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Mowat-Wilson Syndrome

Synonym: Hirschsprung Disease-Mental Retardation Syndrome

, MD, MS, FAAP, FACMG, , MS, LGC, and , PhD, FACMG.

Author Information
, MD, MS, FAAP, FACMG
Associate Professor of Pediatrics, Division of Genetic Medicine
Department of Pediatrics
University of Washington
Seattle, Washington
, MS, LGC
Department of Laboratories
Seattle Children’s Hospital
Seattle, Washington
, PhD, FACMG
Assistant Professor, Human Genetics
Senior Director, Molecular Diagnostic Laboratory
Emory University
Atlanta, Georgia

Initial Posting: ; Last Update: November 26, 2013.

Summary

Disease characteristics. Mowat-Wilson syndrome (MWS) is characterized by the following:

  • Distinctive facial features
  • Structural anomalies including:
    • Hirschsprung disease
    • Genitourinary anomalies (particularly hypospadias in males)
    • Congenital heart defects (particularly abnormalities of the pulmonary arteries and/or valves)
    • Agenesis or hypogenesis of the corpus callosum
    • Eye defects (microphthalmia and Axenfeld anomaly)
  • Functional differences including:
    • Moderate to severe intellectual disability
    • Severe speech impairment with relative preservation of receptive language
    • Seizures
    • Growth retardation with microcephaly
    • Chronic constipation in those without Hirschsprung disease

Diagnosis/testing. Mutations and deletions in ZEB2 (also known as ZFHX1B or SIP-1) cause MWS.

  • Sequence analysis detects mutations in approximately 81% of individuals;
  • FISH detects large deletions encompassing all or part of ZEB2 in approximately 15% of persons;
  • Chromosomal rearrangements that disrupt ZEB2 cause MWS in approximately 2% of individuals;
  • An additional 2% have intermediate-sized deletions that can be detected by techniques such as quantitative PCR, MLPA, or gene-specific array CGH.

Management. Treatment of manifestations: Care by the appropriate specialist for dental anomalies, seizures, ocular abnormalities, congenital heart defects, chronic constipation, Hirschsprung disease, genitourinary abnormalities, and pectus anomalies of the chest and/or foot/ankle anomalies; educational intervention and speech therapy beginning in infancy.

Surveillance: Annual eye examination in childhood to monitor for strabismus and refractive errors; monitoring for otitis media; regular developmental assessments to plan/refine educational interventions; periodic reevaluation by a medical geneticist.

Genetic counseling. Mowat-Wilson syndrome is typically the result of a de novo dominant mutation. When MWS results from a de novo mutation, the risk to the sibs of a proband is small. No individuals with MWS have been known to reproduce. Although the vast majority of MWS occurs as the result of a de novo mutation, molecular genetic testing can be used to evaluate a pregnancy at theoretically increased risk as a result of constitutional and/or germline mosaicism for a ZEB2 mutation in a clinically unaffected parent.

Parents of an individual with MWS resulting from a structural unbalanced chromosome constitution (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement. The risk to sibs of a proband with a structural unbalanced chromosome abnormality depends on the chromosome findings in the parents. Prenatal diagnosis for pregnancies at increased risk because of a parental balanced structural rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.

Diagnosis

Clinical Diagnosis

Consensus clinical diagnostic criteria for Mowat-Wilson syndrome (MWS) have not been established. The diagnosis should be considered in individuals with the following:

  • Typical facial features (see Figure 1). In a study by Zweier et al [2005] all individuals with this combination of characteristics were found to have mutations or deletions in ZEB2:
    • Widely spaced eyes
    • Broad medial eyebrows
    • Low hanging columella
    • Prominent or pointed chin
    • Uplifted earlobes with a central depression. The earlobes have been described as resembling "orechietta pasta" or "red blood corpuscles." The ear configuration does not change significantly with age with the exception of the central depression, which is less obvious in adults.
    • Open-mouthed expression
  • Hirschsprung disease
  • Genitourinary anomalies, particularly hypospadias in males
  • Congenital heart defects, including abnormalities of the pulmonary arteries and/or valves
  • Agenesis or hypogenesis of the corpus callosum
  • Ophthalmologic anomalies, including microphthalmia and Axenfeld anomaly
  • Intellectual disability, typically in the moderate to severe range, with severe speech impairment, but relative preservation of receptive language
  • Seizures
  • Growth retardation with microcephaly
  • Chronic constipation in those without Hirschsprung disease
Figure 1

Figure

Figure 1. An individual with Mowat-Wilson syndrome at (a) one month, (b) two months, (c) five years, (d) 13 years, (e) 20 years, and (f) 21 years. Note how the typical facial features become more pronounced with time.

Additional suggestive facial features include the following [Mowat et al 2003, Adam et al 2006]:

  • Telecanthus
  • Deeply set eyes
  • Wide nasal bridge with prominent and rounded nasal tip
  • Thick or everted vermilion of the lower lip
  • Increased posterior angulation of the ears

Note: The facial phenotype evolves and becomes more pronounced with age (Figure 1), such that the diagnosis is easier to make in older individuals. The nasal tip lengthens and becomes more depressed and the nasal profile becomes more convex. The columella becomes more pronounced, leading to the appearance of a short philtrum. The face tends to elongate and the jaw becomes more prominent. The eyebrows may become heavier, broad, and horizontal [Wilson et al 2003, Horn et al 2004, Garavelli et al 2009].

Testing

Cytogenetic testing. Chromosomal rearrangements that disrupt ZEB2 cause MWS in approximately 2% of cases [Lurie et al 1994, Dastot-Le Moal et al 2007].

FISH analysis. Large deletions encompassing all or part of ZEB2 detectable by FISH have been observed in approximately 15% of persons with a clinical diagnosis of MWS [Mowat et al 2003, Dastot-Le Moal et al 2007]. Note that smaller intragenic deletions will not be detected by FISH analysis.

Molecular Genetic Testing

Gene. Mutations and deletions in ZEB2 (also known as ZFHX1B or SIP-1) are known to cause MWS in approximately 100% of cases [Amiel et al 2001, Kaariainen et al 2001, Wakamatsu et al 2001, Dastot-Le Moal et al 2007, Garavelli et al 2009].

Clinical testing

Table 1. Summary of Testing Used in Mowat-Wilson Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ZEB2Cytogenetic analysis Large-scale rearrangements ~2%
Sequence analysis Sequence variants 4~81% 5, 6
FISH analysisLarge deletions of ZEB2 ~15% 7
Deletion/duplication analysis 8Exonic or whole-gene deletions ~2% 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Approximately 50% of ZEB2 mutations localize to exon 8 [Zweier et al 2005, Dastot-Le Moal et al 2007, Garavelli et al 2009, Saunders et al 2009].

6. Mowat et al [2003], Cerruti Mainardi et al [2004], Garavelli et al [2009], Saunders et al [2009]

7. While whole-gene and some multiexon deletions are detectable by FISH, deletion of a single or several exons is too small to be detected. Detection requires deletion/duplication analysis.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. This testing will also detect large deletions/duplications detectable by FISH analysis.

9. Dastot-Le Moal et al [2007]

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Zollino et al 2011 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • When MWS is suspected, ZEB2 sequence analysis is recommended.
    • Saunders et al [2009] suggested that a cost-effective approach could include evaluation of exon 8 first, followed by sequencing of the remaining exons if exon 8 sequencing is uninformative. However, such partial-gene approaches are becoming less cost effective as the cost of sequencing decreases and the cost of handling samples (e.g., personnel time) increases.
  • If a mutation is not found through sequence analysis:
    • Deletion/duplication analysis can be performed, as about 17% of individuals with MWS have deletions or rearrangements detected by this modality.
    • Alternatively, FISH testing could be pursued to evaluate for large deletions that encompass ZEB2, but this may miss smaller whole-gene or partial-gene deletions. FISH would not be recommended if whole-genome CMA has been previously performed.
  • Whole-genome CMA or conventional cytogenetic analysis can be considered to exclude other large cytogenetic abnormalities or rare chromosomal rearrangements that involve ZEB2, respectively, if the phenotype is consistent with MWS but the above-mentioned studies are all normal [Kluk et al 2011].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Findings in more than 190 individuals with Mowat-Wilson syndrome (MWS) are summarized in this section [Lurie et al 1994, Amiel et al 2001, Yamada et al 2001, Zweier et al 2002, Garavelli et al 2003, Mowat et al 2003, Zweier et al 2005, Adam et al 2006, Dastot-Le Moal et al 2007, Garavelli et al 2009]. Not all features were evaluated in each individual described. The male/female ratio is approximately 1:2 (106:85) [Garavelli et al 2009].

Craniofacial. One of the most specific findings in MWS is the distinctive facial appearance (see Clinical Diagnosis), present in 98% of affected individuals.

At least five individuals have been described with palatal anomalies, including bifid uvula, submucous cleft palate, and cleft of the hard palate [Mowat et al 2003, Ishihara et al 2004]; one individual with atypical MWS had bilateral cleft lip and palate [Heinritz et al 2006].

Velopharyngeal insufficiency with laryngomalacia, glossoptosis, and micrognathia has been reported in one individual [Adam et al 2006]. A high-arched palate has been reported. Congenital tracheal stenosis has been reported in two persons [Ishihara et al 2004, Zweier et al 2005].

Growth parameters. Birth weight and length are typically in the normal range. Short stature (defined as a length or height ≤3rd centile) is present in 50% of persons studied. Growth hormone secretion has not been studied in these individuals.

Microcephaly (head circumference ≤3rd centile) may be present at birth or acquired. Microcephaly was present in 80% of individuals investigated, with at least two having a documented normal head circumference at birth.

Central nervous system anomalies. Agenesis or hypogenesis of the corpus callosum identified on neural imaging is present in approximately 46% of individuals. Less common findings include cerebral atrophy, poor hippocampal formation, frontotemporal hypoplasia, dilation of the occipital and temporal horns of the lateral ventricles with splaying of the frontal horns of the lateral ventricle and upward protrusion of the third ventricle, moderate ventriculomegaly with external hydrocephalus, and mild ventricular and cortical sulcal prominence without frank hydrocephalus.

Seizures. Seizures are present in 70%-75% of affected individuals [Garavelli et al 2009, Cordelli et al 2013a]. Multiple seizure types have been described but most frequently consist of focal and atypical absence seizures. For many individuals the first seizure is a focal seizure associated with fever.

EEG abnormalities may be age-dependent. EEGs performed at seizure presentation frequently demonstrate only mild slowing of background activity or are interpreted as normal. Repeat studies may show irregular diffuse frontally dominant and occasionally asymmetric spike and wave discharges. During slow-wave sleep the abnormalities are accentuated, resulting in continuous or near-continuous spike and wave activity [Cordelli et al 2013a]. Although many individuals with MWS have mild brain malformations, seizure activity in affected individuals does not appear to correlate with structural brain anomalies and the EEG patterns present in most affected individuals appear to be related to the genetic etiology of the condition itself [Cordelli et al 2013b].

Out of 22 affected individuals, seizure onset occurred at a median age of 14.5 months (range 1-108 months) [Cordelli et al 2013a]; however, seizure onset after age ten years has been reported [Wilson et al 2003]. Seizures may be difficult to control – more so in childhood than in adolescence or adulthood. In one affected individual with epilepsy that was refractory to multiple anti-seizure medications, a vagal nerve stimulator implantation resulted in reduction of seizure frequency from eight seizures daily to one seizure bimonthly [Benedetti-Isaac et al 2013]. In at least one other case, anti-seizure medications were discontinued in adulthood with no recurrence of seizures [Adam et al 2006].

Psychosocial and cognitive development. All individuals with MWS have moderate to severe intellectual disability, although the results of formal IQ testing have not been reported in most studies. All individuals over age one year have severely impaired verbal language skills, with either absent or severely restricted speech. Receptive language skills are generally more advanced than expressive language skills. Sign language and communication boards have been used by some affected individuals with success.

Gross motor milestones are generally delayed. Mean age of walking is between ages three and four years (range: 23 months to 8 years) [Zweier et al 2005, Adam et al 2006]. Some individuals do not achieve ambulation [Mowat et al 2003]. The gait is typically wide based with the arms held up and flexed at the elbow.

Many individuals have been described as having a happy demeanor with frequent laughter. Associated behaviors also include an increased rate of repetitive behaviors, oral behaviors, and under-reaction to pain. In comparison to individuals who have moderate to severe cognitive impairment due to other causes, individuals with MWS display similarly high levels of behavior or emotional problems, including disruptive/antisocial behavior, self-absorbed behavior, and anxiety [Evans et al 2012].

Dental. Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, gingival hypertrophy and/or bruxism have been described [Wilson et al 2003, Adam et al 2006, Kiraz et al 2013].

Eyes. About 4% of affected individuals have eye anomalies, including microphthalmia, iris/retinal colobomas, Axenfeld anomaly, peripupillary atrophy, ptosis, cataract, and retinal aplasia [Mowat et al 2003, Zweier et al 2005, Adam et al 2006, Dastot-Le Moal et al 2007, Ariss et al 2012, Kiraz et al 2013]. A more common feature is strabismus [Mowat et al 2003, Adam et al 2006]. Nystagmus has been described in some individuals, particularly in infancy, but this often resolves with age.

Ears. Recurrent otitis media has been described. Sensorineural hearing loss has not been described.

Cardiac. Structural heart defects are present in approximately 54% of individuals with MWS. Cardiac defects can vary but appear to frequently involve the pulmonary arteries and/or valves. Pulmonary artery sling has been described in at least six individuals [Ishihara et al 2004, Zweier et al 2005, Adam et al 2006, Garavelli et al 2009]. Other cardiac anomalies have included patent ductus arteriosus, atrial septal defects, ventricular septal defects, tetralogy of Fallot, coarctation of the aorta, bicuspid aortic valve, and aortic valve stenosis [Mowat et al 2003].

Gastrointestinal. MWS was initially described as a syndromic form of Hirschsprung disease (HSCR); however, only 54% of individuals with MWS have biopsy-proven HSCR.

Chronic constipation has been described in about 30% of persons with MWS without documented HSCR [Zweier et al 2005, Adam et al 2006, Garavelli et al 2009]. It is unclear whether chronic constipation results from ultrashort HSCR or the presence of some other partial defect in ganglion function [Yamada et al 2001].

Surgical outcomes for Hirschsprung disease in individuals with MWS are generally worse than surgical outcomes for those with nonsyndromic HSCR; complications may include prolonged need for total parenteral nutrition (TPN) and/or recurrent enterocolitis [Bonnard et al 2009, Smigiel et al 2010]. The increased complication rate may be due in part to a generalized gut motility disorder.

Other gastrointestinal problems include pyloric stenosis in 5% of affected individuals and (rarely) dysphagia [Garavelli et al 2009, Prijoles & Adam 2010].

Genitourinary. Approximately 52% of persons with MWS have some type of urogenital or renal anomaly, with 56% of males having hypospadias. Clinical findings can also include cryptorchidism (37% of males), bifid scrotum, vesicoureteral reflux (VUR), hydronephrosis, short penile chordee or "webbed penis," septum of the vagina, duplex kidney, pelvic kidney, hydrocele, and multicystic renal dysplasia.

Pubertal development. Very little has been written regarding pubertal development in MWS. One 17-year-old female underwent menarche at age 15 years but had inconsistent menstruation. One male underwent normal pubertal development. One male had mildly delayed pubertal development [Adam et al 2006].

Skeletal. A variety of skeletal manifestations have been described in MWS. Among the most common skeletal manifestations are long, slender, tapered fingers. In later childhood and adulthood, the interphalangeal joints may become prominent. Calcaneovalgus deformity of the feet has been described.

The following features have been reported in at least one affected individual: short and broad thumbs, broad halluces, unilateral duplication of the hallux, mild pectus anomalies that did not require surgery, ulnar deviation of the hands, proximally placed thumbs, delayed bone age, significant scoliosis, and camptodactyly [Mowat et al 2003, Adam et al 2006, Dastot-Le Moal et al 2007].

Skin. At least two individuals have been described with a fair complexion compared to their family background [Adam et al 2006]. One individual with MWS has been described as having gradual onset of widespread "raindrop" depigmentation in the truncal region [Wilson et al 2003].

Other. Each of the following findings has been described in a single affected individual. It is unclear whether these are rare features of MWS or if they represent rare unrelated co-occurrences.

Genotype-Phenotype Correlations

ZEB2 deletions and truncating mutations result in the typical facial features of MWS. Deletion sizes and breakpoints vary widely, with no obvious correlation between the phenotype and the size of the deletion [Zweier et al 2003], except for several individuals with extremely large deletions (>5 Mb) who were more severely affected [Ishihara et al 2004] than those with other types of mutations.

Rare missense, spice site, or in-frame mutations in ZEB2 lead either to a milder form of MWS or to individuals with atypical features. Individuals reported in the literature with atypical features of MWS include the following:

  • Three missense mutations in the highly conserved C-zinc-finger domain of ZEB2 appear to lead to the facial gestalt of MWS with moderate intellectual impairment but without other features of MWS [Ghoumid et al 2013].
  • An adult with mild intellectual disability, atypical facial features, and megacolon had a 3-bp in-frame deletion of ZEB2 [Yoneda et al 2002].
  • A person with trisomy 21 in addition to a ZEB2 point mutation had Hirschsprung disease, intellectual disability, ocular colobomas affecting the iris and retina, and atypical facial features [Gregory-Evans et al 2004].
  • A person with mild facial features (atypical but reminiscent of the MWS gestalt) had only mild speech delay and a novel splice site mutation in the 5'UTR [Zweier et al 2006].
  • A person with a missense mutation had cleft lip/palate, brachytelephalangy, and atypical eyebrows [Heinritz et al 2006].

Positive predictors of a ZEB2 mutation in those with the typical facial features of MWS include HSCR, agenesis of the corpus callosum, and urogenital anomalies (particularly hypospadias) [Zweier et al 2005].

Penetrance

Penetrance appears to be complete.

Anticipation

To date, anticipation has not been observed.

Prevalence

The prevalence of MWS has been estimated at between 1:50,000 and 1:70,000 live births [Mowat & Wilson 2010]; a higher prevalence has been suggested by some [Mowat et al 2003, Adam et al 2006].

MWS has been described in whites, Hispanics, Asians, and African Americans [Ishihara et al 2004, Adam et al 2006].

Differential Diagnosis

Many of the congenital anomalies seen in Mowat-Wilson syndrome (MWS) can be seen as isolated anomalies in an otherwise normal individual.

Disorders with overlapping features include the following:

  • Goldberg-Shprintzen syndrome, characterized by Hirschsprung disease, microcephaly, and intellectual disability and caused by recessive mutations in KIAA1279 [Brooks et al 2005]. However, the facial features and spectrum of congenital anomalies differ from those of MWS and include a higher frequency of cleft palate, ptosis, and ocular coloboma than are observed in MWS.
  • Other syndromic forms of HSCR. For a full review of syndromic and nonsyndromic forms of HSCR, see Hirschsprung Disease Overview.
  • Angelman syndrome (AS), particularly absent speech, hypopigmentation, seizures, microcephaly, ataxic-like gait, and happy demeaner. AS is caused by absence of maternal expression of UBE3A and may be diagnosed in about 80% of affected individuals using methylation analysis of chromosome 15. In infancy, only hypotonia may be evident. However, the multitude of congenital anomalies and characteristic facial features of MWS distinguish these two conditions.
  • Smith-Lemli-Opitz syndrome (SLOS), particularly hypospadias and intellectual disability in males. SLOS is associated with elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol:cholesterol ratio. Mutation of DHCR7 causes SLOS.
  • Rubenstein-Taybi syndrome (RSTS), particularly the nasal configuration and intellectual disability. Several individuals with MWS have had broad thumbs and great toes, and at least one had radial deviation of the thumbs and great toes [Mowat et al 2003, Adam et al 2006]. Mutations or deletions in CREBBP or mutations in EP300 are identified in approximately 70% of persons with RSTS. The facial features and spectrum of congenital anomalies distinguish RSTS from MWS.
  • Pitt-Hopkins syndrome (PTHS), particularly significant intellectual impairment with mean age of walking at four to six years, absent or severely impaired verbal language, behavioral issues, hand stereotypic movements, seizures, microcephaly, and constipation. However, the distinctive facial features in PTHS are different from those in MWS and individuals with PTHS may have episodic hyperventilation and/or breath holding while awake, which is not a feature of MWS. PTHS is caused by mutation or deletion of TCF4.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Mowat-Wilson syndrome (MWS), the following evaluations are recommended:

  • Baseline echocardiogram
  • Baseline dental evaluation in early childhood
  • Baseline ophthalmology evaluation
  • Baseline audiology evaluation
  • Review history for evidence of chronic constipation
  • Review history for evidence of seizures
  • Renal ultrasound examination to assess for structural renal anomalies
  • Genitourinary evaluation, particularly for hypospadias and cryptorchidism in males
  • Physical examination for pectus anomalies and foot/ankle malpositioning
  • Genetics consultation

Treatment of Manifestations

Treatment includes the following:

  • Dental. Referral to an orthodontist if significant dental anomalies are present
  • Neurologic. Referral to a pediatric neurologist if signs or symptoms suggest seizures. An EEG and/or head MRI may be warranted for diagnostic purposes or refractory seizures. Standard anti-epileptic drugs (AEDs) should be used, as indicated.
  • Developmental. Educational intervention and speech therapy beginning in infancy because of the high risk for motor, cognitive, speech, and language delay
  • Ophthalmologic. Treatment and/or following of ocular abnormalities by a pediatric ophthalmologist
  • Cardiovascular. Referral to a cardiologist or cardiothoracic surgeon for treatment of congenital heart defects
  • Gastrointestinal. Referral to a gastroenterologist for evaluation and treatment when chronic constipation is present; evaluation for HSCR and ultrashort HSCR. See Hirschsprung Disease Overview.
  • Genitourinary. Referral to a urologist or nephrologist as indicated
  • Musculoskeletal. Referral to an orthopedist for significant pectus anomalies of the chest and/or foot/ankle anomalies

Surveillance

Surveillance includes the following:

  • Annual eye examination in childhood to monitor for strabismus and refractive errors
  • Monitoring for the development of otitis media (OM); for those individuals with chronic OM, referral to an otolaryngologist
  • Regular developmental assessments to plan and refine educational interventions
  • Periodic reevaluation by a medical geneticist to apprise the family of new developments and/or recommendations

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mowat-Wilson syndrome (MWS) is typically the result of a de novo dominant mutation.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. MWS typically occurs as a de novo mutation; however, recurrence of MWS in siblings has been reported four times in the literature (see Risk to Family Members — Autosomal Dominant Inheritance, Parents of a proband). Therefore, the risk to sibs is low (1%-2%) but greater than that of the general population because of the possibility of constitutional and/or germline mosaicism.

Offspring of a proband. There have been no reports of individuals with MWS reproducing.

Other family members of a proband. Because MWS typically occurs as a de novo mutation, other family members of a proband are not at increased risk.

Risk to Family Members — Chromosomal Inheritance

Parents of a proband. Parents of a proband with a structural unbalanced chromosome constitution (e.g., deletion, duplication) are at risk of having balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband

  • The risk to sibs of a proband with a structural unbalanced chromosome constitution depends upon the chromosome findings in the parents.
  • If neither parent has a structural chromosome rearrangement, the risk to sibs is negligible.
  • If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. Individuals with MWS and an unbalanced chromosome rearrangement are not likely to reproduce.

Carrier testing. If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent has a balanced chromosome rearrangement, his or her family members are at risk and can be offered chromosome analysis.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Although the vast majority of MWS occurs as the result of a de novo mutation, prenatal diagnosis can be used to evaluate a pregnancy at theoretically increased risk because of the presence of constitutional and/or germline mosaicism in a clinically unaffected parent. In such cases, DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation is analyzed. The disease-causing allele of an affected family member should be identified before prenatal testing can be performed.

Prenatal diagnosis for pregnancies at increased risk because of parental balanced structural rearrangement is possible by chromosome analysis of fetal cells obtained by amniocentesis or chorionic villus sampling.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Congenital Heart Information Network (CHIN)
    101 North Washington Avenue
    Suite 1A
    Margate City NJ 08402-1195
    Phone: 609-822-1572
    Fax: 609-822-1574
    Email: mb@tchin.org
  • International Foundation for Functional Gastrointestinal Disorders (IFFGD) - Pediatric
    PO Box 170864
    Milwaukee WI 53217-8076
    Phone: 888-964-2001 (toll-free); 414-964-1799
    Fax: 414-964-7176
    Email: iffgd@iffgd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • Pull-thru Network (PTN)
    2312 Savoy Street
    Hoover AL 35226-1528
    Phone: 205-978-2930
    Email: PTNmail@charter.net

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Mowat-Wilson Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ZEB22q22​.3Zinc finger E-box-binding homeobox 2ZEB2 homepage - Mendelian genesZEB2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Mowat-Wilson Syndrome (View All in OMIM)

235730MOWAT-WILSON SYNDROME; MOWS
605802ZINC FINGER E BOX-BINDING HOMEOBOX 2; ZEB2

Normal allelic variants. ZEB2 comprises nine coding exons (exons 2-10). Exon 1 is non-coding. A rare G>A single nucleotide polymorphism (SNP) at amino acid Tyr310 has been observed in African-derived populations (dbSNP reference rs6711223). Because this G>A SNP does not result in an amino acid change, the variant is unlikely to be pathogenic.

Pathogenic allelic variants. All ZEB2 mutations described to date in classic MWS are either large deletions or frameshift or nonsense mutations [Lurie et al 1994, Amiel et al 2001, Cacheux et al 2001, Kaariainen et al 2001, Wakamatsu et al 2001, Yamada et al 2001, Nagaya et al 2002, Zweier et al 2002, Garavelli et al 2003, Mowat et al 2003, Cerruti Mainardi et al 2004, Dastot-Le Moal et al 2007, Garavelli et al 2009]. These results indicate that loss of a single ZEB2 allele is required to cause classic MWS. To date, more than 180 different pathogenic mutations in ZEB2 have been described [Ghoumid et al 2013].

Evidence suggests that less severe mutations result in milder or atypical presentations of MWS.

  • Missense mutations in the highly conserved C-zinc-finger domain of ZEB2 (p.Tyr1055Cys, p. Ser1071Pro, and p.His1045Arg) appear to lead to the facial gestalt of MWS with moderate intellectual disability but without other features of MWS [Ghoumid et al 2013].
  • Yoneda et al [2002] reported a 3-bp in-frame deletion in a woman with intellectual disability and late-onset megacolon but no typical facial features of MWS.
  • A splice mutation in the ZEB2 5'UTR was described in an individual with mild MWS-like facial features and developmental delays [Zweier et al 2006].
  • A missense mutation was reported in a child with mild features of MWS [Heinritz et al 2006].

Normal gene product. ZEB2 is a novel member of the two-handed zinc-finger/homeodomain transcription factor family, ΔEF1/Zfh-1. The protein encoded by ZEB2 is widely expressed in the developing mouse and plays an important role in the development of the neural crest. The ZEB2 protein, like other ΔEF1 family members, interacts with SMAD proteins and functions as a transcriptional repressor in response to TGF-β signaling [Verschueren et al 1999]. ZEB2 down-regulates E-cadherin expression, a key step in allowing epithelial cell tumor invasion [Comijn et al 2001].

Studies in mouse models have shown that murine Zeb2 is required for differentiation and guidance of cortical neurons, a process critical for proper neurodevelopment. This may underlie the mechanism that leads to seizures in individuals with MWS [McKinsey et al 2013, van den Berghe et al 2013]. Murine Zeb2 interacts with Sox10, a protein critical for development of the enteric nervous system, providing insight into the molecular basis of Hirschsprung disease in humans [Stanchina et al 2010].

Abnormal gene product. All ZEB2 mutations associated with classic MWS described to date result in loss of one copy of ZEB2 either by deletion or premature truncation of the protein. The clinical features of MWS are consistent with haploinsufficiency of ZEB2 having a negative impact on neural crest development. Homozygous Zeb2 knock-out mice fail to develop because of abnormalities of the neural crest [Van de Putte et al 2003, Bassez et al 2004].

In vitro studies demonstrated that the three missense mutations in the C-zinc-finger domain of ZEB2 that resulted in atypical MWS (p.Tyr1055Cys, p.Ser1071Pro, and p.His 1045Arg) were not able to bind to or repress the E-cadherin promoter. However, rescue of mutant zebrafish embryos using wild-type and the missense mutant ZEB2 mRNAs was variable and correlated with the severity of the phenotype observed in the affected individual with the missense mutation. Therefore, the role of ZEB2 may not be restricted to E-cadherin repression [Ghoumid et al 2013].

Studies suggest that ZEB2 expression is up-regulated in tumor cells [Maeda et al 2005, Lombaerts et al 2006]. To date only one individual with MWS has been reported with central nervous system tumors (medulloblastoma and glioblastoma) [Valera et al 2013]; it is unclear whether this finding is a rare feature of MWS or if it represents a rare unrelated co-occurrence.

References

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Chapter Notes

Author Notes

Web site: http://www.genetics.emory.edu

Acknowledgments

Author History

Margaret P Adam, MD, MS, FAAP, FACMG (2006-present)
Lora JH Bean, PhD, FACMG (2006-present)
Jessie Conta, MS, LCG (2013-present)
Vanessa Rangel Miller, MS, CGC; Emory University (2006-2013)

Revision History

  • 26 November 2013 (me) Comprehensive update posted live
  • 11 February 2008 (cd) Revision: del/dup analysis available clinically
  • 28 March 2007 (me) Review posted to live Web site
  • 1 December 2006 (vrm) Original submission
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