Sotos Syndrome 1

A number sign (#) is used with this entry because Sotos syndrome-1 (SOTOS1) is caused by heterozygous mutation in the NSD1 gene (606681) or by a deletion in the 5q35 region including genomic sequence in addition to the NSD1 gene.

Sotos syndrome-2 (SOTOS2; 614753) is caused by mutation in the NFIX gene (164005) on chromosome 19p13, and SOTOS3 (617169) is caused by mutation in the APC2 gene (612034) on chromosome 19p13.

Weaver syndrome (277590), which shows considerable phenotypic overlap with Sotos syndrome, has been shown to be caused by mutation in the EZH2 gene (601573) on chromosome 7q36.

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.

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 an 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.

Tatton-Brown et al. (2005) reviewed the clinical phenotype of 239 individuals with NSD1 abnormalities and found that facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of individuals; however, both height and head circumference were within the normal range in 10% of individuals, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype: individuals with identical mutations had different phenotypes, all features present in patients with microdeletions were also observed in patients with mutations, and there was no correlation between deletion size and clinical phenotype.

Kotilainen et al. (2009) studied the dental manifestations of Sotos syndrome and found that one or more premolar teeth were absent in 9 (69%) of 13 affected children and adolescents. All of the patients with hypodontia had a heterozygous mutation in the NSD1 gene. The patient with the most severe phenotype of tooth agenesis, involving not only the second premolars and third molars but also 1 mandibular incisor, had a microdeletion encompassing the entire NSD1 gene, whereas the 4 patients with the mildest tooth phenotype included both patients with only missense mutations, suggesting that the severity of tooth agenesis might be related to the type of mutation. More than half of the patients had enamel defects or excessive tooth wear. Dental age, based on tooth formation, was within the normal range.

Fryssira et al. (2010) reported 2 boys with typical features of Sotos syndrome and mutations in the NSD1 gene; 1 patient also had cryptorchidism and vertebral anomalies. The authors noted that despite the wide range of phenotypic features, molecular analysis can correctly identify Sotos syndrome.

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.

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.

Melchior et al. (2005) developed a denaturing high-performance liquid chromatography (DHPLC) screening protocol for mutation detection in NSD1 that achieved an efficiency of mutation detection comparable to that of direct sequencing.

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.

Nomenclature

Fryns (1988) referred to cases of the fragile X syndrome (FXS; 300624) 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. 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.

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. Butler and Meaney (1986) provided an update on the MCPP.

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.

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.

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.

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.

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.

Douglas et al. (2003) evaluated 75 patients with childhood overgrowth for intragenic mutations and large deletions in NSD1. Before molecular analyses, the patients were phenotypically scored into 4 groups: 37 patients comprising group 1 had a phenotype typical of Sotos syndrome; 13 patients comprising group 2 had a Sotos-like phenotype but with some atypical features; 7 patients comprising group 3 had been diagnosed with Weaver syndrome (277590); and 18 patients comprising group 4 had an overgrowth condition that was neither Sotos nor Weaver syndrome. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, as 28 of 37 patients (76%) in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had alterations in NSD1. Three of the 7 patients who had been diagnosed with Weaver syndrome had NSD1 mutations (see 606681.0006). Tatton-Brown et al. (2005) reviewed the phenotype of the 3 patients who carried a diagnosis of Weaver syndrome and in whom Douglas et al. (2003) had identified mutations in the NSD1 gene, and on the basis of multiple pictures at different ages, reclassified 2 of them as having 'typical Sotos syndrome' and the third as 'possible Sotos syndrome.' Tatton-Brown et al. (2005) noted that none of the patients in their series with 'classic' Weaver syndrome had NSD1 mutations, and they concluded that a diagnosis of Weaver syndrome should be given only if the presence of NSD1 abnormalities has been excluded.

Kurotaki et al. (2005) characterized 2 complex mosaic low-copy repeats (LCRs) that are centromeric and telomeric to NSD1, which they designated proximal Sos-REP (Sos-PREP, approximately 390 kb) and distal Sos-REP (Sos-DREP, approximately 429 kb), respectively. Among 8 Sotos patients with a common deletion, an approximately 550-kb junction fragment was detected that was generated by nonallelic homologous recombination between Sos-PREP C and Sos-DREP C-prime subunits. This patient-specific junction fragment was not present in 51 Japanese and non-Japanese controls. Kurotaki et al. (2005) identified a 2.5-kb unequal crossover hotspot region in 6 of 9 analyzed Sotos patients with the common deletion.

Douglas et al. (2005) did not find truncating mutations or gene deletions in NSD2 (602952) and NSD3 (607083) in 78 overgrowth syndrome cases in which NSD1 mutations and deletions had been excluded.

Through analyses of 530 individuals with diverse phenotypes, Tatton-Brown et al. (2005) identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing the NSD1 gene. Of 166 patients with NSD1 abnormalities for whom photographs were available, Sotos syndrome was clinically diagnosed in 164 (99%) independent of the molecular analysis, indicating that NSD1 aberrations are essentially specific to this condition. Analysis of 124 patients from the United Kingdom suggested that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. Tatton-Brown et al. (2005) identified only 13 familial cases and noted that familial cases were more likely than nonfamilial cases to carry missense mutations (p = 0.005), suggesting that the underlying NSD1 mutation mechanism in Sotos syndrome may influence reproductive fitness.

Van Haelst et al. (2005) reported a 3-generation family with gigantism in whom they identified a missense mutation in the NSD1 gene (C2202Y; 606681.0013). Manifestations in this family included dramatically increased height, weight, and head circumference, long face, large mandible, and large ears. All affected members had normal intelligence.

In a female infant with features of both Sotos syndrome and Nevo syndrome (see 225400), Kanemoto et al. (2006) identified heterozygosity for a 2.2-Mb deletion (606681.0001) encompassing the NSD1 gene on chromosome 5. The patient was born with flexion contractures of the hands and feet, muscular hypotonia, and hyperbilirubinemia. Her growth was accelerated, but motor and speech development were delayed. At age 17 months, the patient did not speak and had generalized hypotonia, thoracic kyphosis, dolichocephaly, a narrow high-arched palate, large abnormal low-set ears, webbed neck, volar edema, wrist drop, and spindle-shaped fingers. Echocardiography revealed an atrial septal defect and patent ductus arteriosus. Bilateral hydronephrosis was seen by ultrasound, and voiding cystoureterography revealed bilateral vesicoureteral reflux.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 5q35 deletion was identified in 8 cases and no controls for a p value of 0.026 and a frequency of 1 in 1,969 cases.

Genotype/Phenotype Correlations

Hirai et al. (2011) studied the craniofacial and oral features of 8 Japanese children with Sotos syndrome, including 5 with a submicroscopic deletion at 5q35 and 3 with a mutation in the NSD1 gene. All 8 patients had high palate, excessive tooth wear, and crowding, and all but 1 had hypodontia and deep bite. Hypodontia involved only the second premolars, and there were no differences in the number of missing teeth between patients with the microdeletion or a mutation. Features that were more frequent and more pronounced in patients with the microdeletion included mandibular recession, scissors or posterior crossbite, and small dental arch with labioclination of the maxillary central incisors. Other features seen in a few patients included enamel hypoplasia and ectopic tooth eruption. Hirai et al. (2011) concluded that Sotos syndrome patients should be observed closely for possible dental and oral complications, especially for malocclusion in patients with the microdeletion.