What is the management and treatment approach for Weavers syndrome?

Management and Treatment of Weaver Syndrome

Surveillance for Malignancy Risk

Clinical vigilance and prompt workup of potential tumor-related symptoms, especially for neuroblastoma, are essential in Weaver syndrome, though routine tumor surveillance is not currently recommended. 1

The cancer risk in Weaver syndrome appears slightly elevated but remains incompletely defined. Specific malignancies reported include:

• Neuroblastoma - The most concerning malignancy, with cases documented at ages 4 years and 13 months 1
• Acute lymphoblastic leukemia - Reported in at least one mutation-positive individual at 13 months 1
• Lymphoma - Documented in one EZH2 mutation-positive patient at age 13 years 1

Practical Surveillance Approach

While formal screening protocols are not established, clinicians should:

• Maintain heightened awareness for symptoms suggesting neuroblastoma (abdominal mass, bone pain, periorbital ecchymosis, unexplained fever) 1
• Investigate any concerning symptoms promptly with appropriate imaging and laboratory studies 1
• Avoid routine urinary VMA/HVA screening, as false positive rates may be problematic 1
• Consider discussing chest X-ray surveillance with families as an optional tool for neuroblastoma detection, though this is not part of standard recommendations 1

The absolute cancer risk remains too small to calculate definitive screening protocols, but the numbers are sufficient to warrant clinical vigilance. 1

Growth Management

Tall stature is the most consistent feature of Weaver syndrome, present in >90% of affected individuals, and typically requires monitoring rather than intervention. 2

Growth Pattern Characteristics

• Birth parameters: Often show length above the 97th percentile (birth length SDS commonly +2 to +3) with normal or slightly reduced birth weight 3
• Postnatal growth: Height typically tracks parallel to or above the 97th percentile throughout childhood 3
• Height SDS exceeds target height SDS - A key diagnostic clue distinguishing syndromic from familial tall stature 3
• Advanced bone age is characteristic and should be monitored 1, 2

Growth Monitoring Protocol

• Plot growth on standard curves at each visit, comparing to parental target height 3
• Obtain bone age radiographs periodically to track skeletal maturation 1, 2
• Avoid unnecessary endocrine investigations when growth pattern is consistent with Weaver syndrome 3
• Reassure families that growth typically follows a predictable pattern without pathological acceleration 3

Developmental and Neurological Management

Intellectual disability affects approximately 80% of individuals with Weaver syndrome but is highly variable and frequently mild, requiring individualized educational and therapeutic support. 2

Developmental Assessment and Intervention

• Early intervention services should be initiated promptly when developmental delays are identified 2
• Cognitive assessment is recommended to establish baseline function and guide educational planning 2
• Speech and language therapy may be beneficial, particularly given the characteristic low, hoarse cry 2
• Occupational therapy can address motor coordination difficulties and camptodactyly 2

Educational Planning

• Intellectual disability ranges from mild to moderate, necessitating individualized education plans 2
• Regular developmental reassessment helps adjust support services as the child matures 2

Orthopedic Management

Camptodactyly and joint contractures are common features requiring orthopedic evaluation and potential intervention. 1, 2

Musculoskeletal Manifestations

• Camptodactyly (fixed flexion of fingers, typically the fifth digit) is a characteristic finding 1, 3, 2
• Club feet may be present at birth and require early orthopedic consultation 4
• Poor coordination is frequently reported and may benefit from physical therapy 1
• Hyper- or hypotonia can affect motor development 1

Orthopedic Intervention Strategy

• Evaluate camptodactyly severity and functional impact at diagnosis 2
• Consider splinting or surgical release for functionally limiting contractures 2
• Provide physical therapy for coordination difficulties and tone abnormalities 1
• Monitor for progressive skeletal abnormalities given advanced bone age 1

Genetic Counseling and Family Management

Weaver syndrome demonstrates autosomal dominant inheritance, requiring genetic counseling for affected families regarding recurrence risk and testing of relatives. 4, 5, 2

Molecular Diagnosis

• EZH2 mutations are the primary cause, with mutations occurring throughout the gene but clustering in the SET domain 5, 2
• EED mutations represent a second genetic cause, establishing locus heterogeneity 5
• Missense mutations are most common (44/48 cases), while truncating mutations are rare and limited to the final exon 2

Genetic Testing Strategy

• Obtain whole exome sequencing when clinical features suggest Weaver syndrome but diagnosis is uncertain 3, 5
• Re-analyze negative exome data as new gene-disease associations emerge, as EED was identified through this approach 5
• Test apparently unaffected parents, as subtle manifestations (macrosomia, macrocephaly) may represent mild expression 4

Family Counseling Points

• Recurrence risk is 50% for affected individuals 4
• Sporadic cases predominate, but familial cases demonstrate clear autosomal dominant transmission 4
• Phenotypic variability is substantial, even within families 4, 2
• Reproductive options include prenatal diagnosis and preimplantation genetic testing 5

Differential Diagnosis Considerations

Considerable phenotypic overlap exists between Weaver and Sotos syndromes, making molecular confirmation valuable for distinguishing these conditions. 1, 2

Distinguishing Features

• Sotos syndrome (NSD1 mutations) shares tall stature, advanced bone age, and developmental delay 1
• Weaver syndrome more commonly features camptodactyly, soft doughy skin, and umbilical hernia 2
• Facial features can be subtle in both conditions, particularly in older individuals 2
• Molecular testing provides objective distinction when clinical features overlap 2

Multisystem Monitoring

Dermatologic Features

• Soft, doughy skin is characteristic and requires no specific intervention 1, 2
• Document this finding as it aids diagnostic confirmation 2

Abdominal Wall Defects

• Umbilical hernia is common and may require surgical repair if persistent or symptomatic 1, 2
• Evaluate at each visit during infancy and early childhood 2

Craniofacial and Oral Manifestations

• Bifid uvula has been documented and should be assessed during oral examination 6
• Macroglossia may be present and can affect speech and feeding 6
• Malocclusion and maxillary atresia are common, requiring orthodontic evaluation 6
• Micrognathia may be mild but should be documented 6
• Dental care under general anesthesia may be necessary given intellectual disability and behavioral challenges 6

Voice Characteristics

• Low, hoarse cry in infancy is a helpful diagnostic clue 1, 2
• Voice quality should be documented as part of the clinical phenotype 2

Long-term Prognosis and Natural History

The natural course of Weaver syndrome involves stabilization of growth velocity in adolescence, with adult height typically very tall but proportionate. 3, 2

• Growth rate normalizes after initial rapid growth phase, tracking parallel to growth curves 3
• Intellectual disability remains stable but may become more apparent with increasing academic demands 2
• Cancer risk appears concentrated in childhood, particularly for neuroblastoma 1
• Life expectancy data are limited but no specific life-limiting features have been identified beyond malignancy risk 1, 2