Reticular dysgenesis (RD) is the most severe and rarest form of severe combined immunodeficiency (SCID), characterized by profound defects in both lymphoid and myeloid lineages and caused by biallelic pathogenic variants in AK2. Due to its rarity, data on the clinical spectrum and hematopoietic stem cell transplantation (HSCT) outcomes remain limited.
We conducted a retrospective single-center study of ten patients with genetically confirmed AK2-related RD managed at King Faisal Specialist Hospital and Research Center between 2005 and 2025. Clinical features, immunologic and hematologic findings, genetic results, transplant characteristics, immune reconstitution, and outcomes were systematically reviewed.
Ten patients from eight unrelated families were included; parental consanguinity was present in eight cases. All patients presented in the neonatal period with severe bacterial infections and profound neutropenia refractory to granulocyte colony-stimulating factor, and all had bilateral sensorineural hearing loss. Nine patients shared the same homozygous missense variant (AK2 c.524G>C; p.Arg175Pro), suggesting a founder effect, while one patient carried a start-loss mutation (c.1A>G). Seven patients underwent HSCT at a median age of 4 months using matched sibling, haploidentical, or umbilical cord blood donors. Six of seven transplanted patients survived, with a post-transplant survival rate of 85.7% after a median follow-up of 9 years. All transplanted survivors achieved full engraftment of donor myeloid and lymphoid cells, with robust immune reconstitution.
AK2-related RD presents with a distinctive neonatal phenotype and high pre-transplant mortality. Early HSCT enables durable engraftment and favorable long-term outcomes. These findings highlight the critical importance of early diagnosis and support newborn screening for SCID in high-consanguinity populations.
