Cerebral gigantism nevo type, Sotos Syndrome
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)
Treatment might include surgery for the physical anomolies, therapy for the motor development complications and the establishment of a lymphedema mangement program.
June 8, 2008
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.
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.
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.
McKusick - updated : 3/20/1998
Michael J. Wright - updated : 7/3/1997
Iosif W. Lurie : 9/26/1996
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
............................Further delineation of Nevo syndrome.
D I S E A S E : Nevo syndrome
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)*.
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)
Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome?
Department of Pediatrics, Ibaraki Seinan Medical Center Hospital, Sakai 2190, Sashima, Ibaraki 306-0433, Japan. email@example.com
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.
Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA).
Am J Med Genet A. 2005 Mar
Division of Metabolism & Molecular Pediatrics, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
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. , 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.
Alternative titles; symbolsCEREBRAL GIGANTISMGene map locus 5q35
A number sign (#) is used with this entry because Sotos syndrome is caused by mutation in the NSD1 gene (606681).
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.
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.
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).
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%.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)/46,XY). 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.
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.
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.
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.
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.
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.
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