Arthrogryposis With CNS Involvement in AFF3-Related KINSSHIP Syndrome: A Detailed Phenotypic Characterization From a...

Arthrogryposis Multiplex Congenita (AMC) is a heterogeneous group of disorders characterized by multiple contractures, often associated with central nervous system (CNS) involvement. To date, advances in Next Generation Sequencing (NGS) have enabled the identification of more than 400 genes implicated in AMC. Genetic causes of AMC and CNS involvement are especially challenging due to their heterogeneous clinical presentation, overlapping phenotypes, and often uncertain etiology. Pathogenic variants in AFF3 degron motif were identified as a cause of KINSSHIP syndrome (MIM #619297) which is clinically characterized by horseshoe kidney, Nievergelt/Svarirayan type of mesomelic dysplasia, seizures, generalized hypertrichosis, intellectual disability, and pulmonary involvement. We describe a patient presenting distal contractures at birth and neurodevelopmental delay, in whom Whole Genome Sequencing (WGS) revealed a previously reported missense variant in AFF3. We also conducted a literature review of published cases associated with this gene. This case highlights the importance of recognizing and characterizing the phenotypic presence of multiple congenital contractures and neurodevelopmental impairment as a clinical pattern that may prompt consideration of AFF3-related KINSSHIP syndrome among the differential diagnoses. Our findings underscore the relevance of integrating genomic testing into the evaluation of patients with AMC and CNS involvement to support accurate diagnostic classification.