モワット・ウィルソン症候群

BACKGROUND AND OBJECTIVES: Next-generation phenotyping (NGP) tools, such as GestaltMatcher, have revolutionized the diagnosis of rare genetic disorders through computational facial analysis. While NGP has been widely integrated into differential diagnosis workflows, its application in variant reclassification within the ACMG framework remains underexplored. METHODS: We applied GestaltMatcher to a 4-year-old patient with an undiagnosed neurodevelopmental disorder, suspected Mowat-Wilson syndrome (MWS), and a de novo ZEB2 variant. In addition to facial image analysis, we used the PEDIA framework, integrating Human Phenotype Ontology (HPO) terms and simulated exome data to refine variant prioritization. Bayesian likelihood modeling was used to establish Gestalt score thresholds for PP4 evidence levels (supporting, moderate, strong, and very strong). Brain MRI analysis was also performed to assess structural abnormalities characteristic of MWS. RESULTS: GestaltMatcher ranked MWS as the top differential diagnosis, and PEDIA integration further confirmed ZEB2 as the most likely disease-causing gene. Three of the patient's 4 facial images met the PP4 moderate threshold, while one met PP4 supporting. MRI analysis revealed subtle corpus callosum thinning, consistent with MWS. In addition, an exploratory case of an infant with molecularly confirmed MWS demonstrated the capability of GestaltMatcher to prioritize the diagnosis solely based on infant facial features. DISCUSSION: This study highlights the potential of NGP-driven facial phenotyping and multimodal integration in dysmorphology. The results support the broader application of AI-assisted phenotyping to improve diagnostic accuracy, particularly in neurodevelopmental disorders with distinct facial features.

Cutis tricolor (CT) is a rare pigmentary mosaicism characterized by the coexistence of hyperpigmented and hypopigmented areas on a background of normal skin; its syndromic form, Ruggieri-Happle syndrome (RHS), is associated with neurodevelopmental delay, facial dysmorphism, skeletal abnormalities, and other systemic defects. We report a 16-year-old girl with molecularly confirmed Mowat-Wilson syndrome caused by a de novo pathogenic ZEB2 frameshift variant, who presented with extensive CT-like pigmentary mosaicism and marked phenotypic overlap with RHS. Brain MRI disclosed bilateral microphthalmia, optic nerve hypoplasia, coloboma, a shortened corpus callosum, a brainstem segmentation defect, and inferior vermian hypoplasia. This observation expands the cutaneous phenotype of ZEB2-related disease and suggests possible shared developmental pathways between Mowat-Wilson syndrome and RHS.

BACKGROUND: Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells. Five percent of cases are associated with syndromic conditions, one of which is Mowat-Wilson syndrome (MWS), with an incidence rate of 50%. HSCR may be the first feature of this syndrome to be diagnosed. MWS is an autosomal dominant genetic disorder caused by a variant in the ZEB2 gene (ZFHX1B). OMIM #235730. It involves severe clinical manifestations such as ocular hypertelorism, intellectual disability, congenital heart defects, epilepsy, and HSCR. The association between MWS and HSCR is regarded as a serious condition with unpredictable post-operative outcomes, and many reported complications related to motility disorders are noted. METHODS: We conducted a retrospective study and reviewed the medical records of patients with MWS treated at our center. We examined the relationship among HSCR, clinical features, molecular characteristics, surgical complications, and pre-operative and post-operative enterocolitis events. RESULTS: The study included four patients with MWS. Three (75%) were found to be associated with HSCR. Rectal biopsy confirmed HSCR in all patients. Two patients underwent a transanal pull-through Swenson procedure, and both experienced surgical complications. Both cases encountered multiple episodes of enterocolitis, and one of them required a permanent stoma. The third patient has not undergone surgical correction but has responded well to medical treatment (laxatives). CONCLUSIONS: The association between MWS and HSCR presents a severe condition with high morbidity. The outcome after the pull-through procedure is unpredictable. Further studies are necessary to gain a deeper understanding of this condition. We recommend evaluating these patients in a multidisciplinary consensus based on the existing literature and our findings. Those without recurrent enterocolitis or chronic motility disorders are suitable candidates for conservative management.

BACKGROUND: Intestinal dysfunction is prevalent in children with Mowat-Wilson syndrome (MWS), yet its underlying mechanisms remain unclear. This study aimed to characterize intestinal symptoms, feeding patterns, and fasting plasma neurotransmitter profiles in patients with MWS, and to explore their potential relationships. METHODS: Three complementary assessments were conducted, including a questionnaire assessing defecation difficulties and stool characteristics; a structured questionnaire assessing feeding difficulties, caregiver-reported dietary composition (including the proportion of meat), and complementary feeding practices; and targeted fasting plasma neurotransmitter profiling using UPLC-TQ-MS. RESULTS: Among 35 patients with MWS, 86% had intestinal symptoms, including constipation (69%) and Hirschsprung disease (17%). In the feeding/diet analysis, 44.4% (4/9) of patients with MWS reported feeding difficulties. Compared with age-matched healthy controls (n = 10), patients with MWS (n = 9) had a significantly lower proportion of meat and delayed introduction of meat-based complementary foods (10.5 months vs. 7.9 months). In the plasma analysis, patients with MWS (n = 6) exhibited significantly reduced plasma levels of serotonin and taurine, alongside elevated levels of GABA and dopamine, compared with age-matched healthy controls (n = 10). CONCLUSION: These findings confirm the high prevalence of constipation-predominant intestinal dysfunction in patients with MWS. Collectively, our findings support further investigation of associations among feeding difficulties, a lower proportion of meat in dietary composition, and an altered fasting plasma neurotransmitter profile (including lower serotonin in a small subset), which may be relevant to gut dysmotility in patients with MWS. This diet-neurotransmitter axis offers a working model for understanding intestinal dysfunction in patients with MWS, yet direct quantification of dietary and circulating tryptophan in future studies is needed to validate this pathway.