Mowat-Wilson Syndrome
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Introduction[edit | edit source]
Mowat-Wilson syndrome (MWS) can be defined as a rare autosomal dominant syndrome characterized by distinctive facial features, congenital heart defects, Hirschsprung disease, genitourinary anomalies, various structural brain anomalies, and intellectual disability.[1][2]It was was clinically delineated by David R. Mowat and Meredith J. Wilson in 1998.[3]It is also called as Hirschsprung disease-intellectual disability syndrome.[2]
MWS is associated with a range of physical symptoms as well as intellectual disability. Most people with MWS have a severe intellectual disability, though a small number have milder features and only moderate intellectual disability.[1]
Etiology and Prevalence[edit | edit source]
The ZEB2 gene is responsible for production of a protein that plays a critical role in the formation of many organs and tissues before birth. Researchers believe that the ZEB2 protein is involved in the development of tissues that give rise to the nervous system, digestive tract, facial features, heart, and other organs. The ZEB2 protein has special features like :
- It shows intrauterine activity- particularly important for the development of the neural crest.
- It is also involved in the development of the digestive tract, skeletal muscles, kidneys, and other organs.[4][5]
MWS is mainly autosomal dominant mutation in heterozygous variants in the zinc finger E-box-binding homeobox 2 gene, ZEB2 (2q22.3). Loss of one working copy of the ZEB2 gene in each cell or deletion of the entire gene may lead to MWS. Over 100 variants have been reported in patients with a typical phenotype; variants are usually whole/partial gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism[4].
Genotype-phenotype analysis shows that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, missense variants affecting a functional domain of the ZEB2 protein can lead to an atypical phenotype.[5]
Mutations within the gene lead to the production of an abnormally short, nonfunctional version of the ZEB2 protein leading to a shortage of this protein disrupting the normal development of many organs and tissues, which causes the varied signs and symptoms of Mowat-Wilson syndrome[6].
Prevalence of MWS is estimated at 1/50,000-70,000 live births. Over 300 patients have been reported so far. It seems probable that Mowat-Wilson syndrome (MWS) is underdiagnosed, particularly in patients without HSCR.
Clinical Presentation[edit | edit source]
Mowat-Wilson syndrome clinically tends to present as[7]:
- Prominent Facial features: a square-shaped face with deep-set, widely spaced eyes, broad nasal bridge with a rounded nasal tip; a prominent and pointed chin; large, flaring eyebrows; and uplifted earlobes with a dimple in the middle. Affected people tend to have a smiling, open-mouthed expression, and they typically have friendly and happy personalities.
- Neurological impairments: microcephaly, structural brain abnormalities, and intellectual disability ranging from moderate to severe.[8]
- Affected Speech: Speech is absent or severely impaired, and affected people may learn to speak only a few words.
- Delayed gross motor skills.
- Hirschsprung disease - an intestinal disorder is present in 50% of MWS; it can cause severe constipation, intestinal blockage, and enlargement of the colon.
- Cardiac and respiratory anomalies: patent ductus arteriosus, ventricular septal defect, valvular pulmonary stenosis, pulmonary artery sling, with or without tracheal stenosis.
- Chronic constipation
- MWS individuals may also have short stature, seizures, heart defects, and abnormalities of the urinary tract and genitalia.
Diagnosis[edit | edit source]
Outcome Measures[edit | edit source]
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Management / Interventions
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Differential Diagnosis
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Resources
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References[edit | edit source]
- ↑ 1.0 1.1 Adam MP, Conta J, Bean LJH. Mowat-Wilson Syndrome. 2007 Mar 28 [Updated 2019 Jul 25]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1412/
- ↑ 2.0 2.1 Ayyildiz Emecen D, Isik E, Utine GE, Simsek-Kiper PO, Atik T, Ozkinay F. Clinical and Molecular Spectrum of Four Patients Diagnosed with Mowat-Wilson Syndrome. Mol Syndromol. 2020 Dec;11(5-6):296-301. doi: 10.1159/000511609.
- ↑ Mowat, DR; Croaker, GD; Cass, DT; Kerr, BA; Chaitow, J; Adès, LC; Chia, NL; Wilson, MJ. "Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: Delineation of a new syndrome and identification of a locus at chromosome 2q22-q23". Journal of Medical Genetics. 1998, 35 (8): 617–23. doi:10.1136/jmg.35.8.617
- ↑ 4.0 4.1 "ZEB2 - zinc finger E-box binding homeobox 2". HUGO Gene Nomenclature Committee. 29 August 2019. Retrieved 30 August 2019.
- ↑ 5.0 5.1 Saunders CJ, Zhao W, Ardinger HH. Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Am J Med Genet A 2009; 149A: 2527-2531.
- ↑ Yamada Y, Nomura N, Yamada K, Matsuo M, Suzuki Y, Sameshima K, et al. The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations. Am J Med Genet A. 2014 Aug;164A(8):1899-908. doi: 10.1002/ajmg.a.36551. Epub 2014 Apr 8. Erratum in: Am J Med Genet A. 2015 Jun;167(6):1428. PMID: 24715670.
- ↑ Ivanovski I, Kjuric O, Broccoli S, et al. Mowat-Wilson syndrome: growth charts. Orphanet J Rare Dis. 2020; 15:151. PMID 32539836.
- ↑ Valera ET, Ferraz ST, Brassesco MS, Zhen X, Shen Y, dos Santos AC et al. Mowat-Wilson syndrome: the first report of an association with central nervous system tumors. Childs Nerv Syst 2013; 29: 2151-2155. doi: 10.1007/s00381-013-2283-5.
