Weaver Syndrome

A number sign (#) is used with this entry because of evidence that Weaver syndrome (WVS) is caused by heterozygous mutation in the EZH2 gene (601573) on chromosome 7q36.

Description

Weaver syndrome comprises pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance, and developmental delay. Most cases are sporadic, although autosomal dominant inheritance has been reported. Although there is phenotypic overlap between Weaver syndrome and Sotos syndrome (117550), distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand in Weaver syndrome, whereas in Sotos syndrome carpal bone development is at or behind that of the rest of the hand (summary by Basel-Vanagaite, 2010).

The 'Weaver-like' syndrome reported by Stoll et al. (1985) in a mother and son may be a separate entity.

Sotos syndrome (117550), which shows considerable phenotypic overlap with Weaver syndrome, is caused by mutation in the NSD1 gene (601573) on chromosome 5q35.

Clinical Features

Weaver et al. (1974) described 2 'strikingly similar' unrelated male infants who had accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Dysmorphic facial features included large bifrontal diameter, flat occiput, large ears, ocular hypertelorism, long philtrum, and relative micrognathia. Reports by Gemme et al. (1980), Weisswichert et al. (1981), Hall (1985), and Ardinger et al. (1986) suggested that the Weaver syndrome (also called the Weaver-Smith syndrome) is a distinct entity. Other features included psychomotor delay, looseness of skin, and hernias.

Roussounis and Crawford (1983) reported affected sibs. However, Cole et al. (1992) reported on a follow-up of the surviving sib; chromosome analysis showed a 46,XX,5p- karyotype, indicating that this recognized chromosomal syndrome was the likely diagnosis.

Dawood (1985) reported a patient whose case was also pictured by Beighton (1988). The child weighed 10.2 kg at birth and had large ears, long philtrum, and protuberant lower lip, as well as an umbilical hernia and excessive skin folds. At the age of 14 months, he weighed 30 kg, and progressive thoracolumbar kyphosis associated with platyspondyly and vertebral wedging had developed.

Teebi et al. (1989) noted that most of the approximately 21 cases reported after the original article by Weaver et al. (1974) were sporadic, and that because the diagnosis in all cases has not been considered completely certain (see Fitch, 1985), it was difficult to draw any definite conclusions about a possible genetic basis. Teebi et al. (1989) described a brother and sister, born to consanguineous Bedouin parents, who manifested features resembling those of Weaver syndrome. Both had accelerated growth of prenatal onset, hypotonia, psychomotor retardation, excess loose skin, peculiar craniofacial and acral anomalies, dental dysplasia and/or serrated gums, joint laxity, and hoarse, low-pitched cry. One of them had accelerated harmonic skeletal maturation. The acral anomalies included short fifth digit with clinodactyly V. However, Cole et al. (1992) questioned that either case reported by Teebi et al. (1989) had the Weaver-Smith (WSS) syndrome. The younger sib did not exhibit accelerated growth and had delayed bone maturation at the age of 13 months.

Greenberg et al. (1989) described a patient with presumed Weaver syndrome who was followed for more than 20 years. At the age of 25, her height (187 cm), as well as her weight and head circumference, was above the 98th centile.

Cole et al. (1992) presented the details of 4 new cases of Weaver-Smith syndrome and reviewed the published reports. They suggested that in the early years of life the facial features are characteristic; despite retrognathia, the chin is distinctive and may be dimpled. Bone age is advanced. Cole et al. (1992) pointed out that WSS may be difficult to differentiate from Sotos syndrome (117550), but early photographs may be distinguishing because there is likely to be a longer face and jaw in Sotos syndrome than in WSS.

Dumic et al. (1993) described unlike-sex twins with this disorder, thought to be in classic form, and their mildly affected mother. They suggested autosomal dominant inheritance. The twins showed overgrowth, macrocephaly, and unusual facial features. The mother showed macrocephaly, long philtrum, hoarse voice, large ears, and hyperextensibility of the fingers--all features found in both twins. All 3 showed palmar and plantar hyperhidrosis, and the twins showed nail dysplasia. Fryer et al. (1997) questioned the certainty of the diagnosis in the cases described by Dumic et al. (1993), but provided further evidence for autosomal dominant inheritance by describing an affected father and daughter. The daughter had accelerated growth, advanced bone age, characteristic facial features, flat, deep-set nails, and developmental delay. The father had had accelerated growth in childhood and exhibited macrocephaly, large hands, deep-set nails, and facial features similar to those of his daughter.

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.

Proud et al. (1998) noted that although there had been 3 reports of close relatives (sibs or both parent and offspring) affected with Weaver syndrome, the disorder generally occurs sporadically, and the recurrence risk in sporadic cases appears to be low. Proud et al. (1998) reported a family in which the propositus and his sister were born with the facial phenotype, clubfeet, and macrosomia characteristic of Weaver syndrome. Their father had macrosomia and macrocephaly as an adult, and childhood photos showed clearly that he had Weaver syndrome. Two sisters of the propositus had normal growth and development. Proud et al. (1998) advanced this family as an example of autosomal dominant inheritance. The father was 193 cm tall and weighed 124.1 kg. The occipital-frontal circumference was 62.8 cm (+5 SD). The hands measured large. At birth the propositus was noted to have macrocephaly, ocular hypertelorism, downslanting palpebral fissures, micrognathia, finger contractures, and dislocated left hip in addition to bilateral talipes equinovarus.

Freeman et al. (1999) described pachygyria in an infant thought to have Weaver syndrome.

Derry et al. (1999) reported a mother and son with probable Weaver syndrome. The mother had developed an ovarian endodermal sinus tumor at the age of 17 years. Derry et al. (1999) pointed out the association of other overgrowth syndromes with neoplasia.

Kelly et al. (2000) described half brothers with Weaver syndrome whose father had essentially normal physical findings apart from tall stature, but who, like his sons, had cervical spine anomalies. Although these anomalies are variable, they may represent a consistent radiographic finding in Weaver syndrome that can aid in the diagnosis of affected adults. One of the brothers had a sacrococcygeal teratoma that was resected at birth; the authors stated that he represented the third reported patient with Weaver syndrome and neoplasia.

Basel-Vanagaite (2010) described a 4.5-year-old girl with 'typical' Weaver syndrome, born of nonconsanguineous Jewish parents, who developed acute lymphoblastic leukemia. She exhibited speech and motor delays, with relatively normal cognitive abilities, and had a hoarse voice. Examination revealed somewhat sparse hair, broad forehead, broad straight eyebrows, hypertelorism, prominent wide philtrum, wide cupid bow, mild micrognathia, broad face and neck, fleshy earlobes, sloping shoulders, broad thumbs, deep-set and narrow nails, loose palmar skin, and mild hypertrichosis. Her hands and feet were large, and she had mild scoliosis and joint hyperlaxity. Neurologic, eye, and hearing findings were normal. At the chronologic age of 4.3 years, carpal bone age was compatible with 7.8 years, whereas the distal radial and ulnar epiphyses were compatible with a bone age of 5.75 years. At 4.3 years of age, evaluation of severe back pain with vertebral changes resulted in a diagnosis of acute lymphoblastic leukemia. Microarray analysis and sequencing of the NSD1 gene (601573) were negative. Basel-Vanagaite (2010) stated that tumors or hematologic malignancy in Weaver syndrome had previously been reported in 6 patients, for an overall frequency of approximately 11%, but noted that this was likely to be an overestimate, biased by failure to report cases without tumors and overreporting of cases with this rare association.

Gibson et al. (2012) provided follow-up on 'patient 1,' the 18-month-old male infant originally reported by Weaver et al. (1974), then 30 years of age, and described 2 additional unrelated patients with Weaver syndrome, an 11-year-old girl and a 19-year-old woman. Features shared by all 3 patients included excessive growth of prenatal onset, accelerated osseous maturation, hoarse low-pitched cry, mild intellectual disability, poor fine motor coordination, poor balance and gravitational insecurity, macrocephaly, large bifrontal diameter, large ears, downslanting palpebral fissures, long philtrum, retrognathia, prominent digit pads, thin deep-set nails, umbilical hernia, and 10- to 20-degree scoliosis.

Diagnosis

There has been considerable debate whether Sotos and Weaver syndromes are representative of locus or allelic heterogeneity (Cole, 1998; Opitz et al., 1998). The facial appearance is somewhat similar in the 2 disorders, but experienced dysmorphologists believe they are distinct. Clinical features occurring in Weaver syndrome include a hoarse low-pitched cry, metaphyseal flaring of the femurs, deep-set nails, prominent fingertip pads, and camptodactyly.

Opitz et al. (1998) discussed the differentiation of the 2 overgrowth syndromes, that of Sotos and that of Weaver, and the question of whether the similarities are sufficient to consider them 1 entity. Possible phenotypic differences between the 2 syndromes 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.

Gibson et al. (2012) stated that features distinguishing Weaver syndrome from Sotos syndrome include retrognathia with a prominent chin crease, sometimes described as a 'stuck-on chin,' increased prenatal growth, and a carpal bone age that is greatly advanced compared to metacarpal and phalangeal age.

Molecular Genetics

Gibson et al. (2012) performed exome sequencing in 2 unrelated patients with Weaver syndrome, including 1 of the patients originally described by Weaver et al. (1974), and their 4 unaffected parents. In both patients, heterozygous de novo mutations were identified in the EZH2 gene (Y153del, 601573.0001 and H694Y, 601573.0002, respectively); the presence of the mutations and their de novo status were confirmed by Sanger sequencing. Sequencing of EZH2 in a third patient with Weaver syndrome revealed heterozygosity for another de novo missense mutation (P132S; 601573.0003). Gibson et al. (2012) noted that a somatic mutation at his694 had previously been found in chronic myelomonocytic leukemia (see 252270), as well as mutations in nearby residues at positions 690 and 693 in other hematologic malignancies (Makishima et al., 2010). Given that patients with Weaver syndrome had been reported to develop tumors or malignancies, including acute lymphoblastic leukemia, Gibson et al. (2012) suggested that constitutive EZH2 mutations might confer a mild predisposition to malignancy.