Journal Article

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

Arnaout, Rand, Alsaud, Bander, Al-Mousa, Hamoud, Alaqeel, Bothainah, Al-Ahmari, Ali, Mohammed, Reem, Ayas, Mouhab, Alazami, Anas M, Alsaedi, Hawazen, Elshorbagi, Sahar, Alrumayan, Nora, Albuhairi, Sultan, Aljohani, Faiz

2026

Overview

Reticular dysgenesis (RD), caused by biallelic variants in , 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. In this retrospective single-center study, we analyzed genetically confirmed -related RD cases managed at King Faisal Specialist Hospital and Research Centre between 2005 and 2025, reviewing clinical, immunologic, genetic, and transplant-related data. 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 ( : 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. These findings demonstrate that -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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Adenosine / Adenylate Kinase / adenylate kinase 2 / AK2 / Birth weight / Blood & organ donations / Blood donors / Bone marrow / Consanguinity / Cord blood / Cytomegalovirus / Disease prevention / Drug dosages / Family medical history / Female / Females / Genomes / Graft versus host disease / Hearing loss / hematopoietic stem cell transplant / Hematopoietic Stem Cell Transplantation - methods / Hematopoietic stem cells / Humans / Immune reconstitution / Immune system / immunodeficiency / Immunoglobulins / Immunology / inborn error of immunity / Infant / Infant, Newborn / Kinases / Laboratories / Leukocytes (granulocytic) / Leukopenia / Lymphocytes / Male / Neonates / Neutropenia / Original Research / Patients / Phenotypes / reticular dysgenesis / Retrospective Studies / Severe combined immunodeficiency / Severe Combined Immunodeficiency - diagnosis / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - therapy / Stem cell transplantation / Stem cells / Steroids / Transplants & implants / Treatment Outcome / Umbilical cord