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.