Weaver syndrome (WVS)

What is Weaver syndrome (WVS)?

Weaver syndrome is characterized by excessive physical growth in an individual, this rapid osseous growth usually starts prenatally.

Males have been found to be three times more likely to be affected by the syndrome than females.

Syndrome Synonyms:
Weaver-smith Syndrome; Wss

What gene changes cause Weaver syndrome (WVS)?

It is caused by mutations in the EXH2 gene, and though most mutations are are mutations, it can also be inherited in an autosomal dominant pattern.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

What are the main symptoms of Weaver syndrome (WVS)?

Rapid growth is the main symptom. This may include a tall head, but not in every case. Faster bone development is part of this rapid growth.

Other physical features include increased muscle tone, exaggerated reflexes, and the slower development of voluntary movements.

Babies with the syndrome have a distinct, hoarse, low pitched cry.

Unique facial features of the syndrome include very wide set eyes, eye folds, a flat back of the head, thin hair, a broad forehead, very large ears, a smaller jaw, broad thumbs, bent fingers, a very high arch, malformed toes and a clubfoot.

Possible clinical traits/features:
Behavioral abnormality, Calcaneovalgus deformity, Broad thumb, Broad foot, Accelerated skeletal maturation, Absent septum pellucidum, Abnormally low-pitched voice, Abnormality of thumb phalanx, Abnormal fingernail morphology, Broad forehead, Hernia of the abdominal wall, Hydrocele testis, Delayed speech and language development, Depressed nasal bridge, Global developmental delay, Cognitive impairment, Kyphosis, Hypertelorism, Hypertonia, Hypoplasia of penis, Hypoplastic toenails, Short ribs, Hypoplastic iliac wing, Joint contracture of the hand, Joint hypermobility, Large hands, Macrotia, Limited elbow extension, Limited knee extension, Mandibular prognathia, Micrognathia, Metatarsus adductus, Low-set, posteriorly rotated ears, Long philtrum, Muscular hypotonia, Tall stature, Inverted nipples, Inguinal hernia, Intellectual disability, Deep philtrum, Limitation of joint mobility, Finger syndactyly, Fine hair, Flared humeral metaphysis, Flared femoral metaphysis, Cryptorchidism, Coxa valga, Cutis laxa, Dilation

How does someone get tested for Weaver syndrome (WVS)?

The initial testing for Weaver syndrome (WVS) can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Weaver syndrome

There have been about twenty cases of this overgrowth syndrome reported in the literature. Most patients are large at birth, but overgrowth may not be apparent until a few months of age. In addition to the large size, the bone age is significantly advanced. Final adult height has been reported to be large in one patient, but others have shown deceleration of growth in childhood. Voorhoeve et al., (2002) point out that standard height prediction from bone age may not necessarily predict final height accurately. The face may be distinctive with a broad forehead, large ears, hypertelorism, micrognathia (but with a prominent, dimpled chin) and a long philtrum. There might be a positional deformity of the elbows and knees with limitation of extension, as well as camptodactyly. The thumbs may be broad and prominent volar (fingertip) pads are seen. A general connective tissue abnormality is suggested by loose skin and hernias. An important additional feature is flaring of the metaphyses. Development is usually mildly delayed but can be normal. The condition is well reviewed by Cole et al., (1992). Ramos-Arroyo (1991) reported a case with severe retardation where overgrowth was only evident after 11 months when feeding difficulties in infancy were resolved. Imaging studies of the brain have shown a variety of disorders including cysts in the septum pellucidum, non-specific cerebral atrophy and pachygyria (Freeman et al., 1999).
Although reports of possible autosomal recessive or autosomal dominant inheritance have been reported (Roussounis and Crawford, 1983; Dumic et al., 1993), the actual diagnosis in these cases is open to debate. Cole et al., (1992) report that the surviving sib reported by Roussounis and Crawford (1983) has a 5p- karyotype. The mother and son reported by Nishimura et al., (1996) are also doubtfully affected. Likewise the suggestion of dominant inheritance in case one of Ardinger et al., (1986) and case two of Majewski et al., (1981) must be considered with caution. Fryer et al., (1997) reported a possibly affected father and daughter, although convincing early infant photographs were not published. However, Proud et al., (1998) reported a convincingly affected father and two children. Derry et al., (1999) reported a possibly affected boy whose mother had mild features of the condition. The mother had a ovarian endodermal sinus tumour in her teenage years. Kelly et al., (2000) reported two male half-sibs with some features of the condition. The father was tall but otherwise did not have features of Weaver syndrome. One brother had a sacrococcygeal teratoma. Both children had a cervical kyphosis with underdevelopment of the mid-cervical vertebral bodies. Huffman et al., (2001) reported a boy with Weaver syndrome who had a neuroblastoma associated with a VSD and PDA.
Scarano et al., (1996) reported a male with features of the condition, however he was severely mentally retarded and x-rays showed demineralisation of the bones of the hands and feet.
Van Asperen et al., (1998) reported a mother and son with NF1 who both had an overgrowth syndrome resembling Weaver syndrome. They were shown to have a large deletion of 17q11.2 encompassing the entire NF1 gene. Three similar patients with overgrowth, advanced bone age, and facial features resembling Weaver syndrome were reported by Spiegel et al., (2005).
Douglas et al., (2003) studied 7 patients with Weaver syndrome and found NSD1 mutations in 3. Tatton-Brown et al., (2005) re-evaluated these patients and concluded that 2 definitively had classical Sotos syndrome, and 1 had possible Sotos syndrome. These were all situated between amino acids 2142 and 2184. There is an excellent review by Tatton-Brown et al., (2013)
Rio et al., (2003) found NSD1 mutation in 3 out of 6 Weaver syndrome cases. Turkmen et al., (2003) studied 5 patients but found no NSD1 mutations. Mutations in EZH2 were identified by Gibson et al., (2011).
Cooney et al. (2016) described a third patient, a female with Weaver syndrome and heterozygous mutation in EED. The patient was large for gestational age. Dysmorphic features at birth included bilateral cleft palate, posterior ear pits, capillary hemangioma of the back, and umbilical hernia. She had nephromegaly and a duplicated collecting system. She also had tracheomalacia. Brain MRI at age two years showed white matter volume loss and thinning of the corpus callosum. She had advanced bone age. At age 14 years, she underwent cervical laminectomy with arthrodesis for cervical spine stenosis. Skeletal survey showed small iliac wings, coxa valga, wide metaphyses, and osteopenia. She had multiple musculoskeletal problems including hernias, poor wound healing, recurrent dislocation of the patellae, pes planovalgus, and camptodactyly. She was diagnosed with an atrial septal defect and mitral regurgitation. She had conductive hearing loss. Eye abnormalities included exotropia, astigmatism, and bilateral ptosis. Intellectual disability was moderate. Her speech was horse and hypernasal. At 16 years of age she showed overgrowth. Her clinical features included a broad face with short forehead and relative depression of the supraorbital ridges, low set ears with posterior helical pits, ear lobe creases, thick eyebrows, hypertelorism, down slanting almond-shaped palpebral fissures, wide and depressed nasal bridge, broad neck, narrow and sloping shoulders. The patient had long, broad palms, long fingers, broad thumbs, camptodactyly, small nails, joint laxity and soft, doughy skin. The authors compared the characteristics of the patient to the previously described cases with EED mutations and EZH2 mutations. Advanced osseous maturation has been described in all patients with EZH2 and EED mutations. Broad metaphyses were not always present in patients with EZH2 mutations but were found in all EED patients. Excessive postnatal growth has been described in 91% of EZH2 patients, and in all EED cases. Developmental delay was present in 82% patients with EZH2 mutations and in all patients with EED mutations. Macrocephaly was present in 46% of EZH2 and in all EED cases.

* This information is courtesy of the L M D.
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