Reticular dysgenesis caused by AK2 deficiency: clinical spectrum and hematopoietic stem cell transplantation outcomes in 10 patients from a single-center

Introduction Reticular dysgenesis (RD), caused by biallelic variants in AK2 , represents the most severe and rare form of Severe Combined Immunodeficiency, characterized by profound defects in lymphoid and myeloid lineages; however, data on its clinical spectrum and hematopoietic stem cell transplantation (HSCT) outcomes remain scarce. Methods In this retrospective single-center study, we analyzed genetically confirmed AK2 -related RD cases managed at King Faisal Specialist Hospital and Research Centre between 2005 and 2025, reviewing clinical, immunologic, genetic, and transplant-related data. Results Ten patients from eight unrelated families were included, most with parental consanguinity, all presenting in the neonatal period with severe infections, neutropenia unresponsive to granulocyte colony–stimulating factor, and bilateral sensorineural hearing loss. A recurrent homozygous missense variant ( AK2 : NM_001625.4: c.524G>C; p. Arg175Pro) was identified in nine patients, while one patient harbored a start-loss variant. Seven patients underwent HSCT at a median age of 4 months using matched sibling, haploidentical, or cord blood donors; six survived, yielding a post-transplant survival of 85.7% with a median follow-up of 10 years, and achieved full donor myeloid and lymphoid engraftment with robust immune reconstitution. Discussion These findings demonstrate that AK2 -related RD presents with a distinctive neonatal phenotype and carries high pre-transplant mortality, while early HSCT enables durable engraftment and favorable long-term outcomes, supporting the importance of early diagnosis and newborn screening in high-consanguinity populations.