Mimicking congenital disorders of glycosylation: Pitt-Hopkins syndrome — clinical case reports

Abstract

Summary Introduction: Pitt-Hopkins Syndrome (PTHS) is a rare autosomal dominant neurodevelopmental disorder caused by molecular variants or microdeletions of the TCF4 gene (locus 18q21.2), which is critical for neuronal differentiation. The clinical phenotype is characterized by distinct facial dysmorphism, severe psychomotor retardation, profound intellectual disability, and irregular breathing patterns. Materials and Methods: Two male patients with clinical features suggestive of PTHS underwent evaluation at the Institute of Mother and Child in Chisinau, Republic of Moldova. Comprehensive clinical, neuroimaging (CT, MRI), and paraclinical (EEG, echocardiography) assessments were performed. The clinical scoring systems developed by Whalen et al. and Marangi et al. were applied to guide the selection of patients for genetic testing. Genetic testing included conventional karyotyping, CGH-array, Trio-Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). Results: Patient 1: Exhibited severe neurodevelopmental delay, absent expressive speech, corpus callosum hypoplasia, mega cisterna magna, dolichosigma, and severe chronic constipation. Trio-WES analysis identified a de novo heterozygous microdeletion on the long arm of chromosome 18: del(18)(q21.2q21.2), spanning ~0.75 Mb, confirming PTHS. Patient 2: Presented with generalized hypotonia, post-vaccination motor regression (at 4 months), facial dysmorphism, atrial septal defect, hypospadias, and localized yelloworange skin pigmentation. WGS identified a pathogenic heterozygous missense variant c.1739G>A in the TCF4 gene, along with a heterozygous likely pathogenic deletion c.2282_2285del in the FLG gene (associated with ichthyosis vulgaris). Discussion: Both cases highlight the molecular heterogeneity of PTHS, illustrating how identical clinical suspicion can arise from either structural deletions or point mutations. The neurological and gastrointestinal findings align with established literature. The unusual orange-yellow palmar and facial skin discoloration observed in both patients warrants further metabolic or clinical investigation, while the FLG mutation in P2 explains the concurrent dermatological signs. Conclusions: Advanced genetic screening (WES/WGS) is indispensable for confirming a definitive diagnosis of PTHS, facilitating precise genotype-phenotype correlations, accurate genetic counseling, and tailored multidisciplinary management.