Familial Reticular Dysgenesis Due to Adenylate Cyclase 2 (AK2) Deficiency: Insights from a Three-Sibling Case Series

Reticular dysgenesis (RD) is a rare, severe form of severe combined immunodeficiency (SCID) caused by biallelic AK2 mutations, leading to profound defects in lymphoid and myeloid maturation. Unlike other SCID phenotypes, infants may present within days to weeks of life with infections due to profound neutropenia and sensorineural hearing loss. Hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. We describe three siblings with genetically confirmed RD, highlighting phenotypic variability, immunologic features, and transplant outcomes. Sibling A, born to Amish consanguineous parents, presented at 1 year with Pseudomonas and Haemophilus influenzae bacteremia, chronic diarrhea, and failure to thrive; sensorineural hearing loss was later identified. Immunologic evaluation revealed neutropenia (absolute neutrophil count [ANC] 830 cells/uL), severe CD4 lymphopenia (CD4+ 15 cells/uL), and elevated IgA (281 mg/dL). SCID newborn screening (NBS) was not performed in 2011. He received antimicrobial prophylaxis with acyclovir, itraconazole, trimethoprim/sulfamethoxazole (TMP-SMX), and intravenous immunoglobulin (IVIG). Filgrastim was initiated but discontinued after rash and biopsy-confirmed Sweet syndrome. At age 4, he underwent a 7/8 HLA-matched maternal-donor HSCT using reduced-intensity conditioning (RIC) with alemtuzumab, fludarabine, melphalan, and ThioTepa. Complications included CMV viremia, steroid-refractory chronic cutaneous graft versus host disease (GVHD), disseminated non-mucor zygomycosis, and graft loss with partial donor T cell chimerism. A second 7/8 HLA-matched maternal-donor HSCT (CD3/CD19 depletion, busulfan-based conditioning) was performed 708 days later but was complicated by engraftment syndrome and severe hepatorenal failure; he died 22 days post-transplant. Postmortem exome sequencing confirmed homozygous AK2 c.622T>C (p.Ser208Pro). Sibling B was diagnosed at birth through targeted genetic testing. He had neutropenia (ANC 1,600), panlymphopenia, hypogammaglobulinemia, and a failed newborn hearing screen with normal SCID NBS. Filgrastim was avoided due to concern for RD-associated myelodysplasia. He underwent an 8/8 sibling HSCT at 2 months using RIC (hydroxyurea, PK-guided busulfan, alemtuzumab, and fludarabine) and is now 5 years post-transplant with successful T and B cell reconstitution. Sibling C, also identified at birth after a failed hearing screen, had panlymphopenia with mild neutropenia (ANC 3,000) and a normal SCID NBS. She remains clinically stable on antimicrobial prophylaxis while awaiting HSCT. This series highlights marked phenotypic variability in RD, underscores limitations of SCID NBS in detecting RD, and emphasizes the importance of early genetic diagnosis and timely HSCT. Tabular data are included as downloadable supplement files.