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Nevo Syndrome  

Synonym: 

Cerebral gigantism nevo type, Sotos Syndrome

Prevalence: Exceptional
Inheritance:
  • Autosomal recessive

Causes: 

Mutations in the gene encoding lysyl hydroxylase, PLOD1, (chromosome locus 1p36.3-36.2) and is thus allelic to EDS VIA.

Diagnosis:

Family history and physical examination would be the central diagnostic tools.  Lymphatic dysplasia could be verified through the use of a lymphoscintigraphy test. 

Symptoms: (Nevo Syndrome) 

Complications:

Treatment:

Treatment might include surgery for the physical anomolies, therapy for the motor development complications and the establishment of a lymphedema mangement program. 

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

Pat O'Connor

June 8, 2008

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NEVO SYNDROME

#601451

TEXT

Nevo et al. (1974) described an inbred Israeli family in which 2 sibs and their cousin had increased growth, kyphosis, prominent forehead, volar edema, spindle-shaped fingers, wrist drop, talipes, hyperbilirubinemia, and generalized hypotonia. Although the authors considered their cases to be an autosomal recessive variant of Sotos syndrome (117550), Cohen (1989) proposed that these patients had a separate entity, which they called the Nevo syndrome. A fourth case was reported by Hilderink and Brunner (1995). Their patient, a boy born to consanguineous parents, had neither lens luxation nor aortic dilatation. 30 MEDLINE Neighbors

Al-Gazali et al. (1997) described 2 further male cases from unrelated Arab families with features similar to those described by Nevo et al. (1974) but without hyperbilirubinemia. Both had delayed motor development. Cognitive function was normal in one at 2 years 10 months of age. While the other was too young to assess, social responses appeared normal. MRI studies in the older child revealed extreme hyperlordosis of the cervical spine and a wide spinal canal suggestive of dural ectasia. 30 MEDLINE Neighbors

The patient reported by Dumic et al. (1998) manifested intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large and low-set ears, cryptorchidism, delayed neuropsychologic development, hypotonia, edema and contractures of the hands and feet, a single transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were markedly accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. Dumic et al. (1998) presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his 'overgrowth without growth hormone,' at least in the last 12 months of life after severe brain damage. 30 MEDLINE Neighbors

SEE ALSO

Cohen (1989)

REFERENCES

1. Al-Gazali, L. I.; Bakalinova, D.; Varady, E.; Scorer, J.; Nork, M. :
Further delineation of Nevo syndrome. J. Med. Genet. 34: 366-370, 1997.
PubMed ID : 9152832
2. Cohen, M. M., Jr. :
A comprehensive and critical assessment of overgrowth and overgrowth syndromes.In: Harris, H.; Hirschhorn, K. (eds.) : Advances in Human Genetics. Vol. 18. New York: Plenum Press 1989. Pp. 181-303 and 373-376.
3. Dumic, M.; Vukelic, D.; Plavsic, V.; Cviko, A.; Sokolic, L.; Filipovic-Grcic, B. :
Nevo syndrome. Am. J. Med. Genet. 76: 67-70, 1998.
PubMed ID : 9508068
4. Hilderink, B. G. M.; Brunner, H. G. :
Nevo syndrome. Clin. Dysmorph. 4: 319-323, 1995.
PubMed ID : 8574422
5. Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J. :
Evidence for autosomal recessive inheritance in cerebral gigantism. J. Med. Genet. 11: 158-165, 1974.
PubMed ID : 4841084

CONTRIBUTORS

Victor A. McKusick - updated : 3/20/1998
Michael J. Wright - updated : 7/3/1997

CREATION DATE

Iosif W. Lurie : 9/26/1996

EDIT HISTORY

alopez : 3/23/1998
terry : 3/20/1998
mimman : 10/3/1997
alopez : 8/27/1997
alopez : 8/7/1997
jamie : 11/1/1996
carol : 9/27/1996

Copyright © 1966-2004 Johns Hopkins University

http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601451

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

Nevo syndrome.

Dumic M, Vukelic D, Plavsic V, Cviko A, Sokolic L, Filipovic-Grcic B.

Department of Pediatrics, University Hospital, Zagreb, Croatia.

We report on a patient with Nevo syndrome manifesting intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large, low-set ears, cryptorchidism, delayed neuropsychological development, hypotonia, adema, contractures of the hands and feet, a single a transverse palmar crease, and tapering digits. After meningococcal sepsis at age 6 months, he remained decerebrate. Thereafter, overgrowth and especially weight gain were extremely accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg. In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed. It is presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his "overgrowth without growth hormone," at least in the last 12 months of life after severe brain damage.

Publication Types:

PMID: 9508068 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9508068&dopt=Abstract

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

Further delineation of Nevo syndrome.

al-Gazali LI, Bakalinova D, Varady E, Scorer J, Nork M.

Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE.

Nevo syndrome is an autosomal recessive syndrome characterised by prenatal overgrowth, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Four children from two families have been reported previously. We report two further children from two unrelated Arab families from two different tribes. Both presented at birth with hypotonia, joint laxity, kyphosis, wrist drop, spindle shaped fingers, and volar oedema. Both have delayed motor development at the ages of 2 years 10 months and 3 months respectively. Cognitive development is normal in one, and the other case appears to be developing normally at 3 months of age. One has, in addition, a wide spinal canal on MRI of the spine indicating some degree of dural ectasia. This report brings the total number of children reported with this syndrome to six from four families; three of these families are Arab. This indicates that the gene for this syndrome is probably commoner in Arabs than in other populations.

Publication Types:

PMID: 9152832 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9152832&dopt=Abstract

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

D I S E A S E : Nevo syndrome

Summary

Nevo syndrome is a rare entity characterized by prenatal and postnatal overgrowth, joint laxity, kyphosis, wrist drop and long spindle shaped fingers, and volar edema. Approximately ten cases have been described worldwide, with the majority of these patients being of Arab ethnicity. Some consider that Nevo syndrome is a variant of the kyphoscoliotic type of Ehlers-Danlos syndrome type VIA (EDS VIA), an inherited connective tissue disorder characterized by severe muscular hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin fragility. In contrast, other authors consider it to be a separate entity. Additional clinical signs are a prominent forehead, delayed gross motor development, moderately advanced bone age, dorsiflexion contractures of the feet, hyperbilirubinemia, generalized hypotonia, osteopenia, and lymphedema. Nevo syndrome is transmitted as an autosomal recessive trait. It is caused by mutations in the gene encoding lysyl hydroxylase, PLOD1, (chromosome locus 1p36.3-36.2) and is thus allelic to EDS VIA. Both entities have a very similar clinical phenotype but if there is a difference between Nevo syndrome and EDS VIA, it is in the severity of the joint hypermobility and skin fragility. Management is symptomatic only. Referral to an orthopedic surgeon should be considered and prevention of the secondary complications should be offered. *Author: Orphanet (May 2007)*.

Clinical Signs:

  advanced bone age (Very frequent sign)
   blepharophimosis/short palp. fissures (Very frequent sign)
   build/stature/survival anomalies (Very frequent sign)
   eyes anomalies (Very frequent sign)
   foot anomalies (Very frequent sign)
   high vaulted/narrow palate (Very frequent sign)
   hip anomalies (Very frequent sign)
   hypotonia (Very frequent sign)
   knee anomalies (Very frequent sign)
   large hand (Very frequent sign)
   long/large/bulbous nose (Very frequent sign)
   micrognatia/retrognatia (Very frequent sign)
   myopia (Very frequent sign)
   narrow rib cage (Very frequent sign)
   narrow/sloping shoulders (Very frequent sign)
   osteoporosis (Very frequent sign)
   respiratory distress (Very frequent sign)
   scoliosis (Very frequent sign)
   shoulder dislocation (Very frequent sign)
   undescended/ectopic testes (Very frequent sign)
   wrist anomalies (Very frequent sign)

Outpatient clinic(s)

Orphanet

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

Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome?

2006 Jan

Kanemoto N, Kanemoto K, Nishimura G, Kamoda T, Visser R, Shimokawa O, Matsumoto N.

Department of Pediatrics, Ibaraki Seinan Medical Center Hospital, Sakai 2190, Sashima, Ibaraki 306-0433, Japan. syouni-kanemoto@seinan-mch.or.jp

A 17-month-old girl with clinical manifestations of Nevo syndrome and NSD1 (nuclear receptor binding SET domain protein 1) deletion is described. Nevo syndrome is a rare overgrowth syndrome showing considerable phenotypic overlap with Sotos syndrome-another, more frequent overgrowth syndrome caused by NSD1 mutations or deletions. About a half of Japanese Sotos syndrome patients carry a 2.2-Mb common deletion encompassing NSD1 and present with frequent brain, cardiovascular, or urinary tract anomalies. The girl we described had the common deletion and showed patent ductus arteriosus, atrial septal defect, vesicoureteral reflux, and bilateral hydronephrosis. It was thus concluded that the clinical manifestations, including the Nevo syndrome phenotype, were caused by the microdeletion. 

Wiley InterScience

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

Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA).

Am J Med Genet A. 2005 Mar

Giunta C, Randolph A, Al-Gazali LI, Brunner HG, Kraenzlin ME, Steinmann B.

Division of Metabolism & Molecular Pediatrics, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.

Keywords:

We report on seven patients affected with Nevo syndrome, a rare, autosomal recessive disorder characterized by increased perinatal length, kyphosis, muscular hypotonia, and joint laxity. Since its first description by Nevo et al. [1974], only a few cases have been reported. Because some of these patients present clinical features similar to those of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA), an inherited connective tissue disorder characterized by a deficiency of lysyl hydroxylase due to mutations in PLOD1, we studied seven patients with Nevo syndrome, three of whom have previously been reported, and four of whom are new. In the five patients from whom urine was available, the ratio of total urinary lysyl pyridinoline (LP) to hydroxylysyl pyridinoline (HP) was elevated (8.2, 7.8, 8.6, 3.5, and 4.8, respectively) compared with that in controls (0.20 +/- 0.05, range 0.10-0.38), and similar to that observed in patients with EDS VIA (5.97 +/- 0.99, range 4.3-8.1). Six patients were homozygous for a point mutation in exon 9 of PLOD1 causing a p.R319X nonsense mutation, while one patient was homozygous for a large deletion comprising exon 17 of PLOD1. We conclude that the Nevo syndrome is allelic to and clinically indistinguishable from EDS VIA, and present evidence that increased length at birth and wristdrop, in addition to muscular hypotonia and kyphoscoliosis, should prompt the physician to consider EDS VIA earlier than heretofore. Wiley-Liss, Inc.

Wiley InterScience

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SOTOS SYNDROME

Alternative titles; symbols

CEREBRAL GIGANTISMGene map locus 5q35

TEXT

A number sign (#) is used with this entry because Sotos syndrome is caused by mutation in the NSD1 gene (606681).

CLINICAL FEATURES

Sotos et al. (1964) described 5 children with a disorder characterized by excessively rapid growth, acromegalic features, and a nonprogressive cerebral disorder with mental retardation. High-arched palate and prominent jaw were noted in several of them. Birth length was between the 90th and 97th centiles in all. Bone age was advanced in most. 30 MEDLINE Neighbors

Hook and Reynolds (1967) reported that affected children have large hands and feet from birth. Growth is rapid in the first years of life but final height may not be excessive. Bone age is advanced. The skull is large with moderate prognathism. Mild dilation of the cerebral ventricles, nonspecific EEG changes, and seizures have been observed. Poor coordination and mental retardation are features. In 2 patients, Bejar et al. (1970) found abnormal dermatoglyphics, normal growth hormone levels, and high levels of valine, isoleucine and leucine in the blood. The glycine-to-valine ratio seemed particularly useful in distinguishing patients from controls. 30 MEDLINE Neighbors

Ruvalcaba et al. (1980) found hamartomatous polyps of the intestine and melanin spots of the penis in 2 males with the Sotos syndrome. Halal (1983) reported that the older of the boys she reported with cerebral gigantism had pigmented spots on the genitalia and that the father had been found to have a rectal polyp--findings like those in the 2 unrelated adult males reported by Ruvalcaba et al. (1980). 30 MEDLINE Neighbors

Kaneko et al. (1987) found congenital heart defects in 5 of 10 patients with typical Sotos syndrome. Noreau et al. (1998) found that 3 of 14 Sotos syndrome patients had congenital heart defects. In a literature review, they found another 17 patients with variable cardiac defects, mostly closure defects, making an overall incidence of approximately 8%. 30 MEDLINE Neighbors

Goldstein et al. (1988) described 2 unrelated children with macrocephaly, excessive growth, strabismus, hypotonia and developmental delay, and improvement with age.

In a review, Cole and Hughes (1990) emphasized that the handicaps in Sotos syndrome are fewer than previously believed and tend to improve with age. The latter feature makes identification of affected adults difficult. Cole and Hughes (1994) clinically assessed 79 patients with a provisional diagnosis of Sotos syndrome and evaluated their photographs between ages 1 and 6 years. These photographs, together with photographs of first-degree relatives, also at ages 1 to 6 years, were reviewed by 4 clinical geneticists. In 41 probands, but no first-degree relatives, the facial gestalt was thought to be characteristic of Sotos syndrome. Comparison of anthropometric measurements, bone age, and developmental delay in these 41 probands showed marked differences between them and the remaining 38 probands. Length was identified as the most significantly increased prenatal parameter. In childhood, occipitofrontal head circumference (OFC), height, and weight were all increased. OFC remained above the 97th percentile in all but one case throughout childhood and adulthood, whereas height and weight had a tendency to return toward the mean. This 'normalization' was more pronounced in females and was probably related to their early puberty. Early developmental delay and an advanced bone age were seen in 100% and 84% of cases, respectively. Cole and Hughes (1994) suggested that facial gestalt, growth pattern, bone age, and developmental delay are the major diagnostic criteria. Using these criteria, no affected first-degree relatives were identified. 30 MEDLINE Neighbors

Scarpa et al. (1994) described a sister and brother with macrocrania and coarse face (frontal bossing, highly arched palate, prognathism, pointed chin, large ears). Psychomotor development of the sister, who also had advanced osseous maturation, improved significantly at the age of 7 years. Accelerated growth with normal bone age, optic atrophy, renal agenesis with contralateral double kidney, and significant mental retardation (IQ, 45) were shown in the brother at 3.5 years of age. The father of these children was tall, with macrocrania and large hands and feet. He had had learning difficulties in school and was a manual laborer. Scarpa et al. (1994) suggested that these children and their father showed different manifestations of Sotos syndrome. Allanson and Cole (1996) presented anthropometric evaluation of the head in 45 patients with Sotos syndrome between age 1 and 25 years. With increasing age, the face lengthens and the chin becomes more striking. 30 MEDLINE Neighbors

Opitz et al. (1998) reported affected mother and daughter. The mother was described as a large infant and 'as tall as her teacher in school.' Her adult height was 185.4 cm, and she had mandibular prognathism and a prominent pointed chin. The daughter showed a prominent forehead with sparseness of frontal hair and a 'ruddy' or flushed complexion, especially of the nose and perioral area. She had prominent features of the congenital hypotonia/lymphedema sequence with hypermobile joints, especially at the knees and ankles, lymphedema nails (especially toenails), and a high total ridge count (TRC) of the fingertip dermatoglyphics. The mother also had a high TRC and a receding frontal hairline. 30 MEDLINE Neighbors

Robertson and Bankier (1999) reported 3 children with anthropometric and dysmorphologic features of classic Sotos syndrome in association with redundant skin folds, joint hypermobility, and, in 2 of the 3, vesicoureteric reflux. Robertson and Bankier (1999) thought the associated features suggested a coexisting connective tissue disorder. All the patients had a normal bone age. Although Sotos syndrome in its classically described form was not present, Robertson and Bankier (1999) concluded that this entity might reflect a related, perhaps allelic, condition. 30 MEDLINE Neighbors

Tumor Formation

Maldonado et al. (1984) reported the association of malignant tumors in Sotos syndrome. Nance et al. (1990) described a 15-month-old child with Sotos syndrome and a paraspinal neuroblastoma. From this and other evidence, they concluded that children with this disorder may be at an increased risk for developing tumors. Gorlin et al. (1990) estimated a risk of 3.9% of benign or malignant tumors in Sotos syndrome. The same excess of neoplasms is present in other overgrowth syndromes. Le Marec et al. (1999) reported that one of a monozygotic twin pair, both of whom had Sotos syndrome, developed a diffuse gastric carcinoma containing signet ring cells at the age of 26. The young age of occurrence of this gastric carcinoma suggested a genetic factor. Leonard et al. (2000) reported 2 children with Sotos syndrome who had benign sacrococcygeal teratomas. Given that Sotos syndrome and sacrococcygeal teratoma are rare events, the authors suggested that these tumors may be due to the effects of overgrowth on tumor development. 30 MEDLINE Neighbors

DIAGNOSIS

Opitz et al. (1998) discussed the differentiation of 2 overgrowth syndromes, Sotos syndrome and Weaver syndrome (277590), and the question of whether the similarities are sufficient to consider them 1 entity. They noted that vertebrate development is constrained into only a very few final or common developmental pathways; therefore, no developmental anomaly seen in humans is unique to ('pathognomonic of') one syndrome. Possible phenotypic differences between the syndromes of Sotos and Weaver pointed out by Opitz et al. (1998) were the following: the Sotos syndrome may be a cancer syndrome, whereas the Weaver syndrome is not (although a neuroblastoma had been reported in the latter disorder). In Sotos syndrome there is remarkably advanced dental maturation; this is rarely commented on in Weaver syndrome. In Weaver syndrome, there are more conspicuous contractures and a facial appearance that experts find convincingly different from that in Sotos syndrome. Opitz et al. (1998) favored allelic heterogeneity as the explanation for the similarities between Sotos and Weaver syndromes. They suggested that mapping and isolation of the causative gene or genes would settle the issue. 30 MEDLINE Neighbors

Differential Diagnosis

Schaefer et al. (1997) concluded that neuroimaging findings of Sotos syndrome are distinct enough to allow differentiation of this syndrome from other mental retardation syndromes with macrocephaly. The most common abnormality of the cerebral ventricles was prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). The supratentorial extracerebral fluid spaces were increased for age in 70% of the patients and the fluid spaces in the posterior fossa were increased in 70% also. A variety of midline abnormalities were noted but anomalies of the corpus callosum were almost universal. 30 MEDLINE Neighbors

NOMENCLATURE

Fryns (1988) referred to cases of the fragile X syndrome (309550) in which Sotos syndrome had been diagnosed; he therefore suggested that this disorder be designated the Sotos sequence or the mental retardation-overgrowth sequence.

INHERITANCE

Most reported cases of Sotos syndrome have been sporadic and may represent new dominant mutations. Hook and Reynolds (1967) reported a concordant set of affected identical twins. Hooft et al. (1968) described cerebral gigantism in 2 first cousins. Nevo et al. (1974) described affected brother and sister and their affected double first cousin in an inbred Arab family in Israel. Two of the 3 showed generalized edema and flexion contractures of the feet at birth. This may represent a distinct disorder; see Nevo syndrome (601451). Hansen and Friis (1976) described affected mother and child. Zonana et al. (1976) described affected mother and 2 children (male and female). The mother's father may have been affected. Zonana et al. (1977) reported 3 families showing vertical transmission and equal severity in males and females; no male-to-male transmission was observed. As an addendum, they commented on a fourth instance of affected mother and son. Smith et al. (1981) observed affected mother and daughter--the presumed fifth instance of dominant inheritance. The mother had primary hypothyroidism due to Hashimoto disease. Halal (1982) reported a family in which the father and 2 of his sons were affected. She knew of no other instance of documented male-to-male transmission. Winship (1985) described a 'Cape Coloured' family with affected father and 4 children by 2 different, unrelated wives. Presumed Sotos syndrome was described in a mother and 2 daughters by Bale et al. (1985). They suggested that instances of seemingly autosomal recessive inheritance may be examples of incomplete penetrance, gonadal mosaicism, or genetic heterogeneity. Minor changes in 2 mothers of 2 unrelated affected infants reported by Goldstein et al. (1988) suggested dominant inheritance of a Sotos sequence. Brown et al. (1998) described a pair of 5-year-old male monozygotic twins who were discordant for Sotos syndrome. 30 MEDLINE Neighbors

The possibility of uniparental disomy in Sotos syndrome was investigated by Smith et al. (1997). Using 112 dinucleotide repeat DNA polymorphisms, they examined parental inheritance of all autosomal pairs, except chromosome 15, in 29 patients with Sotos syndrome. All informative cases showed biparental inheritance and no cases of UPD were found. 30 MEDLINE Neighbors

HETEROGENEITY

In a study of the metacarpophalangeal pattern profile (MCPP) in Sotos syndrome, Butler et al. (1985) found no evidence of heterogeneity and developed a diagnostic tool using MCPP variables, which they suggested may be useful.

MAPPING

Schrander-Stumpel et al. (1990) described a 6-year-old boy with Sotos syndrome who also had a de novo, apparently balanced translocation, t(3;6)(p21;p21). They suggested that the autosomal dominant gene for the Sotos syndrome may be located either at 3p21 or 6p21. Tsukahara and Kajii (1991) could find no abnormality in high resolution-banded chromosomes from 5 patients. Involvement of genes at 3p21 was also suggested by the case reported by Cole et al. (1992); a 22-year-old female with Sotos syndrome, a nonsmoker, died of small cell lung carcinoma (182280) for which genetic determinants in the 3p21 region are suggested by loss-of-heterozygosity studies. Maroun et al. (1994) reported the case of a 4-year-old girl with Sotos phenotype and a de novo balanced translocation between 5q and 15q: 46,XX,t(5,15)(q35;q22). They thus suggested 5q35 or 15q22 as the site of an autosomal dominant gene determining Sotos syndrome. 30 MEDLINE Neighbors

Faivre et al. (2000) reported a child with apparent Sotos syndrome and mosaicism for partial duplication of the short arm of chromosome 20 (46,XY,dup(20)(p12.1-p11.2)[12]/46,XY[66]). The somatostatin receptor-4 (SSTR4; 182454) gene is located at 20p11.2, encompassed by the duplication. The authors proposed that a dosage effect of this gene might be responsible for some of their patient's clinical findings. 30 MEDLINE Neighbors

Imaizumi et al. (2002) described a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8, 46,XX,t(5;8)(q35;q24.1), in a 15-month-old girl with a typical Sotos syndrome phenotype. They proposed that a gene responsible for this disorder is located in the distal long arm region of chromosome 5. 30 MEDLINE Neighbors

MOLECULAR GENETICS

In patients with Sotos syndrome harboring a chromosomal translocation, Kurotaki et al. (2002) isolated the NSD1 (606681) gene from the 5q35 breakpoint. They identified 1 nonsense, 3 frameshift, and 20 submicroscopic deletion mutations of NSD1 among 42 sporadic cases of Sotos syndrome. The results indicated that haploinsufficiency of NSD1 is the major cause of Sotos syndrome. 30 MEDLINE Neighbors

To the 42 cases of Sotos syndrome reported by Kurotaki et al. (2002), Kurotaki et al. (2003) added 70 more cases, 53 of whom were Japanese. Among the 112 total cases, they identified 50 microdeletions (45%) and 16 point mutations (14%). They noted a large difference between Japanese and non-Japanese patients in the frequency of microdeletions, which occurred in 49 (52%) of the 95 Japanese but in only 1 (6%) of the 17 non-Japanese. Most of the microdeletions were confirmed to be identical by FISH analysis. Kurotaki et al. (2003) identified highly homologous sequences, i.e., possible low copy repeats, in regions flanking proximal and distal breakpoints of the common deletion. This suggested that low copy repeats may mediate the deletion. The frequency of such low copy repeats seemed to vary in different populations, and thus the differences in frequency of microdeletions between Japanese and non-Japanese cases may have been caused by patient selection bias. 30 MEDLINE Neighbors

In a Finnish father and son with Sotos syndrome, Hoglund et al. (2003) identified a heterozygous mutation in the NSD1 gene (606681.0009). The authors noted that the findings in this family confirm that familial Sotos syndrome is caused by mutation in the NSD1 gene.

Beckwith-Wiedemann syndrome (BWS; 130650) is, like Sotos syndrome, an overgrowth syndrome. Deregulation of imprinted growth regulatory genes within the 11p15 region is the major cause of BWS. Similarly, defects of the NSD1 gene account for more than 60% of cases of Sotos syndrome. Owing to the clinical overlap between the 2 syndromes, Baujat et al. (2004) investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and 2 NSD1 mutations (606681.0011-606681.0012) were identified in a series of 52 patients with BWS. The results suggested that the 2 disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the 11p15 region. 30 MEDLINE Neighbors

Turkmen et al. (2003) screened the NSD1 gene for mutations in 20 patients and 1 familial case with Sotos syndrome, 5 patients with Weaver syndrome, 6 patients with unclassified overgrowth and mental retardation, and 6 patients with macrocephaly and mental retardation. They identified 19 mutations, 17 previously undescribed, in 18 Sotos patients and the familial case (90%). The best correlation between the molecular and clinical findings was for facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. Turkmen et al. (2003) found no mutations of the NSD1 gene in the patients with Weaver syndrome or other overgrowth phenotypes and concluded that the great majority of patients with Sotos syndrome have mutations in NSD1. 30 MEDLINE Neighbors

SEE ALSO

Boman and Nilsson (1980); Dodge et al. (1983); Stephenson et al. (1968)

REFERENCES

1. Allanson, J. E.; Cole, T. R. P. :
Sotos syndrome: evolution of facial phenotype subjective and objective assessment. Am. J. Med. Genet. 65: 13-20, 1996.
PubMed ID : 8914735
2. Bale, A. E.; Drum, M. A.; Parry, D. M.; Mulvihill, J. J. :
Familial Sotos syndrome (cerebral gigantism): craniofacial and psychological characteristics. Am. J. Med. Genet. 20: 613-624, 1985.
PubMed ID : 2581446
3. Baujat, G.; Rio, M.; Rossignol, S.; Sanlaville, D.; Lyonnet, S.; Le Merrer, M.; Munnich, A.; Gicquel, C.; Cormier-Daire, V.; Colleaux, L. :
Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am. J. Hum. Genet. 74: 715-720, 2004.
PubMed ID : 14997421
4. Bejar, R. L.; Smith, G. F.; Park, S.; Spellacy, W. N.; Wolfson, S. L.; Nyhan, W. L. :
Cerebral gigantism: concentrations of amino acids in plasma and muscle. J. Pediat. 76: 105-111, 1970.
PubMed ID : 4312004
5. Boman, H.; Nilsson, D. :
Sotos syndrome in two brothers. Clin. Genet. 18: 421-427, 1980.
PubMed ID : 7449180
6. Brown, W. T.; Wisniewski, K. E.; Sudhalter, V.; Keogh, M.; Tsiouris, J.; Miezejeski, C.; Schaefer, G. B. :
Identical twins discordant for Sotos syndrome. Am. J. Med. Genet. 79: 329-333, 1998.
PubMed ID : 9781916
7. Butler, M. G.; Meaney, F. J.; Kittur, S.; Hersh, J. H.; Hornstein, L. :
Metacarpophalangeal pattern profile analysis in Sotos syndrome. Am. J. Med. Genet. 20: 625-629, 1985.
PubMed ID : 3993685
8. Cole, T. R. P.; Hughes, H. E. :
Sotos syndrome: a study of the diagnostic criteria and natural history. J. Med. Genet. 31: 20-32, 1994.
PubMed ID : 7512144
9. Cole, T. R. P.; Hughes, H. E. :
Sotos syndrome. J. Med. Genet. 27: 571-576, 1990.
PubMed ID : 2231650
10. Cole, T. R. P.; Hughes, H. E.; Jeffreys, M. J.; Williams, G. T.; Arnold, M. M. :
Small cell lung carcinoma in a patient with Sotos syndrome: are genes at 3p21 involved in both conditions? J. Med. Genet. 29: 338-341, 1992.
PubMed ID : 1316442
11. Dodge, P. R.; Homes, S. J.; Sotos, J. F. :
Cerebral gigantism. Dev. Med. Child Neurol. 25: 248-252, 1983.
PubMed ID : 6602075
12. Faivre, L.; Viot, G.; Prieur, M.; Turleau, C.; Gosset, P.; Romana, S.; Munnich, A.; Vekemans, M.; Cormier-Daire, V. :
Apparent Sotos syndrome (cerebral gigantism) in a child with Trisomy 20p11.2-p12.1 mosaicism. Am. J. Med. Genet. 91: 273-276, 2000.
PubMed ID : 10766982
13. Fryns, J. P. :
The Prader-Willi syndrome and the Sotos syndrome: syndromes or sequences? (Letter) Clin. Genet. 33: 457-458, 1988.
PubMed ID : 3168318
14. Goldstein, D. J.; Ward, R. E.; Moore, E.; Fremion, A. S.; Wappner, R. S. :
Overgrowth, congenital hypotonia, nystagmus, strabismus, and mental retardation: variant of dominantly inherited Sotos sequence? Am. J. Med. Genet. 29: 783-792, 1988.
PubMed ID : 3400723
15. Gorlin, R. J.; Cohen, M. M.; Levin L. S. :
Overgrowth syndromes and postnatal onset obesity syndromes.In: Syndromes of the Head and Neck. : :New York: Oxford Univ. Press (3rd ed.) 1990. Pp. 323-352.
16. Halal, F. :
Male to male transmission of cerebral gigantism. Am. J. Med. Genet. 12: 411-419, 1982.
PubMed ID : 7124794
17. Halal, F. :
Cerebral gigantism, intestinal polyposis, and pigmentary spotting of the genitalia. (Letter) Am. J. Med. Genet. 15: 161, 1983.
PubMed ID : 6859117
18. Hansen, F. J.; Friis, B. :
Familial occurrence of cerebral gigantism, Sotos' syndrome. Acta Paediat. Scand. 65: 387-389, 1976.
PubMed ID : 1274571
19. Hoglund, P.; Kurotaki, N.; Kytola, S.; Miyake, N.; Somer, M.; Matsumoto, N. :
Familial Sotos syndrome is caused by a novel 1 bp deletion of the NSD1 gene. (Letter) J. Med. Genet. 40: 51-54, 2003.
PubMed ID : 12525543
20. Hooft, C.; Schotte, H.; Van Hooren, G. :
Familial cerebral gigantism. Acta Paediat. Belg. 22: 173-186, 1968.
PubMed ID : 5678746
21. Hook, E. B.; Reynolds, J. W. :
Cerebral gigantism: endocrinological and clinical observations of six patients including a congenital giant, concordant monozygotic twins, and a child who achieved adult gigantic size. J. Pediat. 70: 900-914, 1967.
PubMed ID : 4290694
22. Imaizumi, K.; Kimura, J.; Matsuo, M.; Kurosawa, K.; Masuno, M.; Niikawa, N.; Kuroki, Y. :
Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1). Am. J. Med. Genet. 107: 58-60, 2002.
PubMed ID : 11807869
23. Kaneko, H.; Tsukahara, M.; Tachibana, H.; Kurashige, H.; Kuwano, A.; Kajii, T. :
Congenital heart defects in Sotos sequence. Am. J. Med. Genet. 26: 569-576, 1987.
PubMed ID : 3565472
24. Kurotaki, N.; Harada, N.; Shimokawa, O.; Miyake, N.; Kawame, H.; Uetake, K.; Makita, Y.; Kondoh, T.; Ogata, T.; Hasegawa, T.; Nagai, T.; Ozaki, T.; and 22 others :
Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion. Hum. Mutat. 22: 378-387, 2003.
PubMed ID : 14517949
25. Kurotaki, N.; Imaizumi, K.; Harada, N.; Masuno, M.; Kondoh, T.; Nagai, T.; Ohashi, H.; Naritomi, K.; Tsukahara, M.; Makita, Y.; Sugimoto, T.; Sonoda, T.; and 11 others :
Haploinsufficiency of NSD1 causes Sotos syndrome. Nature Genet. 30: 365-366, 2002.
PubMed ID : 11896389
26. Le Marec, B.; Pasquier, L.; Dugast, C.; Gosselin, M.; Odent, S. :
Gastric carcinoma in Sotos syndrome (cerebral gigantism). Ann. Genet. 42: 113-116, 1999.
PubMed ID : 10434127
27. Leonard, N. J.; Cole, T.; Bhargava, R.; Honore, L. H.; Watt, J. :
Sacrococcygeal teratoma in two cases of Sotos syndrome. (Letter) Am. J. Med. Genet. 95: 182-184, 2000.
PubMed ID : 11078573
28. Maldonado, V.; Gaynon, P. S.; Poznanski, A. K. :
Cerebral gigantism associated with Wilms' tumor. Am. J. Dis. Child. 138: 486-488, 1984.
PubMed ID : 6324572
29. Maroun, C.; Schmerler, S.; Hutcheon, R. G. :
Child with Sotos phenotype and a 5:15 translocation. Am. J. Med. Genet. 50: 291-293, 1994.
PubMed ID : 8042674
30. Nance, M. A.; Neglia, J. P.; Talwar, D.; Berry, S. A. :
Neuroblastoma in a patient with Sotos' syndrome. J. Med. Genet. 27: 130-132, 1990.
PubMed ID : 2319581
31. Nevo, S.; Zeltzer, M.; Benderly, A.; Levy, J. :
Evidence for autosomal recessive inheritance in cerebral gigantism. J. Med. Genet. 11: 158-165, 1974.
PubMed ID : 4841084
32. Noreau, D. R.; Al-Ata, J.; Jutras, L.; Teebi, A. S. :
Congenital heart defects in Sotos syndrome. Am. J. Med. Genet. 79: 327-328, 1998.
PubMed ID : 9781915
33. Opitz, J. M.; Weaver, D. W.; Reynolds, J. F., Jr. :
The syndromes of Sotos and Weaver: reports and review. Am. J. Med. Genet. 79: 294-304, 1998.
PubMed ID : 9781911
34. Robertson, S. P.; Bankier, A. :
Sotos syndrome and cutis laxa. J. Med. Genet. 36: 51-56, 1999.
PubMed ID : 9950366
35. Ruvalcaba, R. H. A.; Myhre, S.; Smith, D. W. :
Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin. Genet. 18: 413-416, 1980.
PubMed ID : 7449178
36. Scarpa, P.; Faggioli, R.; Voghenzi, A. :
Familial Sotos syndrome: longitudinal study of two additional cases. Genet. Counsel. 5: 155-159, 1994.
37. Schaefer, G. B.; Bodensteiner, J. B.; Buehler, B. A.; Lin, A.; Cole, T. R. P. :
The neuroimaging findings in Sotos syndrome. Am. J. Med. Genet. 68: 462-465, 1997.
PubMed ID : 9021022
38. Schrander-Stumpel, C. T. R. M.; Fryns, J. P.; Hamers, G. G. :
Sotos syndrome and de novo balanced autosomal translocation (t(3;6)(p21;p21)). Clin. Genet. 37: 226-229, 1990.
PubMed ID : 2323093
39. Smith, A.; Farrar, J. R.; Silink, M.; Judzewitsch, R. :
Investigations in dominant Sotos syndrome. Ann. Genet. 24: 226-228, 1981.
PubMed ID : 6977303
40. Smith, M.; Fullwood, P.; Qi, Y.; Palmer, S.; Upadhyaya, M.; Cole, T. :
No evidence for uniparental disomy as a common cause of Sotos syndrome. J. Med. Genet. 34: 10-12, 1997.
PubMed ID : 9032642
41. Sotos, J. F.; Dodge, P. R.; Muirhead, D.; Crawford, J. D.; Talbot, N. B. :
Cerebral gigantism in childhood: a syndrome of excessively rapid growth with acromegalic features and a nonprogressive neurologic disorder. New Eng. J. Med. 271: 109-116, 1964.
PubMed ID : 14148233
42. Stephenson, J. N.; Mellinger, R. C.; Manson, G. :
Cerebral gigantism. Pediatrics 41: 130-138, 1968.
PubMed ID : 4169648
43. Tsukahara, M.; Kajii, T. :
High resolution-banded chromosomes from patients with Sotos syndrome. (Letter) Clin. Genet. 39: 313-314, 1991.
PubMed ID : 2070551
44. Turkmen, S.; Gillessen-Kaesbach, G.; Meinecke, P.; Albrecht, B.; Neumann, L. M.; Hesse, V.; Palanduz, S.; Balg, S.; Majewski, F.; Fuchs, S.; Zschieschang, P.; Greiwe, M.; Mennicke, K.; Kreuz, F. R.; Dehmel, H. J.; Rodeck, B.; Kunze, J.; Tinschert, S.; Mundlos, S.; Horn, D. :
Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes. Europ. J. Hum. Genet. 11: 858-865, 2003.
PubMed ID : 14571271
45. Winship, I. M. :
Sotos syndrome--autosomal dominant inheritance substantiated. Clin. Genet. 28: 243-246, 1985.
PubMed ID : 4064361
46. Zonana, J.; Rimoin, D. L.; Fisher, D. A. :
Cerebral gigantism--apparent dominant inheritance. Birth Defects Orig. Art. Ser. XII(6): 63-69, 1976
47. Zonana, J.; Sotos, J. F.; Romshe, C. A.; Fisher, D. A.; Elders, M. J.; Rimoin, D. L. :
Dominant inheritance of cerebral gigantism. J. Pediat. 91: 251-256, 1977.
PubMed ID : 889595
 
OMIM

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

External Links: 

I Have Nevo Syndrome

http://www.experienceproject.com/groups/Have-Nevo-Syndrome/93054

Patient Organizations

http://www.orpha.net/consor/cgi-bin/SupportGroup_Search_Simple.php?lng=EN&LnkId=2453&Typ=Pat

Nevo Syndrome

http://www.rightdiagnosis.com/medical/nevo_syndrome.htm

Nevo Syndrome 

http://www.cags.org.ae/FMPro?-DB=ctga.fp5&-Format=ctga/ctga_detail.html&-RecID=33509&-Find

Patient Organizations

http://www.orpha.net/consor/cgi-bin/SupportGroup_Search_Simple.php?lng=EN&LnkId=2453&Typ=Pat

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

Join us as we work for lymphedema patients everywhere:

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/phpBB3/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

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Children with Lymphedema

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

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

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 Lymphe dema 

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

Lymphedema in Children 

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

Lymphoscintigraphy 

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

Magnetic Resonance Imaging 

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

Extraperitoneal para-aortic lymph node dissection (EPLND) 

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

Axillary node biopsy 

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

Sentinel Node Biopsy 

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

Small Needle Biopsy - Fine Needle Aspiration 

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

Magnetic Resonance Imaging 

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

Lymphedema Gene FOXC2

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

 Lymphedema Gene VEGFC

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

 Lymphedema Gene SOX18

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

 Lymphedema and Pregnancy

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

Home page: Lymphedema People

http://www.lymphedemapeople.com

Page Updated: Jan. 9, 2012