Mowat-Wilson Syndrome

Original Editor - Rucha Gadgil
Top Contributors - Rucha Gadgil, Kim Jackson and Kirenga Bamurange Liliane

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 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]

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

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. It is located on chromosome 2 in the region 2q22.3. 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 :

  1. It shows intrauterine activity- particularly important for the development of the neural crest.
  2. 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 Hirschsprung disease. The chance of recurrence for parents who have a child with MWS is approximately 2% or less. [4]

Clinical Presentation[edit | edit source]

Mowat-Wilson syndrome clinically tends to present as[7]:

  1. 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.
  2. Neurological impairments: microcephaly, structural brain abnormalities, and intellectual disability ranging from moderate to severe.[8]
  3. Affected Speech: Speech is absent or severely impaired, and affected people may learn to speak only a few words.
  4. Delayed gross motor skills.
  5. Hirschsprung disease - an intestinal disorder is present in 50% of MWS; it can cause severe constipation, intestinal blockage, and enlargement of the colon.
  6. Cardiac and respiratory anomalies: patent ductus arteriosus, ventricular septal defect, valvular pulmonary stenosis, pulmonary artery sling, with or without tracheal stenosis.
  7. Chronic constipation
  8. MWS individuals may also have short stature, seizures, heart defects, and abnormalities of the urinary tract and genitalia.

Diagnosis[edit | edit source]

MWS is diagnosed during infancy or childhood, based on[1][5]:

  1. Clinical evaluation,
  2. Identification of characteristic physical findings and facial appearance, and
  3. Information from a variety of specialized tests.

Clinical features become more prominent in adult cases making it easier to diagnose them.

Imaging techniques of computerized tomography (CT) scanning , magnetic resonance imaging (MRI) of the brain, kidney ultrasound or heart ultrasound are recommended in addition to the clinical features help in diagnosing the condition.

Molecular genetic testing for mutations in the ZEB2 gene is considered the gold standard for diagnosing MWS. Standard chromosome testing may be undertaken in MWS to exclude a chromosome rearrangement involving chromosome 2q22, which is rare.

Molecular gene testing may include:

  1. Single gene testing
  2. Multi-gene testing.

Another method of testing includes:

Chromosomal microarray analysis (CMA) which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ZEB2) that cannot be detected by sequence analysis. It is followed by exome sequencing to confirm the diagnosis.[1]

Differential Diagnosis[edit | edit source]

Differential Diagnosis for MWS are:

  1. Hirschsprung Disease (HSCR): differentiated on the basis of genetic testing.
  2. Microencephaly
  3. Goldberg-Shprintzen syndrome: clinical features and facial dysmorphism severity differs.
  4. Intellectual Disability
  5. Goldberg-Shprintzen Megacolon Syndrome (GOSHS): differentiated on the basis of genetic testing
  6. Angelman Syndrome: facial characteristics may appear similar, however genetic mark up is varied in the two conditions.

Medical Management[edit | edit source]

There is no set management protocol for MWS because of its genetic make up. The treatment has to be tailored individually and focuses more on symptomatic management. A team of specialists needs to work together and plan for the best strategy to enable each individual to reach their full potential.
Congenital heart disease and HSCR may require surgical interventions along with regular follow-up. Other clinical features like cardiac and respiratory impairments can be managed by periodic clinical testing and interventions by respective specialists.

A team of rehabilitation specialists like speech therapist, physiotherapist, occupational therapist need to be on-board to ensure overall development of an MWS individual.

Genetic counselling and antenatal testing are new advances taking place to identify the risk of MWS and provide medical assistance appropriately.[9]

Physiotherapy Management[edit | edit source]

Physiotherapy management of an individual with MWS has to be in conjunction with his other medical team members.

The treatment strategies focus mainly on symptomatic presentation. Early intervention may be recommended in cases of prenatal and neonatal diagnoses.[5]

Physiotherapy management mainly works to[1]:

  1. Maximize mobility
  2. Reduce the risk for orthopedic complications (e.g., contractures, scoliosis, hip dislocation, fractures).
  3. Identify and consider use of durable medical equipment and positioning devices as needed with the help of prosthetists and orthotists. (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  4. To maintain muscle tone abnormalities.
  5. To improve strength and posture of individuals.

Resources[edit | edit source]

  1. Genetic information
  2. Mowat Wilson Information

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 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:
  2. 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.
  3. 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. 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.
  5. 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.
  6. 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.
  7. Ivanovski I, Kjuric O, Broccoli S, et al. Mowat-Wilson syndrome: growth charts. Orphanet J Rare Dis. 2020; 15:151. PMID 32539836.
  8. 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.
  9. Garavelli, L., Mainardi, P.C. Mowat-Wilson syndrome. Orphanet J Rare Dis 2, 42 (2007).