Definition

Weaver syndrome (OMIM #277590) is a genetic disease caused by mutations in the EZH2 gene. It is characterized by macrosomia, characteristic facies, and variable intellectual impairment.

Key Data

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Synonym EZH2-associated macrosomia
Gene EZH2
Gene product EZH2
Function Histone methyltransferase which functions as a transcription factor
Heredity Autosomal dominant
Prevalence Unknown
Genotype-phenotype correlation None known
Penetrance Incomplete
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Diagnosis

Suspected Diagnosis

Clinical

Weaver syndrome is suspected when the following findings apply:

  • Macrosomia (≥ 97th percentile)

  • Macrocephaly (≥ 97th percentile)

  • Intellectual impairment

  • Characteristic facies:

    • Retrognathia (especially in children < 3 years of age)
    • Large, low-lying ears (especially in children < 3 years of age)
    • Horizontal chin fold, sometimes with a central dimple (especially in children < 3 years of age)
    • Round face (especially in children)
    • Broad forehead
    • Hypertelorism
    • Almond-shaped eyes
  • Lack of coordination

  • Soft and pasty skin

  • Camptodactyly of the fingers and/or toes

  • Umbilical hernia

  • Abnormal muscle tone (central hypotonia and/or peripheral hypertonia)

  • Rough and deep-sounding cries in infants

Radiological

  • Advanced bone age

  • Neuronal migration disorder determined by cranial MRI

Genetic Diagnostics

The diagnosis of “Weaver syndrome” is confirmed by detecting a heterozygous germline mutation in the EZH2 gene through sequence analysis or deletion/duplication analysis. The use of panel examinations including multiple genes may be useful.

Differential Diagnoses

Clinical Presentation

  • Macrosomia (≥ 97th percentile): in nearly all patients

  • Macrocephaly (≥ 97th percentile): in approximately 50% of patients

  • Intellectual impairment: There is usually mild to moderate developmental delay, which may be apparent in speech and as a learning disability. There is considerable overall variability, ranging from normal intellectual development to severe mental retardation.

  • Characteristic facies (see suspected diagnosis)

  • Skeletal manifestations: advanced bone age, scoliosis, camptodactyly, Boutonnière deformity, clubfoot

  • Connective tissue manifestations: soft and pasty skin, hypermobility of the joints, pes planus, umbilical hernia

  • Abnormal muscle tone: Central hypotonia and/or peripheral hypertonia

  • Feeding problems in newborns

  • Rough and deep-sounding cries in infants

  • Neuronal migration disorder determined by cranial MRI

  • Tumors: To date, there are reports on one patient with Non-Hodgkin lymphoma, one patient with neuroblastoma and acute lymphatic leukemia (ALL), and one other patient with neuroblastoma.

Therapeutic Considerations

In light of the large number of potential manifestations, treatment should always be symptom-oriented and interdisciplinary, with involvement of the corresponding specialist disciplines.

Patients with developmental delay and/or a learning disability may benefit from educational, behavioral, and/or speech therapy.

Long-term physical therapy can also help to delay operations and reduce pain.

Surveillance Recommendations

Surveillance Recommendations

There are no standard surveillance recommendations to date. Patients with Weaver syndrome should undergo regular examinations, particularly with regard to cognitive and speech development, camptodactyly, and muscular hypotonia. If no complications are clinically evident, the examination interval can be lengthened starting in adolescence.

If there is scoliosis, care should be provided in line with orthopedic recommendations.

If any additional abnormalities are detected, other examinations should be conducted as needed and the patient should be referred to specialists.

Patients should be made aware of a potentially increased risk of neuroblastoma. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with Weaver Syndrome that we can recommend to you for more information.

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with Weaver Syndrome. We will add new information as it becomes available.