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.
June 17, 2008
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| NEUROFIBROMATOSIS, TYPE I; NF1 | |
Alternative titles; symbols
NEUROFIBROMATOSISGene map locus 17q11.2
TEXT
Neurofibromatosis type I (NF1) is caused by mutation in the neurofibromin gene.
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.
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, 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.
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.
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.
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.
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.
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.
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.
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).
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.
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 search