Weaver syndrome
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A 3-year-old has tall stature (well above the 97th percentile), macrocephaly, and a broad forehead with hypertelorism, large ears, and a small chin. The fingers stay flexed at rest (camptodactyly). Bone age is advanced by several years. Development is mildly delayed.
- EZH2 (chromosome 7q36), the catalytic subunit of the PRC2 polycomb repressive complex
- Autosomal dominant
- Most cases de novo
- Predominantly missense variants clustered in or near the catalytic SET domain (the precise functional consequence is debated)
- Pre- and postnatal overgrowth, tall stature
- Macrocephaly with broad forehead and prominent occiput
- Hypertelorism, large/low-set ears, retrognathia (small lower jaw), almond-shaped eyes
- Camptodactyly of fingers; deep-set nails; broad thumbs in some
- Advanced bone age (often by several years)
- Intellectual disability variable, usually mild to moderate
- Hypertonia in infancy (contrasts with Sotos, which has hypotonia)
- Hoarse / low-pitched cry
- Increased risk of neoplasia in some series (neuroblastoma, leukemia, lymphoma); absolute risk is low but surveillance is sometimes considered
- Clinical suspicion in tall, macrocephalic child with characteristic face and advanced bone age
- EZH2 sequencing
- If negative and overgrowth syndrome still suspected: panel testing covering NSD1 (Sotos), DNMT3A (Tatton-Brown-Rahman), NFIX (Malan), HIST1H1E (Rahman), exome
- Developmental support, occupational therapy for camptodactyly
- Monitor growth trajectory
- Cardiac screening at diagnosis
- Surveillance for neoplasia is debated; individualize based on family history
"Weaver = Way Exceeds AVERage height/HC." The word "Weaver" itself contains the clinical phenotype: Way Exceeds AVERage head circumference and height. The two body parameters that are well above average are the diagnostic anchors.
"Wide-spaced Eyes." Hypertelorism is part of the Weaver gestalt; the W also stands for the Wide eyes.
"EZH2 = EyeZ + (EZ)H²." Decode the gene name as a phenotype mnemonic: Eyes (hypertelorism) plus H × H (Height and Head circumference both raised). Three of the most consistent Weaver features encoded in the gene symbol.
Weaver vs Sotos (the two textbook overgrowth syndromes to distinguish):
| Feature | Sotos (NSD1) | Weaver (EZH2) |
|---|---|---|
| Tone in infancy | Hypotonia | Hypertonia |
| Forehead | Frontal bossing, dolichocephalic | Broad, prominent occiput |
| Hands | Large, soft | Camptodactyly |
| Cry | Normal | Low-pitched, hoarse |
| Bone age | Advanced | Advanced (often more) |
| Polycomb biology | NSD1 adds H3K36me | EZH2 adds H3K27me (PRC2) |
"EZH2 = epigenetic, fingers bent": EZH2 is a histone methyltransferase, and the camptodactyly is the bedside finding that pulls Weaver away from Sotos.