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Mowat-Wilson Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2005, 2006, 2012

NORD is very grateful to Dr. David Mowat, Clinical Geneticist, Sydney Children's Hospital, Australia, for assistance in the preparation of this report.

Synonyms of Mowat-Wilson Syndrome

Disorder Subdivisions

General Discussion

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, 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 (HSCR) 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.

Symptoms

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, a significant degree of intellectual disability 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. 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, wide 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 obvious 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. Comprehension is usually better than speech ability and children may communicate in non-verbal ways such as signing. 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.

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 faeces 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.

Causes

MWS is an autosomal dominant genetic disorder caused by an abnormality (mutation) in the gene called ZEB2. This mutation leads to a loss of function 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 200 or so families 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, the risk would be 50% chance with each pregnancy to have an affected child.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders may overlap with those of Mowat-Wilson syndrome. Comparisons may be useful for a differential diagnosis. There are over 100 syndromes associated with Hirschsprung disease.

Some MWS children have been thought to have Angelman syndrome because both conditions share features such as a happy personality, microcephaly, seizures and poor balance. The facial appearance is quite different in Angelman syndrome, and an experienced clinical geneticist should be able to recognize the difference.

Goldberg-Shprintzen syndrome is also associated with Hirschsprung disease and intellectual disability. This condition is inherited in a different way and caused by mutations in a different gene (called the KIAA1279 gene) than MWS. Individuals with Goldberg-Shprintzen syndrome have a different facial appearance to those with MWS, which can be distinguished by an experienced geneticist.

Goldberg-Shprintzen syndrome (GSS) is a rare genetic disorder characterized by widely spaced eyes (hypertelorism), incomplete closure of the roof of the mouth (cleft palate), absence of tissue from the colored portion of the eye (iris coloboma), droopy eyelids (ptosis), arched eyebrows, and microcephaly. Affected individuals may also experience short stature and learning problems. In GSS, the facial features are different from MWS and there may be additional features, such as a cleft (coloboma) of the iris or retina and arched eyebrows. Goldberg-Shprintzen syndrome is inherited as an autosomal recessive condition.

Smith-Lemli-Opitz syndrome is a rare genetic disorder characterized by growth retardation, developmental delays and a variety of congenital malformations. The most common malformations include facial abnormalities; genitourinary anomalies; heart defects; and microcephaly. Facial abnormalities include low-set ears, droopy eyelids (ptosis), cataracts, a small jaw (micrognathia), a small, upturned nose, and incomplete closure of the roof of the mouth (cleft palate). Genitourinary anomalies may include (hypospadias), undescended testes, and Hirschsprung disease. Affected infants may also have extra fingers or toes (polydactyly), webbing of the toes (syndactyly), and short thumbs. Smith-Lemli-Optiz syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Smith-Lemli-Optiz" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Standard chromosome testing is usually undertaken in MWS to exclude a chromosome rearrangement involving chromosome 2q22, which is rare. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in the ZEB2 gene.

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.

Genetic counseling is beneficial for affected individuals and their families.

Investigational Therapies

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Liz Evans, PhD at the University of New South Wales, Australia, has completed a study of the behavioral, emotional aspects and development of individuals with Mowat-Wilson syndrome. For more information on this study, contact:

Email: lizevans@unsw.edu.au


Contact for additional information about Mowat-Wilson syndrome:

Dr. David Mowat
Clinical Geneticist
Department of Medical Genetics
Sydney Children's Hospital
High Street, Randwick, NSW 2031, Australia
david.mowat@sesiahs.health.nsw.gov.au

Mowat-Wilson Syndrome Resources

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.)

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

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
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.

Zweier C, Thiel CT, Dufke A, et al. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet. 2005;48(2):97-111.

Espinosa-Parrilla Y, Encha-Razavi F, Attié-Bitach T , et al. Molecular screening of the ZFHX1B gene in prenatally diagnosed isolated agenesis of the corpus callosum. Prenat Diagn. 2004;24(4):298-301.

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.

Sztriha L, Espinosa-Parrilla Y, Gururaj A, et al. Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum (Mowat-Wilson syndrome). Neuropediatrics. 2003;34(6):322-5.

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, Bean LJH, Miller VR. (Updated February 11, 2008). Mowat-Wilson Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed July 5, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mowat-Wilson Syndrome. Entry No: 235730. Last Edited April 12, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 5, 2012.

Report last updated: 2012/08/07 00:00:00 GMT+0