Alazami syndrome with a single LARP7 variant and concurrent osteo-oto-hepato-enteric syndrome: A case of complex genetic interplay

Alazami syndrome is a rare autosomal recessive disorder characterized by primordial dwarfism, intellectual disability, and distinct facial features, primarily caused by biallelic mutations in the LARP7 gene. Osteo-oto-hepato-enteric (O2HE) syndrome is another rare autosomal recessive disorder resulting from mutations in the UNC45A gene, presenting with congenital diarrhea, neonatal cholestasis, deafness, and bone fragility. We report a unique case of an 11-month-old male patient exhibiting clinical features consistent with Alazami syndrome, including developmental delay, intellectual disability, and characteristic facial dysmorphisms (triangular face, deep-set eyes, and prominent forehead). Genetic analysis revealed a single pathogenic variant in the LARP7 gene inherited from the father, which is atypical for an autosomal recessive condition. Additionally, the patient presented with features of O2HE syndrome and was found to carry compound heterozygous mutations in the UNC45A gene. The presence of only one LARP7 variant suggests an alternative genetic mechanism, such as uniparental disomy (UPD) or a second undetected variant. This case challenges the conventional autosomal recessive inheritance model of Alazami syndrome by presenting with a single detectable LARP7 variant. It underscores the necessity for comprehensive genetic evaluations, including investigations for UPD or structural variants, in patients with suspected Alazami syndrome but only one identified pathogenic allele. Furthermore, the co-occurrence of O2HE syndrome highlights the complexity of diagnosing patients with multiple overlapping genetic disorders. This report contributes to expanding the genetic and phenotypic spectrum of Alazami syndrome and emphasizes the importance of considering multifactorial genetic mechanisms in rare congenital disorders.