Mowat-Wilson Syndrome

A number sign (#) is used with this entry because Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation in the ZEB2 gene (605802) on chromosome 2q22.

Description

Mowat-Wilson syndrome is an autosomal dominant complex developmental disorder; individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels. Mowat-Wilson syndrome has many clinical features in common with Goldberg-Shprintzen syndrome (609460) but the 2 disorders are genetically distinct (Mowat et al., 2003). Goldberg-Shprintzen syndrome is caused by mutation in the KIAA1279 gene (609367) located on 10q.

Clinical Features

Mowat et al. (1998) described 6 unrelated children with a distinctive facial phenotype in association with mental retardation, microcephaly, and short stature. Four of the children presented with Hirschsprung disease in the neonatal period; a fifth child was diagnosed with Hirschsprung disease after years of constipation. One of the 4 patients had an interstitial deletion of chromosome 2 del(2)(q21q23). All the patients described by Mowat et al. (1998) were isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23.

Among more than 200 cases of Hirschsprung disease, Wakamatsu et al. (2001) found that 5 patients presented with Hirschsprung disease associated with microcephaly, mental retardation, epilepsy, and characteristic facial features. These 5 patients were all isolated cases, and 3 of them were complicated by congenital heart disease, including patent ductus arteriosus and/or ventricular septal defect. All patients had normal birth weights; microcephaly, hypertelorism, convergent strabismus, and wide nasal bridge were observed in all cases, with facial features similar to those previously reported by Mowat et al. (1998). Deafness, pigmentation defects, iris coloboma, ptosis, and cleft palate were not observed. Patient 1 also had a t(2;13)(q22;q22) translocation.

Yamada et al. (2001) demonstrated that Hirschsprung disease was absent in 6 patients with mutations in the ZFHX1B gene who otherwise had features similar to previously reported mutation-positive patients (see, e.g., 605802.0002). All mutations were de novo and occurred in 1 allele. The wide spectrum of features suggested neurocristopathies at the cephalic, cardiac, and vagal levels.

Yoneda et al. (2002) reported a 48-year-old woman, born of nonconsanguineous parents, who had late infantile-onset mental retardation and developed megacolon in adulthood. Although the patient had no typical clinical features of Hirschsprung disease-mental retardation syndrome, a deletion identified in exon 3 of the ZFHX1B gene (605802.0011). She was noted to have mental retardation in childhood but received a full education in elementary school. She sometimes had constipation but did not require medication until age 48 years, when she presented with severe constipation and was found to have megacolon. This patient thus appeared to represent an intermediate stage between the full-blown Hirschsprung disease-mental retardation syndrome and Hirschsprung disease-mental retardation syndrome without Hirschsprung disease.

Amiel et al. (2001) found large-scale ZFHX1B deletions or truncating mutations in 8 of 19 patients with Hirschsprung disease and mental retardation. They found frequent features such as hypospadias and agenesis of the corpus callosum. One of the patients with a deletion mutation had previously been reported by Tanaka et al. (1993) to have Goldberg-Shprintzen syndrome. Amiel et al. (2001) stated that 2 other patients reported to have Goldberg-Shprintzen syndrome (Hurst et al., 1988, patient 3; Ohnuma et al., 1997) most likely had Mowat-Wilson syndrome.

Ohnuma et al. (1997) described a Japanese boy who was noted during the neonatal period to have hypotonia and poor sucking. Emergency colostomy was performed at the age of 6 days because of severe constipation, abdominal distention, and congenital megacolon. Histologic findings of a rectal biopsy showed aganglionosis of the submucosal plexus and confirmed short segment Hirschsprung disease. The patient was referred at the age of 15 months because of epilepsy. He had sparse scalp hair, a sloping forehead, sparse eyebrows, telecanthus, broad nasal bridge, large ears, and pointed chin, ventricular septal defect, hypospadias with bifid scrotum, cutaneous syndactyly between the second and third fingers, and rocker-bottom feet. A brain CT revealed prominent sulci and dilatation of ventricles, indicating brain atrophy or hypoplasia. Brain MRI showed loss of parenchymal volume, especially of the white matter, thin and hypoplastic corpus callosum with absent rostrum, genu, and configuration. The anterior commissure was absent.

Zweier et al. (2002) analyzed the ZFHX1B gene in 5 patients, 3 of whom had Hirschsprung disease syndrome, 2 with and 1 without the facial phenotype described by Mowat et al. (1998), and 2 of whom had the distinct facial gestalt without Hirschsprung disease. Zweier et al. (2002) excluded large deletions in all 5 patients and found truncating ZFHX1B mutations (605802.0007-605802.0010) in all 4 patients with the characteristic facial phenotype but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. Zweier et al. (2002) suggested calling the clinical entity of this distinct facial appearance, mental retardation, and variable MCAs the 'Mowat-Wilson syndrome.'

Wilson et al. (2003) presented clinical data and mutation analyses from a series of 23 patients with Hirschsprung disease-mental retardation syndrome, of whom 21 had proven ZFHX1B mutations or deletions and 15 were previously unpublished. Two patients with the typical features (1 with and 1 without HSCR) did not have detectable abnormalities of ZFHX1B. Wilson et al. (2003) emphasized that this syndrome can be recognized by the facial phenotype in the absence of either HSCR or other congenital anomalies, and that it needs to be considered in the differential diagnosis of dysmorphism with severe mental retardation and presence or absence of epilepsy. They provided numerous photographs illustrating the facial dysmorphism changes with age. Young children tend to have an open-mouthed smiling expression with an uplifted face. The eyebrows are horizontal and wedge-shaped (medially broad) and widely separated. In later childhood, the nasal tip lengthens and depresses, overhanging the philtrum. The upper half of the nasal profile becomes convex, tending to produce an aquiline profile. The chin lengthens and prognathism develops.

Zweier et al. (2003) stated that in addition to severe mental retardation, recognizable facial gestalt, pre- or postnatal microcephaly, and postnatal growth retardation, features of Mowat-Wilson syndrome include seizures (82%) and malformations such as HSCR (67.6%), congenital heart defects (47%), and agenesis of the corpus callosum (35%). Because HSCR occurs in only approximately two-thirds of patients with Mowat-Wilson syndrome, and patients with and without HSCR can be recognized by other features, especially their distinct facial gestalt, Zweier et al. (2003) supported Mowat-Wilson syndrome as a more appropriate designation. Deletion sizes and breakpoints in these patients vary widely from 300 kb to at least 11 Mb, thus ruling out a true microdeletion syndrome. Parental origin had been determined in 4 patients, and was paternal in all. Patients with deletions were very similar to those with truncating mutations. There was no correlation between the phenotype and size of deletion up to 5 Mb; however, 1 patient with a larger deletion of approximately 11 Mb had early seizures with a lethal course and hypoplasia of the big toes as additional features. Zweier et al. (2003) described 4 patients with Mowat-Wilson syndrome; in 2 the diagnosis was made because of HSCR and associated features, and in the other 2 because of mental retardation associated with the distinct facial gestalt in the absence of HSCR.

Adam et al. (2006) presented detailed clinical features of 12 patients with Mowat-Wilson syndrome. All had a characteristic facial feature of a prominent nasal tip with the columella extending below the ala nasi. Other common facial features included cupped ears with fleshy, upturned lobules, deep-set eyes, hypertelorism, medially flared and broad eyebrows, and pointed chin. Adam et al. (2006) also noted that patients had malpositioning of the teeth and delayed tooth eruption, recurrent otitis media, postnatal growth deficiency in both height and weight, accessory nipples, long, tapering fingers, severely impaired or absent speech, happy demeanor, and pulmonary artery and valve anomalies. Only 6 of the 12 patients had Hirschsprung disease, suggesting that it is not required for the diagnosis.

Strenge et al. (2007) reported a girl with Mowat-Wilson syndrome, confirmed by genetic analysis, who had multiple congenital cardiovascular anomalies, including patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, and a pulmonary artery sling. She also had subglottic stenosis and distal tracheal stenosis. Although she had constipation, she did not have Hirschsprung disease, which the authors noted was not required for diagnosis. Other major clinical features included microcephaly, mental retardation, speech impairment, epilepsy, and characteristic facial phenotype with hypertelorism, downslanting palpebral fissures, broad eyebrows, lateral sparseness, prominent nasal tip, pointed chin, ears with upturned lobules, and a high-arched palate.

Cecconi et al. (2008) reported 2 sisters with Mowat-Wilson syndrome confirmed by genetic analysis. Both showed agenesis of the corpus callosum on prenatal screening at about 20 weeks' gestation. One girl had normal cardiac features, whereas the other had a complex heart malformation with aortic coarctation and valvular stenosis, pulmonary valve stenosis, and multiple septal defects. As neither parent was affected, the authors postulated germline somatic mosaicism.

Garavelli et al. (2009) studied 19 Italian patients with Mowat-Wilson syndrome, including 6 previously reported patients (Garavelli et al., 2003; Cerruti Mainardi et al., 2004; Silengo et al., 2004; Zweier et al., 2005), all of whom had the typical facial gestalt. Garavelli et al. (2009) provided photographs demonstrating changes in the characteristic facies with age. In older children, the face appeared more elongated, with a prominent jaw; the eyebrows tended to become heavier, broad, and horizontal, usually subdivided by a middle longitudinal line and an element of sparseness. The nasal tip lengthened and became more depressed, and the columella was prominent, giving rise to the appearance of a short philtrum, and the nasal profile became more convex. In adolescents and adults, the nasal tip overhung the philtrum, the face tended to lengthen with prognathism, and a long, pointed or 'chisel-shaped' chin might be observed. The uplifted ear lobes did not change much over time, except for the central depression becoming less remarkable. Garavelli et al. (2009) also reviewed the published clinical findings in MOWS patients with ZEB2 mutations.

Cordelli et al. (2013) performed a retrospective study of the seizure phenotype of 22 Italian patients with genetically confirmed MOWS. The patients ranged in age from 2 to 22 years. The mean age at seizure onset was 14.5 months (range, 1-108 months), and all patients presented initially with a focal seizure, often associated with fever, manifest variably as hypomotor, versive, or focal clonic. This type was followed by a high prevalence of atypical absence seizures later in childhood. Focal seizures were more frequent during drowsiness or sleep. At onset of seizures, EEG was normal or showed only mild slowing of background activity. However, most patients later showed spike and wave discharges, predominantly frontal, that were sometimes continuous during sleep. The seizures were difficult to control with medication; only 9 patients achieved remission with multiple medications.

Bourchany et al. (2015) reported 4 unrelated patients with Mowat-Wilson syndrome and mutations in the ZEB2 gene who all exhibited eye malformations. Ocular anomalies included microphthalmia, microcornea, irregular border of pupil, corectopia, focal iris atrophy, goniodysgenesis, iris and retinal coloboma, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes associated with severely reduced vision. All eye malformations were asymmetric and often unilateral, and all eye segments were involved. Noting that eye abnormalities were rarely reported in MOWS, the authors studied the location of ZEB2 mutations in 12 MOWS patients with ocular malformations, but did not discern any genotype/phenotype correlations. They also noted that the sibs described by McGaughran et al. (2005) exhibited intrafamilial variability, with 1 sib having an aplastic optic nerve with central chorioretinal coloboma of the left eye, and the other sib having no eye malformations.

Neuropsychologic Features

Evans et al. (2012) evaluated behavior of 61 MOWS patients using a checklist filled out by parents or caregivers. The data were compared to those from 122 individuals with intellectual disability (ID) from other causes. Patients with MOWS tended to have significantly increased oral behaviors such as chewing or eating non-food items and teeth grinding, increased rate of repetitive behaviors, underreactivity to pain, and happy or elated mood compared to those with other ID causes. Patients with MOWS were significantly less likely to appear depressed, cry easily, not show affection, or remain alone compared to those with other ID causes. The overall MOWS behavioral phenotype was suggestive of a happy affect and sociable demeanor. However, those with MOWS displayed similarly high levels of behavioral problems as those with ID from other causes, with over 30% showing clinically significant levels of behavioral or emotional disturbances such as disruptive behavior, communication disturbances, and anxiety. It was not possible to ascertain IQ levels.

Neuroimaging

Garavelli et al. (2017) reviewed brain MRIs of 54 Mowat-Wilson patients with a proven ZEB2 defect, compared them with features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of the corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia and cortical and cerebellar malformations. Most features were underrepresented in the literature. The literature review included 56 cases in whom MRI had been performed and evaluated in detail.

Inheritance

Most patients with Mowat-Wilson syndrome have de novo heterozygous mutations in the ZEB2 gene (summary by Ghoumid et al., 2013). However, rare affected sibs have been reported, suggesting germline somatic mosaicism in 1 of the parents (McGaughran et al., 2005; Cecconi et al., 2008).

Cecconi et al. (2008) reported 2 sisters with Mowat-Wilson syndrome confirmed by genetic analysis. As neither parent was affected, the authors postulated germline somatic mosaicism. Including previous reports, Cecconi et al. (2008) estimated that the recurrence rate of Mowat-Wilson syndrome could be as high as 2.3% (4 of 175; range, 0.6-5.7%).

Population Genetics

The prevalence of Mowat-Wilson syndrome is estimated to be 1 per 50,000-70,000 live births (summary by Ghoumid et al., 2013).

Cytogenetics

Engenheiro et al. (2008) reported 2 unrelated patients with Mowat-Wilson syndrome associated with cytogenetic abnormalities resulting in disruption of the ZEB2 gene. One patient had an interstitial 0.6-Mb deletion at chromosome 2q22 including the entire ZEB2 gene that was detected by array comparative genomic hybridization (CGH) at age 13 years after conventional cytogenetic analysis reported a normal karyotype. The other patient had a complex balanced chromosomal rearrangement, t(2;12;18)(q22.3;12q22;q21.33), detected by cytogenetics early in childhood. The 2q22 breakpoint was later found to be in intron 2 of the ZEB2 gene when the patient was about 19 years old. The other breakpoints in this patient were not known to disrupt any genes. Engenheiro et al. (2008) noted that both patients were only properly diagnosed with Mowat-Wilson syndrome after initial cytogenetic findings were investigated further, suggesting that the syndrome may be underdiagnosed.

Molecular Genetics

In 4 of 5 patients with Hirschsprung disease associated with microcephaly, mental retardation, epilepsy, and characteristic facial features of Mowat-Wilson syndrome, Wakamatsu et al. (2001) identified pathogenic changes in the ZEB2 gene, including 1 deletion and 3 mutations (see, e.g., 605802.0001-606802.0003). No mutation was identified in ZEB2 in the fifth patient. All of the mutations occurred de novo.

In 3 patients originally described by Mowat et al. (1998), Cacheux et al. (2001) identified mutations in the ZEB2 gene (see, e.g., 605802.0004).

Horn et al. (2004) reported 2 unrelated patients with Mowat-Wilson syndrome diagnosed on the basis of the characteristic facial features; neither patient had HSCR. Both were found to have deletions in the ZFHX1B gene, confirming the diagnosis.

Ishihara et al. (2004) identified 5 novel nonsense and frameshift mutations in the ZFHX1B gene in patients with Mowat-Wilson syndrome and characterized the clinical features and molecular basis of a total of 27 cases with mutations or deletions in ZFHX1B. Two novel features, pulmonary artery sling and vaginal septum, were observed in 2 patients, 1 with a frameshift and 1 with a nonsense mutation, respectively. Repeated vomiting attacks were seen in 5 patients; the authors suggested that the attacks were possibly related to epilepsy, as they were controlled by anticonvulsants in 1 patient. Two of their patients with large deletions (10.42 Mb and 8.83 Mb) had significantly delayed psychomotor development, and 1 of them also had a cleft palate and complicated heart disease, features not previously reported in patients with Mowat-Wilson syndrome.

McGaughran et al. (2005) described a sister and brother with phenotypic Mowat-Wilson syndrome in whom they identified a 1-bp deletion in the ZFHX1B gene (605802.0013). The mutation was not found in the unaffected parents' lymphocyte-derived DNA, suggesting germline mosaicism in the sibs. McGaughran et al. (2005) stated that this was the first report of a sib recurrence of Mowat-Wilson syndrome.

Zweier et al. (2006) reported a 5-year-old boy with facial features of Mowat-Wilson syndrome but who exhibited an unusually mild phenotype and in whom they identified heterozygosity for a splice site mutation in the ZFHX1B gene (605802.0014). The patient had medially flared broad eyebrows, hypertelorism, pointed nose and chin, and prominent, mildly uplifted earlobes, but the overall facial gestalt was less striking than that of most MOWS patients. His psychomotor development was much better than expected for classic MOWS; by age 4 he spoke in full sentences and had sphincter control. Except for increased disposition to seizures on EEG and body measurements at the 3rd centile, he had no other anomalies frequently observed in MOWS such as agenesis or hypoplasia of the corpus callosum, congenital heart defects, urogenital anomalies, Hirschsprung disease, or constipation.

Heinritz et al. (2006) described a 2.5-year-old boy with a de novo heterozygous missense mutation in the ZFHX1B gene (605802.0015) who had the overall facial phenotype of Mowat-Wilson syndrome, but with cleft lip and palate and lacking the characteristic eyebrows. The patient also had brachytelephalangy, which the authors stated had never been described before in Mowat-Wilson syndrome.

Dastot-Le Moal et al. (2007) stated that more than 110 different mutations in the ZEB2 gene had been described. Nonsense mutations accounted for approximately 41% of the known punctual mutations and have been localized mainly in exon 8. No obvious genotype-phenotype correlations have been observed.

De Pontual et al. (2006) genotyped the RET (164761) locus in 30 patients with Mowat-Wilson syndrome who were known to have mutations in the ZFHX1B gene; no significant differences in SNP distribution of the nonsyndromic HSCR-predisposing RET haplotype (ATA) were observed between MOWS patients with and without HSCR. De Pontual et al. (2006) concluded that there are both RET-dependent and RET-independent HSCR cases and suggested that at least 1 more modifier gene must be involved.

Genotype/Phenotype Correlations

The majority of ZEB2 mutations identified in patients with Mowat-Wilson syndrome lead to haploinsufficiency through premature termination or large gene deletions. In 3 unrelated patients with a mild form of MOWS, Ghoumid et al. (2013) identified 3 different heterozygous missense mutations in the ZEB2 gene (see, e.g., S1071P, 605802.0016 and H1045R, 605802.0017). All 3 mutations occurred in the conserved C-terminal zinc finger cluster domain. In vitro functional expression studies showed that these 3 mutant proteins lost the ability to bind to the E-cadherin (CDH1; 192090) promoter and to repress transcription of this target gene, consistent with a loss of function and without a dominant-negative effect. However, these mutant mRNAs showed significant phenotypic rescue of morpholino knockout zebrafish embryos: complete rescue with S1071P (84%) and partial rescue with H1045R (55%), indicating that they are hypomorphic alleles; wildtype mRNA showed 81% rescue. The patients had mild facial gestalt of MOWS and moderate intellectual disability, but no microcephaly, heart defects, or HSCR. The variable embryonic rescue correlated with the severity of the patients' phenotype.