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
[…] foot Broad feet Wide foot [ more ] 0001769 Broad 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 [rarediseases.info.nih.gov]
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]
skeleton (short ribs, disharmonic and advanced bone age, scoliosis, kyphosis, small iliac wings, coxa valga, limited elbow and knee extension, flared metaphyses, camptodactyly, clinodactyly, broad thumbs, feet malformations), genitourinary (GU) (inverted [accessanesthesiology.mhmedical.com]
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]
- Precocious Puberty
Puberty 148 XLMRHypotonic Facies Syndrome 27 Pseudohypoparathyroidism 149 [books.google.de]
Differential Diagnoses Beckwith-Wiedemann Syndrome Congenital Adrenal Hyperplasia Fragile X Syndrome Genetics of Marfan Syndrome Hyperinsulinism McCune-Albright Syndrome Pachydermoperiostosis Precocious Pseudopuberty Precocious Puberty Author Alicia Diaz-Thomas [emedicine.staging.medscape.com]
When intellect is normal, the most common causes of overgrowth are: (1) familial, (2) growth acceleration driven by over-nutrition (includes infants of diabetic mothers), (3) endocrine conditions (such as precocious puberty, hyperthyroidism, congenital [karger.com]
- 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]
Fine hair shaft Fine hair texture Thin hair shaft Thin hair texture [ more ] 0002213 Inguinal hernia 0000023 Joint stiffness Stiff joint Stiff joints [ more ] 0001387 Large hands large hand 0001176 Round face Circular face Round facial appearance Round [rarediseases.info.nih.gov]
The cardinal features are pre- and postnatal accelerated somatic growth, characteristic facial appearance (i.e., 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]
Microphthalmia, cataract, congenital heart disease, sparse body hair, diabetes, deafness, hypothyroidism, and corpus callosum hypoplasia can be seen. [karger.com]
- Advanced Bone Age
Accelerated growth and advanced bone age are consistent findings in Weaver-Smith syndrome (WSS). [ncbi.nlm.nih.gov]
They described the condition in two children who showed advanced bone growth and age, and a characteristic appearance of the face. [medindia.net]
This reports describes affected half-brothers who manifest tall stature, advanced bone age, camptodactyly, characteristic facies, mild contractures of major joints and developmental delay. [nature.com]
- 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]
The newborn's feet and hands can appear large. Low muscle tone causes a floppy appearance, and poor sucking is pronounced; approximately one-third of children with the syndrome must be fed through a gastrointestinal tube. [sotossyndrome.co.uk]
- Coxa Valga
valga, limited elbow and knee extension, flared metaphyses, camptodactyly, clinodactyly, broad thumbs, feet malformations), genitourinary (GU) (inverted nipples, inguinal hernia, hydrocele, cryptorchism), skin (loose skin, thin hair and nails), and central [accessanesthesiology.mhmedical.com]
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]
- Muscle Hypotonia
Intellectual disability, loose muscles (hypotonia) of the core, and rigid muscles (hypertonia) of the limbs with poor coordination are also seen. Physical differences of the face and feet are common. [rarediseases.org]
- Extension of Elbows Limited
elbow extension Decreased elbow extension 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 [rarediseases.info.nih.gov]
- Slurred Speech
After birth, the child is found to grow fast and have mental retardation, slurred speech, a blurred vision, a long face, a protruding forehead, ocular hypertelorism, epicanthus, nasal bridge pit, finger pads on both hands and feet, uncoordinated gaits [pesquisa.bvsalud.org]
[…] and language development Deficiency of speech development Delayed language development Delayed speech Delayed speech acquisition Delayed speech development Impaired speech and language development Impaired speech development Language delay Language delayed [rarediseases.info.nih.gov]
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 .
This paper describes a patient with Weaver syndrome, referred for consultation and treatment of macroglossia, who also suffered from congenital hypothyroidism. [ncbi.nlm.nih.gov]
Is there a treatment? In light of the large number of potential manifestations, treatment should always be symptom-orientated and involve different specialist disciplines working together. [krebs-praedisposition.de]
Management and treatment There is no specific treatment for WVS although individual symptom management may be indicated. [orpha.net]
The treatment of OSAHS should be approached as the treatment for a chronic disease, requiring a long-term multidisciplinary management. [medichub.ro]
Prognosis - Weaver Williams syndrome Not supplied. Treatment - Weaver Williams syndrome Not supplied. Resources - Weaver Williams syndrome Not supplied. [checkorphan.org]
Prognosis With suitable treatment and support, patients with WVS have a normal life. [orpha.net]
Prognosis varies with every case as some patients retain a normal life span and with an ordinary adult height. [cags.org.ae]
Weaver syndrome is a very rare disorder of unknown etiology characterized by accelerated growth of prenatal onset, advanced osseous maturation, special craniofacial features, umbilical hernia, and hoarse low-pitched cry. [ncbi.nlm.nih.gov]
The etiology of the syndrome remains unclear, but if genetic, X-linked recessive inheritance can be excluded. [link.springer.com]
Etiology WVS is caused by mutations in the EZH2 gene (7q35-q36), a histone methyltransferase involved in transcription control. [orpha.net]
The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.de]
Summary Epidemiology Around 50 cases of Weaver syndrome have been reported to date. Precise prevalence and incidence rates are not available. [orpha.net]
Author information 1 Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK. Abstract The biological processes controlling human growth are diverse, complex and poorly understood. [ncbi.nlm.nih.gov]
Statistics: EPIDEMIOLOGY: incidence: rare (over 30 cases reported) age of onset: newborn -> infancy (excessive growth first noted) risk factors: sporadic M > F (3:1) PATHOGENESIS: Background unknown etiology syndrome first described in 1974 by Weaver [sites.google.com]
(Adapted from: http://www.whonamedit.com/synd.cfm/1360.html) Statistics: EPIDEMIOLOGY: - incidence: rare (around 100-150 cases reported worldwide) - age of onset: - newborn -> infancy (excessive growth first noted) - risk factors: - sporadic - M > F [rumeysagelgi.com]
The precise pathophysiology and the etiology of the residual cases remain vague. NSD1 gene provides directions for creating a protein with unknown function. [cags.org.ae]
The pathophysiology of OSAHS is responsible for the signs, symptoms and consequences, and is represented by repetitive episodes of collapse of the upper airway. [medichub.ro]
Pathophysiological relevance and possible prognostic value. Lancet, 1(8175): 947-9 [ PM ] [ EČ ][ GS ] Hulman, G. (1988) Pathogenesis of non-traumatic fat embolism. [scindeks.ceon.rs]
The pathophysiology and the etiology of the other cases remain unknown. Although both sexes are affected, the sex ratio is 2M:1F. [atlasgeneticsoncology.org]
The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. [nature.com]
Prevention How can I prevent Weaver syndrome? There is no known way to prevent Weaver syndrome. Although children can inherit Weaver syndrome from a parent, it also occurs without a family history. [my.clevelandclinic.org]
[…] syndrome Short rib polydactyly syndrome Filippi syndrome 49,XXXXX syndrome Aicardi Goutieres syndrome Allan-Herndon-Dudley syndrome Alpha thalassaemia X-linked mental retardation syndrome Alpha-thalassemia/mental retardation syndrome, deletion type Prevention [checkorphan.org]
Growth disorders are problems that prevent children from developing normal height, weight, sexual maturity or other features. Very slow or very fast growth can sometimes signal a gland problem or disease. [medlineplus.gov]
Recombinant EZH2 activity measured using a fluorescent histone H3 lysine 27 methyltransferase assay. for Recombinant EZH2 protein complex Storage Recombinant proteins in solution are temperature sensitive and must be stored at -80°C to prevent degradation [activemotif.com]
- 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.