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A rare multiple congenital anomaly syndrome characterized by a distinct facial phenotype, intellectual disability, epilepsy, Hirschsprung disease (HSCR) and variable congenital malformations.
ORPHA:2152Classification level: Disorder
Prevalence is estimated at 1/50,000-70,000 live births. Over 300 patients have been reported so far. It seems probable that Mowat-Wilson syndrome (MWS) is underdiagnosed, particularly in patients without HSCR.
The typical characteristic facies of MWS includes a high forehead, frontal bossing, large eyebrows that are medially flaring and sparse in the middle part, hypertelorism, deepset but large eyes, large and uplifted ear lobes with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. The facies becomes more pronounced with age. Associated HSCR causes constipation which frequently persists after surgery. Patients usually have moderate to severe intellectual disability. Speech is absent or limited to a few words, with onset at around 4 years. Seizures are common; all types of seizures (absence, generalized tonic-clonic seizures, myoclonic, and focal seizures) have been reported. Most subjects have a happy demeanor with frequent smiling and a sociable personality. Other associated congenital anomalies can include cerebral (agenesis of the corpus callosum), cardiac (patent ductus arteriosus, ventricular septal defect), respiratory (valvular pulmonary stenosis, pulmonary artery sling, with or without tracheal stenosis), genitourinary (hypospadias, cryptorchidism, vesicoureteral reflux and hydronephrosis), ocular (microphthalmia) and musculoskeletal (pes planus, calcaneovalgus). Asplenia is rare. Affected children tend to have a high pain threshold.
MWS is caused by heterozygous variants in the zinc finger E-box-binding homeobox 2 gene, ZEB2 (2q22.3). To date, over 100 variants have been reported in patients with a typical phenotype; variants are usually whole/partial gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Genotype-phenotype analysis shows that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, missense variants affecting a functional domain of the ZEB2 protein can lead to an atypical phenotype.
Distinct facies is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis in all cases, even in the absence of HSCR. Congenital malformations and seizures require early clinical investigations for which patients should be referred to the relevant specialists (including neonatologists and pediatricians).
Differential diagnoses include Pitt-Hopkins, Goldberg-Shprintzen megacolon, Smith-Lemli-Opitz and Angelman syndromes.
Prenatal diagnosis is available for subsequent pregnancies of parents with an affected child.
MWS is an autosomal dominant disorder; however, the majority of MWS cases reported are sporadic. Germinal mosaicism has been described and recurrence risk has been calculated at 2%.
Management and treatment
Congenital heart disease and HSCR disease may require early surgery during the first days or months of life. Seizures are common and require standard therapy. Genitourinary anomalies may require surgery in the first few years of life. Psychomotor development is delayed in all patients and thus, rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible. Musculoskeletal anomalies may require orthopedic intervention.
Mortality and morbidity depend on the presence and severity of congenital anomalies. Patients have been reported to live into early adulthood but require assistance with activities of daily living.
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