Introduction
Mowat-Wilson syndrome (MWS) can be defined as a rare autosomal dominant syndrome characterized by distinctive facial features, congenital heart defects, Hirschsprung disease, genitourinary abnormalities, and various brain structural abnormalities and mental retardation. [1][2] Clinically passed Proposed by David R. Mowat and Meredith J. Wilson in 1998. [3] It is also known as Hirschsprung’s-intellectual disability syndrome. [2]
MWS is associated with a range of physical symptoms as well as intellectual disability. Most people with MWS have severe intellectual disability, although a few have milder features of only moderate intellectual disability. [1]
Garavelli L Cerruti Mainardi P. Mowat-Wilson syndrome. Orphanet J Rare Dis. 2 1 42. 2007. PMID 17958891. DOI: 10.1186/1750-1172-2-42
The ZEB2 gene is responsible for producing a protein that plays a vital role in the formation of many organs and tissues before birth. It is located in the 2q22.3 region of chromosome 2. The researchers believe that the ZEB2 protein is involved in the development of tissues, resulting in Nervous system, digestive tract, five sense organs, heart and other organs. The ZEB2 protein has the following special functions:
- It showed activity in utero – 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 primarily an autosomal dominant mutation of 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 can cause MWS. More than 100 variants have been reported in typical patients Phenotype; variants are usually whole/partial gene deletions or truncating mutations, suggesting haploinsufficiency as the primary pathological mechanism [4].
Genotype-phenotype analysis revealed that facial gestalt and psychomotor delay were constant clinical features, whereas frequent and severe congenital malformations were variable. In a small number of patients, missense variants affecting the functional domain of the ZEB2 protein can lead to Atypical phenotype. [5]
Mutations within the gene result in the production of an abnormally short, nonfunctional version of the ZEB2 protein, resulting in a shortage of the protein that disrupts the normal development of many organs and tissues, resulting in the various signs and symptoms of Mowat-Wilson syndrome [6].
The prevalence of MWS is estimated to be 1/50,000-70,000 live births. To date, more than 300 patients have been reported. It appears that Mowat-Wilson syndrome (MWS) may be underdiagnosed, especially in patients without Hirschsprung disease. The chances of a parent with a child with MWS recurring are About 2% or less. [4]
Clinical Presentation
Mowat-Wilson syndrome clinically usually presents as[7]:
- Facial Features: deep triangular shaped face with wide spacing wide eyes with rounded nose tip; a prominent and pointed beard; large burning eyes; and raised ears with a hole in the middle. Affected people often have an open smile and they tend to be friendly and cheerful.
- Neurological disorders: microcephaly structural brain abnormalities and intellectual disabilities ranging from moderate to severe.[8]
- Speech Impairment: Speech is absent or extremely weak and affected individuals may learn to speak only a few words.
- Delayed gross motor skills.
- Hirschsprung disease – intestinal inflammation in 50% of MWS; it can cause severe ulceration of the intestine obstruction and constipation.
- Cardiorespiratory disorders: patent ductus arteriosus ventricular septal defect valvular pulmonary artery stenosis pulmonary artery sling with or without pulmonary disease.
- Chronic constipation
- MWS individuals may also have tumors short of cardiac defects and urinary and genital abnormalities.
Diagnosis
MWS is diagnosed in infancy or childhood based on[1][5]:
- Clinical evaluation,
- Identification of characteristic physical findings and facial expressions and
- Data from specialized trials.
Clinical features are more prominent in adult cases making them easier to identify.
Imaging modalities such as computed tomography (CT) scanning magnetic resonance imaging (MRI) for brain kidney ultrasound or cardiac ultrasound are recommended in addition to clinical features that help diagnose the condition.
Molecular genetic testing for mutations in theZEB2gene is considered the gold standard for the diagnosis of MWS. Standardized chromosome testing can be performed in MWS to exclude rare chromosome rearrangements involving chromosome 2q22.
Molecular gene testing may include:
- Single gene testing
- Multi-gene testing.
Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays to detect large genome-wide deletions/duplications (including ZEB2) that cannot be detected by sequencing analysis. It is followed by exome sequencing to confirm the diagnosis.[1]
Differential Diagnosis
Differential Diagnosis for MWS are:
- Hirschsprung disease (HSCR): differentiated on the basis of genetic testing.
- Microencephaly
- Goldberg-Shprintzen syndrome: varying clinical presentation and severity of facial dystrophy.
- Intellectual Disability
- Goldberg-Shprintzen megacolon syndrome (GOSHS): differentiation based on genetic testing
- Angelman Syndrome: facial characteristics may appear similar but genetic markers differ in the two conditions.
Medical Management
There is no predetermined protocol for MWS due to its genetics. Treatment should be individualized and more focused on symptom management. A team of experts must work together and plan the best way to enable each individual to achieve it all potential.Congenital heart disease and HSCR may require routine surgical follow-up. Other clinical factors, such as cardiorespiratory disease, can be addressed through periodic clinical examination and professional intervention.
A team of rehabilitation specialists such as a speech therapist a physical therapist occupational therapist should be on board to ensure an MWS individual has all the progress.
Genetic counseling and prenatal testing are new advances in progress to identify risk factors for MWS and provide appropriate medical intervention.[9]
Physiotherapy Management
An individual with an MWS exercise plan should collaborate with other members of his or her medical team.
Treatment modalities focus primarily on symptom presentation. Early intervention may be recommended in cases of prenatal and neonatal diagnosis.[5]
Resources
- Genetic information
- Mowat Wilson Information
References
- ↑ Jump up to:1.0 1.1 1.2 1.3 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/
- ↑ Jump up to: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
- ↑ Jump up to:4.0 4.1 4.2 “ZEB2 – zinc finger E-box binding homeobox 2”. HUGO Gene Nomenclature Committee. 29 August 2019. Retrieved 30 August 2019.
- ↑ Jump up to:5.0 5.1 5.2 5.3 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.
- ↑ Garavelli, L., Mainardi, P.C. Mowat-Wilson syndrome. Orphanet J Rare Dis 2, 42 (2007). https://doi.org/10.1186/1750-1172-2-42
