Genetic defects included chromosome deletions encompassing the entire ZEB2 gene (PMID:19215041).
The prevalence of MWS in Japan is approximately 1:90,000 (PMID:24715670).
There was no obvious genotype–phenotype correlation among the patients (PMID:24715670).
In PMID:19215041 a total of 19 patients is reported, 8 males and 11 females, ranging in age from 2 months to 21 years. The clinical diagnosis of MWS was confirmed by genetic test in all of them.
Involved genes:
ZEB2 (=SIP1) gene on 2q21–q23 (PMID:19215041),
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 ... 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 megacolon syndrome (609460) but the 2 disorders are genetically distinct (Mowat et al., 2003). Goldberg-Shprintzen megacolon syndrome is caused by mutation in the KIAA1279 gene (609367) located on 10q.
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 ... 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. - 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.
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 ... 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.
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 ... 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.
Consensus clinical diagnostic criteria for Mowat-Wilson syndrome (MWS) have not been established. Individuals with this condition have characteristic facial features, in addition to a variety of congenital anomalies, which suggest the diagnosis. ...
DiagnosisClinical DiagnosisConsensus clinical diagnostic criteria for Mowat-Wilson syndrome (MWS) have not been established. Individuals with this condition have characteristic facial features, in addition to a variety of congenital anomalies, which suggest the diagnosis. The following is a list of 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. FigureFigure 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. Ocular hypertelorism Medially flared and broad eyebrows Prominent 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 Additional suggestive facial features include the following [Mowat et al 2003, Adam et al 2006]:Telecanthus Deep-set eyes Broad nasal bridge with prominent and rounded nasal tip Full or everted lower lip Posteriorly rotated 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 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 with an increased medial flare [Wilson et al 2003, Horn et al 2004]. Structural anomalies include the following: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 Functional differences include the following: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 TestingCytogenetic 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]. Molecular Genetic TestingGene. Mutations and deletions in ZEB2 (also known as ZFHX1B or SIP-1) are known to cause MWS in approximately 81% of cases [Amiel et al 2001, Kaariainen et al 2001, Wakamatsu et al 2001, Dastot-Le Moal et al 2007]. Other loci. The ZEB2 mutation detection rate (sequencing/FISH/QPCR) for individuals with the "typical MWS" facial phenotype, as defined in Clinical Diagnosis, approaches 100% [Zweier et al 2005; D Mowat, personal communication]. There is no evidence of locus heterogeneity for MWS. Clinical testing Sequence analysis. Sequencing of all nine coding exons, splice junctions, and immediate intronic flanking regions of ZEB2 detects mutations in approximately 81% of individuals with a clinical diagnosis of MWS [Mowat et al 2003, Cerruti Mainardi et al 2004, Dastot-Le Moal et al 2007]. Although a study by Zweier et al (2005) demonstrated that all individuals with "typical MWS" features had a detectable deletion or mutation in ZEB2, partial-gene deletions may be too small to be detected on FISH analysis and may not be found by sequence analysis. Deletion testing. Approximately 15% of ZEB2 mutations are large deletions detectable by FISH. An additional 2% of individuals with MWS have an intermediate-sized deletion that is too small to be detectable by FISH analysis and too large to be detected by sequencing. In this situation quantitative PCR, MLPA or gene-specific array GH can be used [Dastot-Le Moal et al 2007]. Table 1. Summary of Testing Used in Mowat-Wilson SyndromeView in own windowGeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityZEB2Cytogenetic analysisLarge-scale rearrangements ~2% ClinicalSequence analysis Nonsense / frameshift mutations~81% FISHLarge deletions ~15% Deletion/duplication analysis 2 Intermediate-sized deletions ~2% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm the diagnosis in a proband When MWS is suspected, ZEB2 sequence analysis is recommended. If a mutation is not found, deletion/duplication analysis and/or FISH testing should be performed, as about 17% of individuals with MWS have deletions or rearrangements detected by these modalities. Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in an affected family member. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with disruptions in ZEB2. It is possible that missense mutations in ZEB2 may lead to a wide range of phenotypes.Note: Six fetuses found on ultrasound evaluation to have agenesis of the corpus callosum did not have deletion or mutation of ZEB2; therefore, disruption of this gene is not likely to be a major cause of isolated agenesis of the corpus callosum [Espinosa-Parrilla et al 2004].
This section summarizes findings in more than 150 individuals with Mowat-Wilson syndrome (MWS) [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]. Not all features were evaluated in each individual described. The male-to-female ratio is approximately 1.4 (92/67) [Dastot-Le Moal et al 2007]. ...
Natural HistoryThis section summarizes findings in more than 150 individuals with Mowat-Wilson syndrome (MWS) [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]. Not all features were evaluated in each individual described. The male-to-female ratio is approximately 1.4 (92/67) [Dastot-Le Moal et al 2007]. Craniofacial. One of the most specific findings in MWS is the distinctive facial appearance (see Clinical Diagnosis). At least three individuals have been described with a bifid uvula/submucous cleft [Mowat et al 2003]. At least one person with a large deletion has been described with a cleft of the hard palate [Ishihara et al 2004] and 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) developed in 17/36 (47%) 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 125/151 (83%) of individuals investigated, with at least two having a documented normal head circumference at birth.Central nervous system. Agenesis or hypogenesis of the corpus callosum identified on neural imaging was present in 60/144 (41%) of individuals examined. 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 were present in 91/128 (70%) of individuals. Multiple seizure types have been described, including focal, myoclonic, generalized, and absence seizures; no particular seizure type is characteristic of MWS. EEG abnormalities were identified in 28/48 (58%) of individuals studied. Seizure onset, typically in the second year of life, ranges from the neonatal period to over age ten years [Wilson et al 2003]. In some cases, seizures have been more difficult to control in childhood as compared to adolescence or adulthood. In at least one case, anti-seizure medications were discontinued in adulthood with no recurrence of seizures [Adam et al 2006].One individual developed severe autonomic dysregulation, with central sleep apnea, episodes of marked somnolence, and labile temperature and blood pressure [D Mowat, personal communication].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 speech or speech restricted to only a few words. One individual with a truncating mutation has over 300 words [D Mowat, personal communication]. 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 eight years) [Zweier et al 2005, Adam et al 2006]. Some individuals do not achieve ambulation [Mowat et al 2003]. The gait is typically widely based with the arms held up and flexed at the elbow.Many individuals have been described as having a happy demeanor with frequent laughter. Hand biting, head banging, and hyperactivity have been described in a few individuals with MWS [Adam et al 2006].Dental. Widely spaced teeth, malpositioned teeth, delayed tooth eruption, malformed teeth, and/or bruxism have been described [Wilson et al 2003, Adam et al 2006]. Eyes. Structural eye anomalies have been described in six individuals, three with microphthalmia, two with iris/retinal colobomas, and one with Axenfeld anomaly [Zweier et al 2005, Dastot-Le Moal et al 2007]. A more common feature is strabismus [Mowat et al 2003, Adam et al 2006]. Several persons have been described with ptosis or cataracts [Mowat et al 2003, Zweier et al 2005, Adam et al 2006]. Nystagmus has been described in some individuals, particularly in infancy, but this often resolves with age. At least two individuals have had myopia. In individuals with blue irides, dark pigmented clumps in the iris may be noted, suggesting heterochromia; however, true iris heterochromia has not been described. Ears. Recurrent otitis media has been described. Sensorineural hearing loss has not been described. Cardiac. Structural heart defects were found in 82/156 (53%) of individuals studied. Cardiac defects can vary but appear to frequently involve the pulmonary arteries and/or valves. Pulmonary artery sling has been described in at least five individuals [Ishihara et al 2004, Zweier et al 2005, Adam et al 2006]. 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 91/159 (57%) of individuals with MWS have biopsy-proven HSCR. In the largest series of mutation-positive cases the frequency of HSCR was 26/57 (46%) suggesting that with increasing clinical experience the diagnosis can more easily be made in the absence of HSCR [Dastot-Le Moal et al 2007]. Chronic constipation has been described in a subset of persons with MWS without documented HSCR [Zweier et al 2005, Adam et al 2006]. 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].Other gastrointestinal problems include pyloric stenosis in eight individuals [Mowat et al 2003, Adam et al 2006, Dastot-Le Moal et al 2007].Genitourinary. Seventy-three of 145 (50%) persons with MWS had some type of genitourinary anomaly, the most common of which is hypospadias in males. Other findings include cryptorchidism, 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]. One male underwent precocious puberty [D Mowat, personal communication]. 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].
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....
Genotype-Phenotype CorrelationsZEB2 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.Because features of those with a deletion and those with truncating mutations are similar, it is hypothesized that haploinsufficiency for ZEB2 is causative. One particular mutation, p.Arg695X, has been identified in 12 individuals (nine males and three females), of whom six had HSCR, three were reported to have constipation, and two had normal bowel function (no clinical information was available in one) [Dastot-Le Moal et al 2007].Those individuals with facial features that are "atypical" or "ambiguous" for MWS generally do not have mutations in ZEB2 [Zweier et al 2005]. Exceptions include the following: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].As yet, no studies have tried to link a particular mutation to an increased risk for the structural anomalies found in MWS. However, at least one individual with a mutation has had the facial phenotype and intellectual disability, but no structural anomalies [Wilson et al 2003].
Many of the congenital anomalies seen in Mowat-Wilson syndrome (MWS) can be seen as isolated anomalies in an otherwise normal individual....
Differential DiagnosisMany 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 found to be 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 mutations of DHCR7 that result in elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol: cholesterol ratio. 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.
To establish the extent of disease in an individual diagnosed with Mowat-Wilson syndrome (MWS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 History of chronic constipation History 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 Treatment of ManifestationsThe following are appropriate: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 SurveillanceAppropriate surveillance includes: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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDZEB22q22.3Zinc finger E-box-binding homeobox 2ZEB2 homepage - Mendelian genesZEB2Data 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) View in own window 235730MOWAT-WILSON SYNDROME 605802ZINC FINGER E BOX-BINDING HOMEOBOX 2; ZEB2Normal allelic variants. ZEB2 has 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. Pathologic allelic variants. All ZEB2 mutations described to date in classic MWS are either large deletions or frame shift 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]. These results indicate that loss of a single ZEB2 allele is required to cause classic MWS. Evidence suggests that less severe mutations result in milder or atypical presentations of MWS. 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 p.Gln1119Arg 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. 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]. 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]. Recent studies suggest that ZEB2 expression is up-regulated in tumor cells [Maeda et al 2005, Lombaerts et al 2006]. 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. Persons with MWS do not have increased ZEB2 expression and, to date, have not been reported to be at an increased risk for tumor development.