stevenson et al. (2006) documented double inactivation of NF1 in pseudarthrosis tissue and suggested that the neurofibromin-Ras signal transduction pathway is involved in this bone dysplasia in NF1. Prospectively acquired tissue from the pseudarthrosis site of 2 individuals with NF1 was used for immunohistochemical characterization and genotype analysis of the NF1 locus. Typical immunohistochemical features of neurofibroma were not observed. Genotype analysis of pseudarthrosis tissue with use of 4 genetic markers spanning the NF1 locus demonstrated loss of heterozygosity. Patient 1 of Stevenson et al. (2006) was a 42-year-old man with a father with NF1 and a brother with NF1 associated with lower limb pseudarthrosis requiring amputation. Patient 2 was a 2-year-old boy whose tibial and fibular bowing presented at birth, with subsequent fibular fracture at age 2 weeks. Clinical findings consistent with NF1 included more than 5 cafe-au-lait macules and tibial pseudarthrosis. The mother had NF1. 

Bausch et al. (2006) reported that 15 (3%) of 565 pheochromocytoma cases in a pheochromocytoma registry had NF1 mutation. In 10 additional cases contributed specifically for a study of pheochromocytoma in NF1, they found 92% had germline NF1 mutations. The 25 patients with NF1 were compared with patients with other syndromes associated with pheochromocytoma: 31 patients with multiple endocrine neoplasia type 2 (MEN2; 171400) due to mutation in the RET gene (164761); 21 patients with paragangliomas-1 (168000) due to mutation in the SDHD gene (602690); 33 patients with paragangliomas-4 (115310) due to mutation in the SDHB gene (185470); 75 patients with von Hippel-Lindau disease (193300) due to mutation in the VHL gene (608537); and 380 patients with pheochromocytoma as a sporadic disease. The characteristics of patients with pheochromocytoma related to NF1 were similar to those of patients with sporadic pheochromocytoma. There were significant differences between the NF1 group and the other respective groups in the age at diagnosis (von Hippel-Lindau disease and paragangliomas-1); in the extent of multifocal tumors (MEN2, von Hippel-Lindau disease, and paragangliomas-1); and in the extent of extraadrenal tumors (MEN2, von Hippel-Lindau disease, paragangliomas-1, and paragangliomas-4). Patients with NF1 had a relatively high (but not significant) prevalence of malignant disease (12%), second only to that among patients with paragangliomas-4 who had a germline mutation in the SDHB gene (24%). Taken together, 33% of all symptomatic patients with pheochromocytoma in the multicenter, multinational registry carried germline mutations in 1 of the 5 genes, including the NF1 gene. 

Bausch et al. (2007) performed mutation scanning of the NF1 gene and loss-of-heterozygosity analysis using markers in and around the NF1 gene in 37 patients, aged 14 to 70 years, with pheochromocytoma and NF1. Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus versus 0 of 12 sporadic tumors (p = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, and 14% had large deletions or duplications; 79% of the mutations were novel. The cysteine-serine rich domain (CSR) was affected in 35%, but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. 

Schievink et al. (2005) detected incidental intracranial aneurysms in 2 (5%) of 39 patients with NF1 who were hospitalized for other reasons. Limiting the patient population to the 22 patients who had brain MRI resulted in a significantly higher detection rate of 9% compared to 0% in 526 control patients with primary or metastatic brain tumors who underwent brain MRI. The findings suggested that patients with NF1 are at an increased risk of developing intracranial aneurysms as a vascular manifestation of NF1. 

Neurofibromatous Neuropathy

Neurofibromatous neuropathy, a common feature of NF2 but an unusual complication of NF1, is characterized by a distal sensorimotor neuropathy associated with diffuse neurofibromatous change in thickened peripheral nerves (Thomas et al., 1990). NF2-associated neurofibromatous neuropathy is entirely different clinically and histologically from NF1-associated neurofibromatous neuropathy (Sperfeld et al., 2002). Ferner et al. (2004) noted that most cases of neuropathy and neurofibromatous previously reported had been associated with NF2. They described 8 patients with NF1 and neurofibromatous neuropathy. The patients were from a clinic serving 600 NF1 patients, a frequency of 1.3%. The patients had an indolent symmetric predominantly sensory axonal neuropathy and unusual early development of large numbers of neurofibromas. The biopsied nerves showed diffuse neurofibromatous change and disruption of the perineurium. Two patients developed a high grade malignant peripheral nerve sheath tumor. Ferner et al. (2004) pictured the side of the neck of a patient with a thickened greater auricular nerve. They also pictured studies of the lumbar spine showing neurofibromas involving all the nerve roots but not causing cord compression. Disease-causing mutations were identified in 2 individuals (162200.0040-162200.0041) and molecular studies did not reveal any whole gene deletions. Ferner et al. (2004) suggested that the cause of neurofibromatous neuropathy may be a diffuse neuropathic process arising from inappropriate signaling between Schwann cells, fibroblasts, and perineurial cells. 

NF1 Microdeletion Syndrome

Approximately 5 to 20% of all NF1 patients carry a heterozygous deletion of approximately 1.5 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al. (2000); Jenne et al., 2001), which is caused by unequal homologous recombination of NF1 repeats (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, and an excessive number of neurofibromas for age (336:Venturin et al., 2004). 

Kayes et al. (1994) investigated the contribution to variability in the clinical phenotype of NF1 by genes either contiguous to or contained within the NF1 gene, by screening 6 NF1 patients with mild facial dysmorphism, mental retardation, and/or learning disabilities for DNA rearrangement of the NF1 region. Five of the 6 patients carried a deletion of more than 700 kb on one chromosome 17. Minimally, each of the deletions involved the entire 350-kb NF1 gene, the 3 genes (EVI2A, EVI2B, and OMG) contained within an NF1 intron, and considerable flanking DNA. In 4 of the patients, the deletion mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele appeared to be producing functional neurofibromin. The data provided compelling evidence that NF1 results from haploid insufficiency of neurofibromin. Of the 3 documented de novo deletion cases, 2 involved the paternal NF1 allele and 1 the maternal allele. All 5 patients were remarkable for the large number of neurofibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development. All had plexiform neurofibromas. Four had hypertelorism, 4 had ptosis, and all had micrognathia. 

Using FISH with intragenic probes, Wu et al. (1995) looked for deletions in 13 unrelated individuals with NF1. Among 6 with severe manifestations, 4 were found to have deletions of the entire gene. All 4 had severe developmental delay, minor and major anomalies (including 1 with bilateral iris colobomas), and multiple cutaneous neurofibromas or plexiform neurofibromas which were present before age 5 years. 

Riva et al. (1996) characterized a 12-year-old male patient with sporadic NF1, dysmorphism, mental retardation, and skeletal anomalies (162200.0017). Karyotyping of the patient revealed a cytogenetically visible deletion at 17q11.2. Analysis of microsatellite markers demonstrated that the patient was hemizygous, due to loss of the paternal allele, at several sites within the NF1 gene and at an extragenic marker distal to the 3-prime end of NF1. The 9-cM deletion in the interval between D17S841 and D17S250 was in agreement with that originally detected cytogenetically. The karyotypes of the parents were normal. The patient had no neurofibromas; the authors attributed this fact to his genetic background, i.e., to the influence of modifying genes. 

Upadhyaya et al. (1996) claimed to have provided the first physical cytogenetic deletion involving the NF1 gene in a patient with sporadic neurofibromatosis, dysmorphic features, and marked developmental delay. Combined evidence of molecular and cytogenetic techniques predicted that the deletion was approximately 7 Mb. 

Wu et al. (1997) described a father and son with NF1 due to deletion of the entire NF1 gene detected by fluorescence in situ hybridization (FISH). Both had severe NF1, including a large number of cutaneous neurofibromas, facial anomalies, large hands, feet, and head, and developmental impairment. Only the 15-year-old son had seizures and plexiform neurofibromas. 

Cnossen et al. (1997) studied DNA from 84 unrelated patients with NF1, unselected for clinical features or severity, screening for deletion with intragenic polymorphic repeat markers and Southern analysis with cDNA probes. Deletion of the entire gene was detected in 5 patients from 4 unrelated families. Their phenotype resembled that of 5 previously reported patients with deletions, including intellectual impairment and dysmorphic features, but they could not confirm the existence of an excessive number of dermal neurofibromas. Postnatal overgrowth suggesting Weaver syndrome (277590) and manifestations somewhat like Noonan syndrome were commented on. Slight micrognathia and extreme overbite of the maxilla were noted in individual cases. 

Using a novel multitrack screening strategy, Upadhyaya et al. (1998) studied 67 NF1 families (54 2-generation, 13 3-generation) with a de novo mutation in the germline of the first generation; 2 extragenic and 11 intragenic markers were employed. The pathologic lesion was identified in 31 cases. Loss of heterozygosity in the affected individual revealed a gross gene deletion in 15 of the 2-generation families; in 12 (80%) of them, the deletion was maternally derived. Eleven patients with a gross deletion exhibited developmental delay, 10 had dysmorphic features, and 6 manifested a learning disability. No gross deletion was apparent in any of the 13 3-generation families, suggesting that such lesions are subject to more intense selection. In these 13 families, the new mutation was of paternal origin in 11 and the underlying mutational event could be characterized in 3 of them. 

Rasmussen et al. (1998) studied 67 patients with NF1 and their parents. Five patients showed loss of heterozygosity, suggesting NF1 gene deletion. These patients did not have severe NF1 manifestations, mental retardation, or dysmorphic features. All 5 deletions were de novo and occurred on the maternal chromosome. Two patients showed partial loss of heterozygosity, consistent with somatic mosaicism for NF1 deletion. 

Streubel et al. (1999) described what they considered to be the third case of NF1 due to mosaicism for a gross deletion in 17q11.2 covering the entire NF1 gene. The deletion was suspected in Giemsa banded chromosomes and was confirmed by fluorescence in situ hybridization using probes spanning the entire 350-kb genomic DNA of the NF1 gene. The deletion was present in 33% of peripheral blood lymphocytes and 58% of fibroblasts. The clinical manifestations in their 6-year-old male patient were especially severe and extended beyond the typical features of NF1. The patient also displayed facial anomalies, severe and early-onset psychomotor retardation, seizures, spasticity, and microcephaly. These features differed from other large-deletion NF1 patients, even nonmosaic cases. Streubel et al. (1999) suggested that the complex phenotype could be explained by the involvement of coding sequences flanking the NF1 gene, thus supporting the existence of a contiguous gene syndrome in 17q11.2. The other cases of somatic mosaicism for a deletion of the entire NF1 gene as identified by FISH were reported by Tonsgard et al. (1997) and Wu et al. (1997)

Jenne et al. (2001) used molecular techniques to characterize the breakpoints and deleted genes in 8 patients with NF1 and 17q11.2 microdeletion syndrome. The interstitial 17q11.2 microdeletion arises from unequal crossover between 2 highly homologous 60-kb duplicons separated by approximately 1.5 Mb. The authors stated that 13 genes had been located in the deleted region. 

An NF1 microdeletion is the single most commonly reported mutation in individuals with neurofibromatosis type I. Individuals with an NF1 microdeletion have, as a group, more neurofibromas at a younger age than the group of all individuals with NF1. De Raedt et al. (2003) reported that NF1 microdeletion individuals additionally have a substantially higher lifetime risk for the development of malignant peripheral nerve sheath tumors than individuals with NF1 who do not have an NF1 microdeletion. 

By combining clinical and genetic evidence from 92 patients with the NF1 microdeletion, Venturin et al. (2004) reviewed specific clinical signs of the NF1 microdeletion syndrome. They found that the most common extra-NF1 clinical signs in patients with the microdeletion were learning disability, cardiovascular malformations, and dysmorphism. They pictured 3 patients with NF1 microdeletion syndrome in whom hypertelorism was a conspicuous feature of the facial dysmorphism. From the gene content of the deleted region, Venturin et al. (2004) proposed that haploinsufficiency of the OMG (164345) and/or CDK5R1 (603460) genes may be implicated in learning disability. In relation to cardiovascular malformations, only JJAZ1 (606245) and CENTA2 (608635) were considered plausible candidate genes, by reason of being significantly expressed in the heart. 

Segmental Neurofibromatosis

Nicolls (1969) described 2 cases of sectorial (or segmental) neurofibromatosis which he plausibly interpreted as representing somatic mutation. One had a mediastinal neurofibroma and, in the skin area corresponding segmentally to the site of the internal lesion, five small neurofibromas. Miller and Sparkes (1977) also reported on this phenomenon. Riccardi and Eichner (1986) referred to the segmental form as neurofibromatosis type V. Combemale et al. (1994) presented 2 new cases of segmental NF1 and reviewed reports concerning 88 cases. One of their patients was a 71-year-old woman with multiple cutaneous tumors limited to the left side of the trunk and present since the age of 41 years. 

In a survey of 56,183 young men, aged 17 and 18 years, Ingordo et al. (1995) found 11 cases of NF1 and 1 case of segmental NF. In this group, the relative frequency was 0.02% for NF and 0.0018% for segmental NF. From November 1988 through August 1995, Wolkenstein et al. (1995) saw 308 patients with NF type I according to the criteria of the National Institutes of Health Consensus Development Conference (1988) and 9 patients with segmental NF according to the classification of Riccardi (1982). These findings and those of Ingordo et al. (1995) suggest that segmental NF is about 30 times less frequent than NF type I. 

Tinschert et al. (2000) provided molecular confirmation that segmental neurofibromatosis represents a postzygotic NF1 gene mutation. Using FISH, they identified an NF1 microdeletion in a patient with segmental NF in whom cafe-au-lait spots and freckles were limited to a single body region. The mutant allele was present in a mosaic pattern in cultured fibroblasts from a cafe-au-lait spot lesion, but was absent in fibroblasts from normal skin as well as in peripheral blood leukocytes. 

NF1 Microduplication Syndrome

Grisart et al. (2008) reported a large family segregating a microduplication of the NF1 microdeletion syndrome region. Two adult brothers had developmental delay and mild mental retardation associated with early onset of baldness around 14 to 15 years of age, mild facial dysmorphism with sparse eyelashes and eyebrows, long midface, malar hypoplasia, nasal deviation, bifid nose tip, flared nares, thin upper lip, dental enamel hypoplasia, and large testes. Family history included a similarly affected father with 3 mentally retarded half-sisters and a mentally retarded half-brother. The deceased grandmother was also reportedly affected. Microarray CGH, FISH analysis, and multiple ligation-dependent probe amplification (MLPA) detected a 1.5- to 1.6-Mb duplication on chromsome 17q11 corresponding perfectly to the NF1 microdeletion syndrome region. This duplication was found in all affected individuals studied, as well as in 2 unaffected family members, indicating reduced penetrance. Grisart et al. (2008) noted that the same mechanism, nonallelic homologous recombination, underlies both microdeletion and microduplication. 

BIOCHEMICAL FEATURES

To study the NF1 gene product, Gutmann et al. (1991) raised antibodies against both fusion proteins and synthetic peptides. A specific protein of about 250 kD was identified by both immunoprecipitation and immunoblotting. The protein was found in all tissues and cell lines examined and was detected in human, rat, and mouse tissues. Based on the homology between the NF1 gene product and members of the GTPase-activating protein (GAP; 139150) superfamily, the name NF1-GAP-related protein (NF1GRP) was suggested. DeClue et al. (1991) raised rabbit antisera to a bacterially synthesized peptide corresponding to the GAP-related domain of NF1 (NF1-GRD). The sera specifically detected a 280-kD protein in lysates of HeLa cells. This protein corresponded to the NF1 gene product, as shown by several criteria. NF1 was present in a large molecular mass complex in fibroblast and Schwannoma cell lines and appeared to associate with a very large (400-500 kD) protein in both cell lines. 

Basu et al. (1992) presented evidence supporting the hypothesis that NF1 is a tumor-suppressor gene whose product acts upstream of RAS (190020). They showed that the RAS proteins in malignant tumor cell lines from patients with NF1 were in a constitutively activated state as measured by the ratio of the guanine nucleotides bound to them, i.e., the ratio of GTP (active) to GDP (inactive). Transforming mutants of p21(ras) bind large amounts of GTP, whereas wildtype p21(ras) is almost entirely GDP-bound. Daston et al. (1992) raised antibodies against peptides coded by portions of the NF1 cDNA. These antibodies specifically recognized a 220-kD protein, called neurofibromin, in both human and rat spinal cord. Neurofibromin was most abundant in the nervous system. Immunostaining of tissue sections indicated that neurons, oligodendrocytes, and nonmyelinating Schwann cells contained neurofibromin, whereas astrocytes and myelinating Schwann cells did not. In schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin is associated with impaired regulation of GTP/RAS. Analysis of other neural crest-derived tumor cell lines showed that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis also contained reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, however, GTP/RAS was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when HRAS was overexpressed (Johnson et al., 1993). These results demonstrated that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggested a tumor-suppressor function for neurofibromin that is independent of RAS GTPase activation. 

Nakafuku et al. (1993) took advantage of the yeast RAS system to isolate mutants in the RAS GTPase activating protein-related domain of the NF1 gene product (NF1-GRD) that can act as antioncogenes specific for oncogenic RAS. They demonstrated that these mutant NF1-GRDs, when expressed in mammalian cells, were able to induce morphologic reversion of RAS-transformed NIH 3T3 cells. 

The NF1 gene encodes neurofibromin, a multidomain molecule with the capacity to regulate several intracellular processes, including the ERK (600997) MAP (see 600178) kinase cascade, adenylyl cyclase, and cytoskeletal assembly. In a review of the molecular neurobiology of human cognition, Weeber and Sweatt (2002) presented an overview of the RAS-ERK-CREB pathway, including the function of NF1. The authors discussed publications that implicated dysfunction of this signal transduction cascade in cognitive defects, including mental retardation caused by mutation in the NF1 gene. 

Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, Ling et al. (2006) found that 1 allele of the IGF2 (147470)/H19 (103280) imprinting control region (ICR) on chromosome 7 colocalized with 1 allele of WSB1 (610091)/NF1 on chromosome 11. Omission of CCCTC-binding factor (CTCF; 604167) or deletion of the maternal ICR abrogated this association and altered WSB1/NF1 gene expression. Ling et al. (2006) concluded that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. 

OTHER FEATURES

Schenkein et al. (1974) reported increased nerve growth stimulating activity in the serum of patients with von Recklinghausen disease. Kanter et al. (1980) showed an increase only in antigenic activity of nerve growth factor in central neurofibromatosis and only in functional activity in peripheral neurofibromatosis. Thus, these disorders may involve different defects in NGF synthesis and/or regulation. 

Fialkow et al. (1971) concluded from analysis of neurofibromas from G6PD A-B heterozygotes with von Recklinghausen disease that each tumor must originate in many cells, perhaps at least 150. Although the benign tumors of neurofibromatosis are multiclonal in nature, the malignant lesion (neurofibrosarcoma) is monoclonal (Friedman et al., 1982). 

In 8 of 30 unrelated females with NF1, Skuse et al. (1989) found heterozygosity for a PGK (311800) RFLP which could be used to test for clonality. In all 8 cases the neurofibromas appeared to be monoclonal in origin. These results supported the suggestion that benign neurofibromas in NF1 arise by a mechanism that is different from that of the malignant tumors. In a neural fibrosarcoma from a patient with NF1, Legius et al. (1993) found a somatic deletion of the NF1 gene on one chromosome and loss of heterozygosity for all chromosome 17 polymorphisms. Thus, homozygous inactivation of NF1 was demonstrated at the molecular level, providing strong support for the view that NF1 is a tumor suppressor gene. 

Colman et al. (1995) examined the '2-hit' hypothesis in relation to benign neurofibromas in NF1. Using both NF1 intragenic polymorphisms as well as markers from flanking and more distal regions of chromosome 17, they investigated loss of heterozygosity (LOH) in 22 neurofibromas from 5 unrelated NF1 patients. Eight of these tumors revealed somatic deletions involving NF1, indicating that inactivation of NF1 is associated with at least some neurofibromas. On the other hand, Stark et al. (1995) found single-cell PCR on neurofibroma Schwann cells and found that both alleles of the NF1 gene were present; i.e., there was no evidence of loss of heterozygosity by a nondisjunction, large deletions, or somatic recombination. They granted that small mutations inactivating the wildtype allele could not be excluded. 

Based on the International Database maintained by the National NF Foundation (NNFF), which contained information on 1,479 probands and 249 of their affected relatives with NF1 at the time of analysis, Friedman and Birch (1997) summarized clinical information about the population. The age of diagnosis of NF1 was 8 years younger in the probands than in the affected relatives. Many of the manifestations of NF1 were more frequent in the probands than in their affected relatives. The age-specific prevalence of most manifestations of NF1 increased with age. Despite biases inherent in a convenience sample from specialist clinics, the frequency of manifestations of NF1 in many of the series was similar to those in 2 smaller population-based studies. Lisch nodules were said to be present in 57% of probands and 69.9% of affected relatives. 

Lammert et al. (2006) found significantly lower mean serum levels of 25-hydroxyvitamin D in 55 NF1 patients compared to controls (14.0 ng/ml in patients, 31.4 ng/ml in controls). Among the NF1 patients, there was a highly significant inverse correlation between serum vitamin D concentration and the number of dermal neurofibromas. Lammert et al. (2006) noted that focal osseous abnormalities and decreased bone mineral density are observed in patients with NF1, which may be related to inadequate circulating vitamin D. The relationship of serum vitamin D to neurofibromas was unclear. 

INHERITANCE

Miller and Hall (1978) found that patients born of affected mothers had more severe disease than those born of affected fathers. (A similar maternal effect was known to occur in myotonic dystrophy (160900) and subsequently a maternal effect on severity was noted in neurofibromatosis type II (101000).) In their series of 62 patients from 54 families, only 16 were new mutations, as contrasted with the figure of 50% arrived at by Crowe et al. (1956). Crowe et al. (1956) estimated the relative fertility of affected males and females to be 0.41 and 0.75, respectively. 

Samuelsson and Akesson (1988) estimated that the relative fertility of neurofibromatosis cases is 78% and the mutation rate somewhere between 2.4 and 4.3 x 10(-5). Ritter and Riccardi (1985) studied 111 3-generation families with NF and found no instance of skipped generation. They suggested that penetrance of NF is complete and that previous impressions to the contrary have failed to recognize heterogeneity, minimal NF expression, and nonpaternity. 

Clementi et al. (1990) used the methods of classic segregation analysis to test whether there was a deviation from the expected mendelian segregation rate in a sample of 129 Italian sibships. With this approach, they obtained a maximum likelihood estimate of the proportion of sporadic cases, and hence they estimated the mutation rate to be 6.5 x 10(-5) gametes per generation. 

Jadayel et al. (1990) used molecular methods to identify the parental origin of new mutations in NF1. They found that in 12 of 14 families analyzed, the new mutation was of paternal origin. The estimated mutation rate, 1 in 10,000 gametes, is one of the highest for a human disorder (Huson et al., 1989) and suggests that the NF1 gene is large or has some other structural peculiarity. The same bias toward paternal origin of new mutations has been demonstrated for retinoblastoma (180200). In both of these disorders, however, there is little or no evidence of paternal age effect in the incidence of mutations. (Riccardi et al. (1984) found increased paternal age.) 

The high mutation rate of NF1 may reflect the fact that the gene is large like that of dystrophin (300377) and/or that it has an unusual internal structure predisposing to deletions and other mutations. Predominant paternal derivation suggests that mutation may occur in the mitotic divisions that take place in male gametogenesis but not in female gametogenesis. Since there is little or no evidence of accumulation of mutations reflected by paternal age effect, mutation may be occurring in cells not involved in the process of replenishment of the germ cell 'bank.' 

In 10 families with an NF1 mutation, Stephens et al. (1992) found that the mutation had occurred in the paternally derived chromosome 17. The probability of observing this result by chance was estimated as less than 0.001, assuming an equal frequency of mutation of paternal and maternal NF1 genes. They suggested a role for genomic imprinting that may either enhance mutation of the paternal NF1 gene or confer protection from mutation to the maternal NF1 gene. 

Lazaro et al. (1994) observed a family in which completely normal parents had a son and daughter with a clinically severe form of NF1. The sibs showed no inheritance of paternal alleles for a marker in intron 38 of the NF1 gene, whereas they received alleles from both parents for other NF1 markers. Analysis with probes from this region of the NF1 gene showed a 12-kb deletion involving exons 32 to 39, in the affected offspring. In the father's spermatozoa, 10% were found to carry the same NF1 deletion, but the abnormality was not detected in DNA from his lymphocytes. Thus, this appeared to be an example of gonadal mosaicism. Colman et al. (1996) identified a new mutation in an NF1 patient who was somatically mosaic for a large maternally derived deletion in the NF1 gene region. The deletion extended at least from exon 4 near the 5-prime end of the gene to intron 39 near the 3-prime end. Thus, 100 kb or more of the gene was lost. Colman et al. (1996) suggested that the deletion occurred at a relatively early developmental time point, since signs of NF1 in this patient were not segmental and both mesodermally and ectodermally derived cells were affected. 

Shannon et al. (1992) reviewed the occurrence of leukemia in NF1. In 16 of 21 cases of juvenile chronic myelogenous leukemia in children with familial NF1, the genetic disorder was inherited from the mother. Of the 21 children, 17 were boys. Myeloid leukemia developed in 12 boys and 4 girls who inherited NF1 from their mothers, and in 5 boys who inherited the disease from their fathers. Father-to-daughter transmission was not observed. Shannon et al. (1992) found that among 5 children with bone marrow monosomy 7 (Mo7), 3 had NF1 and 2 others had suggestive evidence of NF1. Studying DNA extracted from the bone marrow of 11 children with NF1 in whom malignant myeloid disorders had developed, Shannon et al. (1994) found that in samples from 5 there was loss of heterozygosity. In each case, the NF1 allele was inherited from a parent with NF1 and the normal allele was deleted. Loss of constitutional heterozygosity had not been reported in the benign tumors associated with NF1 and had been detected only in a few malignant neural crest tumors and in some tumor-derived cell lines. The data from the study of children with myeloid disorders provided evidence that NF1 may function as a tumor-suppressor allele in malignant myeloid diseases and that neurofibromin is a regulator of RAS in early myelopoiesis. 

CYTOGENETICS

Krone and Hogemann (1986) found monosomy 22 as a predominant numerical anomaly in cultured cells grown from peripheral neurofibromas in patients described simply as suffering 'from sporadic peripheral NF.' Duncan et al. (1987) observed a ring chromosome 22 in a man with an atypical form of neurofibromatosis. He lacked a family history of NF, cafe-au-lait spots, and axillary freckling. He had multiple neurofibromas and a plexiform neuroma. By in situ hybridization, Duncan et al. (1987) showed that both the normal chromosome 22 and the ring chromosome 22 carried this gene. 

Kaneko et al. (1989) found no microscopically detectable chromosome changes in the juvenile chronic myelogenous leukemia associated with neurofibromatosis. However, deletion of the whole or part of certain chromosomes, such as chromosomes 6 or 7, may be an important step towards the evolution of the accelerated blast phase or the development of de novo acute leukemia in a patient. The increased risk of leukemia in NF was thought by the authors to be 'quite low.' 

Gervasini et al. (2002) reported a direct tandem duplication of the NF1 gene identified in 17q11.2 by high-resolution FISH. FISH on stretched chromosomes with locus-specific probes revealed the duplication of the NF1 gene from the promoter to the 3-prime untranslated region (UTR), but with at least the absence of exon 22. Duplication was probably present in the human-chimpanzee-gorilla common ancestor, as demonstrated by the finding of the duplicated NF1 gene at orthologous chromosome loci. The authors suggested that the NF1 intrachromosomal duplication may contribute to the high whole-gene mutation rate by gene conversion, although the functional activity of the NF1 copy remained to be investigated. They also proposed that detection of the NF1 duplicon by high-resolution FISH may pave the way to filling the gaps in the human genomic sequence of the pericentromeric 17q11.2 region. In contrast to the findings of Gervasini et al. (2002), however, Kehrer-Sawatzki et al. (2002) studied a female NF1 patient with reciprocal translocation t(17;22)(q11.2; q11.2) and determined that there is a single NF1 gene in the 17q11.2 region. Kehrer-Sawatzki and Messiaen (2003) analyzed another reciprocal translocation, a t(14;17)(q32;q11.2), described in a large family with NF1, which disrupted the NF1 gene (Messiaen et al., 2000) and again reported findings inconsistent with a duplication of the NF1 gene at 17q11.2 as proposed by Gervasini et al. (2002)

MAPPING

Using 2 RFLPs related to the beta-nerve growth factor gene (162030), Darby et al. (1985) excluded the gene for nerve growth factor as the site of the mutation in 4 families with neurofibromatosis of the classic type. About half of cases are sporadic.

Family studies by Dunn et al. (1985) excluded close linkage of NF1 (lod score less than -2.0) with 8 markers (ABO, Rh, MNSs, GC, PGP, ACP, GPT, and HP). Negative lod scores at all values of theta were obtained with both GC (on 4) and Se (on 19), which others had proposed were linked to NF. Dietz et al. (1985) excluded linkage of NF with GC. Findings of DiLiberti et al. (1982) brought the total lod score over 3.0 for linkage of NF with myotonic dystrophy. Huson et al. (1986) excluded linkage with chromosome 19 markers linked to myotonic dystrophy. Thus, the reports of coinheritance of DM and NF cannot be explained by close linkage of the 2 loci. 

Ledbetter et al. (1989) described a patient in whom a balanced translocation between chromosomes 17 and 22 was found in association with von Recklinghausen neurofibromatosis. The breakpoint on chromosome 17 in this patient was at 17q11.2. Creation of a human-mouse somatic cell hybrid containing the derivative chromosome 22 but not the derivative 17 or normal 17 from this patient allowed rapid localization of ERBA1, ERBB1, and granulocyte colony-stimulating factor (CSF3) distal to the breakpoint, and HHH202 (D17S33) and beta crystallin (CRYB1) proximal to the breakpoint. By linkage analysis of 15 kindreds, Barker et al. (1987) demonstrated that a gene responsible for NF is located near the centromere on chromosome 17. No evidence for heterogeneity was found. 

Because of the high mutation rate in NF, Barker et al. (1987) suggested that the NF1 gene may be unusually large, a situation comparable to that with Duchenne muscular dystrophy (310200). The results of Barker et al. (1987) suggested a genetic distance of approximately 4 cM between NF1 and the centromere. Since recombination is reduced near the centromere, a longer sequence of DNA than one would predict from the usual equation of 1 million bases per cM may separate the 2 landmarks in this instance. The results leave a region of at least 10 megabases on either side of the centromere for the physical location of NF1. Using an alphoid DNA probe that maps to the centromeric region of chromosome 17, Barker et al. (1987) found close linkage of NF1 (theta = 0.04; lod = 4.21). Seizinger et al. (1987) presented evidence that the NF gene is linked to the locus for nerve growth factor receptor (NGFR; 162010) in the region 17q12-q22. A peak lod score of 4.41 was obtained at a theta of 0.14. However, crossovers between the 2 loci suggested that a mutation in NGFR is not the fundamental defect (Seizinger et al., 1987). No loss of alleles at chromosome 17 loci has thus far been found in NF1 tumors (Gusella, 1987). 

On the basis of the occurrence of neurofibromatosis and galactokinase deficiency in a family reported by Fanconi (1933), Stambolian and Zackai (1988) suggested that the NF1 locus may be closely linked to that of galactokinase (230200). One of the affected sibs in this family was the first enzymatically identified case of galactokinase deficiency (Gitzelmann, 1965). The parents of this sibship were first cousins and the mother had NF. 

Vance et al. (1989) reported linkage studies in 6 multigenerational families with NF1 using 9 markers known to map in the pericentromeric region of chromosome 17. The closest marker was HHH202, with a lod score of 3.86 at theta = 0. Two-point lod scores for NF1 versus all the markers studied were presented, and the most likely gene order determined. Similar studies were reported by Seizinger et al. (1989), who performed a multipoint linkage analysis using 6 closely linked markers on chromosome 17. In this study, as in the one reported by Vance et al. (1989), the only probe showing no recombination at a theta of 0 was HHH202, with a lod score of 3.83. The authors concluded, on the basis of the linkage data, that the NF1 gene maps to the long arm rather than the short arm of chromosome 17. 

Further linkage studies involving the NF1 locus and pericentromeric markers on chromosome 17 were reported by Diehl et al. (1989), Mathew et al. (1989), Upadhyaya et al. (1989), Kittur et al. (1989), Goldgar et al. (1989), and Stephens et al. (1989). Goldgar et al. (1989) summarized the results of the international consortium for NF1 linkage. The 8 teams of researchers studied 142 families with more than 700 affected persons, using 31 markers in the pericentric region of chromosome 17. The best gene order derived from these studies was pter--pA10-41--EW301--cen--pHHH202--NF1--EW206--EW207--EW203-- CRI-L581--CRI-L946--HOX2--NGFR--qter. 

Physical mapping data concerning the NF1 region on chromosome 17 were reported by O'Connell et al. (1989), Fountain et al. (1989), and Fain et al. (1989). Menon et al. (1989) studied further the translocation t(1;17) described by Schmidt et al. (1987). In a somatic cell hybrid line containing only the derivative chromosome 1, they showed the breakpoint occurred between SRC2 (164940) and D1S57, which are separated by 14 cM. The translocation breakpoint was located on chromosome 17 between D17S33 and D17S58, markers which also flank NF1 within a region of 4 cM. The findings were considered consistent with the possibility that the translocation event was the cause of NF1 in this family. 

Korenberg et al. (1989) and Pulst et al. (1990, 1991) studied markers flanking the NF1 locus in multiplex families with achondroplasia. By linkage analysis, they excluded the achondroplasia locus from the region between the 2 groups of markers flanking NF1. Thus, the concurrence of achondroplasia and NF1 is a single patient was a matter of chance. 

Fain et al. (1989) and Upadhyaya et al. (1989) described linkage studies of markers around the neurofibromatosis type I locus.

MOLECULAR GENETICS

Skuse et al. (1989) observed loss of DNA markers from the NF1 region of 17q in DNA from malignant tumors from patients with NF1, compared with DNA from nontumor tissue from the same patients. Further, in hereditary cases, they found that the NF1 allele remaining in the tumor was derived from the affected parent. The findings suggested that malignant tumors in NF1 arise as a result of homozygous deficiency of a tumor-suppressor gene. These studies, however, did not detect loss of heterozygosity (LOH) for DNA markers in neurofibromas, the benign tumors of NF1. This finding suggested that neurofibromas are either polyclonal or monoclonal in origin, but arise by a mechanism different from that of NF1 malignancies. 

In a search for deletions in the proximal region of 17q in NF1, Menon et al. (1990) found no deletions in NF1-derived tumor specimens. However, both neurofibrosarcomas from patients with 'atypical' NF and 5 of 6 neurofibrosarcomas from NF1 patients displayed loss of alleles for polymorphic DNA markers on 17p outside the area of mapping of NF1. Since the common region of deletion included the site of the p53 gene (191170), they searched for p53 alterations in neurofibrosarcomas by direct sequencing of PCR-amplified DNA. In 2 of 7 neurofibrosarcomas they found point mutations in exon 4 of the p53 gene. 

Wallace et al. (1989) described a NotI fragment from human chromosome 17q11.2 which detected breakpoints in 2 patients with NF1. Fountain et al. (1989) mapped a series of chromosome 17 NotI-linking clones to proximal 17q and studied them by pulsed field gel electrophoresis in order to define the region of the breakpoint involved in a 17q11.2 balanced translocation present in 2 NF1 patients. One clone, D17S133, identified the breakpoint in 1 of the 2 patients. A pulsed field map indicated that the breakpoint was within 10 to 240 kb of the cloned segment. Similarly, O'Connell et al. (1989) isolated human cosmids and mapped them to the immediate vicinity of NF1. One cosmid probe demonstrated that the breakpoint in both patients (and presumably the NF1 gene) was contained within a 600-kb NruI fragment. 

Yagle et al. (1989) and Xu et al. (1989) described the isolation of cosmid clones flanking the acute promyelocytic leukemia and von Recklinghausen neurofibromatosis loci on chromosome 17.

Yagle et al. (1990) isolated 5 cosmids that map directly proximal to 2 NF1 translocations and 11 cosmids that map directly distal to them. Of these, 2 cosmids in each region were found to be linked to the disease locus and 3 of these 4 cosmids showed no recombination. One distal cosmid detected the 2 NF1 translocations by pulsed field gel analysis and was used by Yagle et al. (1990) to produce a long-range restriction map that covered the translocations. Wallace et al. (1990) identified an Alu insert in the putative NF1 gene. Edwards (1990) commented that such a mechanism of mutation might be a factor in a disorder with a high rate of mutation such as neurofibromatosis. Another disorder in which an Alu-insertion has been identified as causative is ADA deficiency (102700). Most of the ADA (608958) mutations have been single nucleotide substitutions, however. Using pulsed field gel electrophoresis, Upadhyaya et al. (1990) identified a 90-kb deletion in the proximal portion of 17q in 1 of 90 unrelated patients with NF1. Wallace et al. (1990) identified a large transcript from 17q11.2 disrupted in 3 patients with NF1. Viskochil et al. (1990) detected deletions of 190, 40, and 11 kb in the gene located at the translocation breakpoint in 3 patients with NF1. 

Xu et al. (1990) extended the known open reading frame of the NF1 gene by cDNA walking and sequencing. The new sequence predicted 2,485 amino acids of the NF1 peptide. A 360-residue region showed significant similarity to the catalytic domains of both human and bovine GAP. Xu et al. (1990) also pointed out the similarity to the yeast Ira1 product. The findings suggest that NF1 encodes a cytoplasmic GAP-like protein that may be involved in the control of cell growth by interacting with proteins such as the RAS gene product. Mapping of the cDNA clones confirmed that NF1 spans the breakpoint in a t(1;17) translocation. Furthermore, 3 active genes, called OMGP, EVI2B and EVI2A, lie within an intron of NF1 but in opposite orientation. Xu et al. (1992) found a pseudogene of the adenylate kinase-3 gene (103030) in an intron of the NF1 gene. It appeared to be a processed pseudogene since it lacked introns and contained a polyadenylate tract; it nevertheless retained coding potential because the open reading frame was not impaired by any observed base substitutions. 

Marchuk et al. (1991) reported an extensive cDNA walk resulting in the cloning of the complete coding region of the NF1 transcript. Analysis of the sequences revealed an open reading frame of 2,818 amino acids, although alternatively spliced products may code for different protein isoforms. The gene occupies approximately 300 kb on chromosome 17, with its promoter in a CpG-rich island. Heim et al. (1994) cited evidence that the NF1 gene spans approximately 350 kb of genomic DNA, encodes an mRNA of 11 to 13 kb, and contains at least 56 exons. 

Legius et al. (1992) characterized an NF1-related locus on chromosome 15. The nonprocessed NF1 pseudogene (NF1P1) can produce additional fragments in Southern blotting, pulsed field gel, and PCR experiments with some NF1 cDNA probes or oligonucleotides. In addition, certain regions of the NF1 gene cross-hybridize with a locus on chromosome 14. These loci can cause confusion in the mutation analysis of patients with NF1. 

Using Southern blotting and PCR amplification of exons in the 3-prime region of the NF1 gene, followed by single-strand conformation polymorphism (SSCP) analysis, Weiming et al. (1992) found only 2 unequivocal mutations: a 571-bp deletion that removed exon 6 and resulted in a frameshift in exon 7, and a 2-bp deletion in exon 1. They detected mutations in at most 3% of subjects (there was a third mutation of questionable pathologic significance) in an analysis that covered 17% of the coding sequence by SSCP and a larger region by Southern blotting. This experience accorded with that of others. The results suggested that most NF1 mutations lie elsewhere in the coding sequence or outside it. 

DeClue et al. (1992) presented evidence implicating the NF1 protein as a tumor suppressor gene product that negatively regulates p21(ras) and defined a 'positive' growth role for RAS activity in NF1 malignancies. Li et al. (1992) referred to the NF1 gene product as neurofibromin. Neurofibromin contains a GAP-related domain that can downregulate p21(ras) by stimulating its intrinsic GTPase. Li et al. (1992) reasoned that since p21(ras)-GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with RAS signaling pathways and contribute to the development of tumors. In support of this hypothesis, they found an amino acid substitution in the NF1-GRD, altering lys1423 (to either glu or gln) in a colon adenocarcinoma, in anaplastic astrocytoma, and in a myelodysplastic syndrome. A lys1423-to-glu mutation was found in a patient with NF1 and affected members of his family. 

Collins (1993) developed FISH techniques to detect large deletions in the gene.

By denaturing gradient gel electrophoresis (DGGE), Valero et al. (1994) screened 70 unrelated NF1 patients for mutations in exons 29 and 31. Of the 4 mutations that were identified, 3 consisted of C-to-T transitions resulting in nonsense mutations, 2 in exon 29 (C5242T and C5260T) and 1 in exon 31 (C5839T). The fourth mutation consisted of a 2-bp deletion in exon 31, 5843delAA, resulting in a premature stop codon. The C5839T mutation had previously been reported in 3 independent studies, suggesting that this position is a mutation hotspot within the NF1 gene. It occurs in a CpG residue. 

Heim et al. (1994) stated that although mutations had been sought in several hundred patients, by August 1994, only 70 mutations had been reported in a total of 78 individuals; only the R1947X mutation had been seen in as many as 6 unrelated patients. The NF1 mutations that had been identified included 14 large (more than 25 bp) deletions, 3 large insertions, 18 small (less than 25 bp) deletions, 8 small insertions, 6 nonsense mutations, 14 missense mutations, and 7 intronic mutations. At least 56 of the 70 (80%) potentially encode a truncated protein because of premature translation termination. Therefore, Heim et al. (1994) analyzed polypeptides synthesized in vitro from RT-PCR products, using an approach that had been applied successfully to mutation detection in dystrophin and APC genes. 

Li et al. (1995) showed that the 5-prime end of the NF1 gene is embedded in a CpG island containing a NotI restriction site and that the remainder of the gene lies in the adjacent 35-kb NotI fragment. In their efforts to develop a comprehensive screen for NF1 mutations, they isolated genomic DNA clones that together contain the entire NF1 cDNA sequence. They identified all intron-exon boundaries of the coding region and established that it is composed of 59 exons. The 3-prime untranslated region of the NF1 gene was found to span approximately 3.5 kb and to be continuous with the stop codon. 

Heim et al. (1995) used a protein truncation assay to identify abnormal polypeptides synthesized in vitro from 5 RT-PCR products that represented the entire NF1 coding region. Truncated polypeptides were observed in 14 of 20 patients with familial or sporadic NF1 diagnosed clinically and in 1 patient with only cafe-au-lait spots and no other diagnostic criterion. Mutations responsible for the generation of abnormal polypeptides were characterized by DNA sequencing; 13 previously unpublished mutations were characterized in the 14 individuals. The mutation 2027insC was observed in 2 unrelated individuals; the other 12 mutations were unique. Thus, mutations were identified in two-thirds of the patients studied using the protein truncation assay. Because the entire NF1 coding region was spanned in each individual, the distribution of NF1 truncating mutations was discerned for the first time. The mutations were relatively evenly distributed throughout the coding region. 

Upadhyaya et al. (1995) stated that fewer than 90 mutations had been reported to the NF1 mutation analysis consortium and details of only 76 of these mutations had been published. They had previously reported the identification of 14 mutations and described 5 new mutations identified by SSCP analysis and heteroduplex analysis. Three intragenic deletions were also identified by analyzing their families with intron-specific microsatellite markers. 

Vogel et al. (1995) used a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. They showed that both neural crest- and placode-derived sensory neurons isolated from NF1 -/- embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wildtype counterparts die rapidly unless nerve growth factor (162030) or brain-derived neurotrophic factor (113505) is added to the culture medium. Moreover, NF1 -/- sympathetic neurons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. These results were considered by Vogel et al. (1995) as consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons. 

Shen et al. (1996) summarized the molecular genetics of NF1 as follows: the gene spans over 350 kb of genomic DNA and encodes an mRNA of 11 to 13 kb containing at least 59 exons. It is widely expressed in a variety of human tissues. Four alternatively spliced NF1 transcripts have been identified. Three of these transcript isoforms (each with an extra exon: 9br, 23a, and 48a, respectively) show differential to some extent in various tissues, while the fourth isoform (2.9 kb in length) remains to be examined. The protein encoded by NF1, neurofibromin, has a domain homologous to the GTPase activating protein family and downregulates RAS activity. Over 80% of germline mutations appear to predict severe truncation of neurofibromin. The actual mechanisms of tumorigenesis, in which NF1 is involved, remained unknown. No evidence of LOH had been observed in neurofibromas. Shen et al. (1996) speculated that it may be that a second mutation in another gene is required for genesis of neurofibromas, or that they may arise because of the loss of 1 allele. Another possibility is that a second mutation in the NF1 gene is required. In NF2, loss of the wildtype allele is demonstrable in tumors, consistent with the classic Knudson theory of tumor suppressor genes. On the other hand, the effects of the APC gene (611731) in the formation of colonic polyps is apparently not dependent on loss of the wildtype allele. 

Although several observations support the contention that the NF1 gene product is a tumor suppressor involved in the RAS signal transduction pathway, mutations had not been identified in both NF1 alleles in dermal neurofibromas until the report by Sawada et al. (1996). Their patient was previously shown to have large submicroscopic deletions of the NF1 locus by both somatic cell hybrid analysis (Kayes et al., 1994) and FISH of lymphoblastoid cells (Leppig et al., 1996). The deletion extended at least 125 kb centromeric and 135 kb telomeric to NF1. As part of her medical care, the patient electively had a scalp neurofibroma removed surgically. Sawada et al. (1996) showed that the tumor DNA harbored a 4-bp deletion in NF1 exon 4b in the other allele. The authors stated that this was the first reported definitive identification of a somatic mutation limited to the NF1 locus in a benign neurofibroma from an NF1 individual in whom the constitutional NF1 mutation was known. 

The NF1 gene product, neurofibromin, displays partial homology to GAP. The GAP-related domain, encoded by exons 20-27a, is the only region of neurofibromin to which a biologic function has been ascribed. Upadhyaya et al. (1997) screened 320 unrelated NF1 patients for mutations in the GRD-encoding region of the NF1 gene. Sixteen different lesions in the NF1-GRD region were identified in a total of 20 patients. Of these lesions, 14 were novel and together comprised 3 missense, 2 nonsense, and 3 splice site mutations plus 6 deletions of between 1 and 4 bp. 

For the most part the NF1 tumor suppressor acts through the interaction of its GRD with the product of the RAS protooncogene. Skuse et al. (1996) discovered an mRNA editing site within the NF1 mRNA. Editing at this site changes a cytidine at nucleotide 2914 to a uridine, creating an in-frame translation stop codon. The edited transcript, if translated, would produce a protein truncated in the N-terminal region of the GRD, thereby inactivating the NF1 tumor-suppressor function. Analysis of RNA from a variety of cell lines, tumors, and peripheral blood cells revealed that the NF1 mRNA undergoes editing, to different extents, in every cell type studied. Three tumors analyzed as part of their study, an astrocytoma, a neurofibroma, and a neurofibrosarcoma, each had levels of NF1 mRNA editing substantially higher than did peripheral blood leukocytes. To investigate the role played by editing in NF1 tumorigenesis, Cappione et al. (1997) analyzed RNA from 19 NF1 and 4 non-NF1 tumors. (The authors referred to the editing site as nucleotide 3916.) They observed varying levels in NF1 mRNA editing in different tumors, with a higher range of editing in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas had an intermediate range of levels of NF1 mRNA editing. The constitutional levels of NF1 mRNA editing varied slightly in NF1 individuals but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggested to Cappione et al. (1997) that inappropriately high levels of NF1 mRNA editing indeed plays a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor. 

Mukhopadhyay et al. (2002) studied C-to-U RNA editing in peripheral nerve sheath tumor samples (PNSTs) from 34 patients with NF1. Whereas most showed low levels of RNA editing, 8 of the 34 tumors demonstrated 3 to 12% C-to-U editing of NF1 RNA. These tumors demonstrated 2 distinguishing characteristics. First, these PNSTs expressed APOBEC1 (600130) mRNA, the catalytic deaminase of the holoenzyme that edits APOB (107730) RNA. Second, NF1 RNA from these PNSTs contained increased proportions of an alternatively spliced exon, 23A, downstream of the edited base in which editing occurs preferentially. These findings, together with results of both in vivo and in vitro experiments with APOBEC1, strongly suggested an important mechanistic linkage between NF1 RNA splicing and C-to-U editing and provided a basis for understanding the heterogeneity of posttranscriptional regulation of NF1 expression. 

The NF1 tumor suppressor protein is thought to restrict cell proliferation by functioning as a Ras-specific guanosine triphosphatase-activating protein. However, The et al. (1997) found that Drosophila homozygous for null mutations of an NF1 homolog show no obvious signs of perturbed RAS1-mediated signaling. Loss of NF1 resulted in a reduction in size of larvae, pupae, and adults. This size defect was not modified by manipulating RAS1 signaling but was restored by expression of activated adenosine 3-prime, 5-prime-monophosphate-dependent protein kinase (PKA; see 176911). Thus, NF1 and PKA appear to interact in a pathway that controls the overall growth of Drosophila. Guo et al. (1997) showed, from a study of Drosophila NF1 mutants, that NF1 is essential for the cellular response to the neuropeptide PACAP38 (pituitary adenylyl cyclase-adenosine activating polypeptide) at the neuromuscular junction. The peptide induced a 3-prime, 5-prime-monophosphate (cAMP) pathway. This response was eliminated in NF1 mutants. NF1 appeared to regulate the rutabaga-encoded adenylyl cyclase rather than the RAS-RAF pathway. Moreover, the NF1 defect was rescued by the exposure of cells to pharmacologic treatment that increased concentrations of cAMP. 

The risk of malignant myeloid disorders in young children with NF1 is 200 to 500 times the normal risk. Neurofibromin, the protein encoded by the NF1 gene, negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells. This hypothesis was further supported by the demonstration by Side et al. (1997) that both NF1 alleles were inactivated in bone marrow cells from children with NF1 complicated by malignant myeloid disorders. Using an in vitro transcription and translation system, they screened bone marrow samples from 18 such children for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from the affected parents in cases of familial NF1. Side et al. (1997) found that the normal NF1 allele was absent in bone marrow samples from 5 of 8 children who had truncating mutations of the NF1 gene. 

Abernathy et al. (1997) stated that about half of NF1 cases represent new mutations and fewer than 100 constitutional mutations have been reported up to that time, and analyzed the NF1 gene for mutation using a combined heteroduplex/SSCP approach. In a set of 67 unrelated NF1 patients, they identified 26 mutations and/or variants in 45 of the 59 exons tested. Disease-causing mutations were found in 19% (13 of 67) of cases studied. The mutations included splice mutations, insertions, deletions, and point changes. 

Maynard et al. (1997) screened exon 16 of the NF1 gene in 465 unrelated NF1 patients. Nine novel mutations were identified: 3 nonsense, 2 single-base deletions, 1 7-bp duplication, 2 missense, and 1 recurrent splice site mutation. No mutations had been reported previously in exon 16, which is the largest exon (441 bp) of NF1. The previous absence of mutation identification in exon 16 suggested to the authors that codons in this region may have a lower propensity to mutate. 

As reviewed earlier, submalignant tumors occurring in NF1 patients have been found to show loss of heterozygosity consistent with the 2-hit hypothesis of Knudson, with 1 allele constitutionally inactivated and the other somatically mutated. Somatic NF1 deletions in benign neurofibromas were described by Colman et al. (1995) and mutations in both copies of the NF1 gene in a dermal neurofibroma were reported by Sawada et al. (1996). Serra et al. (1997) performed LOH analysis on 60 neurofibromas derived from 17 patients, of whom 9 had a family history of the disease and 8 represented sporadic cases. LOH was found in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, they found that in the neurofibromas of patients from familial cases, the deletions occurred in the allele that was not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Thus, the authors concluded that there appears to be double inactivation of the NF1 gene in benign neurofibromas. 

Eisenbarth et al. (2000) described a systematic approach of searching for somatic inactivation of the NF1 gene in neurofibromas. In the course of these studies, they identified 2 novel intragenic polymorphisms: a tetranucleotide repeat and a 21-bp duplication. Among 7 neurofibromas from 4 different NF1 patients, they detected 3 tumor-specific point mutations and 2 LOH events. The results suggested that small subtle mutations occur with similar frequency to that of LOH in benign neurofibromas and that somatic inactivation of the NF1 gene is a general event in these tumors. Eisenbarth et al. (2000) concluded that the spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variable expressivity of the NF1 phenotype. 

Skuse and Cappione (1997) reviewed the possible molecular basis of the wide clinical variability in NF1 observed even among affected members of the same family (Huson et al., 1989). The complexities of alternative splicing and RNA editing may be involved. Skuse and Cappione (1997) suggested that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tumorigenesis can be expanded to include post-transcriptional mechanisms that regulate NF1 gene expression. Aberrations in these mechanisms may play a role in the observed clinical variability. 

Stop, or nonsense, mutations can have a number of effects. In the case of several genes, they affect mRNA metabolism and reduce the amount of detectable mRNA. Also, in the NF1 gene, a correlation between a high proportion of stop mutations and unequal expression of the 2 alleles is demonstrable. A second, less common outcome is that mRNA containing a nonsense mutation is translated and results in a truncated protein. A third possible outcome is an abnormally spliced mRNA induced by a premature-termination codon (PTC) in the skipped exon. This was demonstrated in several disease genes, including the CFTR gene (Hull et al., 1994) and the fibrillin gene (Dietz et al., 1993). Hoffmeyer et al. (1998) characterized several stop mutations localized within a few basepairs in exons 7 and 37 of the NF1 gene and noticed complete skipping of either exon in some cases. Because skipping of exons 7 and 37 does not lead to a frameshift, premature termination codons (PTCs) are avoided. Hoffmeyer et al. (1998) found that some other stop mutations in the same general region did not lead to a skip. Calculations of minimum-free-energy structures of the respective regions suggested that both changes in the secondary structure of mRNA and creation or disruption of exonic sequences relevant for the splicing process may in fact cause these different splice phenomena observed in the NF1 gene. 

Juvenile myelomonocytic leukemia (JMML; 607785) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis type I. The NF1 gene regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on RAS proteins. Side et al. (1998) undertook a study to determine if the NF1 gene is involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. SSCP analysis was used to detect RAS point mutations in these samples. Side et al. (1998) confirmed mutations of NF1 in 3 cases of JMML, 1 of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested, suggesting that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in 4 patients; as expected, none of these samples harbored NF1 mutations. Because 10 to 14% of children with JMML had a clinical diagnosis of NF1, these data were consistent with the existence of NF1 mutations in approximately 30% of JMML cases. 

Most mutations underlying NF1 result in the loss of 1 allele at the DNA, mRNA, or protein level and thus in loss of any function of the gene product neurofibromin. Simultaneous loss of several different neurofibromin functions was postulated to explain the pleiotropic effects of its loss. However, Klose et al. (1998) identified a novel missense mutation in a family with a classic multisymptomatic NF1 phenotype, including a malignant schwannoma. The mutation specifically abolished the Ras-GTPase-activating function of neurofibromin. The arg1276-to-pro mutation (R127P; 162200.0022) in this family was shown to involve the arginine finger of the neurofibromin GAP-related domain, which is the most essential catalytic element for Ras-GAP activity. Klose et al. (1998) presented data demonstrating that the R1276P mutation, unlike previously reported missense mutations of the GRD region, did not impair the secondary and tertiary protein structure. It neither reduced the level of cellular neurofibromin nor influenced its binding to Ras substantially, but it did completely disable GAP activity. The findings provided direct evidence that failure of neurofibromin GAP activity is a critical element in NF1 pathogenesis. Thus, therapeutic approaches aimed at the reduction of the Ras-GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms. 

Kluwe et al. (1999) stated that plexiform neurofibroma can be found in about 30% of NF1 patients, often causing severe clinical symptoms. They examined 14 such tumors from 10 NF1 patients for loss of heterozygosity at the NF1 gene using 4 intragenic polymorphic markers. LOH was found in 8 tumors from 5 patients, and was suspected in 1 additional tumor from another patient. They interpreted these findings as suggesting that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neurofibromas were also examined for mutation in the TP53 gene; no mutations were found. 

Mutation analysis in NF1 has been hampered by the large size of the gene (350 kb with 60 exons), the high rate of new mutations, lack of mutational clustering, and the presence of numerous homologous loci. Mutation detection methods based on the direct analysis of the RNA transcript of the gene permit the rapid screening of large multiexonic genes. However, detection of frameshift or nonsense mutations can be limited by instability of the mutant mRNA species due to nonsense-mediated decay. To determine the frequency of this allelic exclusion, Osborn and Upadhyaya (1999) analyzed total lymphocyte RNA from 15 NF1 patients with known truncation mutations and a panel of 40 NF1 patients with unknown mutations. The level of expression of the mutant message was greatly reduced in 2 of the 15 samples (13%), and in 3 of the 18 informative samples from the panel of 40. A coupled RT-PCR and protein truncation test method was subsequently applied to screen RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide bands were identified and characterized in 21 samples (53%); each of these had a different mutation. The mutations were uniformly distributed across the gene, and 14 represented novel changes, providing further information on the germline mutational spectrum of the NF1 gene. 

Neurofibromas presumably arise from NF1 inactivation in S100+ Schwann cells. Rutkowski et al. (2000) demonstrated that fibroblasts isolated from neurofibromas carried at least 1 normal NF1 allele and expressed both NF1 mRNA and protein, whereas the S100+ cells from 4 of 7 of these same tumors lacked the NF1 transcript completely. The authors were unable to document second NF1 mutations in the S100+ cell lines from tumors, and speculated that additional molecular events aside from NF1 inactivation in Schwann cells and/or other neural crest derivatives contribute to neurofibroma formation. 

The mutation rate in the NF1 gene is one of the highest known in humans, with approximately 50% of all NF1 patients presenting with novel mutations (reviewed by Huson and Hughes, 1994). Despite the high frequency of this disorder in all populations, relatively few mutations had been identified at the molecular level, with most unique to 1 family. A limited number of mutation 'hotspots' had been identified: R1947X in exon 31 (162200.0012), and the 4-bp region between nucleotides 6789 and 6792 in exon 37, both implicated in about 2% of NF1 patients (reviewed by Upadhyaya and Cooper (1998)). Messiaen et al. (1999) identified another mutation hotspot in exon 10b. By analyzing 232 unrelated NF1 patients, they identified 9 mutations in exon 10b, indicating that this exon is mutated in almost 4% of NF1 patients. Two mutations, Y489C (162200.0023) and L508P (162200.0024), were recurrent, whereas the others were unique. The authors suggested that since 10b shows the highest mutation rate of any of the 60 NF1 exons, it should be given priority in mutation analysis. 

Fahsold et al. (2000) performed a mutation screen of the NF1 gene in more than 500 unrelated patients with NF1. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing of all individual exons. Of the variants found, they concluded that 161 different ones were novel. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for direct sequencing. Of all sequence variants found, less than 20% represented C-to-T or G-to-A transitions within a CpG dinucleotide, and only 6 different mutations also occurred in NF1 pseudogenes, with 5 being typical C-to-T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion can account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in 2 distinct regions, the GAP-related domain and an upstream gene segment comprising exons 11 to 17. The latter forms a so-called cysteine/serine-rich domain with 3 cysteine pairs suggestive of ATP binding, as well as 3 potential cAMP-dependent protein kinase recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggested significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16. 

Faravelli et al. (1999) reported a family in which 7 members developed brain tumors which in 4 were confirmed as gliomas. Three of these individuals had a clinical history strongly suggestive of NF1. Two individuals with very mild features of NF1 insufficient to meet diagnostic criteria carried a splice site mutation in intron 29 of the NF1 gene, creating a frameshift and premature protein termination. Faravelli et al. (1999) noted the unusually high incidence of brain tumors in this family with the NF1 phenotype and suggested that some cases of familial glioma may be explained by mutations in the NF1 gene. 

Ars et al. (2000) applied a whole NF1 cDNA screening methodology to the study of 80 unrelated NF1 patients and identified 44 different mutations, 32 being novel, in 52 of the patients. Mutations were detected in 87% of the familial cases and in 51% of the sporadic ones. At least 15 of the 80 NF1 patients (19%) had recurrence of a previously observed mutation. The study showed that in 50% of the patients in whom the mutations were identified, these resulted in splicing alterations. Most of the splicing mutations did not involve the conserved AG/GT dinucleotides of the donor and acceptor splice sites. One frameshift, 2 nonsense, and 2 missense mutations were also responsible for alterations in mRNA splicing. Location and type of mutation within the NF1 gene and its putative effect at the protein level did not indicate any relationship to any specific clinical feature of NF1. The high proportion of aberrant spliced transcripts detected in NF1 patients stressed the importance of studying mutations at both the genomic and RNA level. Ars et al. (2000) raised the possibility that part of the clinical variability in NF1 is related to mutations affecting mRNA splicing, which is the most common molecular defect in NF1. 

Messiaen et al. (2000) studied 67 unrelated NF1 patients fulfilling the NIH diagnostic criteria (Stumpf et al., 1988; Gutmann et al., 1997), 29 familial and 38 sporadic cases, using a cascade of complementary techniques. They performed a protein truncation test starting from puromycin-treated EBV cell lines and, if no mutation was found, continued with heteroduplex, FISH, Southern blot, and cytogenetic analysis. The authors identified the germline mutation in 64 of 67 patients, and 32 of the mutations were novel. The mutation spectrum consisted of 25 nonsense, 12 frameshift, 19 splice mutations, 6 missense and/or small in-frame deletions, 1 deletion of the entire NF1 gene, and a translocation t(14;17)(q32;q11.2). Their data suggested that exons 10a-10c and 37 are mutation-rich regions and that together with some recurrent mutations they may account for almost 30% of the mutations in classic NF1 patients. Messiaen et al. (2000) found a high frequency of unusual splice mutations outside of the AG/GT 5-prime and 3-prime splice sites. As some of these mutations formed stable transcripts, it remained possible that a truncated neurofibromin was formed. 

Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype that shares morphologic characteristics with nerve sheath tumors. For that reason, Gutzmer et al. (2000) analyzed 15 DNMs and 20 melanomas without morphologic features of desmoplasia or neuroid differentiation (i.e., common melanomas) for LOH at the NF1 locus and flanking regions. Allelic loss was detected in 10 of 15 (67%) DNMs but in only 1 of 20 (5%) common melanomas. LOH was most frequently observed at marker IVS38, located in intron 38 of NF1. These data suggested a role for NF1 in the pathogenesis of DNM and supported the hypothesis that exon 37 may encode a functional domain. 

To identify somatic mutations responsible for tumorigenesis in NF1, John et al. (2000) studied DNA from 82 tumors and blood from 45 patients with NF1. Loss of heterozygosity (LOH) was found in 10 of 82 (12%) tumors studied, and SSCP/heteroduplex analysis identified 2 somatic mutations and 5 novel germline mutations. John et al. (2000) suggested that the low detection rate of somatic mutations might indicate that an alternative mechanism such as methylation is involved in tumor formation in NF1. They also acknowledged, however, that mutations might be present but not identified by reason of size, location, or sensitivity of screening method. 

Serra et al. (2000) cultured pure populations of Schwann cells (SCs) and fibroblasts derived from 10 neurofibromas with characterized NF1 mutations and found that SCs, but not fibroblasts, harbored a somatic mutation at the NF1 locus in all studied tumors. By culturing neurofibroma-derived SCs under different in vitro conditions, 2 genetically distinct SC subpopulations were obtained: NF1 -/- and NF1 +/-. The authors hypothesized that NF1 mutations in SCs, but not in fibroblasts, correlate with neurofibroma formation and that only a portion of SCs in neurofibromas have mutations in both NF1 alleles. 

Serra et al. (2001) pointed out that the large size of the NF1 gene, together with the multicellular composition of neurofibromas, greatly hampers the characterization of the second hit, the somatic NF1 mutation, in these tumors. They presented the somatic NF1 mutation analysis of the whole set of neurofibromas studied by their group and consisting in 126 tumors derived from 32 NF1 patients. They identified 45 independent somatic NF1 mutations, 20 of which were reported for the first time. Among point mutations, those affecting the correct splicing of the NF1 gene were common, coinciding with results reported on germline NF1 mutations. In most cases, they were able to confirm that both copies of the NF1 gene were inactivated. They found that the study of more than 1 tumor derived from the same patient was useful for the identification of the germline mutation. The culture of neurofibromas with clearing of fibroblasts facilitated LOH detection in cases in which it had been otherwise difficult to determine. 

Using polyclonal antibodies to the NF1 protein, Koivunen et al. (2000) found increased expression of NF1 protein in cultured human keratinocytes when induced to differentiate in high calcium media. The NF1 protein appeared to be associated with the intermediate filament cytoskeleton and was expressed at highest levels during the period of desmosome formation. Cultured keratinocytes from patients with NF1 showed increased variability in cell size and morphology in comparison to control keratinocytes, suggesting that NF1 mutations may alter the organization of the cytoskeleton. The authors proposed that the NF1 tumor suppressor gene exerts its effects in part by controlling organization of the cytoskeleton during the formation of cellular contacts. 

Gutmann (2001) reviewed the functions of neurofibromin and merlin, the product of the NF2 gene (607379), in tumor suppression and cell-cell signaling, respectively.

Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. By PCR and fluorescence in situ hybridization, Luijten et al. (2001) studied the extent of the homology of the regions surrounding these NF1 pseudogenes. They found that a fragment of at least 640 kb is homologous between the 3 regions. Based on previous studies and these new findings, they proposed a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, Luijten et al. (2001) identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments. 

Cook et al. (1998) presented the hypothesis that some haploinsufficiency diseases result from an increased susceptibility to stochastic delays of gene initiation or interruptions of gene expression, events that are normally buffered by increased gene copy number and relatively insensitive to dosage compensation. Kemkemer et al. (2002) applied this line of thought to the tumor suppressor gene NF1 and demonstrated that haploinsufficiency of the gene results in an increased variation of dendrite formation in cultured NF1 melanocytes. These morphologic differences between NF1 and control melanocytes were described by a mathematical model in which the cell is considered to be a self-organized automaton. The model described the adjustment of the cells to a set point and included a noise term that allowed for stochastic processes. It described the experimental data of control and NF1 melanocytes. In the cells haploinsufficient for NF1, Kemkemer et al. (2002) found an altered signal-to-noise ratio detectable as increased variation in dendrite formation in 2 of 3 investigated morphologic parameters. They suggested that in vivo NF1 haploinsufficiency results in an increased noise in cellular regulation and that this effect of haploinsufficiency may also be found in other tumor suppressors. 

Upadhyaya et al. (2003) described a Portuguese family in which 3 members had clinical features of NF1 but each had a different underlying defect in the NF1 gene; see 162200.0030-162200.0032. The third affected member of the family reported by Upadhyaya et al. (2003), a first cousin of the father, possessed neither the gross deletion nor the nonsense mutation. Instead, she carried a frameshift mutation in exon 29 of the NF1 gene. Once again, this deletion was not observed in either of the patient's clinically normal parents. Upadhyaya et al. (2003) speculated about the mechanism of this unusual situation. 

The overlap syndrome neurofibromatosis-Noonan syndrome shows features of both disorders, as was first noted by Allanson et al. (1985). Colley et al. (1996) examined 94 sequentially identified patients with NF1 from their genetic register and found Noonan features in 12. Carey et al. (1997) identified a 3-bp deletion of exon 17 of the NF1 gene in a family with NFNS (162200.0033). Stevenson et al. (2006) provided a follow-up of this family. Baralle et al. (2003) identified mutations in the NF1 gene in 2 patients with the overlap syndrome (162200.0034 and 162200.0035). 

Bertola et al. (2005) provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome (163950) in a patient with a de novo missense mutation in the NF1 gene (162200.0043) and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. 

Kluwe et al. (2003) examined 20 patients with spinal tumors from 17 families for clinical symptoms associated with NF1 and for NF1 mutations. Typical NF1 features were found in 12 patients from 11 families. Typical NF1 mutations were found in 10 of the 11 index patients in this group, including 8 truncating mutations, 1 missense mutation, and 1 deletion of the entire NF1 gene. Eight patients from 6 families had no or only a few additional NF1-associated symptoms besides multiple spinal tumors, which were distributed symmetrically in all cases and affected all 38 nerve roots in 6 patients. Only mild NF1 mutations were found in 4 of the 6 index patients in the latter group, including 1 splicing mutation, 2 missense mutations, and 1 nonsense mutation in exon 47 at the 3-prime end of the gene. The data indicated that patients with spinal tumors can have various NF1 symptoms and NF1 mutations; however, patients with no or only a few additional NF1 symptoms may be a subgroup or may have a distinct form of NF1, probably associated with milder NF1 mutations or other genetic alterations. 

The underestimates of NF1 gene mutations in neurofibromatosis type I have been attributed to the large size of the NF1 gene, the considerable frequency of gross deletions, and the common occurrence of splicing defects that are only detectable by cDNA analysis. A number of splicing errors do not affect the canonical GT splice donor or AG splice acceptor, or create novel splice sites, but may exert their effect by means of an altered interaction between an exonic splice enhancer (ESE) and mRNA splicing factors (Messiaen et al., 2000; Liu et al., 2001). Colapietro et al. (2003) reported skipping of exon 7 and sequence alterations in ESEs in a patient with severe NF1 (162200.0036). 

As indicated earlier, the analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients shows that each neurofibroma results from an individual second hit mutation; thus, factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. Wiest et al. (2003) performed a mutational screen of numerous neurofibromas from 2 NF1 patients and found a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations were reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, these results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease. 

Not only can mutations in nucleotides at the ends of introns result in abnormalities of splicing, but nonsense, missense, and even translationally silent mutations have been shown to cause exon skipping. The analysis of individual mutations of this kind can shed light on basic pre-mRNA splicing mechanisms. Using cDNA-based mutation detection analysis, Zatkova et al. (2004) identified 1 missense and 6 nonsense mutations (e.g., 162200.0042) that lead to different extents of exon-lacking transcripts in NF1 patients. They confirmed mutation-associated exon skipping in a heterologous hybrid minigene context. Because of evidence that the disruption of functional ESE sequences is frequently the mechanism underlying mutation-associated exon skipping, Zatkova et al. (2004) examined the wildtype and mutant NF1 sequences with 2 available ESE prediction programs. Either or both programs predicted the disruption of ESE motifs in 6 of the 7 analyzed mutations. To ascertain the function of the predicted ESEs, Zatkova et al. (2004) quantitatively measured their ability to rescue splicing of an enhancer-dependent exon, and found that all 7 mutant ESEs had reduced splicing enhancement activity compared to the wildtype sequences. The results suggested that the wildtype sequences function as ESE elements, whose disruption is responsible for the mutation-associated exon skipping observed in NF1 patients. Furthermore, this study illustrated the utility of ESE prediction programs for delineating candidate sequences that may serve as ESE elements. 

In a study of 17 unrelated subjects with NFNS, De Luca et al. (2005) found NF1 gene defects in 16. Remarkably, a high prevalence of in-frame defects affecting exons 24 and 25 was found. No defect was observed in PTPN11 (176876), which is the usual site of mutations causing classic Noonan syndrome. De Luca et al. (2005) stated that including their study, 18 distinct NF1 gene mutations had been described in 22 unrelated patients with NFNS. 

Maertens et al. (2007) reported 3 unrelated patients with NF1: 1 was mildly affected with both neurofibromas and pigmentary skin changes and 2 had isolated neurofibromas and pigmentary skin changes, respectively, consistent with segmental disease. Detailed molecular analysis of various tissues and cell types showed biallelic NF1 inactivation in Schwann cells from neurofibromas and biallelic NF1 inactivation in melanocytes from cafe-au-lait nodules. The data provided molecular evidence that the distinct clinical picture of the patients was due to somatic mosaicism for the NF1 mutations and that the mosaic phenotype reflected embryonic timing. 

NF1 Microdeletion Syndrome

NF1 patients who have a submicroscopic deletion spanning the NF1 gene are remarkable for an early age at onset of cutaneous neurofibromas, suggesting the deletion of an additional locus that potentiates neurofibromagenesis. Dorschner et al. (2000) constructed a 3.5-Mb BAC/PAC/YAC contig at 17q11.2. Analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb. Deletions encompassed the entire 350 kb NF1 gene, 3 additional genes, 1 pseudogene, and 16 ESTs. In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, which the authors termed NF1REPs. These REPs, or clusters of paralogous loci, are 15 to 100 kb and harbor at least 4 ESTs and an SH3GL pseudogene. The remaining 3 patients had at least 1 breakpoint outside an NF1REP element; 1 had a smaller deletion, thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data showed that the likely mechanism of NF1 microdeletion is homologous recombination between NF1REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements that Dorschner et al. (2000) identified, NF1REP-mediated somatic recombination may be an important mechanism for the loss of heterozygosity at the NF1 locus in tumors of NF1 patients. 

In only 5 to 10% of cases of NF1, a microdeletion including the NF1 gene is found. Correa et al. (2000) analyzed a set of polymorphic dinucleotide-repeat markers flanking the microdeletion on chromosome 17 in a group of 7 unrelated families with a de novo NF1 microdeletion. Six of 7 microdeletions were of maternal origin. The breakpoints of the microdeletions of maternal origin were localized in flanking paralogous sequences termed NF1REPs. The single deletion of paternal origin was shorter, and no crossover occurred on the paternal chromosome 17 during transmission. Five of the 6 cases of maternal origin were informative, and all 5 showed a crossover (between the flanking markers) after maternal transmission. The observed crossovers flanking the NF1 region suggested to the authors that these NF1 microdeletions resulted from an unequal crossover in maternal meiosis I, mediated by a misalignment of the flanking NF1-REPs. 

Shen et al. (2000) found that the SLC6A4 (182138) and CPD (603102) genes were deleted in 1 of 17 NF1 patients carrying submicroscopic NF1 contiguous gene deletions.

Lopez-Correa et al. (2001) mapped and sequenced the microdeletion breakpoints in 54 NF1 patients. In 25 such patients, recombination events occurred in a discrete 2-kb recombination hotspot within each of the flanking NF1REPs. Two recombination events were accompanied by apparent gene conversion. A search for recombination-prone motifs revealed a chi-like sequence. 

Kehrer-Sawatzki et al. (2004) identified a high frequency of mosaicism among patients with NF1 caused by microdeletions resulting from somatic recombination of the JJAZ1 gene (606245). Two types of deletions were observed. The classic 1.4-Mb deletion was found in some patients. These type I deletions encompass 14 genes and have breakpoints in the NF1 low-copy repeats (LCRs). However, Kehrer-Sawatzki et al. (2004) identified a second major type of NF1 microdeletion, which spanned 1.2 Mb and affected 13 genes. This type II deletion was mediated by recombination between the JJAZ1 gene and its pseudogene. The JJAZ1 gene, which was completely deleted in patients with type I NF1 microdeletions and disrupted in deletions of type II, is highly expressed in brain structures associated with learning and memory. Thus, its haploinsufficiency might contribute to mental impairment in patients with constitutional NF1 microdeletions. Conspicuously, 7 of the 8 mosaic deletions were of type II, whereas only 1 was a classic type I deletion. Therefore, the JJAZ1 gene is a preferred target of strand exchange during mitotic nonallelic homologous recombination. Although type I NF1 microdeletions occur by interchromosomal recombination during meiosis, the findings of Kehrer-Sawatzki et al. (2004) implied that type II deletions are mediated by intrachromosomal recombination during mitosis. 

Gervasini et al. (2005) reported an NF1 patient with a 1.5-Mb deletion involving the NF1 gene. High-resolution FISH showed that the centromeric breakpoint was within the SSH2 gene (606779), and the telomeric breakpoint was within IVS23A of the NF1 gene; both breakpoints occurred in Alu sequences. Gervasini et al. (2005) noted that most Alu-mediated deletions are much smaller (up to 200 kb). The patient had a relatively mild phenotype with borderline cognitive deficits and seizures, but no dysmorphism or cardiac anomalies, suggesting that genes mapping downstream from NF1 may account for those manifestations. 

Douglas et al. (2007) identified heterozygous mutations in the RNF135 gene (611358.0001-611358.0004) in 4 of 245 unrelated individuals with an overgrowth syndrome characterized by increased postnatal height and weight, macrocephaly, variable learning disability, and dysmorphic facial features. One additional individual had a microdeletion of RNF135 and 4 other genes, but not NF1. Although none had clinical features of NF1, the facial features were similar to the NF1 deletion syndrome, including broad forehead, down-slanting palpebral fissures, broad nasal tip, long philtrum, and thin upper lip. Variable features in 1 or 2 patients included deafness, optic nerve hypolasia, advanced bone age, ataxia, autistic features, and pulmonary stenosis. Douglas et al. (2007) concluded that haploinsufficiency of RNF135 contributes to the overgrowth and facial dysmorphism that is often present in individuals with NF1 microdeletions, as well as learning disabilities and other congenital anomalies. 

Approximately 5% of patients with NF1 exhibit gross deletions that encompass the NF1 gene and its flanking regions. The breakpoints of the common 1.4-Mb (type 1) deletions are located within low-copy repeats (NF1-REPs) and cluster within a 3.4-kb hotspot of nonallelic homologous recombination (NAHR). Steinmann et al. (2007) presented a comprehensive breakpoint analysis of type 2 deletions. These span 1.2 Mb and are characterized by breakpoints located within the SUZ12 gene (606245) and its pseudogene. Breakpoint analysis of 13 independent type 2 deletions revealed no obvious hotspots of NAHR. However, an overrepresentation of polypyrimidine/polypurine tracts and triplex-forming sequences was noted in the breakpoint regions that could have facilitated NAHR. It was noteworthy that all 13 type 2 deletions identified were characterized by somatic mosaicism, which indicates a positional preference for mitotic NAHR with the NF1 gene region. Whereas interchromosomal meiotic NAHR occurs between the NF1-REPs giving rise to type 1 deletions, NAHR during mitosis appears to occur intrachromosomally between the SUZ12 gene and its pseudogene, thereby generating type 2 deletions. Additionally, 12 of the 13 mosaic type 2 deletions were found in females. The marked female preponderance among mosaic type 2 deletions contrasts with the equal sex distribution noted for type 1 and/or atypical NF1 deletions. Although an influence of chromatin structure was strongly suspected, no sex-specific differences in the methylation pattern exhibited by the SUZ12 were apparent that could explain the higher rate of mitotic recombination in females. 

DIAGNOSIS

Johnson and Charneco (1970) suggested that the cafe-au-lait spot of neurofibromatosis can be distinguished from the innocent spot that occurs in normal persons and from the pigmented areas of Albright disease by the presence of a large number of DOPA-positive melanocytes that have giant pigment granules in the cytoplasm. The plexiform neuroma is specific to von Recklinghausen disease. Only on this can the histopathologist make a definitive diagnosis. 

Ward et al. (1990) estimated that tightly linked, flanking DNA markers available to them permitted prediction of NF1 in a child with greater than 98% accuracy. They predicted that even after the NF1 gene is cloned, linkage testing will probably remain important. This has been the experience with factor VIII deficiency and 21-hydroxylase deficiency, in which linked markers complement the use of direct genetic probes. Linked markers may remain more cost-effective than screening for 1 genetic event among a large number of possible mutations that could be responsible for NF1 in a particular family. 

Gutmann et al. (1997) provided guidelines for the diagnostic evaluation and multidisciplinary management of both NF1 and NF2.

Cnossen et al. (1998) reported a 10-year prospective follow-up study of 209 children suspected of having NF1, 150 of whom were ultimately given this diagnosis. The minor disease features macrocephaly, short stature, hypertelorism, and thorax abnormalities were highly prevalent in children with NF1 and significantly associated with the diagnosis of NF1 at 6 years of age. In addition, children with 3 or more minor disease features were all diagnosed with NF1 under the age of 6 years. Cnossen et al. (1998) concluded that in children aged less than 6 years with insufficient diagnostic criteria, documentation of minor disease features may be helpful in predicting the diagnosis of NF1. 

Park and Pivnick (1998) used a protein truncation assay to screen for mutations in 15 NF1 patients and obtained positive results in 11 (73%) of them. Sequencing of cDNA and genomic DNA yielded identification of 10 different mutations. No correlations between genotype and phenotype were apparent. 

Ablon (2000) interviewed 18 unaffected parents of an affected child to document their experiences in receiving their child's diagnosis of NF1. The author found that methods of disclosure were often at variance with suggestions made in recent years for conveying 'bad news.' She also found that certain factors assist parents in receiving and more positively adapting to their child's diagnosis. These factors include physicians' attention to the setting and style of disclosure, imparting appropriate and positive information, allowing additional time for careful explanation, and scheduling a follow-up appointment. 

Bahuau et al. (2001) reported a family with neurofibromatosis type I, in which 2 female children had congenital megacolon due to intestinal neuronal dysplasia type B (601223). The affected infants were found be doubly heterozygous for a mutation in the NF1 gene and in the GDNF gene (600837). 

Ferner et al. (2007) provided guidelines for the diagnosis and management of NF1 according to organ system, as well as suggestions for genetic counseling.

POPULATION GENETICS

Littler and Morton (1990) reviewed data from 4 studies, with the following results: the carrier incidence at birth is 0.0004; the gene frequency is 0.0002; and the proportion of cases due to fresh mutation is 0.56. Lazaro et al. (1994) gave the incidence of NF1 as approximately 1 in 3,500 and stated that about half of cases are the result of new mutations. 

Garty et al. (1994) found an unusually high frequency of NF1 in young Israeli adults. They surveyed 374,440 17-year-old Jewish recruits for military service and concluded that 390 of them had NF1. The prevalence was 1.04/1,000 (0.94/1,000 for males and 1.19/1,000 for females). This value is 2 to 5 times greater than the previously reported prevalence. NF1 was more common in young adults whose parents were of North African and Asian origin (1.81/1,000 and 0.95/1,000, respectively) and less common in those of European and North American origin (0.64/1,000). All these differences were statistically significant; Garty et al. (1994) suggested that they may be partially explained by the more advanced parental age of the NF group (as suggested by the larger number of children in the North African and Asian families) or by founder effect or both. 

Poyhonen et al. (2000) studied the epidemiology of NF1 in northern Finland. The observed overall prevalence of NF1 was 1 in 4,436 and the incidence 1 in 3,647. There was no evidence of geographic clustering of NF1, nor was there any sign of linkage disequilibrium in DNA studies.

ANIMAL MODEL

Hinrichs et al. (1987) showed that the TAT gene of human T-lymphotropic virus type 1 (HTLV-1) under control of its own long terminal repeat is capable of inducing tumors in transgenic mice. The morphologic and biologic properties of these tumors indicated a close resemblance to NF1. Multiple tumors developed simultaneously in the transgenic tat mice at approximately 3 months of age, and the phenotype was successfully passed through 3 generations. The tumors arose from the nerve sheaths of peripheral nerves and were composed of perineural cells and fibroblasts. Evidence of HTLV-1 infection in patients with neural and other soft tissue tumors is needed in order to establish a link between infection by this human retrovirus and von Recklinghausen disease. 

Buchberg et al. (1990) sequenced a portion of the murine NF1 gene and showed that the predicted amino acid sequence is nearly the same as the corresponding region of the human NF1 gene product. Computer searches identified homology between the mouse NF1 gene and the Ira-1 and Ira-2 genes identified in Saccharomyces cerevisiae, which negatively regulate the RAS-cyclic AMP pathway. RAS proteins are involved in the control of proliferation and differentiation in mammalian cells. Their activity is modulated by their ability to bind and hydrolyze guanine nucleotides. GTP-binding activates RAS, whereas GTP hydrolysis inactivates RAS. Mutant forms of RAS found in human tumors have greatly decreased GTPase activity, resulting in accumulation of RAS in the GTP-bound active form. 

Silva et al. (1997) stated that learning disabilities are said to occur in 30 to 45% of patients with NF1, even in the absence of any apparent neuropathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems, and impairment in spatial cognitive abilities. They cited several studies that suggested a role of neurofibromin in brain function. The expression of the NF1 gene is largely restricted to neuronal tissues in the adult. This GTPase-activating protein may act as a negative regulator of neurotrophin-mediated signaling. They also noted immunohistochemical studies that suggested that activation of astrocytes may be common in the brain of NF1 patients. Silva et al. (1997) described a mouse model (Nf1+/-) for the learning and memory deficits associated with NF1. Importantly related to these observations is the demonstration that mice heterozygous for an Nf1 knockout show a deficit of learning and memory. As in humans, the learning and memory deficits of Nf1+/- mice are restricted to specific types of learning, they are fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning. 

Vogel et al. (1999) identified that 100% of mice harboring null Nf1 and p53 (191170) alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. The sarcomas exhibited loss of heterozygosity (LOH) at both gene loci and expressed phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies. Vogel et al. (1999) concluded that their data and those of Cichowski et al. (1999) indicated that an additional mutation in the p53 tumor suppressor gene is required to predispose Nf1+/- mouse neural crest-derived cells to malignant transformation. Vogel et al. (1999) stated that their analyses provided evidence that NF1-associated rhabdomyosarcomas and leiomyosarcomas may be of neural crest origin and provided a possible explanation for the development of malignant Triton tumors, or MTTs. Cell lines isolated from MTTs express both Schwann cell and smooth muscle markers, often in the same tumor cell. The phenotype of these tumors is consistent with immortalization of a pluripotent neural crest stem cell, which under normal circumstances adopts a glial, smooth muscle, or neuronal fate. Unlike humans, mice that are heterozygous for a mutation in Nf1 do not develop neurofibromas. Cichowski et al. (1999) demonstrated that chimeric mice composed in part of Nf1-/- cells do develop neurofibromas, which demonstrated that loss of the wildtype NF1 allele is rate-limiting in tumor formation. In addition, Cichowski et al. (1999) showed that mice that carry linked germline mutations in Nf1 and p53 develop malignant peripheral nerve sheath tumors, which supported a cooperative and causal role for p53 mutations in malignant peripheral nerve sheath tumor development. Cichowski et al. (1999) concluded that the 2 mouse models, either chimeric for complete loss of Nf1 or carrying Nf1 and p53 LOH, provide the means to address fundamental aspects of disease development and to test therapeutic strategies. 

Children with NF1 are predisposed to JMML (607785). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony-stimulating factor (GMCSF; 138960) in methylcellulose cultures. Birnbaum et al. (2000) generated hematopoietic cells deficient in both Nf1 and Gmcsf to test whether GMCSF is required to drive excessive proliferation of Nf1-deficient cells in vivo. They showed that GMCSF plays a central role in establishing and maintaining the MPD and that recipients engrafted with Nf1- and Gmcsf-deficient hematopoietic cells are hypersensitive to exogenous GMCSF. 

Astrocytomas are the leading cause of brain cancer in humans. Because these tumors are highly infiltrative, current treatments that rely on targeting the tumor mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumor progression and testing therapeutics. Reilly et al. (2000) presented a mouse model of astrocytoma involving mutation of 2 tumor-suppressor genes, NF1 and Trp53 (TP53; 191170). (The conventional symbol for the p53 gene in the mouse is Trp53; in the human it is TP53.) Humans with neurofibromatosis type I have an increased risk of optic gliomas, astrocytomas, and glioblastomas. The TP53 tumor suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastomas involving TP53 loss. This was the first reported mouse model of astrocytoma initiated by loss of tumor suppressors, rather than overexpression of transgenic oncogenes. 

Costa et al. (2001) generated mice lacking the alternatively spliced exon 23a, which modifies the GTPase-activating protein (GAP) domain of NF1, by targeted disruption. Nf1(23a) -/- mice were viable and physically normal and did not have increased tumor disposition, but showed specific learning impairments. These mice specifically lacked the neurofibromin type II isoform. Costa et al. (2001) found that spatial learning is impaired in Nf1(23a) -/- mice but that additional training alleviates learning deficits. Nf1(23a) -/- mice were impaired in contextual discrimination and had delayed acquisition of motor skills. Costa et al. (2001) concluded that it is unlikely that learning deficits of these mice were caused by generalized neurologic problems or poor motor performance, as swimming speed, ability to freeze, ambulance, exploratory behavior, muscular strength, and body weight were not affected by the mutation. The Nf1(23a) -/- mutation did not affect all forms of learning. Costa et al. (2001) demonstrated that the type II isoform of neurofibromin is important for brain function, but not for embryologic development or tumor suppression. Their data indicated that the learning deficits caused by mutations that inactivate NF1 in mice and humans are not the result of developmental deficits or undetected tumors. Instead, they suggested that learning deficits in individuals with NF1 are caused by the disruption of neurofibromin function in the adult brain, a finding with important implications for treatment of the learning disabilities associated with NF1. Exon 23a modifies the GAP domain of NF1, indicating that modulation of the RAS pathway is important to learning and memory. 

Although approximately 10% of Nf1 +/- mice are prone to the development of JMML, they do not manifest pigmentary abnormalities or develop neurofibromas. Neurofibromin negatively regulates Ras activity in mouse hemopoietic cells through the Kit (164920) receptor tyrosine kinase, which is encoded by the dominant white spotting (W) locus. Ingram et al. (2000) generated mice with mutations at both the W locus (val831 to met, termed W41, which results in an abnormal mottled, white coat color) and the Nf1 gene. Mice homozygous for the W41 mutation and heterozygous at Nf1 had 60 to 70% restoration of coat color. However, Nf1 haploinsufficiency increased peritoneal and cutaneous mast cell numbers in wildtype and W41 mice, and it increased wildtype and W41/W41 bone marrow mast cells in in vitro cultures containing Steel factor (184745), the mouse Kit ligand and a mast cell mitogen. Ingram et al. (2000) proposed that increasing the neurofibromin-specific GAP for Ras activity could be a strategy for preventing or treating the complications of NF1. 

Gutmann et al. (1999) reported that astrocytes from mice heterozygous for a targeted mutation in the Nf1 gene (Nf1 +/- astrocytes) exhibit a cell autonomous growth advantage associated with increased RAS pathway activation. In addition, Gutmann et al. (2001) demonstrated that Nf1 astrocytes exhibit decreased cell attachment, actin cytoskeletal abnormalities during the initial phases of cell spreading, and increased cell motility. Whereas these cytoskeletal abnormalities were also observed in Nf1 -/- astrocytes, astrocytes expressing a constitutively active RAS molecule showed increased cell motility and abnormal actin cytoskeleton organization during cell spreading, but exhibited normal cell attachment. Increased expression of 2 proteins implicated in cell attachment, spreading, and motility were seen in Nf1 +/- and Nf1 -/- astrocytes: GAP43 (162060) and T-cadherin (CDH13; 601364). The authors hypothesized that tumor suppressor gene heterozygosity may result in abnormalities in cell function that may contribute to the pathogenesis of nontumor phenotypes in NF1. 

Costa et al. (2002) crossed Nf1 heterozygote mice with mice heterozygous for a null mutation in the Kras gene (190070) and tested the Nf1 descendants. They found that the double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. Costa et al. (2002) also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Costa et al. (2002) concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. 

Through use of a conditional (cre/lox) allele, Zhu et al. (2002) demonstrated that loss of NF1 in the Schwann cell lineage is necessary, but not sufficient, to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in nonneoplastic cells, particularly mast cells. Zhu et al. (2002) concluded that the requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers. Zhu et al. (2002) identified a non-cell-autonomous role for the development of tumors in NF1. The onset, growth potential, and multicellular nature of the NF1 -/- neurofibromas was suppressed when the cellular environment retained both functional NF1 alleles. Zhu et al. (2002) ruled out trivial explanations for the observed difference in tumor incidence that relate to the potential relative inefficiency of the Cre transgene. The fact that NF1 +/- mast cells invade preneoplastic nerves and remain present throughout the development of the tumor is in stark contrast to the absence of NF1 +/+ mast cells in the NF1 flox/flox;Krox20-cre hyperplasias that fail to form frank neurofibromas. Zhu et al. (2002) suggested that sensitized heterozygous mast cells homing to nullizygous NF1 Schwann cells in peripheral nerves would create a cytokine-rich microenvironment that is apparently permissive for tumor growth. 

Although NF1 is characterized by proliferation and malignant transformation of neural-crest derivatives, affected individuals often have disorders that seem unrelated to the neural crest, including hypertension, renal artery stenosis, increased incidence of congenital heart disease (Friedman et al., 2002), especially valvular pulmonic stenosis, and vascular abnormalities in the CNS known as moyamoya (252350). Attempts to produce animal models of NF1 have been hampered by the fact that inactivation of Nf1 in mice leads to midgestation lethality from cardiovascular abnormalities. These defects include structural malformations of the outflow tract of the heart and enlarged endocardial cushions, which are the anlage of cardiac valves. Using tissue-specific gene inactivation, Gitler et al. (2003) showed that endothelial-specific inactivation of Nf1 recapitulates key aspects of the complete null phenotype, including multiple cardiovascular abnormalities involving the endocardial cushions and myocardium. This phenotype is associated with an elevated level of Ras signaling in Nf1 -/- endothelial cells and greater nuclear localization of the transcription factor NFATC1 (600489). Inactivation of NF1 in the neural crest does not cause cardiac defects but results in tumors of neural-crest origin resembling those seen in humans with NF1. These results established a new and essential role for NF1 in endothelial cells and confirmed the requirement for neurofibromin in the neural crest. 

Ruiz-Lozano and Chien (2003) commented on how it is possible to apply Cre-loxP technology to track the cardiac morphogenic signals mediated by neurofibromin. A growing list of mouse lines that express Cre in specific cardiovascular cell lineages was available.

Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation (Zhu et al., 2002). Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1 +/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that remodel the extracellular matrix and initiate angiogenesis. Yang et al. (2003) showed that homozygous Nf1 mutant (Nf1 -/-) Schwann cells secrete Kit ligand (KITLG; 184745), also known as mast cell growth factor (MGF), which stimulates mast cell migration. They also showed that Nf1 +/- mast cells are hypermotile in response to Kit ligand. Thus, these studies identified a novel interaction between Schwann cells carrying a homozygous Nf1-null mutation and mast cells heterozygous for the Nf1 mutation. 

Viskochil (2003) pointed out that Riccardi (1981) had presented an 'NF cellular interaction hypothesis,' implicating that the mast cell is a major player in neurofibroma formation. He posited that 'the mast cell now is seen not as a secondary arrival in a developing neurofibroma but as an inciting factor contributing in a primary, direct fashion to tumor development.' 

Tong et al. (2007) investigated the pathophysiology of neurofibromatosis-1 in Drosophila melanogaster by inactivation or overexpression of the NF1 gene. NF1 gene mutants had shortened life spans and increased vulnerability to heat and oxidative stress in association with reduced mitochondrial respiration and elevated production of reactive oxygen species (ROS). Flies overexpressing NF1 had increased life spans, improved reproductive fitness, increased resistance to oxidative and heat stress in association with increased mitochondrial respiration, and a 60% reduction in ROS production. These phenotypic effects proved to be modulated by the adenylyl cyclase/cyclic AMP (cAMP) protein kinase A (see 176911) pathway, not the Ras/Raf pathway. Treatment of wildtype D. melanogaster with cAMP analogs increased their life span, and treatment of NF1 mutants with metalloporphyrin catalytic antioxidant compounds restored their life span. Thus, Tong et al. (2007) concluded that neurofibromin regulates longevity and stress resistance through cAMP regulation of mitochondrial respiration and ROS production. They suggested that NF1 may be treatable using catalytic antioxidants. 

HISTORY

Although the Elephant Man (Howell and Ford, 1980) has often been thought to have had von Recklinghausen disease, it has been suggested (Pyeritz, 1987) that Proteus syndrome (176920) is a more likely diagnosis. After considering several diagnostic possibilities, Cohen (1988) also concluded that the skeletal findings in Joseph Merrick are most consistent with Proteus syndrome. He pointed out that the 'moccasin' lesions of the feet are particularly characteristic of that disorder. See the study of the case of Joseph Merrick by Graham and Oehlschlaeger (1992)

Ruggieri and Polizzi (2003) found several historical examples of what they interpreted as mosaicism in neurofibromatosis. They suggested that the segmental lesions can be limited either to the affected area showing the same degree of severity as that found in the corresponding nonmosaic trait (type 1 segmental involvement) or may be markedly more pronounced and superimposed on a milder, nonsegmental, heterozygous manifestation of the same trait (type 2 segmental involvement). 

ALLELIC VARIANTS
(selected examples)

.0001 NEUROFIBROMATOSIS, TYPE I [NF1, ALU INS]

Wallace et al. (1991) demonstrated a de novo Alu repetitive element insertion into an intron of the NF1 gene, which resulted in deletion of the downstream exon during splicing and consequently shifted the reading frame. This previously undescribed mechanism of mutation indicated that Alu retrotransposition is an ongoing process in the human germline. The patient was an isolated case in his family. The insertion, 300-500 bp, began 44 bp upstream of exon 6. This appears to have been the first report of a disease-causing mutation consisting of a de novo Alu insertion. Alu elements had been involved in the generation of disease mutation by recombination (e.g., in familial hypercholesterolemia (143890) and ADA deficiency) or point mutation (e.g., in ornithine aminotransferase deficiency [258870]), but not as a new element. 

.0002 NEUROFIBROMATOSIS, TYPE I [NF1, 5-BP DEL]

In 2 NF1 patients, a 35-year-old man and his daughter, Stark et al. (1991) demonstrated a 5-bp deletion (CCACC or CACCT) and an adjacent transversion, located about 500 bp downstream from the region that codes for a functional domain of the NF1 gene product. The mutation was demonstrable by heteroduplex analysis. The deletion removed the proximal half of a small potential stem-loop and interrupted the reading frame in exon 1. A severely truncated protein with a grossly altered carboxy terminus lacking one-third of its sequence was the predicted consequence. Stark et al. (1992) found that both alleles were expressed in primary cultures of neurofibroma cells and melanocytes from a cafe-au-lait macule of the proband. Thus, loss of heterozygosity was excluded. Furthermore, they used the 5-bp deletion for the presymptomatic diagnosis of the 18-month-old third son of the proband. 

.0003 NEUROFIBROMATOSIS, TYPE I [NF1, LEU348PRO]

Cawthon et al. (1990) identified point mutations in a 4-kb sequence of the transcript of the gene at a translocation breakpoint associated with NF1. One mutant allele contained a T-to-C transition that caused a leu348-to-pro substitution, and the second harbored a C-to-T insertion that changed an arg365 to a stop codon (162200.0004). 

.0004 NEUROFIBROMATOSIS, TYPE I [NF1, ARG365TER]

Independently, Cawthon et al. (1990) and Estivill et al. (1991) identified a new mutation in exon 4 of the NF1 gene; a C-to-T transition at nucleotide 1087 of the cDNA (numbering of Cawthon et al., 1990), changing an arginine to a stop codon at amino acid position 365. Although a different numbering system was used, this is the same mutation as that found by Valero et al. (1994) and designated C5242T in exon 29. They proposed that this site, in a CpG residue, is a hotspot for mutation in the NF1 gene. 

.0005 NEUROFIBROMATOSIS, TYPE I [NF1, LYS1423GLU]

Li et al. (1992) found an AAG-to-GAG transition at codon 1423, resulting in the substitution of glutamic acid for lysine in a patient with NF1 and affected members of his family. The same mutation or a mutation in the same codon leading to substitution of glutamine for lysine through an A-to-C transversion was also observed by Li et al. (1992) as a somatic mutation in adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma. 

.0006 NEUROFIBROMATOSIS, TYPE I [NF1, 1-BP INS, FS1841TER ]

In 2 unrelated patients with type I neurofibromatosis, Upadhyaya et al. (1992) found insertion of a cytosine within codon 1818 that changed the reading frame and resulted in 23 altered amino acids prior to the inappropriate introduction of a stop codon at amino acid 1841. The insertion created a recognition site for enzyme MnlI. (The authors incorrectly stated in their abstract and the legend of their Figure 3 that there was a nucleotide insertion at 'codon 5662.' The nucleotide insertion at residue 5662 occurs within codon 1818 in their cDNA clone of NF1, as correctly represented in the sequence shown in their Figure 3.) 

.0007 NEUROFIBROMATOSIS, TYPE I [NF1, 1-BP INS, FS1841TER]

In a patient with neurofibromatosis type I, Upadhyaya et al. (1992) found an insertion of thymidine in codon 1823 resulting in a shift of the reading frame, the generation of 18 amino acids different from those of the normal protein, and a gene product that terminated prematurely at amino acid 1840 by the creation of a stop codon at 1841. 

.0008 NEUROFIBROMATOSIS, TYPE I [NF1, LEU2143MET]

In a patient with neurofibromatosis type I, Upadhyaya et al. (1992) found a C-to-A transversion at nucleotide 6639 changing amino acid 2143 from leucine to methionine.

.0009 NEUROFIBROMATOSIS, TYPE I [NF1, TYR2213ASN]

In a patient with neurofibromatosis type I, Upadhyaya et al. (1992) found a T-to-G transversion at nucleotide 6724 resulting in substitution of asparagine for tyrosine at amino acid 2213.

.0010 WATSON SYNDROME [NF1, 42-BP DUP]

In a family in which Watson syndrome (193520) had occurred in 3 generations, Tassabehji et al. (1993) demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classic NF1 which result predominantly in null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. The affected mother had multiple cafe-au-lait patches, freckling in the axillary and groin, low-set posteriorly rotated ears, a squint, and an IQ of 56. She had no Lisch nodules or neurofibromata. A daughter, aged 3.5 years, had multiple cafe-au-lait spots, mild pectus carinatum, hypertelorism with epicanthic folds, a squint, low-set posteriorly rotated ears, and moderate global developmental delay. Her twin brother had ptosis, mild cubitus valgus, bilateral undescended testes, and mild pulmonic valvular stenosis by echocardiography. Neither child had Lisch nodules or neurofibromata. 

.0011 WATSON SYNDROME [NF1, 80-KB DEL]

Upadhyaya et al. (1992) found an 80-kb deletion at the NF1 locus in a patient with Watson syndrome (193520).

.0012 NEUROFIBROMATOSIS, TYPE I [NF1, ARG1947TER]

A C-to-T transition changing arginine-1947 to a stop codon has been described in multiple Caucasian and Japanese families suggesting that this codon, CGA, is a hotspot for mutation, presumably because it contains a CpG dinucleotide. (Numbering of codons is based on Marchuk et al. (1991).) The mutation was described in 3 unrelated Caucasians (Ainsworth et al., 1993; Cawthon et al., 1990; Estivill et al., 1991); at least 2 of these cases were sporadic. Horiuchi et al. (1994) reported the same mutation in 2 unrelated familial cases of NF1. That these represented independent mutations was indicated by the fact that in the 2 families the affected individuals differed with regard to a polymorphism located within the NF1 gene. The frequency of the arg1947-to-ter mutation may be as high as 8% in Japanese and at least 1% in Caucasians. Studying one of the patients with the arg1947-to-ter mutation, Horiuchi et al. (1994) showed that both the normal and the mutant allele were transcribed in a lymphoblastoid cell line. 

Heim et al. (1994) referred to the arg1947-to-ter mutation as having been identified in 6 unrelated patients with NF1.

Lazaro et al. (1995) presented 2 further cases of the arg1947-to-ter mutation in the NF1 gene. They stated that a total of 9 cases of the R1947X mutation had been reported, giving a frequency of about 2%. The mutation occurs within a CpG dinucleotide. They developed an allele-specific oligonucleotide hybridization assay for the efficient screening of a large number of samples for this relatively common recurrent mutation. 

In a sample of 56 unrelated Korean patients with NF1, Park et al. (2000) identified 1 with the R1947X mutation.

.0013 NEUROFIBROMATOSIS, TYPE I [NF1, IVS18DS, G-A, +1]

Purandare et al. (1995) identified a G-to-A transition at position +1 of intron 18 of the NF1 gene in a 41-year-old Caucasian female in whom the diagnosis of neurofibromatosis was first made at the age of 28 years when she was admitted to hospital for a grand mal seizure. A son was also affected. The mutation resulted in skipping of exon 18 which did not cause a shift in the reading frame but resulted in an in-frame loss of 123 nucleotides from the mRNA and the corresponding 41 amino acids from the protein. Purandare et al. (1995) referred to 3 previously reported splice donor site mutations in the NF1 gene. 

.0014 NEUROFIBROMATOSIS, TYPE I [NF1, 2-BP DEL ]

The arg1947-to-ter mutation (162200.0012) is one of the few recurrent mutations found in NF1 but is not a frequent recurrence, having been found in only 6 of 363 patients. Robinson et al. (1996) described a recurrent 2-bp deletion in exon 10c of the NF1 gene in 2 unrelated patients: one sporadic and another familial case. The mutation was designated 1541delAG by the authors. 

.0015 NEUROFIBROMATOSIS, TYPE I [NF1, MET1035ARG ]

Wu et al. (1996) suggested that some patients diagnosed with LEOPARD syndrome may have a mutation in the NF1 gene, whereas others may have a mutation in a different gene. They found a de novo M1035R missense mutation resulting from a T-to-G transversion in exon 18 of the NF1 gene in a 32-year-old woman with a prior diagnosis of LEOPARD syndrome. At birth, a heart murmur was detected resulting from subvalvular muscular aortic stenosis and valvular aortic stenosis. The skin showed multiple dark lentigines together with a few larger cafe-au-lait patches. The same lentigines were present in the armpits and groin and were not raised. The patient attended a special school for mildly mentally retarded children. At the age of 21 years, mitral insufficiency was demonstrated resulting from a double orifice mitral valve. The patient had macrocrania (head circumference 58 cm), apparent hypertelorism, and a coarse face with broad neck. Neurofibromas were not present at the age of 32, and no Lisch nodules were seen by slit-lamp examination. The mutation was absent in the parents, who were clinically normal. 

.0016 NEUROFIBROMATOSIS, TYPE I [NF1, ARG1391SER ]

Upadhyaya et al. (1997) identified 14 novel mutations in the GAP-related domain of neurofibromin in patients with NF1. One of these mutations was a change in nucleotide 4173 from A to T, changing codon 1391 from AGA (arg) to AGT (ser). The effect of this R1391S missense mutation was studied by in vitro expression of a site-directed mutant and by GAP activity assay. The mutant protein was found to be some 300-fold less active than wildtype NF1 protein. 

.0017 NEUROFIBROMATOSIS, TYPE I [NF1, 250-KB DEL ]

In a 12-year-old male patient with sporadic NF1, dysmorphism, mental retardation, and severe skeletal anomalies, but no neurofibromas, Riva et al. (1996) found a deletion in the NF1 gene of at least 250 kb, indicating the absence of a large 5-prime portion of the NF1 gene, as well as a contiguous extragenic region. A cytogenetically visible 17q11.2 deletion was visible in the patient's karyotype; by microsatellite marker LOH analysis, the deletion was found to lie within the D17S841 to D17S250 interval. The patient was diagnosed on the basis of cafe-au-lait spots and inguinal freckling. The authors attributed the patient's lack of neurofibromas to the influence of modifying genes. Riva et al. (1996) considered the patient a possibly important resource in the identification of genes downstream of NF1 that may contribute to extra-NF1 clinical signs. 

.0018 NEUROFIBROMATOSIS, FAMILIAL SPINAL [NF1, 1-BP INS, 8042A]

In 5 affected members of a family with spinal neurofibromatosis with cafe-au-lait macules (162210), Ars et al. (1998) identified a 1-bp insertion (8042insA) in exon 46 of the NF1 gene. The mutation was predicted to result in a truncated protein.

.0019 LEUKEMIA, JUVENILE MYELOMONOCYTIC [NF1, TRP1538TER ]

Among 20 children with juvenile myelomonocytic leukemia (JMML; 607785), Side et al. (1998) found 3 with truncating mutations of NF1. One of them, a 3-year-old boy with JMML, had a G-to-A transition at nucleotide 4614, which converted codon 1538 from tryptophan to stop in exon 27a.

.0020 LEUKEMIA, JUVENILE MYELOMONOCYTIC [NF1, IVS34, G-A, +18 ]

In a 19-month-old boy with juvenile myelomonocytic leukemia (JMML/Mo7; 607785), Side et al. (1998) found in cloned cDNA aberrant splicing resulting in a shift in the reading frame. Genomic DNA showed an alteration (6579,G-A,+18) in the splice donor consensus sequence flanking exon 34. This mutation introduced an additional 17 nucleotides containing a novel BglI restriction enzyme site into the patient's cDNA. Side et al. (1998) were able to show the presence of this restriction site in amplified cDNA derived from the patient's EBV cell line RNA, thus confirming that this mutation existed in the germline. Furthermore, loss of heterozygosity was demonstrated, indicating inactivation of another NF1 allele. 

.0021 LEUKEMIA, JUVENILE MYELOMONOCYTIC [NF1, IVS11, A-G, -8]

In a 6-month-old boy with JMML (607785), Side et al. (1998) described a splice mutation. Cloned cDNA showed abnormal splicing of 7 nucleotides between exons 10c and 11. They had previously found the same mutation in a child with familial NF1 and myelodysplasia syndrome (Side et al. (1997)); genomic DNA sequence showed an abnormal splice acceptor sequence upstream of exon 11 (1642,A-G,-8) creating a cryptic splice site and consequent frameshift and premature stop codon at codon 555. 

.0022 NEUROFIBROMATOSIS, TYPE I [NF1, ARG1276PRO ]

In a family with a classic multisymptomatic NF1 phenotype, including a malignant schwannoma, Klose et al. (1998) found an arg1276-to-pro (R1276P) mutation. Based on complex biochemical studies as well as the analysis of the crystal structure of the GTPase-activating protein (GAP) domain of p120GAP in the presence of RAS, Klose et al. (1998) unequivocally identified a mutated amino acid as the arginine finger of the neurofibromin GAP-related domain (GRD), which is the most essential catalytic element for Ras-GAP activity. The proband was the first child of unaffected, nonconsanguineous parents. She developed multiple cafe-au-lait spots within the first year of life. Her language and motor development were mildly retarded, and she complained of incoordination throughout life. Around puberty, multiple cutaneous neurofibromas developed which worsened at the time of each of her 3 pregnancies. At the age of 31 years, routine MRI of the brain revealed multiple areas of increased T2 signal intensity in the midbrain and a small optic glioma. Because of recurrent paresthesias in her left leg, an MRI scan of the spine was done 2 years later which revealed multiple schwannomas within the vertebral foramina. The largest tumor in the lumbar region, with a volume of approximately 8 ml, was surgically removed. Histologically, there was no evidence of malignancy at that time. Eight months later, the patient suffered a relapse with rapid tumor growth. At the time of reoperation, the retroperitoneal tumor had reached a volume of 800 ml and showed numerous necrotic and anaplastic areas with a proliferation rate up to 60%. The patient died of widespread metastatic disease at the age of 34 years. Her 3 male children, ages 4, 8, and 12 years, all fulfilled the NF1 diagnostic criteria. The 2 elder sons were macrocephalic. Language and motor development of all children was retarded to a similar extent and on the same time scale as in their mother. A cranial MRI scan in the 2 elder brothers showed increased T2 signal intensities similar to those in their mother. 

.0023 NEUROFIBROMATOSIS, TYPE I [NF1, TYR489CYS ]

Among the 9 NF1 exon 10b mutations identified by Messiaen et al. (1999) in 232 unrelated patients, 2 were recurrent: an A-to-G transition at nucleotide 1466, resulting in a tyr489-to-cys substitution (Y489C), and a T-to-C transition at nucleotide 1523, resulting in a leu508-to-pro substitution (L508P; 162200.0024). The Y489C mutation caused skipping of the last 62 nucleotides of exon 10b, while the L508P mutation was undetectable by the protein truncation test. 

.0024 NEUROFIBROMATOSIS, TYPE I [NF1, LEU508PRO ]

See 162200.0023 and Messiaen et al. (1999).

.0025 NEUROFIBROMATOSIS, TYPE I [NF1, IVS9DS, G-A, +1]

In a patient with type I neurofibromatosis, Eisenbarth et al. (2000) identified a germline G-to-A transition at nucleotide 1260+1, the splice donor site of intron 9 of the NF1 gene, leading to the inclusion of 13 bp of intervening sequence into the NF1 messenger. The mutant allele was present in all tissues tested. In a neurofibroma from this patient, an additional C-to-T transition at nucleotide 4021 (162200.0026), a presumed 'second hit' somatic mutation, was identified. Another neurofibroma from the same patient showed a C-to-T transition at nucleotide 4084 (162200.0027), a presumed further 'second hit' somatic mutation. Both somatic mutations led to premature stop codons in the NF1 message. 

.0026 NEUROFIBROMATOSIS, TYPE I [NF1, GLN1341TER]

See 162200.0025 and Eisenbarth et al. (2000).

.0027 NEUROFIBROMATOSIS, TYPE I [NF1, ARG1362TER]

See 162200.0025 and Eisenbarth et al. (2000).

.0028 NEUROFIBROMATOSIS, FAMILIAL SPINAL [NF1, LEU2067PRO]

In a patient with spinal neurofibromatosis but without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified a leu2067-to-pro (L2067P) mutation in exon 33 of the NF1 gene. Her clinically unaffected 61-year-old father had the same NF1 mutation in his blood cells. Additional molecular investigations to exclude mosaicism were not feasible and additional clinical investigations through MRI scans could not be performed. The L2067P mutation yielded an unstable product of approximately 50% normal neurofibromin levels, indicating functional haploinsufficiency. 

.0029 NEUROFIBROMATOSIS, TYPE I [NF1, IVS31, A-G, -5 ]

NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED

In a patient with neurofibromatosis type I, Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to exon 32 and a premature stop codon at amino acid 1995.

In affected members of a family with spinal neurofibromatosis without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified the exon 31 splice site mutation. Noting that the same mutation had been reported in a patient with classic NF1, the authors concluded that a modifying gene may compensate for some of the effects of neurofibromin deficiency. The splice site NF1 mutation resulted in instability of the neurofibromin protein. 

.0030 NEUROFIBROMATOSIS, TYPE I [NF1, DEL]

Upadhyaya et al. (2003) described a Portuguese family in which 3 members had clinical features of NF1 and each had a different underlying defect in the NF1 gene. A 12-year-old boy who had multiple cafe-au-lait spots on his trunk and legs as well as developmental delay had a heterozygous 1.5-Mb deletion including the entire NF1 gene. The mutation was associated with the maternally derived chromosomal haplotype. His 10-year-old brother, who exhibited multiple cafe-au-lait spots and macrocephaly but whose development was within the normal range, was heterozygous for a CGA-to-TGA transition in exon 22 of the NF1 gene, resulting in an arg1241-to-ter mutation (162200.0031). This mutation has previously been described; its recurrence was thought to have been mediated by 5-methylcytosine deamination because it occurred in a hypermutable CpG dinucleotide. The brothers' 26-year-old female first cousin once removed (a first cousin of their father) exhibited multiple cafe-au-lait spots, bilateral Lisch nodules, and multiple dermal neurofibromas. She also showed severe scoliosis and several plexiform neurofibromas in the clavicular region, but her development was within the normal range. She was found to carry a frameshift mutation, 5406insT (162200.0032), in exon 29 of the NF1 gene. None of the parents had any clinical evidence of NF1 and none had a mutation in the NF1 gene. There was also no evidence of mosaicism. Upadhyaya et al. (2003) speculated about the mechanism of this unusual situation. 

.0031 NEUROFIBROMATOSIS, TYPE I [NF1, ARG1241TER]

Fahsold et al. (2000) described a CGA-to-TGA transition in the NF1 gene, resulting in an arg1241-to-ter mutation, as the cause of neurofibromatosis type I. Also see 162200.0030 and Upadhyaya et al. (2003).

.0032 NEUROFIBROMATOSIS, TYPE I [NF1, 1-BP INS, 5406T ]

See 162200.0030 and Upadhyaya et al. (2003).

.0033 NEUROFIBROMATOSIS-NOONAN SYNDROME [NF1, 3-BP DEL, 2970AAT ]

WATSON SYNDROME, INCLUDED

Carey et al. (1997) described a 3-bp deletion in exon 17 of the NF1 gene in affected members of a family with neurofibromatosis-Noonan syndrome (601321). The 2970delAAT mutation resulted in deletion of met991. The clinical features of the 3 subjects were tabulated by De Luca et al. (2005). Stevenson et al. (2006) reported a follow-up of this family. 

Upadhyaya et al. (2007) reported this mutation in 47 affected individuals from 21 unrelated families with a similar phenotype, lacking cutaneous neurofibromas or clinically obvious plexiform neurofibromas. One of the families had been reported by Stevenson et al. (2006); another was reported by Castle et al. (2003) and had a diagnosis of Watson syndrome (193520). The in-frame 3-bp deletion in exon 17 was predicted to result in the loss of 1 of 2 adjacent methionines, either codon 991 or codon 992, in conjunction with a silent ACA-to-ACG change of codon 990. These 2 methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. This was said to have been the first study to correlate a specific small mutation of the NF1 gene with the expression of a particular clinical phenotype. 

.0034 NEUROFIBROMATOSIS-NOONAN SYNDROME [NF1, 3-BP DEL, 4312GAA]

In a patient with neurofibromatosis-Noonan syndrome (601321), Baralle et al. (2003) identified a 3-bp deletion, 4312delGAA, in exon 25 of the NF1 gene. The patient was a 6-year-old boy with more than 6 cafe-au-lait macules. There were no other features of neurofibromatosis type I, but his mother had a single cafe-au-lait macule and Lisch nodules, low hairline, and short neck. He had ptosis, epicanthal folds, low posterior hairline, and low-set ears. On echocardiogram he had pulmonic stenosis. No neurofibromas were present. 

.0035 NEUROFIBROMATOSIS-NOONAN SYNDROME [NF1, 2-BP INS, 4095TG]

In a patient with neurofibromatosis-Noonan syndrome (601321), Baralle et al. (2003) identified a 2-bp insertion, 4095insTG, in exon 23-2 of the NF1 gene. The patient was a 20-year-old man with 7 cafe-au-lait macules, axillary freckling, 10 neurofibromas, Lisch nodules, and scoliosis with a structural cervical vertebral abnormality. He had downslanting palpebral fissures, ptosis, a short, broad neck, widely spaced nipples, and an atrial septal defect. He was of short stature and needed extra help in mainstream school. There was no family history of similar findings. 

.0036 NEUROFIBROMATOSIS-NOONAN SYNDROME [NF1, 20075G-A, 20076C-A ]

In a patient with severe neurofibromatosis type I, Colapietro et al. (2003) found a G-to-A transition and a C-to-A transversion at nucleotide positions 57 and 58, respectively, of the 154-bp long NF1 exon 7, neither of which was present in the proband's parents or 50 healthy controls. RT-PCR analysis showed the expected fragment from exon 4b to 8 together with a shortened one with in-frame skipping of exon 7. Direct sequencing of genomic DNA revealed 2 exonic heterozygous changes at nucleotides 20075 (G-A transition) and 20076 (C-A transversion), which belong to contiguous codons. The first substitution occurred in the third base of the codon, changing it from CAG to CAA, both encoding glutamine (Q315Q); the second changed the CTG codon for leucine to the ATG codon for methionine (L316M). The use of previously established sequence matrices for the scoring of putative ESE motifs showed that the adjacent silent and missense mutations were located within highly conserved overlapping stretches of 7 nucleotides with a close similarity to the ESE-specific consensus sequences recognized by the SC35 and SF2/ASF arginine/serine-rich (SR) proteins. The combined occurrence of both consecutive alterations decreased the motif score for both SR proteins below their threshold levels. As the aberrant transcript was consistently expressed, a protein lacking 58 amino acids was predicted. Thus, the contiguous internal exon 7 mutations appear to have caused exon 7 skipping as a result of the missplicing caused by abrogation of functional ESEs. The male proband in the study of Colapietro et al. (2003) was the third child of healthy unrelated parents. At the age of 1 year, he underwent uronephrectomy because of right renal dysplasia. At the age of 3 years, an optic glioma was identified and surgically excised. The diagnosis of NF1 was made when he was 9 years old on the basis of the presence of cafe-au-lait spots, optic glioma, and Lisch nodules of the iris. Cerebral MRI at the age of 11 years revealed multiple hamartomas and a right hemisphere cerebral venous angioma. The patient showed borderline mental retardation, a height in the 10th percentile, and an occipitofrontal head circumference in the 97th percentile. At the age of 20 years, he showed macrocephaly, numerous cafe-au-lait spots, small cutaneous neurofibromas, a plexiform neck neurofibroma, and axillary and inguinal freckling. Scoliosis, winged scapulae, and bilateral genu valgum were also present. 

.0037 NEUROFIBROMATOSIS, TYPE I [NF1, 1-BP DEL, 3775T]

In a patient with neurofibromatosis type I, Maris et al. (2002) identified a 1-bp deletion in the NF1 gene, 3775delT. The mutation was not present in the patient's parents.

Mosse et al. (2004) showed that the patient originally described by Maris et al. (2002) was also affected with neuroblastoma (256700) and Hirschsprung disease (142623), which were caused by a 1-bp deletion in the PHOX2B gene (676delG; 603851.0007).

.0038 NEUROFIBROMATOSIS, TYPE I [NF1, LEU357PRO ]

NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED

In a patient with neurofibromatosis type I, Fahsold et al. (2000) identified a 1070T-C transition in exon 8 of the NF1 gene, resulting in a leu357-to-pro (L357P) substitution.

In 7 affected members of a family with spinal neurofibromatosis (162210) originally reported by Poyhonen et al. (1997), Messiaen et al. (2003) identified the L357P mutation. The mutation was not detected in 200 normal chromosomes.

.0039 NEUROFIBROMATOSIS, FAMILIAL SPINAL [NF1, IVS39DS, A-C, +3]

In affected members of a family with spinal neurofibromatosis (162210) originally reported by Pulst et al. (1991), Messiaen et al. (2003) identified an A-to-C transversion at position +3 of the donor splice site of exon 39 of the NF1 gene (7126+3A-C), resulting in the skipping of exon 39. 

.0040 NEUROFIBROMATOSIS, TYPE I [NF1, 1-BP DEL, 4071C]

In a patient with NF1 who had onset of neurofibromatous neuropathy at the age of 42 years, Ferner et al. (2004) identified a 1-bp deletion (4071delC) in exon 23.2 of the NF1 gene, resulting in a premature stop codon. The deletion was predicted to generate a truncated neurofibromin of 1,383 amino acids. Neuroimaging studies showed the presence of multiple spinal nerve root neurofibromas. A high-grade malignant peripheral nerve sheath tumor (MPNST) had been removed from the left iliac fossa previously, with no recurrence. Benign flexiform neurofibroma was present in the left abdominal wall. 

.0041 NEUROFIBROMATOSIS, TYPE I [NF1, LEU1243PRO ]

In a patient with NF1 who had onset of neurofibromatous neuropathy at the age of 17 years, Ferner et al. (2004) identified a 1243T-C transition in the NF1 gene, resulting in a leu1243-to-pro (L1243P) substitution.

.0042 NEUROFIBROMATOSIS, TYPE I [NF1, GLU1904TER]

By cDNA-based mutation detection analysis, Zatkova et al. (2004) studied 7 nonsense or missense alleles of NF1 that caused exon skipping and showed that disruption of exonic splicing enhancer (ESE) elements was responsible. One of the 7 mutations was a novel nonsense mutation, a 5719G-T transversion resulting in a glu1904-to-ter (G1907X) substitution in exon 30. 

.0043 NEUROFIBROMATOSIS, TYPE I [NF1, LEU844ARG]

Bertola et al. (2005) described a 14-year-old girl with neurofibromatosis type I and Noonan syndrome (163950) who had a de novo mutation in the NF1 gene and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The NF1 mutation was a 2531A-G transition resulting in a leu844-to-arg substitution. The proband had pulmonary stenosis and aortic coarctation requiring surgery and also had a pilocytic astrocytoma in the suprasellar region involving the optic chiasm and forming the third ventricle. She had cafe-au-lait spots and axillary freckling typical of neurofibromatosis and marked hypertelorism characteristic of Noonan syndrome. 

.0044 PSEUDARTHROSIS, TIBIAL, IN NEUROFIBROMATOSIS [NF1, DEL ]

In studies of 2 cases, Stevenson et al. (2006) demonstrated loss of heterozygosity at the NF1 locus consisting of double inactivation of the NF1 gene in neurofibrosis with tibial pseudarthrosis.

SEE ALSO

Abeliovich et al. (1995); Barker et al. (1987); Bidot-Lopez and Frankel (1983); Boudin et al. (1970); Buntin and Fitzgerald (1970); Cartegni et al. (2002); Cawthon et al. (1990); Charron and Gariepy (1970); Clark et al. (1977); Cotlier (1977); Dunn et al. (1976); Fabricant and Todaro (1981); Fain et al. (1989); Fairbrother et al. (2002); Ferner (1998); Fienman and Yakovac (1970); Fountain et al. (1989); Hochberg et al. (1974); Holt (1978); Izumi et al. (1971); Kaplan et al. (1982); Kohn (1979); Lund and Skovby (1991); Miles et al. (1969); Miller and Hall (1978); Muller-Wiefel (1978); Nager (1964); Newman and So (1971); O'Connell et al. (1989); Obringer et al. (1989); Pellock et al. (1980); Perry and Font (1982); Philippart (1961); Riccardi (1981); Riccardi and Mulvihill (1981); Rockower et al. (1982); Sands et al. (1975); Satran et al. (1980); Seizinger et al. (1987); Siggers et al. (1975); Skuse et al. (1991); Smith et al. (1970); Taylor (1962); Upadhyaya et al. (1989); von Recklinghausen (1882); Wallis et al. (1970)

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CONTRIBUTORS

Cassandra L. Kniffin - updated : 5/30/2008

OMIM

===========================

Support Groups:

Neurofibromatosis, Inc.

P.O.Box 18246
Minneapolis, MN 55418
301-918-4600
1-800-942-6825
E-mail: info@nfinc.org

Children's Tumor Foundation

formerly known as the National Neurofibromatosis Foundation
95 Pine Street 16th Floor
New York, NY 10005
Phone: 1-800-323-7938
Email: info@ctf.org

Neurofibromatosis Foundation

Neuerofibromatosis Clinics Association

Texas Neurofibromatosis Foundation

Neurofibromatosis Association of  the UK

Neurofibromatosis Network of Europe

Neurofibromatosis Association of Australia

Neurofibromatosis Clinical Trials - US National Institutes of Health

===========================

References:

Neurofibromatosis - Neurology (1)

Von Recklinghausen's Neurofibromatosis - Oncology Encyclopedia (2)

Neurofibromatosis Type 1 (NF-1) - Peace Health (3)

Neurofibromatosis - Wedmd

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Diagnostic Images:

Otolaryngology Houston

Google

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Codes and Classifications:

ICD-10

Q85.0 

Neurofibromatosis (nonmalignant)
Von Recklinghausen's disease

ICD-9

2008 ICD-9-CM Diagnosis 237.71

Neurofibromatosis type 1 von recklinghausen's disease

  • An autosomal dominant inherited disorder (with a high frequency of spontaneous mutations) that features developmental changes in the nervous system, muscles, bones, and skin, most notably in tissue derived from the embryonic NEURAL CREST. Multiple hyperpigmented skin lesions and subcutaneous tumors are the hallmark of this disease. Peripheral and central nervous system neoplasms occur frequently, especially OPTIC NERVE GLIOMA and NEUROFIBROSARCOMA. NF1 is caused by mutations which inactivate the NF1 gene (GENES, NEUROFIBROMATOSIS 1) on chromosome 17q. The incidence of learning disabilities is also elevated in this condition. (From Adams et al., Principles of Neurology, 6th ed, pp1014-18) There is overlap of clinical features with NOONAN SYNDROME in a syndrome called neurofibromatosis-Noonan syndrome. Both the PTPN11 and NF1 (GENES, NF1) gene products are involved in the SIGNAL TRANSDUCTION pathway of Ras (RAS PROTEINS).
  • except of bone
  • NF1. A rare genetic condition that causes brown spots and tumors on the skin, freckling in skin areas not exposed to the sun, tumors on the nerves, and developmental changes in the nervous system, muscles, bone, and skin.
  • Type 1 (peripheral) neurofibromatosis (von Recklinghausen's disease), is the most common type of neurofibromatosis. It is characterized clinically by cutaneous and subcutaneous tumors with patches of hyperpigmentation. The hyperpigmented skin areas, are present from birth and found anywhere on the body surface. They can vary markedly in size and color. The dark brown areas are called cafe-au-lait spots. The multiple cutaneous and subcutaneous tumors are nerve sheath neoplasms, called neurofibromas. They can develop anywhere along the peripheral nerve fibers. Neurofibromas can become quite large, causing a major disfigurement, eroding bone, and compressing various peripheral nerve structures. Type 1 neurofibromatosis has dominant inheritance, with a gene locus on the proximal long arm of chromosome 17. -- 2003
  • 237.71 is a specific code that can be used to specify a diagnosis
  • 237.71 contains 13 index entries
  • View the ICD-9-CM Volume 1 237.* hierarchy

OMIM - 162200

EMedicine derm/287 

                     neuro/248

                     oph/338

                     radio/474

MeSH - D009456

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Ultrastructural synaptic changes associated with neurofibromatosis type 1: A quantitative analysis of hippocampal region CA1 in a Nf1(+/-) Mouse Model.

Nov 2011

Armstrong BC, Leboutillier JC, Petit TL.

Source

Department of Psychology and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, 15213.

Abstract

Neurofibromatosis type 1 (NF1) is one of the most frequently diagnosed autosomal dominant inherited disorders resulting in neurological dysfunction, including an assortment of learning disabilities and cognitive deficits. To elucidate the neural mechanisms underlying the disorder, we employed a mouse model (Nf1(+/-) ) to conduct a quantitative analysis of ultrastructural changes associated with the NF1 disorder. Using both serial light and electron microscopy, we examined reconstructions of the CA1 region of the hippocampus, which is known to play a central role in many of the dysfunctions associated with NF1. In general, the morphology of synapses in both the Nf1(+/-) and wild-type groups of animals were similar. No differences were observed in synapse per neuron density, pre- and post- synaptic areas, or lengths. However, concave synapses were found to show a lower degree of curvature in the Nf1(+/-) mutant than in the wild type. These results indicate that the synaptic ultrastructure of Nf1(+/-) mice appears relatively normal with the exception of the degree of synaptic curvature in concave synapses, adding further support to the importance of synaptic curvature in synaptic plasticity, learning and memory. 

http://www.ncbi.nlm.nih.gov/pubmed/22121000

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Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease). Nov 2011

http://www.ncbi.nlm.nih.gov/pubmed/22120694

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Alternative splicing of the neurofibromatosis type I pre-mRNA. Apr 2012

http://www.ncbi.nlm.nih.gov/pubmed/22115364

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Gastrointestinal stromal tumor with KIT mutation in neurofibromatosis type 1. Oct 2011


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219854/?tool=pubmed
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Neurofibromatosis

http://www.nejm.org/doi/full/10.1056/NEJMicm1103859

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PubMed Search Page - Neurofibromatosis type 1

http://www.ncbi.nlm.nih.gov/pubmed?term=%20Neurofibromatosis
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Neurofibromatosis

http://www.medstudents.com.br/neuro/neuro7.htm


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von Recklinghausen's Neurofibromatosis

http://www.healthline.com/galecontent/von-recklinghausens-neurofibromatosis

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Dermatologic Manifestations of Neurofibromatosis Type 1

http://emedicine.medscape.com/article/1112001-overview

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Lymphedema People / Advocates for Lymphedema

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet?  Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more.  Come and take a stroll! 

Lymphedema Glossary 

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing 

Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema 

Arm Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema 

Leg Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema 

Acute Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema 

The Lymphedema Diet 

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet 

Exercises for Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema 

Diuretics are not for Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=diuretics_are_not_for_lymphedema 

Lymphedema People Online Support Groups 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_people_online_support_groups 

Lipedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lipedema 

Treatment 

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment 

Lymphedema and Pain Management 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pain_management 

Manual Lymphatic Drainage (MLD) and Complex Decongestive Therapy (CDT)

http://www.lymphedemapeople.com/wiki/doku.php?id=manual_lymphatic_drainage_mld_complex_decongestive_therapy_cdt 

Infections Associated with Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema 

How to Treat a Lymphedema Wound 

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound 

Fungal Infections Associated with Lymphe dema 

http://www.lymphedemapeople.com/wiki/doku.php?id=fungal_infections_associated_with_lymphedema 

Lymphedema in Children 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children 

Lymphoscintigraphy 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphoscintigraphy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Extraperitoneal para-aortic lymph node dissection (EPLND) 

http://www.lymphedemapeople.com/wiki/doku.php?id=extraperitoneal_para-aortic_lymph_node_dissection_eplnd 

Axillary node biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=axillary_node_biopsy

Sentinel Node Biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=sentinel_node_biopsy

Small Needle Biopsy - Fine Needle Aspiration 

http://www.lymphedemapeople.com/wiki/doku.php?id=small_needle_biopsy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Lymphedema Gene FOXC2

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_foxc2

 Lymphedema Gene VEGFC

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_vegfc

 Lymphedema Gene SOX18

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_sox18

 Lymphedema and Pregnancy

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pregnancy

Home page: Lymphedema People

http://www.lymphedemapeople.com

Page Updated: Nov. 29, 2011