Mowat–Wilson Syndrome

In 1998, Mowat et al. described a new syndrome, now

known as Mowat–Wilson syndrome (MWS),

consisting of Hirschsprung disease or severe constipa-

tion, microcephaly, mental retardation, and character-

istic facial features, including hypertelorism, medially

flared and broad eyebrows, prominent columella,

pointed chin, and uplifted earlobes.

The prevalence of MWS is currently unknown.

However, it seems probable that the syndrome is

underdiagnosed, particularly in patients without

Hirschsprung disease. Approximately 171 patients

with ZEB2 mutations, deletions or cytogenetic abnor-

malities have been reported and over 100 mutations

have been described.

Synonyms and Related Disorders

Hirschsprung disease-mental retardation syndrome;

Microcephaly, mental retardation, and distinct facial

features with or without Hirschsprung disease

Genetics/Basic Defects

1. Caused by heterozygous mutations and deletions

in the gene ZEB2 on chromosome 2 (also known

as ZFHX1B or SIP-1) in approximately 81% of

cases

2. Typically resulting from a de novo dominant

mutation

3. Cytogenetic deletions or translocations of the chro-

mosome 2q21-q23 region were found in several

patients

Clinical Features

1. Typical facial features

a. Seen in all individuals with this combination of

characteristics were found to have mutations or

deletions in the ZEB2 gene (Zweier et al. 2005)

i. Ocular hypertelorism

ii. Medially flared and broad eyebrows

iii. Prominent columella

iv. Prominent or pointed chin

v. Open-mouthed expression

vi. Uplifted earlobes with a central depression

a) Earlobes described as resembling

“orechietta pasta” or “red blood

corpuscles.”

b) Ear configuration not changing signifi-

cantly with age with the exception of

the central depression, which is less

obvious in adults.

b. Additional suggestive facial features (Mowat

et al. 2003; Adam et al. 2006)

i. Telecanthus

ii. Deep-set eyes

iii. Broad nasal bridge with prominent and

rounded nasal tip

iv. Full or everted lower lip

v. Posteriorly rotated ears

c. Natural history of facial phenotype (Wilson et al.

2003; Horn et al. 2004)

i. More pronounced facial phenotype with

age, making diagnosis easier in older

individuals

ii. Lengthening of the nasal tip and becoming

more depressed

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_160,# Springer Science+Business Media, LLC 2012

1391

iii. More pronounced columella, leading to

appearance of a short philtrum

iv. Elongation of the face

v. More prominent jaw

vi. Eyebrows becoming heavier with an

increased medial flare

2. Spectrum of structural anomalies

a. Gastrointestinal anomalies

i. Hirschsprung disease

a) A strong cross-reference marker when

present

b) Not a constant finding

c) Present in approximately 57–63% of

cases

ii. Pyloric stenosis

b. Genitourinary anomalies, particularly hypospa-

dias in males

c. Congenital heart defects, including abnormali-

ties of the pulmonary arteries and/or valves

d. Agenesis or hypogenesis of the corpus callosum

e. Ophthalmologic anomalies, including

microphthalmia and Axenfeld anomaly

f. Teeth anomalies

i. Widely spaced teeth

ii. Dental crowding

iii. “Malpositioned” teeth

iv. Delayed tooth eruption

3. Other features

a. Mental retardation, typically in the moderate

to severe range, with severe speech impairment

but relative preservation of receptive language

b. Seizures

c. Growth retardation (short stature) with

microcephaly

d. Chronic constipation in those without

Hirschsprung disease

Diagnostic Investigations

1. Cytogenetic testing

a. Chromosomal rearrangements that disrupt the

ZEB2 gene cause MWS in approximately 2% of

cases

b. FISH analysis. Large deletions encompassing all

or part of the ZEB2 gene detectable by FISH in

approximately 15% of cases

2. Molecular genetic testing

a. ZEB2 mutation detection rate by sequencing/

FISH/QPCR for individuals with the “typical

MWS” facial phenotype approaches 100%

b. No evidence of locus heterogeneity for MWS

3. Hirschsprung disease evaluation

4. MRI imaging of the brain for CNS anomalies

5. Echocardiograph for congenital heart disease

6. Ophthalmologic evaluation for eye anomalies

7. Renal ultrasound for renal anomalies

8. EEG for seizures

Genetic Counseling

1. Recurrence risk

a. Patient’s sib

i. De novo mutation: low recurrence risk

ii. Possibility of constitutional and/or germline

mosaicism: low recurrence risk but greater

than that of the general population (1–2%)

a) Possibility of germline mosaicism

suggested in two families with two and

three affected sibs, respectively

b) Low-level paternal mosaicism observed

in a family with two affected sibs has

been reported

b. Patient’s offspring: individuals with MWS and

an unbalanced chromosome rearrangement

unlikely to reproduce

2. Prenatal diagnosis

a. Prenatal diagnosis of a pregnancy at theoretically

increased risk because of constitutional and/or

germline mosaicism in a clinically unaffected

parent.

i. Disease-causing allele of an affected family

member being identified prior to prenatal

diagnosis

ii. Molecular genetic analysis on DNA extracted

from fetal cells obtained by amniocentesis or

chorionic villus sampling

b. Prenatal diagnosis of a pregnancy at increased

risk because of parental balanced structural

rearrangement: possible by chromosome analy-

sis of fetal cells obtained by amniocentesis or

chorionic villus sampling.

c. Preimplantation genetic diagnosis: available for

families at increased risk because of parental

1392 Mowat–Wilson Syndrome

mosaicism in which the disease-causing muta-

tions have been identified.

3. Management

a. Mostly supportive including seizure control and

developmental intervention

b. Specific management for structural anomalies,

including Hirschsprung disease

References

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Mowat–Wilson syndrome. GeneReviews. Updated February

11, 2008. Available at: http://www.ncbi.nlm.nih.gov/books/

NBK1412/.

Adam, M. P., Schelley, S., Gallagher, R., et al. (2006). Clinical

features and management issues in Mowat-Wilson syn-

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scale deletions and SMADIP1 truncating mutations in

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Mowat–Wilson Syndrome 1393

a b

cd

Fig. 1 (a–d) A three-and-a-half-year-old boy was noted to have

Mowat–Wilson syndrome. Note the unusual facies

(hypertelorism, telecanthus, strabismus, wide prominent nasal

bridge, an unusual nose with a rounded tip and prominent colu-

mella, a prominent chin, and unusual ears with fleshy uplifted ear

lobes), long tapering fingers, and an unusual stereotypic use of

his hands in which he moves his fingers in front of his face and

regards them. He is severely developmentally delayed and has

hypotonia. Chromosome microarray analysis revealed a loss in

copy number in the long arm of chromosome 2, detected with

two clones, spanning at least 100 kb (including the ZFHX1B

gene), and confirmed by FISH analysis. Deletions in this region

have been associated with Mowat–Wilson syndrome

1394 Mowat–Wilson Syndrome