Interleukin-2 receptor alpha chain (IL2RA, CD25) deficiency is a rare autosomal recessive inborn error of immunity characterized by profound immune dysregulation, susceptibility to infections, and autoimmunity. Only 13 cases of IL2RA deficiency have been reported worldwide since its first description in 1997, and experience with allogeneic hematopoietic stem cell transplantation (HSCT) for this condition remains very limited. This study aimed to describe the clinical, immunological, genetic, and HSCT outcomes of two siblings with IL2RA deficiency with a novel homozygous frameshift mutation and to review previously reported cases. The clinical course, laboratory findings, genetic diagnosis, and transplant outcomes of two patients managed at King Faisal Specialist Hospital & Research Centre were retrospectively reviewed. A comprehensive literature review was conducted to contextualize these cases. Both patients presented with severe enteropathy, eczema, recurrent respiratory infections, growth failure, and features of allergic disease in early childhood. Immunological evaluation revealed hypergammaglobulinemia, impaired T-cell proliferation, reduced CD19+ B cells, inverted CD4/CD8 ratio, and absence of CD25 expression. Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs). Both patients underwent HSCT with myeloablative conditioning. The younger sibling received marrow from a matched unrelated donor and achieved full donor chimerism with complete clinical and immunological recovery, remaining well 6 years after HSCT. The older sibling received marrow from a matched related donor and is alive and stable at 5 years of follow-up, with sustained donor chimerism and resolution of autoimmunity, complicated only by transient mild chronic graft-versus-host disease. The two cases expand the mutational and clinical spectrum of IL2RA deficiency and provide long-term evidence that HSCT can cure immune dysregulation and susceptibility to infection. The findings underscore the importance of early genetic diagnosis and timely consideration of HSCT as definitive therapy for this rare but life-threatening disorder.

Interleukin 2 receptor alpha chain (IL-2Rα or CD25) deficiency (OMIM #606367) is an immune dysregulation disorder segregating in autosomal recessive form. The disease is caused by biallelic variants in the IL-2Rα gene encoding IL-2Rα also known as CD25 protein. IL-2Rα combines with γ and β chains of interleukin 2 receptor to form a functional interleukin 2 receptor (IL-2R). In the present study, we identified a Pakistani family presenting a unique presentation of IL-2Rα deficiency. Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene. American College of Medical Genetics (ACMG) guidelines interpreted the identified variant as likely pathogenic. The IL-2Rα gene mutation usually presents with autoimmunity and immunodeficiency but in our patient, it presents with congenital diarrhea, metabolic crisis, and strong family history of death in infancy due to the similar complications. Her congenital diarrhea is attributed to autoimmunity in the form of autoimmune enteropathy and eczema. The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels. This is a new presentation of IL-2Rα gene mutation. The present study highlights the importance of clinical whole exome sequencing in the correct diagnosis of congenital disorders. The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.

CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.

CD25 deficiency (Interleukin-2 receptor alpha deficiency) is a rare subtype of combined B- and T-cell immunodeficiency. Recurrent infections and lymphocyte infiltration of multiple tissues are the main clinical presentations. Only four patients have been reported in whom ophthalmological findings were not described. In this article, ocular findings of CD25 deficiency in a 12-year-old child are highlighted.