Mowat-Wilson syndrome (MOWS)

What is Mowat-Wilson syndrome (MOWS)?

Mowat-Wilson syndrome is a genetic disorder that often presents with Hirschsprung disease, which is an intestinal disorder.

Intellectual disability, delayed mental and motor development, as well as a wide variety of neurocristopathies (abnormalities of cells derived from the embryonic cellular structure known as neural crest) are frequently found in this syndrome.

Syndrome Synonyms:
HIRSCHSPRUNG DISEASE-MENTAL RETARDATION SYNDROME Mowat-Wilson Mowat-Wilson Syndrome

What gene changes cause Mowat-Wilson syndrome (MOWS)?

The syndrome is caused by mutations in the ZEB2 gene. The majority of cases of this rare disease are due to a new gene mutation.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Mowat-Wilson syndrome (MOWS)?

The main symptoms of the syndrome are global developmental delay including intellectual disability and delayed motor development. Individuals develop very limited, or no speech although their verbal reasoning is usually better than their actual ability to speak. Individuals with the syndrome are also often characterized by their happy personality.

Hirschsprung disease, and intestinal health issues are a major symptom of the syndrome and these issues can cause chronic constipation.

Physical features of the syndrome include a short stature, extremely small heads, low muscle tone, distinctive eyebrows which are thicker in the center, uplifted earlobes, misaligned, deep set eyes, a broad nasal bridge and pointed nose tip.

Other health conditions associated with the syndrome may include congenital heart defects, as well as seizures and epilepsy.

Possible clinical traits/features:
Iris coloboma, Pectus excavatum, Abdominal distention, Abnormal localization of kidney, Low-set, posteriorly rotated ears, Tapered finger, Intellectual disability, Intellectual disability, moderate, Muscular hypotonia, Microcephaly, Strabismus, Camptodactyly of finger, Frontal bossing, Uplifted earlobe, Ptosis, Happy demeanor, Supernumerary nipple, Vomiting, Preaxial foot polydactyly, Ventricular septal defect, Tetralogy of Fallot, Pulmonic stenosis, Prominent nasal tip, Pulmonary artery stenosis, Pulmonary artery sling, Cupped ear, Cryptorchidism, Everted lower lip vermilion, Esotropia, Deeply set eye, Epicanthus, Finger syndactyly, Fine hair, External ear malformation, Constipation, Low hanging columella, Broad columella, Cleft upper lip, Deep plantar creases, Delayed eruption of teeth, Motor delay, Ventriculomegaly, Displacement of the urethral meatus, Downslanted palpebral fissures, Agenesis of corpus callosum, Drooling, Cleft palate, Cerebral cortical atrophy, Wide nasal bridge, Broad eyebrow, Atrial sep

How does someone get tested for Mowat-Wilson syndrome (MOWS)?

The initial testing for Mowat-Wilson syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Mowat-Wilson syndrome

Mowat-Wilson syndrome is characterized by distinctive facial features; a range of structural anomalies that may include Hirschsprung disease, congenital heart defects, and eye anomalies; and functional differences, such as intellectual disability, seizures, and growth retardation with microcephaly. Pathogenic variants and deletions in the ZEB2 gene (also known as ZFHX1B, SIP1 or SMADIP1) cause Mowat-Wilson syndrome.

Mowat et al., (1998) reported six children with the combination of Hirschsprung disease, microcephaly (postnatal), intellectual disability, and distinctive facies. The face was characterized by deep-set, large eyes, a broad low nasal bridge, a rounded nasal tip. a prominent columella, an open-mouthed expression, a short philtrum, a triangular jaw, a prominent chin, and large uplifted, fleshy ear lobules with a central depression (orecchietti pasta). The eyebrows are horizontal, wedge-shaped (medially broad) and widely separated.

Some have disordered growth patterns (Wilson et al., 2003). Five had proven Hirschsprung disease (four short segment), but one case just had chronic constipation with a normal rectal biopsy. There was prenatal short stature, slender tapered fingers, and bilateral calcaneovalgus deformity of the feet. Congenital heart disease was present in three cases (PDA, ASD, pulmonary stenosis, pulmonary atresia). Four cases developed epilepsy. Two cases had proven agenesis of the corpus callosum.

One case had a del (2q22-2q23). The authors also identify a report by Lurie et al., (1994) of a child with a similar 2q deletion and similar clinical features. The authors also consider that the case reported by Tanaka et al., (1993) and Hurst et al., (1988) (Case 3) had similar features.

Wakamatsu et al., (2001) and Cacheux et al., (2001) reported dominant mutations in the ZEB2/SIP1/ZFHX1B/SMADIP1 gene. The gene encodes Smad interacting protein-1. This is a member of a family of two-handed zinc finger/homeodomain proteins. The mutations all result in lost of function.

Further mutations were reported by Yamada et al., (2001). None of these patients had Hirschsprung disease, but all had significant microcephaly and hypertelorism.

Greco et al., (2001) reported a case with somewhat similar features but with a normal head circumference and proximal muscle weakness.

Sztriha et al., (2003) emphasize the neurological features in their report of a patient with a 7 bp deletion of the zinc finger homeobox 1B gene.

The case with ""cutis tricolor"" reported by Ruggieri et al., (2003) looks like she may have Mowat-Wilson syndrome.

Further cases with and without Hirschsprung disease were reported by Zweier et al., (2002). Amiel et al., (2001) studied 19 patients with Hirschsprung disease and intellectual disability and identified SIP1 mutations in eight of them.

Mowat et al., (2003) provide an excellent review. Wilson et al., (2003) report further mutation cases and provide a good review. Kaariainen et al., (2001) reported five cases with similar features and provide a good review.

Gonadal mosaicism might be a problem in counselling. McGaughran et al., (2005) reported sibs with the same mutation that could not be found in their phenotypically normal parents. Ohtsuka et al., (2008) reported three sibs with a mutation. Gonadal mosaicism was again postulated.

Zweier et al., (2003) present evidence that cases with deletions are similar to those with point mutations up to a size of 5 MB. However, they also reported hypoplastic big toes, early seizures and lethality in a case who had an 11 MB deletion.

Zweier et al., (2005) looked at 28 phenotypically classic cases and found ZFHX1B deletions in all. In the 42 atypical cases, no deletions were found.

Some patients have a very mild phenotype that might be difficult to identify clinically (Zweier et al., 2006). Some with a mutation (Heinritz et al., 2006) have an atypical phenotype (cleft lip and palate, normal eyebrows).

Adam et al., (2006) studied an American cohort of patients, and they suggest the condition should be considered in those with absent speech, seizures, and anomalies involving the pulmonary arteries. The diagnosis should also be considered in those with CHARGE-like features, especially those with mild intellectual disability, colobomas and choanal atresia (Wenger et al., 2014).

A pulmonary artery sling and tracheal stenosis have also been reported (Strenge et al., 2009).

With age (adolescence and adulthood), the nasal tip overhangs the philtrum, and the face lengthens. A long, pointed or chisel-shaped chin can be observed (Garavelli et al., 2009). These authors reviewed 19 cases. Microcephaly was present in 14, congenital heart defect in 12, urogenital defects in eight of 17, cleft palate in 10%, hypoplasia/agenesis of the corpus callosum in 74% and short stature in 53%.

The behavioural phenotype was reported by Evans et al., (2012). Those involved are generally happy and sociable, but some show a repetitive pattern with mouthing, teeth grinding, and an under-reaction to pain.

Ariss et al., (2012) reported a female with a ZEB2 mutation who had microphthalmia, optic nerve hypoplasia, severely undeveloped retina and severe retinal pigment epithelium atrophy.

Ghoumid et al., (2013) found three cases of ZEB2 mutations with the facial gestalt of Mowat-Wilson syndrome and moderate intellectual disability, but without much else.

Polymicrogyria was reported by Murray et al., (2015).

The ophthalmological features (iris/retinal coloboma, absence or hypoplasia of the optic nerve, hyphema) are reviewed by Bourchany et al., (2015).

Garavelli et. al., (2017) reviewed the brain MRI characteristics of 54 patients with mutations in the ZEB2 gene. Abnormal findings were present in 96% of patients: 79.6% showed abnormalities of corpus callosum (partial or complete agenesis and hypoplasia), 77.8% had abnormal hippocampus (morphological and positional), and 68.5% had ventriculomegaly.

Ivanovski (2018) et al. analyzed data from 87 patients with Mowat-Wilson syndrome and heterozygous mutations in ZEB2. Clinical features included dysmorphic features, short stature, Hirschsprung disease, pulmonary artery sling, various ophthalmological findings, decreased sensitivity to pain, and seizures.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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