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LYMPHEDEMA HEREDITARY SYNDROMES

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Related Terms: MILROY'S SYNDROME, MEIGE LYMPHEDEMA SYNDROME, LYMPHEDEMA PRAECOX, YELLOW NAIL SYNDROME, STEWART-TREVES SYNDROME, HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME, TURNER SYNDROME, KLIPPEL-TRENAUNAY-WEBER SYNDROME, NOONAN'S SYNDROME, LYMPHEDEMA-DISTICHIASIS SYNDROME, LYMPHEDEMA-CHOLESTASIS SYNDROME, LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME, LYMPHEDEMA-HYPOPARATHYROIDISM SYNDROME, LYMPHEDEMA-HYPOPARATHYROIDISM SYNDROME, LYMPHEDEMA, CONGENITAL RECESSIVE SYNDROME, LYMPHEDEMA AND PTOSIS SYNDROME, HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA SYNDROME,ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS AND LYMPHEMA, OLEDAID, LYMPHEDEMA AND CEREBRAL ARTERIOVENOUS AND CEREBRAL ATERIOVENOUS ANOMALY, HEREDITARY LYMPHEDEMA TYPE I,  HEREDOTARY LYMPHEDEMA TYPE II]],  HEREDITARY LYMPHEDEMA TYPE III

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Syndromes associated with hereditary lymphedema

MILROY'S SYNDROME

See also: Nonne-Milroy lymphedema, Milroy's Disease, Primary congenital hereditary lymphedema, hereditary lymphedema I,  Lymphedema Praecox, Lymphedema Tarda

Milroy's Syndrome is an old term used to describe hereditary congenital lymphedema. It is a congenital familial primary lymphedema which results from veritical autosomal inheritance of a single gene. The gene has been identified as VEGFR3. The condition usually presents itself at birth with the swelling of one or even both legs.

If the condition is unilateral (single leg), the other leg may continue in the latency stage for years before expressing itself. The same is indicated for arm lymphedema.

It is the rarest of the inherited lymphedema, accounting for approximately 2% of hereditary lymphedemas.

Hereditary lymphedema was first described by Nonne in 1891, however in 1892 Dr. William F. Milroy described a missionary who had returned from work in India who had swollen legs his entire life. His mother likewise was afflicted with the same condition. Milroy had also, previously studied the 250 year history of a family and had been able to identify 22 persons with this condition through 6 generations. He was also able to pinpoint when the condition entered the family through a marriage in 1768.

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MEIGE LYMPHEDEMA SYNDROME

See also:Praecox Meige Syndrome,  Nonne-Milroy-Meige Syndrome, Meige's lymphedema, Hereditary lymphedema II, familial lymphedema praecox

Named after French physician Dr. Henri Meige who first described hereditary lymphedema in 1891. This form of lymphedema which usually presents itself at or during puberty is the most common of the hereditary lymphedemas, account for 65-80% of all diagnosed cases.

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YELLOW NAIL SYNDROME

Yellow nail syndrome is a very rare disorder often associated with lymphedema of the lower extremities. It is also associated with lung disorders. Other associated indications are rhinosinusitis, pleural effusions, bronchiectasis.

The syndrome is characterized by yellow nails that lack a cuticle, grow slowly and are loose or detached. The nails also become dystrophic with longitudinal or transverse ridging.

There is no treatment or cure specifically for the resolution of the condition.

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STEWART-TREVES SYNDROME

See also: lymphangiosarcoma

Stewart-Treves Syndrome is a rare, aggressive and cutaneous angiosarcoma often associated with long standing lymphedema.

Most cases arise from lymphedema induced by a radical mastectomy in breast cancer patients. Although there has also been significant reports regarding development from Milroy lymphedema and in idiopathic, congenital, traumatic, or filarial lymphedema.

The three main indications for the development of Stewart Treves in a lymphedemous limb appear to be radiation, extensive fibrosis and recurrent or chronic infection.

The sarcoma first appears as a bruised area or a purplish discoloration in an extremity. It progresses to an ulcer with crusting and finally to an extensive necrosis involving the skin and subcutaneous tissue. It metastasizes widely and there is no effective therapy.

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HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME

Classified as a developmental disorder of the lymphatics. First described by Dutch physician R.C.M. Hennekam in 1989. Characteristics include Intestinal or pleural lymphangiectasia was accompanied by the usual hypoproteinemia, hypogammaglobulinemia, and lymphocytopenia. Facial anomalies included flat face, flat nasal bridge, hypertelorism, epicanthal folds, small mouth, tooth anomalies, and ear defects. Complications involve severe lymphedema cellulitis and erysipelas

There is no specific treatment for the condition, only management of the complications.

Also, related to Turner Syndrome.

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LYMPHANGIECTASIA, INTESTINAL

TEXT

Homburger and Petermann (1949) described a disorder, which they called 'familial idiopathic dysproteinemia,' characterized by edema of the legs, with ulcers in the males and 'functional vascular changes' in the females; dysproteinemia of variable type, sometimes discernible only by electrophoresis; a number of congenital malformations; and a high incidence of stillbirths. Persons in 3 generations were affected and male-to-male transmission occurred. Subsequently these patients were found to have intestinal loss of protein, presumably because of lymphangiectasia (Waldmann et al., 1961; Waldmann and Schwab, 1965). Murphy (1972) gave clinical follow-up. Lymphopenia due to exaggerated intestinal loss is also a feature. Double vortex pilorum ('hair whorl') and usually prominent 'floating ribs' (ribs 11 and 12) were present. Parfitt (1966) described 3 sibs (2 females, 1 male) affected out of 5. All had neonatal edema. The small bowel showed dilated lymphatic spaces and partial villous atrophy. Cottom et al. (1961) reported neonatal hypoproteinemia in 2 sibs, and other probable cases are known. See also hereditary lymphedema I (153100) and protein-losing enteropathy (226300). Patients with intestinal lymphangiectasia have hypogammaglobulinemia, lymphocytopenia, skin anergy and impaired allograft rejection. Peripheral blood lymphocytes show impaired in vitro blastic transformation (Weiden et al., 1972). This is attributable to depletion of lymphocytes necessary for transformation. The situation is comparable to experimental thoracic duct drainage. 30 MEDLINE Neighbors

REFERENCES

1. Cottom, D. G.; London, D. R.; Wilson, B. D. R. :
Neonatal oedema due to exudative enteropathy. Lancet II: 1009-1012, 1961.
2. Homburger, F.; Petermann, M. L. :
Studies on hypoproteinemia. II. Familial idiopathic dysproteinemia. Blood 4: 1085-1108, 1949.
3. Murphy, E. A. :
Familial lymphatic dysplasia with intestinal lymphangiectasia.In: The Clinical Delineation of Birth Defects. G. I. Tract Including Liver and Pancreas. : : Baltimore: Williams and Wilkins (pub.) Part XIII 1972. Pp. 180-181.
4. Parfitt, A. M. :
Familial neonatal hypoproteinaemia with exudative enteropathy and intestinal lymphangiectasis. Arch. Dis. Child. 41: 54-62, 1966.
PubMed ID : 5948410
5. Waldmann, T. A.; Schwab, P. J. :
IgG(7S gamma globulin) metabolism in hypogammaglobulinemia: studies in patients with defective gamma globulin synthesis, gastrointestinal protein loss, or both. J. Clin. Invest. 44: 1523-1533, 1965.
PubMed ID : 14332165
6. Waldmann, T. A.; Steinfeld, J. L.; Dutcher, T. F.; Davidson, J. D.; Gordon, R. S., Jr. :
The role of the gastrointestinal system in 'idiopathic hypoproteinemia.'. Gastroenterology 41: 197-207, 1961.
PubMed ID : 13782654
7. Weiden, P. L.; Blaese, R. M.; Strober, W.; Block, J. B.; Waldmann, T. A. :
Impaired lymphocyte transformation in intestinal lymphangiectasia: evidence for at least two functionally distinct lymphocyte populations in man. J. Clin. Invest. 51: 1319-1325, 1972.
PubMed ID : 4554185

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

joanna : 3/18/2004
carol : 11/19/2003
mimadm : 11/6/1994
davew : 8/2/1994
warfield : 3/1/1994
supermim : 3/16/1992
carol : 6/13/1990
supermim : 3/20/1990

http://omim.org/entry/152800

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TURNER SYNDROME

Named after Dr. Henry Turner who was one of the first to describe its features in the 1930's. An internist at the University of Oklahoma, he first identified a common set of traits or physical features in seven of his patients in an article published in 1938. This is a chromosomal condition caused when one of the two x chromosomes normally found in females is missing or incomplete. However, the actual chromosomal deficiency was not identified until 1959.

The condition is diagnosed, or confirmed by a blood test called a kerotype. The test analyzes the chromosomal composition of the individual. Another unique feature of Turner Syndrome is that is occurs only in females.

Characteristics include short stature, lack of ovarian development, webbed neck and/or arms, low hairline at the base of the neck. Other reported signs include cardio-vascular difficulties, kidney and thyroid problems, and scoliosis. Another complication of Turner Syndrome is lymphedema.

Because this is a chromosomal based disorder there is no cure. There are treatments however that can lesson the symptoms. These include growth hormone, estrogen replacement therapy.

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Klippel-Trenaunay-Weber Syndrome

First described by French physicians Klippel and Trenaunay in 1900, this syndrome is characterized by port-wine stain (capillary hemangioma), varicose veins and bony and soft tissue hypertrophy involving an extremity. 
Please note that there is still much on-going debate as to whether or not this is a hereditary condition.

Other features involve lymphedema or lymphatic obstruction, cellulitis, chronic venous insufficiency, stasis dermatitis, poor wound healing, ulceration, thrombosis, and emboli.

Treatment is varied for the different symptoms present. Compression garments are used to control the lymphedema, prophylactic antibiotics are of course, used to treat the cellulitis and lymphangitis spells. Orthopedic procedures are available for the limb hypertrophy and wound treatment is sometimes necessary for ulcerations.

Other treatments for the symptoms or complications include lasers for the hemangiomas, and surgical intervention for the vascular anomalies may be called for.

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NOONAN'S SYNDROME

A familial condition similar to both Turner Syndrome. It is different however, in that here is no comromosomal defect as is involved with Turner and unlike Noonan's, this condition can affect both sexes.

Though an early description of the syndrome is credited to a Russian medical student, Koblinsky, at the Russian/Estonian University at Dorpat, the condition is named after an American cardiologist, Jacquline A. Noonan. She and pediatrician Dorothy Ehmke conducted an extensive clinical study of 833 children with congenital heart disease. Their findings were published and reported to the Midwest Society of Pediatric Research held in Cincinnati in 1962.

Cardiac abnormalities occur in 50% of patients: these include pulmonary valve stenosis, thick and dysplastic pulmonary valves, right heart anomalies and left ventricular cardiomyopathy.

Symptoms of the disorder include not only heart indications but valvular pulmonary stenosis, short stature, hypertelorism and skeletal anomalies, and, in boys, retention testis.

Skin manifestations present as transient lymphedema, in the dorsal hands during infancy and progresses to stasis in adulthood. Scalp findings include low posterior neck hairline and coarse curly hair. Scanty pubic, axillary, and beard hair growth has been noted. Nails show short and wide dystrophic changes.

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NOONAN SYNDROME 1; NS1

Alternative titles; symbols

NOONAN SYNDROME
MALE TURNER SYNDROME
FEMALE PSEUDO-TURNER SYNDROME
TURNER PHENOTYPE WITH NORMAL KARYOTYPE
PTERYGIUM COLLI SYNDROME, INCLUDEDGene map locus 12q24.1

TEXT

A number sign (#) is used with this entry because of evidence that one form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in PTPN11 (176876), a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which contains 2 Src homology-2 (SH2) domains (Tartaglia et al., 2001). Tartaglia et al. (2001) found that mutations in the PTPN11 gene accounted for about half the patients studied. Mutations in the neurofibromin gene (NF1; 162200), which is the site of mutations causing classic neurofibromatosis type I, have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321). 30 MEDLINE Neighbors

DESCRIPTION

Noonan syndrome is a dysmorphic syndrome characterized by hypertelorism, a downward eyeslant, and low-set posteriorly rotated ears (Shah et al., 1999). Other features include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, epicanthic folds, deafness, motor delay, and a bleeding diathesis. 30 MEDLINE Neighbors

CLINICAL FEATURES

The disorder now known as Noonan syndrome bears similarities to the disorder described by Turner (1938) and shown by Ford et al. (1959) to have its basis in a 45,X chromosomal aberration. (With considerable justification, Ullrich's name is combined with that of Turner as the designation for the 45,X syndrome. Ullrich described the disorder 8 years before Turner. Wiedemann and Glatzl (1991) provided a follow-up of Ullrich's original patient with Ullrich-Turner syndrome and demonstrated that the restudy in 1987, when the patient was 66 years old, confirmed the 45,X chromosome constitution.) 30 MEDLINE Neighbors

Noonan (1968) reported 19 cases of whom 17 had pulmonary stenosis and 2 had patent ductus arteriosus (see 607411). Twelve were males and 7 were females. Deformity of the sternum with precocious closure of sutures was a frequent feature. Kaplan et al. (1968) described 2 brothers with elevated alkaline phosphatase levels, one of whom also had malignant schwannoma of the forearm. Nora and Sinha (1968) observed mother-to-offspring transmission in 3 families; in 1 family, transmission was through 3 generations. They suggested X-linked dominant inheritance of either a single mutant gene or a submicroscopic deletion. Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968) found the Turner phenotype in 8. In 5 of these, karyotyping was performed. In 4 the chromosomes were normal. In one an extra acrocentric chromosome was present. 30 MEDLINE Neighbors

Abdel-Salam and Temtamy (1969) reported 2 affected sibs from a first-cousin marriage. A deceased female sib may have been affected also. They suggested autosomal recessive inheritance. Baird and De Jong (1972) described 7 cases in 3 generations. One affected woman had 5 affected children (out of 6) with 2 different husbands. Seizures and anomalous upper lateral incisors may have been coincidental. Diekmann et al. (1967) described 2 brothers and a sister, with normal and unrelated parents, who had somatic characteristics of the Noonan syndrome, particularly pterygium colli and deformed sternum, and had myocardiopathy leading to death at ages 12 and 10 in two of them. Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with somatic features of the Turner syndrome. In 1 family, 2 brothers had webbing of the neck, coarctation of the aorta, and cryptorchidism. In the second, a brother and sister were affected. 30 MEDLINE Neighbors

Simpson et al. (1969) reported experiences suggesting that rubella embryopathy may result in the Turner phenotype, thereby accounting for either the male Turner syndrome or the female pseudo-Turner syndrome. A particularly convincing pedigree for autosomal dominant inheritance was reported by Bolton et al. (1974), who found the condition in a man and 4 sons (in a sibship of 10). Four of the 5 affected persons had pulmonic stenosis. Father-to-son transmission was reported by Qazi et al. (1974). 30 MEDLINE Neighbors

Koretzky et al. (1969) described an unusual type of pulmonary valvular dysplasia which showed a familial tendency with either affected parent and offspring or affected sibs. Although some relatives had pulmonary valvular stenosis of the standard dome-shaped variety, the valvular dysplasia in others was characterized by the presence of three distinct cusps and no commissural fusion. The obstructive mechanism was related to markedly thickened, immobile cusps, with disorganized myxomatous tissue. Other features were retarded growth, abnormal facies (triangular face, hypertelorism, low-set ears and ptosis of the eyelids), absence of ejection click, and unusually marked right axis deviation by electrocardiogram. It now seems clear that the patients of Koretzky et al. (1969) had the Noonan syndrome. 30 MEDLINE Neighbors

Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the LEOPARD syndrome (151100) 'are essentially indistinguishable from the Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of lymphedema in Noonan syndrome. When it does occur, it opens the possibility of prenatal diagnosis by imaging methods or by AFP level. Noonan syndrome was one of the causes found for posterior cervical hygroma in a series of previable fetuses studied by Kalousek and Seller (1987). The authors found, furthermore, that 45,X Turner syndrome lethal in the fetal period showed a constant association of 3 defects, posterior cervical cystic hygroma, generalized subcutaneous edema, and preductal aortic coarctation. 30 MEDLINE Neighbors

Evans et al. (1991) found a large cutaneous lymphangioma of the right cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome. Donnenfeld et al. (1991) presented a case of Noonan syndrome in which posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of gestation by ultrasonography. The hygroma had regressed by the time of birth leaving nuchal skin fold redundancy and pterygium colli. On the basis of studies of genital tract function in 11 adult males with Noonan syndrome, Elsawi et al. (1994) concluded that bilateral testicular maldescent was a main factor in contributing to impairment of fertility. Four of the 11 men had fathered children. 30 MEDLINE Neighbors

Thrombocytopenia occurs in some cases of the Noonan syndrome (Goldstein, 1979). Partial deficiency of factor XI was described by Kitchens and Alexander (1983). Out of 9 patients with Noonan syndrome, de Haan et al. (1988) found 4 with partial deficiency of factor XI (30-65% of normal). They reviewed the other reports of bleeding tendency associated with thrombocytopenia or with abnormal platelet function. Witt et al. (1988) described bleeding diathesis in 19 patients with Noonan syndrome. Several different defects were identified in the coagulation and platelet systems, occurring singly or in combination; for example, 2 patients had factor XI deficiency, 3 had presumptive von Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an unusually pungent odor of urine and sweat was noted by parents. One of these patients was reported by Humbert et al. (1970) as a case of trimethylaminuria (136131) and another patient was suspected of having this condition. Sharland et al. (1990) also described a variety of coagulation factor deficiencies. The most common abnormality was a partial factor XI deficiency in the heterozygote range, found in 21 of 31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4 years) by Sharland et al. (1992), 47 (65%) had a history of abnormal bruising or bleeding. In 29 patients (40%), prolonged activated partial thromboplastin time was found. In 36 patients (50%) specific abnormalities were found in the intrinsic pathway of coagulation, i.e., partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple abnormalities among these 36 patients included combined deficiencies of factors XI and XII (4 patients), of factors XI and VIII (4 patients), and of factors VIII, XI, and XII (1 patient). In 5 families, similar coagulation-factor deficiencies were present in first-degree relatives. Sharland et al. (1992) suggested that because of the involvement of several factors, either singly or in combination, there are likely to be regulatory factors that control the intrinsic (contact activation) system; that these factors are under chromosomal genetic control; and that abnormalities of this regulation occur in Noonan syndrome. 30 MEDLINE Neighbors

Allanson et al. (1985) studied the changes in facial appearance with age. They pointed out that the manifestations may be subtle in adults. Ranke et al. (1988) analyzed the clinical features of 144 patients from 2 West German centers. The size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd percentile until puberty, but decreased transiently due to an approximately 2-year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the second decade of life. The mean adult height was 162.5 cm in males and 152.7 cm in females, respectively. Allanson (1987) provided a useful review. The fetal primidone syndrome, occurring in the offspring of mothers taking this anticonvulsant, closely simulates the Noonan syndrome. Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2 girls) with a Noonan-like syndrome associated with sparse hair as a conspicuous feature. 30 MEDLINE Neighbors

Leichtman (1996) reported a family suggesting that cardiofaciocutaneous syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He described a 4-year-old girl who had all of the manifestations of CFC syndrome (characteristic facial and cardiac anomalies, developmental delay, hypotrichosis, eczematic eruption with resistance to treatment), whose mother had typical characteristics of Noonan syndrome. Lorenzetti and Fryns (1996) reported a 13-year-old boy with Noonan syndrome and retinitis pigmentosa. Because similar eye defects are found in CFC syndrome, the authors suggested that CFC and Noonan syndromes might be variable manifestations of the same entity. However, Neri and Zollino (1996) noted distinctions between the patient reported by Lorenzetti and Fryns (1996) and CFC syndrome, and stated that similarity of eye defects is not enough to conclude that CFC and Noonan syndromes are the same condition. 30 MEDLINE Neighbors

Early feeding difficulties are common in Noonan syndrome but often go unrecognized. Shah et al. (1999) studied a consecutive series of children with Noonan syndrome whose diagnosis had been confirmed by a clinical geneticist. Sixteen had poor feeding (poor suck or refusal to take solids or liquids) and symptoms of gastrointestinal dysfunction (vomiting, constipation, abdominal pain, and bloating). All 16 had required nasogastric tube feeding. Seven of the 25 had foregut dysmotility and gastroesophageal reflux. In 4 of these, electrogastrography and antroduodenal manometry demonstrated immature gastric motility reminiscent of that of a preterm infant of 32 to 35 weeks' gestation. Other children had less severe forms of gastric dysmotility. The authors highlighted the importance of recognizing this common, treatable feature of Noonan syndrome. 30 MEDLINE Neighbors

Lemire (2002) described a father, son, and daughter with an apparently autosomal dominant disorder characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart defects with normal psychomotor development. Some clinical features such as webbed neck, low-set ears, low posterior hairline, and widely spaced nipples suggested Noonan syndrome. Alternatively, a previously unrecognized disorder was considered. The paternal age at the father's birth was 50 years. The father presented at age 13 years when postductal coarctation of the aorta was discovered during routine physical examination. Preoperative evaluation showed hypertrophied interventricular septum with pulmonic stenosis and bicuspid aortic valve in addition to the aortic coarctation. At age 22 years, echocardiogram showed marked systolic thickening of interventricular septum and posterior wall of the left ventricle and concentric left ventricular hypertrophy. He later developed atrial flutter and congestive heart failure. His son was recognized at birth to have 2 small ventricular septal defects, mildly hypoplastic aortic arch, and coarctation of the aorta. The coarctation was repaired at age 14 days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he was found to have congestive heart failure due to a restrictive cardiomyopathy. At age 10 months, studies confirmed the presence of spongy myocardium with much impaired diastolic function. He died of early acute graft failure at age 14 months after heart transplantation. Autopsy showed restrictive cardiomyopathy with generalized myocardium hypertrophy. The daughter was found at birth to have a small ventricular septal defect, small patent ductus arteriosus, aneurysm of the atrial septum, and coarctation of the aorta. Cardiomyopathy was suspected on the basis of excessive thickening of the lower two-thirds of the interventricular septum and of the free wall of the right ventricle. Coarctation of the aorta was repaired surgically at age 19 days. At age 10.5 months, she was noted to have plagiocephaly, facial asymmetry with left side smaller than the right, webbed neck, asymmetric chest with widely spaced nipples, and edema of the dorsum of the feet. At age 2 years, bicuspid aortic valve and diffuse concentric hypertrophy of the left ventricle were noted. 30 MEDLINE Neighbors

Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et al., 1997; Choong et al., 1999).

Holder-Espinasse and Winter (2003) described a 6-year-old girl with clinical features of Noonan syndrome, short stature, and headache who was noted to have Arnold-Chiari malformation (207950) on MRI. They cited 3 previous reports of Noonan syndrome and Chiari malformation and/or syringomelia (Peiris and Ball, 1982; Gabrielli et al., 1990; Colli et al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari malformation should be considered part of the Noonan syndrome spectrum and that brain and cervical spine MRI should be required in patients with Noonan syndrome, particularly if headaches or neurologic symptoms are present. 30 MEDLINE Neighbors

For a comprehensive review of Turner syndrome, including clinical management, see Ranke and Saenger (2001).

Noonan et al. (2003) reported their findings in 73 adults over 21 years of age with Noonan syndrome. In 30%, adult height was in the normal range between the 10th and 90th percentiles. More than half of the females and nearly 40% of males had an adult height below the third percentile. The presence or severity of heart disease was not a factor, and none of the adults with normal height had been treated with growth hormone. Serial measurements of height over many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggested that catch up may occur in late adolescence. The possible benefit of growth hormone therapy could not be evaluated. 30 MEDLINE Neighbors

Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (176876.0007).

MAPPING

Using a number of probes at the neurofibromatosis type I locus in the study of 11 families with Noonan syndrome in 2 or 3 generations, Sharland et al. (1992) excluded proximal 17q as the location of the gene. Studying six 2-generation families with classic Noonan syndrome, Flintoff et al. (1993) could find no evidence of linkage of this disorder to NF1 on 17q or to NF2 (101000) on 22q. Edman Ahlbom et al. (1995) likewise could find no evidence of linkage between NF1 and Noonan syndrome with cafe-au-lait spots. 30 MEDLINE Neighbors

By means of a genomewide linkage analysis in a large Dutch kindred with autosomal dominant Noonan syndrome, Jamieson et al. (1994) localized the gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage analysis using chromosome 12 markers in 20 smaller, 2-generation families gave a maximum lod of 2.89 at theta = 0.07, but haplotype analysis showed nonlinkage in 1 family. These data suggested that a gene for Noonan syndrome is located in the 12q22-qter region between markers D12S84 and D12S366. Clinical studies in this kindred were reported by van der Burgt et al. (1994). 30 MEDLINE Neighbors

Brady et al. (1997) further analyzed the 3-generation Dutch family studied by Jamieson et al. (1994) using newly isolated CA-repeat markers derived from the interval between D12S84 and D12S366. In this way they were able to reduce the localization to an interval bounded by markers D12S105 and NOS1 (163731), which has been mapped to 12q24.2-q24.31. 30 MEDLINE Neighbors

Legius et al. (1998) performed linkage analysis in a 4-generation Belgian family with Noonan syndrome in some individuals and CFC syndrome in others. Clinical and linkage data in this family indicated that the 2 syndromes result from variable expression of the same genetic defect. They found a maximum lod score of 4.43 at zero recombination for marker D12S84 in 12q24. A crossover in this pedigree narrowed the candidate gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable feature of the family studied by Legius et al. (1998) was the presence of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic twin pair was observed in the offspring of an affected female in the family in which linkage was studied by Jamieson et al. (1994). It is possible that an increased frequency of dizygotic twinning is associated with NS1/CFC linked to 12q24. The fragile X syndrome (309550) is another mendelian disorder with a possibly increased frequency of dizygotic twinning (Partington et al., 1996; Schwartz et al., 1994). 30 MEDLINE Neighbors

In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8 (600206) and DCN (125255) from the critical region by FISH analysis. They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation analysis.

CYTOGENETICS

Robin et al. (1995) described 6 patients with Noonan syndrome who underwent molecular evaluation for submicroscopic deletion of chromosome 22q11. None of these patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This patient had Noonan-like manifestations without clinical manifestations of DiGeorge (188400) or velocardiofacial (192430) syndromes. Digilio et al. (1996) studied 4 patients with Noonan syndrome and tetralogy of Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis showed no hemizygosity for the 22q11 region in any of the patients. 30 MEDLINE Neighbors

DIAGNOSIS

Butler et al. (2000) used metacarpophalangeal pattern profile (MCPP) analysis to evaluate 15 individuals with Noonan syndrome. Discriminant analysis resulted in the correct classification of 93% of Noonan syndrome patients based on 2 MCPP variables (metacarpal 1 and middle phalanx 3). The authors suggested that MCPP analysis may be useful as a diagnostic tool in screening subjects for Noonan syndrome. 30 MEDLINE Neighbors

CLINICAL MANAGEMENT

MacFarlane et al. (2001) reported growth data from the first 3 years of a multicenter study examining the efficacy and safety of recombinant human GH in 23 children with Noonan syndrome. Sixteen male and 7 female patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD; range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting treatment. Comparisons were made with a group of 8 subjects (6 males and 2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome and not treated with recombinant GH, and measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 three years later. This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/- 1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The authors concluded that the increase in growth rate in Noonan syndrome resulting from 1 year of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of recombinant GH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy. 30 MEDLINE Neighbors

Kirk et al. (2001) presented data on 66 Noonan syndrome patients (54 males) treated with growth hormone. Treatment improved height velocity in the short term, but longer-term therapy resulted in a waning of effect. The study indicated that final height is not substantially improved in most patients. 30 MEDLINE Neighbors

MOLECULAR GENETICS

After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect. 30 MEDLINE Neighbors

In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses.

Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients and identified 15 missense mutations in 32 patients (33%). No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of their patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the 64 patients without PTPN11 mutations indicated further genetic heterogeneity. Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. 30 MEDLINE Neighbors

HISTORY

Cole (1980) pointed out that the blacksmith in the famous painting 'Among Those Left' by Ivan Le Lorraine Albright appears to have had Noonan syndrome. The contour of the sternum, the low-set ears, and the short stature are suggestive. Genetic confirmation was provided by studies of a great-grandson with general features of the Noonan syndrome and cardiac abnormalities consistent with that diagnosis (pulmonic stenosis and regurgitation, abnormal architecture of the left ventricular musculature). Opitz and Pallister (1979) reproduced the first published illustration of the Noonan syndrome by Kobylinski (1883), and Opitz (1985) republished the photograph of Rickey E., the first patient with 'her' syndrome studied at the State University of Iowa by Jacqueline A. Noonan. 30 MEDLINE Neighbors

SEE ALSO

Alslev and Reinwein (1958); Char et al. (1972); Duncan et al. (1981); Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992); Wiedemann (1991); Witt et al. (1985)

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CONTRIBUTORS

Marla J. F. O'Neill - updated : 5/12/2004
Marla J. F. O'Neill - updated : 4/2/2004
Natalie E. Krasikov - updated : 3/29/2004
Siobhan M. Dolan - updated : 2/19/2004
Victor A. McKusick - updated : 1/14/2004
Victor A. McKusick - updated : 5/15/2003
Victor A. McKusick - updated : 5/13/2003
Cassandra L. Kniffin - updated : 1/9/2003
Victor A. McKusick - updated : 11/27/2002
Victor A. McKusick - updated : 11/12/2001
Victor A. McKusick - updated : 8/6/2001
John A. Phillips, III - updated : 7/10/2001
Michael J. Wright - updated : 5/21/2001
Sonja A. Rasmussen - updated : 10/12/2000
Paul Brennan - updated : 4/10/2000
Victor A. McKusick - updated : 4/30/1998
Victor A. McKusick - updated : 12/19/1997
Iosif W. Lurie - updated : 1/8/1997
Iosif W. Lurie - updated : 9/12/1996

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

carol : 5/13/2004

http://omim.org/entry/163950

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LYMPHEDEMA-DISTICHIASIS SYNDROME

Gene Map Locus: 16q24.3

Genetics: Mutation in the forkhead family transcription factor gene MFH1 (FOX2; 602402). Related disorders with overlapping features include hereditary lymphedema II. (Meige Syndrome); lymphedema with ptosis and lymphedema with yellow nail syndrome.

Description: Expressed as the characteristic "double-row" of eye lashes. Usually not detected or observed until a complication such as corneal irritation or ulceration brings it to the attention of the patient or physician.

Related genetic features (lymphedema): Cardiac defects, cleft-palate, spinal extradural cysts and photofobia.

*****

DISTICHIASIS

Alternative titles; symbols

EYELASHES, TWO ROWS OF

TEXT

Fox (1962) reviewed the heredity of this anomaly. Dominant pedigrees were presented by Erdmann (1904) and by Cockayne (1933). Blatt (1924) traced double rows of eyelashes through 3 generations. See tristichiasis (190800). (The terms 'districhiasis' and 'tristrichiasis' refer to 2 or 3 hairs per follicle. Much confusion exists, however, and 'distichiasis' and 'districhiasis' are often used interchangeably to mean 'two rows of eyelashes.') In 3 generations of a family, Pico (1957) found 11 persons with congenital ectropion of whom 8 also had distichiasis. Two persons had distichiasis alone. Histologic study in 2 showed absence of Meibomian glands and replacement of the dense collagenous tissue of the tarsal plates by loose areolar tissue. The observation by Szily (1923) suggested recessive inheritance. Maumenee (1982) questioned the existence of mendelian distichiasis except as part of the syndrome of lymphedema with distichiasis (153400). Study of a family with both distichiasis and atypical serum cholinesterase indicated that the 2 traits are not closely linked (Shammas et al., 1976). 30 MEDLINE Neighbors

Howard and Wilson (1993) used the term pseudodistichiasis for the double row of eyelashes seen in association with anhidrotic ectodermal dysplasia (305100). They pointed out that the double row of eyelashes should not be confused with the misdirection of normal lashes referred to as trichiasis. A similar but distinct eyelash anomaly was reported in association with the Setleis forceps marks syndrome (227260) by Frederick and Robb (1992). In true distichiasis, a second row of eyelashes merges from the meibomian gland orifices; in pseudodistichiasis, the double row of eyelashes exit anterior to the meibomian orifices. 30 MEDLINE Neighbors

SEE ALSO

Pico (1959)

REFERENCES

1. Blatt, N. :
Districhiasis congenita vera. Z. Augenheilk. 53: 325-338, 1924.
2. Cockayne, E. A. :
Inherited Abnormalities of the Skin and Its Appendages. London: Oxford Univ. Press (pub.) 1933.
3. Erdmann, P. :
Ein Beitrag zur Kenntnis der Distichiasis congenita (hereditaria). Z. Augenheilk. 11: 427-444, 1904.
4. Fox, S. A. :
Distichiasis. Am. J. Ophthal. 53: 14-18, 1962.
PubMed ID : 13894397
5. Frederick, D. R.; Robb, R. M. :
Ophthalmic manifestations of Setleis forceps marks syndrome: a case report. J. Pediat. Ophthal. Strabismus 29: 127-129, 1992.
PubMed ID : 1588476
6. Howard, G. R.; Wilson, M. E. :
Pseudodistichiasis as a manifestation of anhidrotic ectodermal dysplasia. J. Pediat. Ophthal. Strabismus 30: 204-205, 1993.
PubMed ID : 8350233
7. Maumenee, I. H. :
Personal Communication. Baltimore, Md., 2/11/1982.
8. Pico, G. :
Congenital ectropion and districhiasis. Etiologic and hereditary factors: a report of cases and review of the literature. Trans. Am. Ophthal. Soc. 55: 663-700, 1957.
9. Pico, G. :
Congenital ectropion and distichiasis. Etiology and hereditary factors: a report of cases and review of the literature. Am. J. Ophthal. 47: 363-387, 1959.
PubMed ID : 13627093
10. Shammas, H. F.; Tabbara, K. F.; Der Kaloustian, V. M. :
Atypical serum cholinesterase in a family with congenital distichiasis. J. Med. Genet. 13: 514-515, 1976.
PubMed ID : 1018310
11. Szily, A. :
Ueber Haarbildung in der Meibomschen Druese und ueber behaarte Meibomdruesen (sogenannte Districhiasis congenita vera). Klin. Mbl. Augenheilk. 70: 16-45, 1923.

CREATION DATE

Victor A. McKusick : 6/4/1986

EDIT HISTORY

alopez : 3/18/2004
davew : 6/27/1994
mimadm : 6/25/1994
warfield : 4/8/1994
carol : 3/30/1994
carol : 7/22/1993
supermim : 3/16/1992

http://omim.org/entry/126300

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LYMPHEDEMA-CHOLESTASIS SYNDROME

Gene Map Locus: 15q

Related terms: Aagenaes syndrome, Cholestasis Syndrome-Lymphedema

Complication associated with primary hereditary lymphedema. First study of this condition took place in 2 Norwegian families with recurrent cholestasis and lymphedema. Patients experienced jaundice soon after birth and edema of the legs was caused by hypoplasia of the lymphatics. Liver histology showed giant cell transformation in infancy and some fibrosis or cirrhosis in later childhood.

Extremely rare disorder with limited clinical studies available.

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LYMPHEDEMA, MICROCEPHALY, CHORIORETINOPATHY SYNDROME

Genetics: Autosomal recessive; indication of X-linkage.

Description: Retinal fold with microcephaly and microphthalmos, included.

Other indications observed in this disorder include: congenital lymphedema and/ora delay in the maturation of the lymphatic system, lymphedema nails (usually in the toes), coarseness of the hair follicles over the dorsum of the hands and feet. While normal intelligence was the more common pattern, there also have been unusually high incidences of slow learning, mental retardation or attention deficit disorder. Psychomotor development is normal.

The most extensive clinical study was involving 5 members of a Chinese family, involving 4 generations, giving clear indications of familial (male) transmission (Leung 1985).

******

MICROCEPHALY WITH CHORIORETINOPATHY

Alternative titles; symbols

CHORIORETINAL DYSPLASIA-MICROCEPHALY-MENTAL RETARDATION SYNDROME, AUTOSOMAL DOMINANT FORM

TEXT

Microcephaly with chorioretinopathy (of a type that suggests congenital infection) occurs as an autosomal recessive (251270); in addition, autosomal dominant inheritance with variable expressivity has been reported by Alzial et al. (1980) and by Tenconi et al. (1981). Warburg and Heuer (1983) presented the cases of 2 brothers and their mother who had the combination of microcephaly and lacunar depigmentation of the retina. Microcephaly was slight and the foreheads were bulging. Mental retardation was also mild. A 5-year follow-up demonstrated that visual function was stable (Warburg and Heuer, 1994). Manning et al. (1990) reported the electroretinographic findings in members of a possible third family. Male-to-male transmission was observed for the first time in a family reported by Sadler and Robinson (1993); also see Robinson and Sadler (1993). A father and 2 sons were affected. Polycystic kidney disease was segregating in the family, apparently independently of the microcephaly syndrome. Hordijk et al. (1996) described a father and son with this syndrome. In addition to the usual manifestations, both had microcornea and overgrowth of the conjunctiva over the corneoscleral junction. The father had microphthalmia, and his son was severely mentally retarded. Microphthalmia, microcornea, and severe mental retardation had not been reported in other families with the autosomal dominant form of the syndrome. 30 MEDLINE Neighbors

This disorder may be identical to the lymphedema, microcephaly, chorioretinopathy syndrome (152950), an autosomal dominant trait.

REFERENCES

1. Alzial, C.; Dufier, J. L.; Brasnu, C.; Aicardi, J.; de Grouchy, J. :
Microcephalie 'vraie' avec dysplasie chorio-retinienne a heredite dominante. Ann. Genet. 23: 91-94, 1980.
PubMed ID : 6967291
2. Hordijk, R.; van de Logt, F.; Houtman, W. A.; van Essen, A. J. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome: another family with autosomal dominant inheritance. Genet. Counsel. 7: 113-122, 1996.
3. Manning, F. J.; Bruce, A. M.; Berson, E. L. :
Electroretinograms in microcephaly with chorioretinal degeneration. Am. J. Ophthal. 109: 457-463, 1990.
PubMed ID : 2330949
4. Robinson, L. K.; Sadler, L. S. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. (Abstract) Proc. Greenwood Genet. Center 12: 54 only, 1993.
5. Sadler, L. S.; Robinson, L. K. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome: report of an American family. Am. J. Med. Genet. 47: 65-68, 1993.
PubMed ID : 8368255
6. Tenconi, R.; Clementi, M.; Battista Moschini, G.; Casara, G.; Baccichetti, C. :
Chorio-retinal dysplasia, microcephaly and mental retardation: an autosomal dominant syndrome. Clin. Genet. 20: 347-351, 1981.
PubMed ID : 7333029
7. Warburg, M.; Heuer, H. E. :
Autosomal dominant microcephaly with lacunar retinal hypopigmentations.In: Henkind, P. : XXIV International Congress Ophthalmology. Philadelphia: J. B. Lippincott (pub.) 1983.
8. Warburg, M.; Heuer, H. E. :
Chorioretinal dysplasia-microcephaly-mental retardation syndrome. (Letter) Am. J. Med. Genet. 52: 117 only, 1994.
PubMed ID : 7977454

CONTRIBUTORS

Victor A. McKusick - updated : 2/10/2000
Iosif W. Lurie - updated : 9/24/1996

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

carol : 2/10/2000
alopez : 7/16/1997
carol : 9/24/1996
mimadm : 11/6/1994
carol : 10/24/1994
carol : 9/1/1993
carol : 7/2/1993
supermim : 3/16/1992
http://omim.org/entry/156590

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LYMPHEDEMA-HYPOPARATHYROIDISM SYNDROME

Dahlberg et al. (1983) described 2 adult brothers with congenital lymphedema, hypoparathyroidism, nephropathy, mitral valve prolapse and brachytelephalangy. The older sib was found to have bilateral cataracts on routine examination at age 19 years. Swelling of his arms and legs, noted soon after his birth, increased after he began walking. Progressive renal failure necessitated renal transplantation at age 26 years. The brother had similar findings. Both have a broad nasal bridge and lateral displacement of the inner canthi. Pulmonary lymphangiectasia (see 265300) was suspected on the basis of radiologic findings. The mode of inheritance is not clear but includes autosomal recessive and X-linked recessive inheritance.

*Online Mendelian Inheritance in Man - John Hopkins University*

http://omim.org/entry/247410

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LYMPHEDEMA, CONGENITAL RECESSIVE SYNDROME

The possibility of an autosomal recessive form of congenital lymphedema was raised by Kajii and Tsukahara (1985), who described brother and sister. The parents were not known to be related but came from an island with a population of 1,500 in the Sea of Japan. Kajii and Tsukahara (1986) cited a similar experience of brother and sister with congenital lymphedema of the lower extremities and no associated malformations. Mucke et al. (1986) observed 2 brothers with chronic congenital lymphedema and proposed the existence of an X-linked or recessive form. In addition to edema of the limbs, they had abnormalities of the external genitalia as a deformation sequence resulting from intrauterine edema and had intestinal lymphedema. A prominent feature also was chemosis and injection of the conjunctiva

*Online Mendelian Inheritance in Man*

http://omim.org/entry/247440

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LYMPHEDEMA AND PTOSIS SYNDROME

Gene Map Locus: 16q24.3

Disorder associated with dominantly inherited lymphedema caused by a mutation in the forkhead family transcription factor MHF1 (FOXC2).

Ptosis, commonly referred to as "droopy eyelids" in lymphedema is associated with Noonan Syndrome and lymphedema with distichiasis. In one study, leg lymphedema was present in 5 generations, with 6 affected persons in 3 consecutive generations exhibiting ptosis.

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HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA SYNDROME

Alternative titles; symbols

HLTSGene map locus 20q13.33

TEXT

A number sign (#) is used with this entry because the hypotrichosis-lymphedema-telangiectasia syndrome is caused by mutation in the transcription factor gene SOX18 (601618).

CLINICAL FEATURES

Irrthum et al. (2003) described 3 families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. In the first family, previously reported by Devriendt et al. (2002), a boy and girl, offspring of first-cousin Belgian parents, were affected. The boy was born at 32 weeks' gestation and presented with respiratory distress. A normal amount of scalp hair was present at birth but decreased progressively to the extent of total alopecia at age 6 months. The hair remained very sparse with absent eyebrows and eyelashes; sweating, nails, and teeth were normal. The skin over the hands and feet was thin and transparent, with visible blood vessels. Bilateral hydrocele was surgically corrected at age 12 years. Beginning at approximately 15 years of age, the patient progressively developed lymphedema of the legs. At 25 years of age, a doppler ultrasonogram of the venous system of the legs was normal. At that time, however, lymphatic scintigraphy with radiolabeled tracer showed no evidence of lymphatic flow from the dorsum of the foot. His younger sister presented with a similar phenotype. At birth she had normal black hair. A vascular nevus was present on the palm of the right hand and faded during childhood. During infancy, her hair diminished progressively, and from approximately 2 years of age her hair was very sparse with no eyebrows or eyelashes, and she did not develop axillary or pubic hair at puberty. Around puberty, she developed progressive lymphedema of the legs. At age 26 years she showed normal teeth, nails, and sweating, but her skin was thin. The skin over her hands and feet was transparent, and dilated veins and varicosities were apparent on the palm of her right hand. The single affected individual in the second family studied by Irrthum et al. (2003) was a 12-year-old girl, the offspring of unaffected first-cousin Turkish parents, who had previously been described in detail by Glade et al. (2001). Lymphedema of the legs appeared at age 4 years. Scalp hair had always been sparse; eyebrows and eyelashes were missing. Palms and soles showed multiple telangiectasias, with ectatic capillaries and cutis marmorata-like lividity of the skin. The index patient in the third family described by Irrthum et al. (2003), whose parents were normal and nonconsanguineous, had sparse hair at birth and presented with swelling of the upper eyelids, scrotal edema, and very large bilateral hydroceles. Hair loss began at approximately 6 months of age, accompanied by a lightening of its color. At 6 years of age, alopecia was almost complete, including eyebrows and eyelashes. The patient presented mild eczema on the cheeks and telangiectasias on the scalp, scrotum, and legs. His nails and teeth were normal. His brother died in utero at 30 weeks' gestation. The fetus had nonimmune hydrops fetalis, with chylous effusions in the pleural and peritoneal cavities. The lungs presented generalized vascular congestion and a mild dilatation of lymphatic vessels. 30 MEDLINE Neighbors

MOLECULAR GENETICS

In each of the 3 HLTS families they described, Irrthum et al. (2003) identified a mutation in the SOX18 gene. In the first and second families, both consanguineous, they identified homozygosity for the mutations ala104 to pro (A104P; 601618.0001) and trp95 to arg (W95R; 601618.0002), respectively. In the third family, which was nonconsanguineous, they identified a heterozygous cys240-to-ter mutation (C240X; 601618.0003) in the 2 affected brothers, which indicated that they had a dominant form of HLTS, apparently inherited from a parent who had the disorder in probable gonadal mosaicism. 30 MEDLINE Neighbors

REFERENCES

1. Devriendt, K.; Vikkula, M.; Irrthum, A.; Mattjijs, G.; Mertens, A.; Fryns, J.-P. :
Autosomal recessive alopecia and lymphedema. (Abstract) Genet. Counsel. 13: 74-75, 2002.
2. Glade, C.; van Steensel, M. A.; Steijlen, P. M. :
Hypotrichosis, lymphedema of the legs and acral telangiectasias--new syndrome? Europ. J. Derm. 11: 515-517, 2001.
3. Irrthum, A.; Devriendt, K.; Chitayat, D.; Matthijs, G.; Glade, C.; Steijlen, P. M.; Fryns, J.-P.; Van Steensel, M. A. M.; Vikkula, M. :
Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am. J. Hum. Genet. 72: 1470-1478, 2003.
PubMed ID : 12740761

CREATION DATE

Victor A. McKusick : 5/23/2003

EDIT HISTORY

tkritzer : 5/28/2003
tkritzer : 5/23/2003
Copyright © 1966-2004 Johns Hopkins University

http://omim.org/entry/607823

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LYMPHEDEMA AND CEREBRAL ARTERIOVENOUS ANOMALY

TEXT

Avasthey and Roy (1968) reported a woman with lymphedema of the feet beginning in her teens and a cerebrovascular anomaly indicated by a loud systolic bruit over the temples and transmitted down the carotids. A son, aged 20 years, likewise had foot lymphedema and a cranial bruit and by angiogram a large extracranial arteriovenous malformation over the parietal region. Two other sons had lymphedema, cerebrovascular malformation, and primary pulmonary hypertension. One son was normal and the only daughter had lymphedema of both feet and bilateral temporoparietal bruit. 30 MEDLINE Neighbors

REFERENCES

1. Avasthey, P.; Roy, S. B. :
Primary pulmonary hypertension, cerebrovascular malformation, and lymphoedema feet in a family. Brit. Heart J. 30: 769-775, 1968.
PubMed ID : 5718986

CREATION DATE

Victor A. McKusick : 6/2/1986

EDIT HISTORY

mimadm : 11/6/1994
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
marie : 3/25/1988
reenie : 6/2/1986

Copyright © 1966-2004 Johns Hopkins University

http://omim.org/entry/152900

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ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS, AND LYMPHEDEMA; OLEDAID
Gene map locus Xq28

TEXT

A number sign (#) is used with this entry because the phenotype is caused by hypomorphic mutations in NEMO (IKBKG; 300248).

Doffinger et al. (2001) examined 2 unrelated male patients who presented with the novel OL-EDA-ID syndrome. Both were sons of mothers with mild incontinentia pigmenti (308300), and both died of overwhelming multiple infections at 2.5 and 1.5 years of age, respectively. Both had osteopetrosis, lymphedema, and anhidrotic ectodermal dysplasia. Immunologic variables in the second patient showed a poor inflammatory response and increases in the levels of blood inflammatory markers with fever either absent or delayed during infection. Blood monocytes and polymorphonuclear cells were normal in number and morphology. The B- and T-cell counts and responses to vaccine protein antigens were normal. Serum titers of antibodies against S. pneumoniae were low, despite proven infection. Serum titers of isohemagglutinins were low. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. Both patients carried an X420W mutation in IKBKG, or NEMO (300248.0002). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutational events. Both patients died of overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. There were impaired cellular responses to TNF-alpha (191160). Doffinger et al. (2001) compared the induction of IFN-gamma (147570) by peripheral blood mononuclear cells (PBMC) from one of the patients and a control. The patient's PBMC displayed a lower level of IFN-gamma production upon costimulation with IL12 (see 161560) and various concentrations of IL1-beta (147720) or IL18 (600953) than the control PBMC. There were impaired cellular responses to lipopolysaccharide in this patient. The patient also exhibited dissociated cellular responses to CD154 (CD40LG; 300386), suggesting that some but not all CD40 (109535)-mediated signals are NEMO-dependent in both dentritic cells and B cells. 30 MEDLINE Neighbors

REFERENCES

1. Doffinger, R.; Smahi, A.; Bessia, C.; Geissmann, F.; Feinberg, J.; Durandy, A.; Bodemer, C.; Kenwrick, S.; Dupuis-Girod, S.; Blanche, S.; Wood, P.; Rabia, S. H.; and 16 others :
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285, 2001.
PubMed ID : 11242109

CREATION DATE

Ada Hamosh : 3/2/2001

EDIT HISTORY

carol : 4/8/2002
terry : 11/14/2001
alopez : 4/26/2001
alopez : 4/24/2001
alopez : 3/5/2001
alopez : 3/2/2001

Copyright © 1966-2004 Johns Hopkins University

hhttp://omim.org/entry/300301

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LYMPHEDEMA, ATRIAL SEPTAL DEFECT, AND FACIAL CHANGES

TEXT

Irons et al. (1996) reported 2 brothers with association of lymphedema of the lower limbs, hydrocele, atrial septal defects (ASD), epicanthus, and wide nasal bridge. Their stillborn sister, who was born after a pregnancy complicated by preeclampsia, had severe hydrops fetalis, omphalocele, ASD, and polysplenia. The family history was unremarkable. Irons et al. (1996) considered this complex to be a previously unknown syndrome with autosomal recessive inheritance. 30 MEDLINE Neighbors

REFERENCES

1. Irons, M. B.; Bianchi, D. W.; Geggel, R. L.; Marx, G. R.; Bhan, I. :
Possible new autosomal recessive syndrome of lymphedema, hydroceles, atrial septal defect, and characteristic facial changes. Am. J. Med. Genet. 66: 69-71, 1996.
PubMed ID : 8957515

CONTRIBUTORS

Iosif W. Lurie - updated : 8/5/1997

CREATION DATE

Iosif W. Lurie : 7/29/1997

EDIT HISTORY

jenny : 8/5/1997

Copyright © 1966-2004 Johns Hopkins University

http://omim.org/entry/601927

=======Internal Links===========

HEREDITARY LYMPHEDEMA TYPE I

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

HEREDiTARY LYMPHEDEMA TYPE II  

http://www.lymphedemapeople.com/thesite/lymphedema_praecox_meige_syndrome.htm

HEREDITARY LYMPHEDEMA TYPE III

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

STEWART-TREVES SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_stewart_treves_syndrome.htm

YELLOW NAIL SYNDROME

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

HENNEKAM LYMPHANGIECTASIA

http://www.lymphedemapeople.com/thesite/lymphedema_hennekam_lymphangiect.htm

TURNER SYNDROME

 http://www.lymphedemapeople.com/thesite/lymphedema_turner_syndrome.htm

KLIPPEL-TRENAUNAY-WEBER SYNDROME

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

NOONAN'S SYNDROME

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

LYMPHEDEMA-DISTICHIASIS SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_distichiasis.htm

LYMPHEDEMA-CHOLESTASIS SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_cholestasis_syndrome.htm

LYMPHEDEMA, MICROCEPHALY

http://www.lymphedemapeople.com/thesite/lymphedema_microcephaly_chorioretinopathy.htm

LYMPHEDEMA CHORIORETINOPATHY SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_microcephaly_chorioretinopathy.htm

LYMPHEDEMA-HYPOPARATHYROIDISM SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_hypoparathyroidism2.htm

 LYMPHEDEMA, CONGENITAL RECESSIVE SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_congenital_recessive_.htm

HYPOTRICHOSIS-LYMPHEDEMA-TELANGIECTASIA SYNDROME

LYMPHEDEMA AND PTOSIS SYNDROME

http://www.lymphedemapeople.com/thesite/hypotrichosis_lymphedema.htm

LYMPHEDEMA AND CEREBRAL ARTERIOVENOUS ANOMALY  (and/or)

LYMPHEDEMA AVASTHEY ROY SYNDROME

http://www.lymphedemapeople.com/thesite/lymphedema_avasthey_roy_syndrome.htm

ECTODERMAL DYSPLASIA ANHIDROTIC WITH IMMUNODEFICIENCY

http://www.lymphedemapeople.com/thesite/ectodermal_dysplasia_hypohidrotic_immune_deficiency.htm

OSTEOPETROSIS AND LYMPHEDEMA

http://www.lymphedemapeople.com/thesite/lymphedema_osteopetrosis_ectodermal.htm

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

Join us as we work for lymphedema patients everywehere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

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

Subscribe: AdvocatesforLymphedema-subscribe@yahoogroups.com

Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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

For information about Lymphedema

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

For Information about Lymphedema Complications

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

For Lymphedema Personal Stories

http://www.lymphedemapeople.com/phpBB2/viewforum.php?f=3

For information about How to Treat a Lymphedema Wound

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

For information about Lymphedema Treatment 

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

For information about Exercises for Lymphedema 

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

For information on Infections Associated with Lymphedema

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

For information on Lymphedema in Children

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

Lymphedema Glossary

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

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

Lymphedema People - Support Groups

-----------------------------------------------

Children with Lymphedema

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

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

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

......................

Lipedema Lipodema Lipoedema

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

Come join, be a part of the family!

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

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

......................

MEN WITH LYMPHEDEMA

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

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

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

......................

All About Lymphangiectasia

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

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

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

......................

Lymphatic Disorders Support Group @ Yahoo Groups

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

DISCRIPTION

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

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

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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

Lymphedema People New Wiki Pages

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

Lymphedema Glossary 

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

Lymphedema 

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

Arm Lymphedema  

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

Leg Lymphedema 

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

Acute Lymphedema 

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

The Lymphedema Diet 

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

Exercises for Lymphedema  

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

Diuretics are not for Lymphedema 

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

Lymphedema People Online Support Groups 

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

Lipedema 

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

Treatment 

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

Lymphedema and Pain Management 

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

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

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

Infections Associated with Lymphedema 

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

How to Treat a Lymphedema Wound 

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

Fungal Infections Associated with Lymphedema 

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

Lymphedema in Children 

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

Lymphoscintigraphy 

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

Magnetic Resonance Imaging 

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

Extraperitoneal para-aortic lymph node dissection (EPLND) 

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

Axillary node biopsy 

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

Sentinel Node Biopsy 

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

 Small Needle Biopsy - Fine Needle Aspiration 

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

Magnetic Resonance Imaging 

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

Lymphedema Gene FOXC2

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

 Lymphedema Gene VEGFC

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

 Lymphedema Gene SOX18

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

 Lymphedema and Pregnancy

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

Home page: Lymphedema People

http://www.lymphedemapeople.com

Page Updated: Dec. 28, 2011