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Last updated:
July 16, 2020
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NORD gratefully acknowledges Margaret Adam, MD, Clinical Geneticist and Professor of Pediatrics, University of Washington, Seattle, WA, and the Mowat-Wilson Syndrome Foundation, for assistance in the preparation of this report.
Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene that is usually the result of a new genetic change (mutation) in the affected person.
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. People who have MWS typically have a distinctive facial appearance, absent or severely limited speech, and often have seizures. Some physical problems may present at birth or infancy. These include the intestinal disorder Hirschsprung disease in about half, problems with development of the kidneys and male genitalia (hypospadias), congenital heart defects, eye problems and absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). Later features may include small head size (microcephaly) and short stature. MWS specific growth charts now are available to track growth. Chronic constipation may occur even in those who do not have Hirschsprung disease. Constipation in people with MWS needs investigation in view of the possibility of very short segment HSCR.
The distinctive facial appearance of people with MWS is the most consistent feature of this condition, and can be recognized by an experienced medical specialist. Common features include a high forehead, broad eyebrows that are wide apart centrally, widely spaced eyes (hypertelorism) that are large and deep set, uplifted ear lobes with a central depression, relatively small nose (in babies) with a prominent rounded nasal tip, prominent portion between nostrils (columella), open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. These features may not all be obvious in babies. Some facial features become more apparent with time, so a diagnosis of MWS is easier to make in older children.
Children with MWS make their developmental progress (such as sitting, crawling, and walking) at a significantly slower rate than average. Speech is often delayed or absent, with few exceptions (see mild Mowat-Wilson syndrome). Comprehension is usually better than speech ability and children may communicate in non-verbal ways such as signing or use of a communication device. They usually have a happy demeanor and smile frequently.
Seizures are common, occurring in approximately 90% of individuals by 10 years of age. Seizures can be difficult to control in childhood but are not usually a major problem in adulthood. A small subset of individuals will have electrical status epilepticus during sleep (ESES) that can lead to loss of some developmental and physical skills if it continues untreated.
Although a variety of congenital abnormalities may occur in infants with MWS, it is important to note that affected infants will not have all of the anomalies associated with the condition. One common congenital abnormality is Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive). Short stature is common in MWS, although some people have normal stature.
One rare finding is lack of a spleen, an organ that helps to fight certain types of infections. All individuals with MWS should be checked at the time of diagnosis to see if they have a spleen. This can be done through an ultrasound of the abdomen. Blood testing can sometimes also suggest that the spleen is absent.
Mild Mowat-Wilson Syndrome
A subset of individuals with MWS has been identified who have mild features. Such individuals may have no malformations or may have fewer facial features, sometimes making the diagnosis harder to appreciate based on physical findings alone. Additionally, such individuals may have intellectual disability that falls in the moderate, as opposed to severe, range. Speech capabilities are more advanced, with some able to speak in short sentences by mid-childhood. Individuals who have mild MWS typically have a missense mutation in the ZEB2 gene, leading to a protein that has decreased function as opposed to absent function (see Causes section).
MWS is an autosomal dominant genetic disorder caused by an abnormality (mutation) in the gene called ZEB2. This mutation leads to either loss of function (common) or decreased function (rare) of this gene. The ZEB2 gene (previously called ZFHX1B or SIP1) is located on chromosome 2 in the region 2q22.3. Genes provide the instructions for making a protein that plays a critical role in the formation of many organs and tissues of the body before birth. When a mutation occurs in one copy of this gene, the protein produced may be faulty, inefficient, or absent. This affects the development of many organs and tissues throughout the body especially the brain. MWS almost always occurs as a new (sporadic or de novo) mutation. This means that in nearly all cases, the gene mutation has occurred at the time of formation of the egg or sperm for that child only, and no other family member will be affected. It is usually not inherited from, or “carried” by, a healthy parent.
In a very small number of families, more than one child has been affected with MWS. Of the more than 300 individuals described in the literature, recurrence of MWS has only been reported in 5 families. The chance of recurrence for parents who have a child with MWS is thus approximately 2% or less. This could happen if one parent has a proportion of cells in their ovaries or testes that have a mutation which causes MWS. This is called germ-line mosaicism.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Due to the severity of the condition, affected persons are unlikely to have children of their own and there have been no reports of individuals with MWS reproducing. If an affected person were to reproduce, there would be a 50% chance with each pregnancy to have an affected child.
MWS affects both males and females. It is estimated to occur in 1 in 50,000-100,000 births. MWS has been described in many different countries and ethnic groups around the world.
MWS is usually diagnosed during infancy or childhood, based upon a thorough clinical evaluation, identification of characteristic physical findings and facial appearance, and information from a variety of specialized tests. Many of these features become more pronounced with time and so the diagnosis is easier to make in older individuals.
Checking for features may include imaging techniques such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain, kidney ultrasound or heart ultrasound.
The clinical diagnosis can be confirmed by molecular genetic testing for mutations in the ZEB2 gene. Standard chromosome testing may be undertaken in MWS to exclude a chromosome rearrangement involving chromosome 2q22, which is rare.
Treatment
The treatment of individuals with MWS should be directed towards the needs of each individual. It may be necessary for a team of specialists to work together and plan for the best strategy to enable each individual to reach their full potential. Just like each individual will be different, the treatment plan will be unique and best discussed with the health professionals involved in the care plan.
In MWS, associated conditions including Hirschsprung disease, heart abnormalities and seizures require intervention of relevant specialists, such as neurologists, cardiologists, and surgeons. Physical therapy, occupational therapy and speech therapy may all be useful in helping children with developmental delay reach their full potential.
Treatment of Hirschsprung disease usually involves surgery to relieve bowel obstruction. A temporary bowel opening of the colon is made in the abdominal wall (colostomy) and a second surgery is performed later to remove the non-functioning section of the colon and rejoin the healthy sections of bowel. Other surgeries may be performed to treat specific congenital anomalies such as heart defects and urinary tract abnormalities.
In some cases, seizures have been resistant to treatment in childhood but appear to be more easily managed in adolescents and adults. It is rare for an individual with MWS to regress in their cognitive or motor skills. However, a subset of individuals who have regression have been found to have electrical status epilepticus during sleep (ESES), that once treated, has resulted in improvements in skills that were lost.
In individuals who do not have a functional spleen, giving specific immunizations and sometimes daily antibiotics may be considered.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
A patient registry for Mowat-Wilson Syndrome has been created. To join the registry, please contact:
Mowat-Wilson Syndrome Patient Registry
Mowat-Wilson Syndrome Foundation
4009 Tyler William Lane
Las Vegas NV 89130-2628
Phone: 702-658-5391
https://mowat-wilson.org/registry/
Contact for additional information about Mowat-Wilson syndrome:
Dr. Margaret Adam
Clinical Geneticist
Department of Pediatrics
Seattle Children’s Hospital
4800 Sand Point Way NE
PO Box 5371/OC.9.850
Seattle, WA 98105
margaret.adam@seattlechildrens.org
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., Hirschsprung disease, heart disease, etc.)
TEXTBOOKS
Mowat D, Wilson M. Mowat-Wilson Syndrome. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 3rd ed. New York, NY: John Wiley and Son, Inc.; 2010:517-527.
Wilson M, Goossens M, Dastot-Le Moal F, Mowat D. ZEB2 and Mowat-Wilson syndrome. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2nd ed. New York, NY: Oxford University Press, Inc.; 2008:425-432.
JOURNAL ARTICLES
Ivanovski I, Kjuric O, Broccoli S, et al. Mowat-Wilson syndrome: growth charts. Orphanet J Rare Dis. 2020; 15:151. PMID 32539836.
Ivanovski I, Djuric O, Caraffi SG,et al. Phenotype and genotype in 87 patients with Mowat-Wilson syndrome and recommendations for care. Genet Med. 2018; 20(9):965-975. PMID 29300384.
Wenger TL, Horton M, Ricciardi S, et al. CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases. Am J Med Genet Part A 2014;164(10):2557-2566.
Ghoumid J, Drevillon L, Alavi-Naini SM, et al. ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Hum Mol Genet 2013;22(13):2652-2661.
Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype of Mowat-Wilson syndrome. Am J Med Genet A. 2012;158A(2):358-66.
McGaughran J, Sinnott S, Dastot-Le Moal F, et al. Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation. Am J Med Genet A. 2005;137A(3):302-4.
Bassez G, Camand OJ, Cacheux V, et al. Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of “Mowat-Wilson” syndrome. Neurobiol Dis. 2004;15(2):240-50.
Mowat DR, Wilson MJ, Goossens M. Mowat-Wilson syndrome. J Med Genet. 2003;40(5):305-10.
Wilson M, Mowat D, Dastot-Le Moal F, et al. Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B. Am J Med Genet A. 2003;119A(3):257-65.
Zweier C, Albrecht B, Mitulla B, et al. “Mowat-Wilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1 B gene. Am J Med Genet. 2002;108(3):177-81.
Mowat DR, Croaker GD, Cass DT, et al. Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet. 1998;35(8):617-23.
INTERNET
Adam MP, Conta J, Bean LJH. Mowat-Wilson Syndrome. 2007 Mar 28 [Updated 2019 Jul 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1412/ Accessed July 16, 2020.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mowat-Wilson Syndrome. Entry No: 235730. Last Updated 08/02/2019. Available at: https://omim.org/entry/235730 Accessed July 16, 2020.
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