Weaver syndrome
| Weaver syndrome | |
|---|---|
| Other names | Weaver–Smith syndrome |
| Specialty | Medical genetics  |
Weaver syndrome is an extremely rare autosomal dominant genetic disorder associated with rapid growth beginning in the prenatal period and continuing through the toddler and youth years. It is characterized by advanced osseous maturation and distinctive craniofacial, skeletal and neurological abnormalities.[1] It is similar to Sotos syndrome and is classified as an overgrowth syndrome.
Its genetic cause was identified in 2011 as mutations in the EZH2 gene.[2] Forty-eight cases had been documented and confirmed as of December 2013[update],[3] and its prevalence is estimated to be similar to that of Sotos syndrome, around 1 in 15,000.[4] It was first described by American physician David Weaver in 1974.[5]
Signs and symptoms
[edit]Children with Weaver syndrome tend to look similar and have distinctive physical and craniofacial characteristics, which may include several, but not all, of the following features: [6]
- Macrocephaly
- Large bifrontal diameter
- Flattened occiput
- Long philtrum
- Retrognathia
- Round face in infancy
- Prominent chin crease
- Large ears
- Strabismus
- Hypertelorism
- Epicanthal folds
- Downslanting palpebral fissures
Other features may include loose skin, thin deep-set nails, thin hair, short ribs, limited elbow and knee extension, camptodactyly, and a coarse, low-pitched voice. Delayed development of motor skills such as sitting, standing, and walking are commonly exhibited in early childhood. Patients with Weaver syndrome typically have mild intellectual disability with poor coordination and balance.[7] They also have some neurological abnormalities such as speech delay, epilepsy, intellectual disability, hypotonia or hypertonia, and behavioral problems.[citation needed]
Cause
[edit]The cause for Weaver syndrome was identified in 2011 as autosomal dominant mutations in the EZH2 gene on chromosome 7q36.[2] EZH2 (Enhancer of Zeste, Drosophila, homolog 2) is the second histone methyltransferase associated with human overgrowth. It encodes the catalytic component of the PRC2 protein complex (Polycomb Repressive Complex 2), which regulates chromatin structure and gene expression, and has been found to repress transcription. EZH2 also has critical roles in stem cell maintenance and cell lineage determination, such as osteogenesis, myogenesis, lymphopoiesis and hematopoiesis.
It can also be associated with mutations in the histone methyltransferase NSD1 gene on chromosome 5q35. The functions of NSD1 are not clearly known, but it is thought to act as a factor in influencing transcription, which contains domains involved in chromatin-mediated regulation during development.[8]
Most cases are found to be sporadic, with no family history of the syndrome, although there have been a few cases in families where autosomal dominant inheritance has been reported.[9]
Diagnosis
[edit]Differential diagnosis
[edit]Weaver syndrome and Sotos syndrome are often mistaken for one another due to their significant phenotypic overlap and similarities.[10] Clinical features shared by both syndromes include overgrowth in early development, advanced bone age, developmental delay, and prominent macrocephaly.[11] Mutations in the NSD1 gene may also be another cause for confusion. The NSD1 gene provides instructions for making a protein that is involved in normal growth and development. Deletions and mutations in the NSD1 gene is a common cause for patients with Sotos syndrome and in some cases for Weaver syndrome as well. [6]
Features distinguishing Weaver syndrome from Sotos syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep-set nails, retrognathia with a prominent chin crease, increased prenatal growth, and a carpal bone age that is greatly advanced compared to metacarpal and phalangeal bone age.[12]
Treatment
[edit]There is no cure available for Weaver syndrome. However, with multidisciplinary management such as neurological, pediatric, orthopedic and psychomotor care and genetic counseling, symptoms can be managed. Surgery may be used to correct any skeletal issues. Physical and occupational therapy are considered an option to help with muscle tone. Also, speech therapy is often recommended for speech related problems.[medical citation needed]
Prognosis
[edit]With appropriate treatment and management, patients with Weaver syndrome appear to do well, both physically and intellectually, throughout their life and have a normal lifespan.[medical citation needed] Their adult height can reach 7–8 feet (213.36–243.84 cm).[13]
Epidemiology
[edit]The incidence of Weaver syndrome is uncertain, as the causative mutation was only identified in 2011. As of December 2013[update], 48 cases of Weaver syndrome had been documented and confirmed.[3][14] In 2012, the South West Thames Regional Genetic Service at St George's Hospital in London, based on their detection rate among a cohort of patients within their Childhood Overgrowth Study, estimated a prevalence rate similar to that of Sotos syndrome, around 1 in 15,000.[4]
See also
[edit]References
[edit]- ^ CRAWFORD, MARK W., and DENISE ROHAN. "The Upper Airway In Weaver Syndrome." Pediatric Anesthesia 15.10 (2005): 893-896. Health Source: Nursing/Academic Edition.
- ^ a b Gibson, William T.; Hood, Rebecca L.; Zhan, Shing Hei; Bulman, Dennis E.; Fejes, Anthony P.; Moore, Richard; Mungall, Andrew J.; Eydoux, Patrice; Babul-Hirji, Riyana; An, Jianghong; Marra, Marco A. (2012-01-13). "Mutations in EZH2 cause Weaver syndrome". American Journal of Human Genetics. 90 (1): 110–118. doi:10.1016/j.ajhg.2011.11.018. ISSN 1537-6605. PMC 3257956. PMID 22177091.
- ^ a b Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M.; Clericuzio, Carol L.; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances (December 2013). "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype" (PDF). American Journal of Medical Genetics. Part A. 161A (12): 2972–2980. doi:10.1002/ajmg.a.36229. ISSN 1552-4833. PMID 24214728. S2CID 24616267.
- ^ a b "Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier/Additional Provider" (PDF). UK Genetic Testing Network. September 2012. Archived from the original (PDF) on 5 November 2019. Retrieved 5 November 2019.
- ^ Weaver DD, Graham CB, Thomas IT, Smith DW (1974). "A new overgrowth syndrome with accelerated skeletal maturation, unusual facies, and al=J. Pediatr". The Journal of Pediatrics. 84 (4): 547–52. doi:10.1016/s0022-3476(74)80675-x. PMID 4366187.
- ^ a b Rio, M (2003-06-01). "Spectrum of NSD1 mutations in Sotos and Weaver syndromes". Journal of Medical Genetics. 40 (6). BMJ: 436–440. doi:10.1136/jmg.40.6.436. ISSN 1468-6244. PMC 1735492. PMID 12807965.
- ^ Genetics Home Reference. "Weaver syndrome". U.S. National Library of Medicine. Retrieved 9 November 2013.
- ^ Douglas J, Hanks S, Temple IK, et al. (2003). "NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes". Am. J. Hum. Genet. 72 (1): 132–43. doi:10.1086/345647. PMC 378618. PMID 12464997.
- ^ Cole, Trevor R.P., N.R. Dennis, and Helen E. Hughes. "Weaver Syndrome: Seven New Cases and a Review of the Literature." In Congenital Malformation Syndromes. New York: Chapman and Hall Medical, 1995, pp. 267-280.
- ^ NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes Jenny Douglas, Sandra Hanks, I. Karen Temple, Sally Davies, Alexandra Murray, Meena Upadhyaya, Susan Tomkins, Helen E. Hughes, Trevor R. P. Cole, Nazneen Rahman Am J Hum Genet. 2003 January; 72(1): 132–143. Published online 2002 December 2.
- ^ Gibson, William T; Hood Rebecca L, Zhan Shing Hei, Bulman Dennis E, Fejes Anthony P, Moore Richard, Mungall Andrew J, Eydoux Patrice, Babul-Hirji Riyana, An Jianghong, Marra Marco A, Chitayat David, Boycott Kym M, Weaver David D, Jones Steven J M (Dec. 2011). "Mutations in EZH2 Cause Weaver Syndrome". American Journal of Human Genetics (in ENG) 90 (1): 110–8.
- ^ Gibson, William T; Hood Rebecca L, Zhan Shing Hei, Bulman Dennis E, Fejes Anthony P, Moore Richard, Mungall Andrew J, Eydoux Patrice, Babul-Hirji Riyana, An Jianghong, Marra Marco A, Chitayat David, Boycott Kym M, Weaver David D, Jones Steven J M (Dec. 2011). "Mutations in EZH2 Cause Weaver Syndrome". American Journal of Human Genetics (in ENG) 90 (1): 110–8.
- ^ "Weaver Syndrome".
- ^ Reference, Genetics Home. "Weaver syndrome". Genetics Home Reference. Retrieved 2019-11-05.