Weaver syndrome is a very rare genetic disorder that presents with a range of musculoskeletal, cutaneous, cognitive, and facial symptoms. Excessive growth in early life is the most prominent finding, followed by intellectual disability of various degrees and connective tissue disorders such as laxity of ligaments. The diagnosis rests on a thorough clinical assessment, which is the only tool to raise sufficient evidence for genetic testing.
Initially described in the 1970s, Weaver syndrome is a very rare congenital genetic disorder, with little over 50 cases described in the literature    . Until recently, the exact pathogenesis of this condition was unknown, but new results strongly point toward mutations of the Enhancer of Zeste Drosophila homolog 2 (EZH2) gene     . EZH2 is an important regulator of epigenetic functions and the process of transcription and is well-known for its prominent role in the maturation of skeletal, muscle, lymphoid, and blood cells  . The exact mechanism of mutation is yet to be solidified, although missense mutations were most frequently identified so far  . The clinical presentation involves several organ systems from early life and the most important component is excessive generalized growth leading to tall stature   . Hypertelorism and advanced bone age are frequent findings, whereas other notable findings of the musculoskeletal system are scoliosis, talipes equinovarus, and camptodactyly (fixed flexion of fingers)   . Cranial abnormalities, such as macrocephaly, and several characteristic features of the face (retrognathia, a broad forehead, round facies, large ears, and very wide eyes) are commonly present  . Intellectual impairment is an equally important component of the clinical presentation, varying from mild to severe and debilitating IQ deficits  . Poor coordination, owing to the extreme laxity of ligaments, and very loose skin are additional findings in patients suffering from Weaver syndrome .
Entire Body System
- Broad Thumb
Limb abnormalities include prominent finger pads, camptodactyly, broad thumbs, thin and deep-set nails, clinodactyly, limited elbow and knee extension, wide distal long bones, and foot deformities (clubfoot, pes calcaneovalgus, and metatarsus adductus [sites.google.com]
thumb Broad thumbs Wide/broad thumb [ more ] 0011304 Camptodactyly of finger Permanent flexion of the finger 0100490 Deep philtrum 0002002 Feeding difficulties in infancy 0008872 Fine hair Fine hair shaft Fine hair texture Thin hair shaft Thin hair texture [rarediseases.info.nih.gov]
Limb abnormalities consist of prominent finger pads, thin and deeply-set nails, camptodactyly, wide distal long bones, foot deformities, and broad thumbs. [cags.org.ae]
Limb anomalies: campotodactyly, prominent finger pads, clinodactyly of fifth finger and toes, broad thumbs, foot deformities (talipes equinovarus, talipes calcaneovalgus, metatarsus adductus, pes adductus and pes cavus), broad iliac wings, cervical kyphosis [atlasgeneticsoncology.org]
Rubinstein–Taybi Syndrome Rubinstein–Taybi syndrome (RSTS) is characterized by facial features, including down-slanting palpebral fissures, low columella, high palate, grimacing smile, and talon cusps, broad thumbs and great toes, short stature, and intellectual [clincancerres.aacrjournals.org]
An 11-month-old Turkish female infant with Weaver syndrome together with atrial septal defect and patent ductus arteriosus which was operated successfully is reported. [ncbi.nlm.nih.gov]
- Failure to Thrive
Pediatr Radiol 5:53–57 Google Scholar Marshall RE, Graham CB, Scott CR, Smith DW (1971) Syndrome of accelerated skeletal maturation and relative failure of thrive: A newly recognized clinical growth disorder. [link.springer.com]
Widened middle and proximal phalanges, failure to thrive, craniofacial abnormalities (small face, prominent eyes, blue sclera, flat nose with anteverted nares, choanal atresia, and glossoptosis). [icd10data.com]
Regarding differential diagnoses to outline conditions that are not overgrowth syndromes by strict definition, Table 2 presents syndromes associated with macrosomia at birth that later usually progress to normal growth parameters or failure to thrive. [karger.com]
- Sparse Hair
Tall, broad, prominent forehead, sparse hair in frontotemporal region. Hypertelorism, downslanting palpebral fissures, epicanthal folds Retrognathia & with prominent chin crease ("stuck on chin"). [genetics4medics.com]
hair 0008070 Strabismus Cross-eyed Squint Squint eyes [ more ] 0000486 Umbilical hernia 0001537 [rarediseases.info.nih.gov]
macrocephaly, prominent jaw, and a high hairline with sparse hair growth), advanced bone age, and developmental delay (Cole and Hughes 1994 ). [ncbi.nlm.nih.gov]
Facial features included sparse hair, prominent forehead, proptosis, downslanting palpebral fissures, wide nasal bridge, thin upper lip, and a pointed chin. [karger.com]
- Hyperconvex Nails
Other clinical features included prominent finger pads, narrow hyperconvex nails, small and narrow chest, unilateral dislocated distal ulna, and abnormal thoracic vertebrae. [ncbi.nlm.nih.gov]
Other clinical features included prominent finger pads, narrow hyperconvex nails, small and narrow chest, unilateral dislocated distal ulna, and abnormal thoracic vertebrae. Type: Article Title: A girl with the Weaver syndrome. [discovery.ucl.ac.uk]
- Advanced Bone Age
Accelerated growth and advanced bone age are consistent findings in Weaver-Smith syndrome (WSS). [ncbi.nlm.nih.gov]
Weaver syndrome is a genetic disorder in which children show accelerated bone growth, advanced bone age and a characteristic appearance of the face. Weaver syndrome or Weaver-Smith syndrome was first described in 1974 by Weaver and his colleagues. [medindia.net]
- Large Hand
Weaver's syndrome is characterised by excessive growth, large ears, large hands and thumb, protuberant lower lip, hypertelorism, limited knee and elbow extension, kyphosis and mental retardation. [gpnotebook.co.uk]
hands large hand 0001176 Round face Circular face Round facial appearance Round facial shape [ more ] 0000311 5%-29% of people have these symptoms Abnormality of cardiovascular system morphology 0030680 Cryptorchidism Undescended testes Undescended testis [rarediseases.info.nih.gov]
In addition to her abnormally tall height, and large hands and feet, Rumeysa also has a very large head which is characteristic of the Weaver’s syndrome. [futurescienceleaders.com]
hands and feet Persistent feeding difficulties and / or reflux Characteristic structural changes in the brain on MRI Down-slanting palpebral fissues or "antimongoloid slant" ASMS Heart defects Treatment for Sotos syndrome is based upon the symptoms the [sotossyndrome.co.uk]
- Coxa Valga
valga 0002673 Cutis laxa Loose and inelastic skin 0000973 Delayed speech and language development Deficiency of speech development Delayed language development Delayed speech Delayed speech acquisition Delayed speech development Impaired speech and language [rarediseases.info.nih.gov]
- Extension of Elbows Limited
Elbow limited extension Limitation of elbow extension Limited extension at elbows Limited forearm extension Restricted elbow extension [ more ] 0001377 Limited knee extension 0003066 Mandibular prognathia Big lower jaw Increased projection of lower jaw [rarediseases.info.nih.gov]
Face, Head & Neck
Given the very rare occurrence of Weaver syndrome (and its still incompletely understood mechanism of inheritance), the diagnosis can be quite difficult to make. For this reason, the physician should obtain a comprehensive patient history that will cover the onset of symptoms and their progression, as well as severity. Because isolated cases of parent-to-child transmission were confirmed , a thorough family history may yield important information and should not be overlooked in patients with undisclosed complaints from early life. A detailed physical examination should follow history taking, during which the assessment of growth curves, facial features, and cognitive status must be evaluated. The initial recognition of Weaver syndrome primarily rests on clinical criteria, but the nonspecific clinical presentation that often lacks some of its main components significantly impedes recognition . In order to confirm the diagnosis, genetic testing needs to be employed . Detection of a pathogenic variant of EZH2 through molecular and proband testing strengthens the diagnosis . In addition to clinical and laboratory studies, imaging techniques, such as magnetic resonance imaging (MRI), may be useful for patients in whom macrocephaly is suspected, as ventriculomegaly and several other findings can be observed .
- Tatton-Brown K, Rahman N. EZH2-Related Overgrowth. 2013 Jul 18 [Updated 2015 Aug 6]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
- Tatton-Brown K, Murray A, Hanks S, et al. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype. Am J Med Genet A. 2013;161A:2972–80.
- Fryer A., Smith C., Rosenbloom L., Cole T. Autosomal dominant inheritance of Weaver syndrome. J. Med. Genet. 1997;34:418–419
- Gibson WT, Hood RL, Zhan SH, et al. Mutations in EZH2 Cause Weaver Syndrome. Am J Hum Genet. 2012;90(1):110-118.
- Bansal N, Bansal A. Weaver syndrome: A report of a rare genetic syndrome. Indian J Hum Genet. 2009;15(1):36-37.
- Tatton-Brown K, Hanks S, Ruark E, et al. Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height. Oncotarget. 2011;2(12):1127-1133.
- Chou RH, Yu YL, Hung MC. The roles of EZH2 in cell lineage commitment. Am J Transl Res. 2011;3:243–250.