What is Weaver syndrome?

The Weaver's syndromealso called syndrome Weaver-Smithis an extremely rare genetic syndrome characterized by skeletal abnormalitiessome typical facial features and a intellectual disability moderate to severe.

It was first described by David Weaver in 1974 and is very similar to Sotos syndrome. It is one of the rarest syndromes known, there are hardly any described 50 cases in the medical literature and a prevalence of less than 1/1,000,000 is estimated, although there are no precise data.

Symptoms and description

Weaver syndrome is usually classified as a overgrowth disorder. Its most typical characteristic is that bones grow more than normalboth in speed and size.

Bone overgrowth causes considerably higher height to the average, but also accompanied by a premature bone aging.

Other common characteristics, although not all of them are always present, are macrocephaly with flattened occipital bone, eyes widely separated (hypertelorism), epicanthal folds and strabismus.

The ears may be long and set low, and the jaw may be set back (retrognathia or short jaw). The tone of the voice can be low and the mouth small with a long nasolabial fold.

Loose skin, fine hair, short ribs, and limited extension of some joints, including the interphalangeal joints (camptodactyly), shoulders, and knees, may also occur.

It is common delayed development of motor skills such as sitting, standing, or walking, along with poor coordination.

Also typical is a delay in variable intellectual development which can become severe, behavioral problems and neurological conditions such as speech delay, hypotonia and hypertonia.

Causes

The cause of Weaver syndrome is a genetic mutationthe most frequently identified being the mutation of the EZH2 gene (from the English Enhancer of zeste homolog 2). This gene, located on chromosome 7, codes for the enzyme histone-lysine methyltransferase EZH2.

EZH2 represses gene transcription and is key in the regulation of gene expression. It forms the catalytic component of PRC2 (Polycomb Repressive Complex 2) that catalyzes DNA methylation and facilitates the formation of heterochromatin, the conformation of DNA in which transcription not possible.

EZH2 also plays a critical role in cell differentiation, affecting, among others, embryonic development, osteogenesis, myogenesis, lymphogenesis, and hematopoiesis.

In some cases, mutations have been observed in the NSD1 geneon chromosome 5. The function of this gene is not well understood but it also appears to influence transcription.

Mutation of the NSD1 gene is the main cause of Sotos syndromewith symptoms very similar to Weaver syndrome, but is very rare in other overgrowth syndromestwo.

inheritance pattern

Weaver syndrome has a pattern of inheritance autosomal dominantwhich means that the mutation of one of the two copies of the gene in each cell is enough to cause the disease.

Most cases occur in people no family historywhich indicates that it is due to new mutations during the formation of gametes or during embryonic development, and no to inherited mutationsalthough patients with Weaver syndrome would transmit the mutation to 100% of their offspring.

New dominant mutation
Dominant new mutation pattern

Diagnosis and treatment

Differential diagnosis requires genetic testing for mutations in the EZH2 gene, usually by PCR amplification.

Disease management has a multidisciplinary approach that includes, among others, neurology, pediatrics, orthopedics, physiotherapy and occupational therapy. Speech therapy is also usually recommended.

There is no cure for Weaver syndrome, but with proper management, patients with Weaver syndrome can have an acceptable quality of life and normal life expectancy.

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