Expanding the phenotypic spectrum of Alkuraya-Kucinskas syndrome: defining the mildest end

Abstract

Alkuraya-Kucinskas syndrome (ALKKUCS, OMIM #617822) is a recently described, ultra-rare autosomal recessive neurodevelopmental disorder characterized by structural, cortical and parenchymal brain abnormalities, global developmental delay/intellectual deficit and joint contractures. The phenotypic spectrum of 15 previously reported cases range from mild-to-moderate intellectual deficit with microcephaly to a phenotype characterized by severe ventriculomegaly and/or brainstem dysgenesis with intrauterine or neonatal death. Only three children survived till childhood. We here report two new ALKKUCS cases from two unrelated consanguineous families. The first patient was presented with antenatal ultrasound findings of severe hydrocephaly, interhemispheric cyst, hydropic changes with cystic hygroma and joint contractures. Pedigree analysis showed two similarly affected siblings and four affected cousins. Postmortem examination was compatible with a lethal contracture phenotype. Whole exome sequencing (WES) revealed a ‘likely pathogenic’ homozygous variant in the KIAA1109 gene. The second patient was consulted at 9 years of age. She had a history of NICU care due to poor sucking/weak swallowing reflex and cardiac arrest in early neonatal period. Clinical findings included mild myopathy of the neck muscles, pes equinovarus, scapula alata and camptodactyly. Identification of a homozygous variant in the KIAA1109 gene, segregating with the phenotype, made the diagnosis of ALKKUCS possible, placing the case to the mildest end of the phenotypic spectrum. Cases we here report highlights the power of WES in identifying genetic etiopathogenesis of rare disorders; and expand the phenotypic spectrum of ALKKUCS.