Mowat-Wilson Syndrome

Option 1

When the phenotypic findings suggest the diagnosis of MWS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of ZEB2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
  Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  Note: Larger deletions or duplications of chromosome 2q22.3 that include ZEB2 and adjacent genes will be detected through gene-targeted deletion/duplication analysis, but such testing cannot determine how large the deletion or duplication is or whether adjacent genes are involved. Chromosomal microarray in this scenario could be used to determine this information.
• An intellectual disability or seizure disorder multigene panel that includes ZEB2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of MWS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Chromosomal microarray analysis (CMA) is often performed first. If CMA is normal, exome sequencing is the most commonly used next genomic testing method; genome sequencing is also possible.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ZEB2) that cannot be detected by sequence analysis.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis or may be too small to be detected by CMA.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Karotype. If the phenotype is consistent with MWS but the above-mentioned studies do not detect a pathogenic variant involving ZEB2, conventional cytogenetic analysis can be considered to exclude other large cytogenetic abnormalities or rare chromosome rearrangements that involve ZEB2 [Kluk et al 2011].

Craniofacial Features

Distinctive craniofacial features are one of the most specific findings (see Suggestive Findings), present in more than 90% of affected individuals.

The facial phenotype evolves and becomes more pronounced with age (Figure 1), such that the diagnosis is easier to make in older individuals [Garavelli et al 2009]:

• The eyebrows may become heavier, broad, and horizontal.
• 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.

However, the ear configuration does not change significantly with age, with the exception of the central depression, which is less obvious in adults.

Additional suggestive facial features include the following:

• 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

Other rare craniofacial findings include the following:

• Palatal anomalies (bifid uvula, submucous cleft palate, and cleft of the hard palate)
• Right unicoronal craniosynostosis [Wenger et al 2014]

Growth

Birth weight and length are typically in the normal range.

Microcephaly (head circumference ≥2 SD below the mean) is most often acquired but can be present at birth.

Short stature (defined as length or height 2 SD below the mean) typically develops over time, with a mean adult height of 165.1 cm in males and 150.5 cm in females [Ivanovski et al 2018].

Body habitus is frequently lean and slender, with about 30% of affected individuals having a weight below the third centile for age and sex.

Eyes

Strabismus is the most common finding, present in more than half of affected individuals. Astigmatism and myopia are also common findings. Nystagmus has been described in some individuals, particularly in infancy; it often resolves with age.

About 10% of affected individuals have structural eye anomalies, including the following [Ivanovski et al 2018]:

• Microphthalmia
• Iris/retinal colobomas, which sometimes can lead to a suspicion of CHARGE syndrome [Wenger et al 2014] (See Differential Diagnosis.)
• Axenfeld anomaly
• Ptosis
• Cataract
• Retinal aplasia

Ears

Recurrent otitis media, which can cause conductive hearing loss, has been described in about one third of affected individuals. Due to a high pain threshold seen in many affected individuals (see Psychosocial and Cognitive Development), unexplained fever should prompt the clinician to consider otitis media as a potential cause.

Sensorineural hearing loss has only rarely been described [Abdalla & Zayed 2014, Ivanovski et al 2018].

Dental Findings

Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, dental crowding, gingival hypertrophy, and/or bruxism have been described [Kiraz et al 2013, Ivanovski et al 2018].

Cardiovascular Defects

Structural heart defects are present in almost 60% of individuals with MWS. The most common findings are septal defects and patent ductus arteriosus. More complex congenital heart defects, however, have been reported and include the following [Ivanovski et al 2018]:

• Pulmonary stenosis (in ≤20%)
• Coarctation of the aorta (in ≤10%)
• Bicuspid aortic valve
• Aortic valve stenosis
• Tetralogy of Fallot
• Pulmonary artery sling, with or without congenital tracheal stenosis (<4%). However, this finding is even less common in the general population, and thus pulmonary artery sling alone should prompt the clinician to consider a diagnosis of MWS.

Gastrointestinal Issues

MWS was initially described as a syndromic form of Hirschsprung disease (HSCR); however, only 44% of individuals with MWS have biopsy-proven HSCR.

Chronic constipation has been described in about 30% of persons with MWS without documented HSCR [Garavelli et al 2009, Ivanovski et al 2018]. It is unclear whether chronic constipation results from ultrashort HSCR or the presence of some other partial defect in ganglion function.

Chronic constipation typically becomes more common with age, likely due to a combination of factors, including insufficient liquid intake, low-fiber diet, and less vigilance in tracking stool output and consistency by caregivers [Niemczyk et al 2017].

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 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 the following:

• Repeated vomiting attacks in about 20% [Ivanovski et al 2018]
• Pyloric stenosis in 5% of affected individuals
• Dysphagia (rare) [Garavelli et al 2009, Prijoles & Adam 2010]

Renal Anomalies

Renal anomalies are present in about one quarter of affected individuals and most commonly consist of vesicoureteral reflux and hydronephrosis. Other, less common findings may include duplex kidney, pelvic kidney, and multicystic renal dysplasia.

Genital Anomalies

About 60% of males have hypospadias, while about 40% have cryptorchidism. Less common findings in males may include bifid scrotum, penile chordee or "webbed penis," micropenis, or hydrocele.

Septum of the vagina has been described rarely in females.

Pubertal Development

Very little has been written regarding pubertal development in MWS. One female age 17 years 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]. In the experience of the authors, most affected adults undergo typical pubertal development.

Skeletal Findings

A variety of skeletal manifestations have been described in individuals with 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 is also common.

Findings seen in up to 50% of affected individuals include the following:

• Pectus anomalies (excavatum or carinatum)
• Scoliosis
• Adducted thumbs
• Ulnar deviation of the hands
• Mild contractures of the joints and/or camptodactyly
• Genu valgus
• Pes planus
• Long toes with or without long and/or broad halluces
• Hallux valgus
• Delayed bone age
• Syndactyly

Rarely, individuals with MWS have sustained frequent fractures that responded to bisphosphonate therapy [Author, personal observation]. This is most likely a secondary finding due to decreased weight-bearing activity.

Neurologic Findings

Neurologic findings are very common in individuals with MWS.

Tone. A majority of individuals younger than age one year have hypotonia. Hypotonia occasionally transitions to spasticity in adolescence or adulthood. Spasticity can lead to joint contractures and mobility issues, which in turn can cause decreased weight-bearing activity and an increased risk of low bone mineral density with propensity to fractures.

Seizures are one of the most common neurologic issues in individuals with MWS, present in almost 80% [Cordelli et al 2013, Ivanovski et al 2018].

Mean age of onset is around three years, although first presentation of seizure as early as age one month and as late as 11 years has been reported [Ivanovski et al 2018].

Multiple seizure types have been described; types most frequently seen are focal and atypical absence seizures. For many individuals, the first seizure is a focal seizure associated with fever.

Up to 25% of affected individuals have seizures that are difficult to control (more so in childhood than in adolescence or adulthood) or refractory to conventional anti-seizure medications:

• Vagal nerve stimulator implantation resulted in reduction of seizure frequency in at least two affected individuals.
• In at least one other case, anti-seizure medications were discontinued in adulthood with no recurrence of seizures.

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 2013].

• Electrical status epilepticus during sleep (ESES) has been described in several individuals who have undergone overnight EEG studies [Bonanni et al 2017].
• The presence of ESES can negatively affect behavior as well as motor and cognitive function.
• Evaluation for ESES should be considered in any affected individual who has experienced regression in cognitive function or motor skills, such as the development of ataxia or dyspraxia.
• Seizure activity does not appear to correlate with structural brain anomalies.

Central Nervous System

Central nervous system anomalies are present in approximately half of individuals who have been imaged. The most common findings are abnormalities of the corpus callosum (i.e., hypoplasia, partial or complete agenesis). A variety of other anomalies, including the following [Garavelli et al 2017], have been described.

• Ventricular enlargement (lateral ventricle or ventricular temporal horn)
• Abnormalities of the hippocampus
• Cortical malformations (polymicrogyria, periventricular heterotopia, focal cortical dysplasia)
• Reduction of white matter thickness
• Localized signal alterations of the white matter
• Posterior fossa malformations (absent or small cerebellar vermis, macrocerebellum)
• Large basal ganglia

Psychosocial and Cognitive Development

All individuals with classic MWS have moderate to severe intellectual disability, although the results of formal IQ testing have not been reported in most studies. Individuals with pathogenic missense variants may have milder features, including milder cognitive disabilities (see Genotype-Phenotype Correlations).

Speech. The vast majority of affected individuals older than age one year have severely impaired verbal language skills, with either absent or severely restricted speech. Rare individuals with classic MWS have some speech capabilities, including the ability to use short sentences [Author, personal observation].

• Receptive language skills are generally more advanced than expressive language skills.
• Sign language and communication boards have been used by some affected individuals with limited success.

Gross motor milestones are generally delayed.

• Mean age of walking is between ages three and four years (range: 23 months to 8 years); some individuals do not achieve ambulation.
• The gait is typically wide based with the arms held up and flexed at the elbow.

Fine motor skills are also delayed. Most affected individuals require lifelong help with dressing and other activities of daily living.

Toileting. Most individuals with MWS remain incontinent of both feces and urine throughout life [Niemczyk et al 2017].

• Adaptive toileting skills (waking at night to urinate, using the toilet) improve with age, although most affected individuals are unable to be completely toilet trained.
• Treatment of chronic constipation may help with urinary incontinence (see Gastrointestinal Issues).

Behavior. Many individuals have been described as having a happy demeanor with frequent laughter. In comparison to individuals who have moderate-to-severe cognitive impairment due to other causes, individuals with MWS display similarly high levels of behavioral or emotional problems, including disruptive/antisocial behavior, self-absorbed behavior, and anxiety [Evans et al 2012]. Other associated behaviors seen in more than half of affected individuals include:

• Repetitive behaviors
• Oral behaviors, including mouthing and/or chewing objects or body parts
• Underreaction to pain

Sleep. About half of individuals with MWS have some degree of sleep disturbance, which may include frequent nighttime waking and early morning wakening [Evans et al 2016]. Clinicians should consider screening individuals with MWS for features of sleep disturbance, with referral to a sleep disorders clinic if there are clinical concerns.

Immunologic Findings

Asplenia has been reported in several individuals with MWS; one individual had a severe course that included purpura fulminans [Nevarez Flores et al 2019]. Immunodeficiency in individuals with MWS has not been systematically studied, although several affected individuals have required treatment with intravenous immunoglobulin (IVIG) for antibody deficiency leading to recurrent infections [Author, personal observation].

Anesthesia Risk

The most common management issue is the rare finding of a difficult airway at the time of intubation [Deshmukh et al 2016, Packiasabapathy et al 2016]. Other reported anesthetic challenges have included longer time to wean respiratory support, presence of anemia, and concomitant lower respiratory-tract infection [Spunton et al 2018]. However, there does not appear to be a true increased risk of adverse outcome from anesthesia due to this condition itself.

Additional Findings

The following findings have each been described in one affected individual. It is unclear whether these are rare features of MWS or if they represent unrelated co-occurrences.

• Cholestasis with histopathologic features of biliary atresia [Cui et al 2011]
• Medulloblastoma and glioblastoma [Valera et al 2013]
• Rhabomyosarcoma [Rogac et al 2017]
• Supernumerary intestinal muscle coat [Leong et al 2010]

Prognosis

It is unknown if life span in individuals with Mowat-Wilson syndrome is abnormal. One reported individual is alive at age 60 years [Author, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.