Weaver syndrome (ORPHA:3447)
Weaver syndrome (WVS) is a rare, multisystem disorder characterized by tall stature, a typical facial appearance (hypertelorism, retrognathia) and variable intellectual disability. Additional features may include camptodactyly, soft doughy skin, umbilical hernia, and a low hoarse cry.
Epidemiology
Around 50 cases of Weaver syndrome have been reported to date. Precise prevalence and incidence rates are not available.
Clinical description
WVS is an overgrowth disorder that covers a very wide clinical spectrum: some affected individuals have only tall stature while others have a classic Weaver clinical picture. Tall stature (≥ two standard deviations above the mean) is found in 90% of mutation-positive individuals and most affected patients have higher than normal birth weight and length. The subtle but characteristic facial appearance is most easily recognized in early childhood when there is ocular hypertelorism, large fleshy ears and retrognathia with the appearance of a ''stuck-on'' chin with associated horizontal skin crease. About 80% of patients have mild intellectual disability. A smaller number have moderate intellectual disability with a greater impact on autonomy, while severe deficits are rare. Other variable features include macrocephaly, joint laxity, mild to severe scoliosis, pectus excavatum, hypo- and/or hypertonia, poor coordination, soft skin, clinodactyly, camptodactyly of the fingers and/or toes, umbilical hernia, and a hoarse low cry in infancy. A slightly higher risk of neuroblastoma is suspected. There is currently no data to support an increased risk of other malignancies.
Etiology
WVS is caused by mutations in the EZH2 gene (7q35-q36), a histone methyltransferase involved in transcription control. Currently there are no other known causes of WVS although there has been a single case report of an individual in whom there was a clinical suspicion of WVS and a mutation within EED, which complexes with EZH2.
Diagnostic methods
The clinical suspicion of WVS is confirmed through molecular genetic testing and the identification of a heterozygous germline mutation in EZH2. Given the subtle phenotype associated with WVS, if a germline EZH2 mutation is not identified, alternative diagnoses should be sought.
Differential diagnosis
The main differential diagnosis is Sotos syndrome (see this term) which has considerable overlap with WVS. Other disorders to consider include Beckwith-Wiedemann, Simpson-Golabi-Behmel, Malan overgrowth, tall stature-intellectual disability-facial dysmorphism and Marfan syndromes (see these terms).
Antenatal diagnosis
Prenatal diagnosis in at-risk pregnancies is possible.
Genetic counseling
WVS follows an autosomal dominant pattern of inheritance although the majority of cases to date have arisen de novo. Genetic counseling should be provided to affected families.
Management and treatment
There is no specific treatment for WVS although individual symptom management may be indicated. No specific tumor surveillance is currently recommended but clinical vigilance and early investigation for possible tumor (particularly neuroblastoma)-related symptoms are recommended.
Prognosis
With suitable treatment and support, patients with WVS have a normal life.

                            Last update: 
                            January 2016


                            - Expert reviewer(s): 
                            Dr Katrina TATTON BROWN