Mowat-Wilson Syndrome: Comprehensive Imaging Guide and Clinical Overview
Overview
Mowat-Wilson syndrome (MWS) is a rare genetic disorder caused by mutations in the ZEB2 gene, leading to loss of function of the ZEB2 protein, a transcription factor critical for early embryonic development. The syndrome was named after the physician who first described it, highlighting its distinctive constellation of clinical features. MWS manifests with characteristic facial dysmorphisms including ocular hypertelorism, broad eyebrows, and a prominent chin, as well as moderate to severe intellectual disability. Congenital malformations commonly involve the nervous, gastrointestinal (notably Hirschsprung disease), genitourinary, and cardiac systems. MWS follows an autosomal dominant inheritance pattern, typically arising from de novo mutations or deletions affecting one copy of the ZEB2 gene.[1][2][4]
Key Imaging Features
- Magnetic resonance imaging (MRI) frequently demonstrates abnormalities of the corpus callosum, including hypoplasia or agenesis, present in approximately 80% of patients.
- Hippocampal malformations, such as malrotation or hypoplasia, are found in nearly 78% of cases, contributing to neurodevelopmental impairment.
- Ventriculomegaly or enlargement of the cerebral ventricles is observed in about 68% of patients, reflecting disrupted brain morphogenesis.
- White matter abnormalities include thinning of the cerebral white matter and localized signal changes on T2-weighted MRI sequences, documented in over 40% and 20% of cases respectively.
- Additional imaging findings often reveal large basal ganglia and variable cortical and cerebellar malformations, including dysplasia.
- Ultrasound imaging of the abdomen and pelvis may identify genitourinary anomalies and Hirschsprung disease, supporting clinical diagnosis.
Pathophysiology
The ZEB2 gene encodes a zinc-finger E-box-binding homeobox 2 protein that regulates gene expression during embryonic development. Its deficiency disrupts neural crest cell migration and differentiation, impairing formation of midline brain structures such as the corpus callosum and hippocampus. This neurodevelopmental disruption manifests on imaging as agenesis or hypoplasia of these structures and white matter anomalies. Ventricular enlargement likely results from abnormal brain development and volume loss. Additionally, aberrant ZEB2 function affects development of other organ systems, explaining multisystemic congenital anomalies observed clinically and on imaging.[1][4]
Differential Diagnosis
| Condition | Distinguishing Imaging Features | Key Clinical Differences |
|---|---|---|
| Agenesis of Corpus Callosum (Isolated) | Partial or complete corpus callosum absence without hippocampal or widespread white matter abnormalities | Lacks facial dysmorphisms and multisystem involvement of MWS |
| Hirschsprung Disease with Syndromic Associations | No distinctive brain malformations on MRI | Absence of intellectual disability and craniofacial anomalies associated with MWS |
| Other Genetic Syndromes with Intellectual Disability (e.g., Pitt-Hopkins syndrome) | Different patterns of brain malformations, such as thickened corpus callosum or absent septum pellucidum | Distinct facial features and genetic mutations differentiate them from MWS |
Imaging Protocols and Techniques
For optimal detection and characterization of brain anomalies in Mowat-Wilson syndrome, high-resolution brain MRI is the modality of choice, ideally performed on 3 Tesla scanners for enhanced spatial resolution. Protocols should include:
- T1-weighted images in axial, coronal, and sagittal planes focused on midline structures to assess the corpus callosum and hippocampus morphology.
- T2-weighted and FLAIR sequences for evaluation of white matter signal abnormalities and ventriculomegaly.
- Diffusion tensor imaging (DTI) can provide additional insights into white matter integrity, though not routinely mandated.
- Volumetric sequences facilitate precise measurements of brain structures, supporting longitudinal monitoring of developmental progression or atrophy.
- Abdominal and pelvic ultrasound are adjunct tools for screening genitourinary anomalies and intestinal complications such as Hirschsprung disease.
Imaging pearls include close inspection of the hippocampal formation for rotation anomalies and meticulous corpus callosum segmentation analysis to detect subtle hypoplasia. Pitfalls include misinterpreting ventricular enlargement as hydrocephalus rather than primary brain maldevelopment; correlation with clinical data is essential.
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