Interleukin-2 (IL-2) is a central cytokine in adaptive immunity, essential for T-cell activation, proliferation, and the maintenance of immune homeostasis (1, 2). IL-2 signaling is mediated through the interleukin-2 receptor (IL-2R) complex, which is composed of three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and the common γ chain (CD132) (3). The IL-2Rβ and γc subunits are responsible for signal transduction and are shared with other cytokine receptors, including those for IL-4, IL-7, IL-9, IL-15, and IL-21 (4). In contrast, IL-2Rα (CD25) is unique to the IL-2 receptor complex and has no signaling capability on its own. Its principal function is to enhance receptor affinity for IL-2, allowing efficient ligand capture even at low cytokine concentrations (5). In conventional T lymphocytes, CD25 expression is transiently induced upon activation and generally remains of low intensity, in contrast to the constitutive and high-level expression observed on regulatory T lymphocytes (Tregs), where it plays a pivotal role in mediating IL-2-driven STAT5 activation. This signaling is essential for the development, stability, and function of Tregs, and thereby critical for maintaining self-tolerance and immune homeostasis (5, 6). Although the impact of CD25 deficiency has been predominantly described in T lymphocytes, accumulating evidence indicates that certain NK cell populations particularly the CD56^bright subset constitutively express CD25 and can assemble a high-affinity IL-2 receptor, enabling them to respond to low concentrations of IL-2. For instance, Caldirola et al. reported impaired NK cell maturation and function in a patient carrying an IL2RA mutation, highlighting the importance of the IL-2/CD25 axis in NK cell biology (7). In addition, Hirakawa et al. demonstrated that CD56^bright NK cells are activated in response to low-dose IL-2 through high-affinity IL-2 receptors, further supporting the contribution of CD25 to NK cell IL-2 sensitivity (8).

CD25 deficiency is a very rare autosomal recessive monogenic immunodeficiency marked by profound immune dysregulation (9). Clinical manifestations usually begin in early infancy, with patients presenting with recurrent bacterial, viral, and fungal infections, failure to thrive, and autoimmune manifestations such as enteropathy, cytopenias, eczema, and endocrinopathies (10–18). The first human case was reported in 1997 and involved a child with severe T-cell dysfunction and diffuse lymphocytic organ infiltration (10). A decade later, it was shown that CD25 deficiency can mimic IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome, even in the absence of FOXP3 mutations (11). In such cases, defective IL-10 production by CD4⁺ T cells illustrates the failure of immune regulation (11).

Over the past two decades, fewer than twenty patients with IL2RA mutations have been reported worldwide (10–18). These cases confirmed that loss of CD25 expression results in defective IL-2 signaling and a breakdown of peripheral immune tolerance. Moreover, beyond these rare loss-of-function cases, common IL2RA polymorphisms have been linked to susceptibility to several autoimmune diseases in the general population, including type 1 diabetes, multiple sclerosis, and juvenile idiopathic arthritis (19–23). Such observations underscore the broader importance of the IL-2/CD25 axis in immune regulation.

Here we present the first two confirmed cases of IL2RA (CD25) deficiency in Morocco. We describe their clinical phenotypes, immunological profiles, and the discovery of two novel biallelic IL2RA mutations. To our knowledge, no molecularly confirmed cases of CD25 deficiency have previously been reported from Morocco or North Africa. These findings expand the known genotypic spectrum of IL2RA mutations and reinforce the diagnostic importance of CD25 staining by flow cytometry in patients with IPEX-like syndromes (Figure 1). Given the high rate of consanguinity in the region and the availability of curative hematopoietic stem cell transplantation, early recognition of this rare but life-threatening disorder is crucial.

We report two pediatric cases of complete IL-2Rα (CD25) deficiency, each caused by novel homozygous mutations, representing the first documented patients from Morocco and, to our knowledge, the North African region. These patients underscore key features of this syndrome and have implications for diagnosis and management in our context. CD25 deficiency results in a distinctive immunological phenotype that combines features of immunodeficiency with severe autoimmunity (10–18). Due to the absence of CD25, IL-2 signaling through the IL-2R is virtually absent in patient T cells, especially affecting regulatory T cells that require IL-2 for survival and function. As a consequence, patients are unable to maintain normal immune tolerance, leading to multi-organ autoimmunity, such as enteropathy, endocrinopathies, dermatitis, and cytopenias, early in life (12–14). At the same time, IL-2 is critical for effective immune responses; thus these patients also experience vulnerability to infections despite having normal or even expanded T-cell numbers (15, 16). The combination of recurrent infections (often opportunistic or chronic viral infections) with IPEX-like autoimmune disease is a hallmark of CD25 deficiency (17). Both of our patients exhibited this combination, with persistent viral infections and severe chronic diarrhea and endocrine autoimmunity akin to IPEX syndrome. Indeed, CD25 deficiency has been described as an “IPEX-like” disorder in the literature (11), since the clinical presentation overlaps considerably with FOXP3-deficient IPEX, apart from the inheritance pattern (CD25 deficiency is autosomal recessive, affecting both genders equally, unlike X-linked IPEX). One distinguishing feature observed in prior CD25-deficient cases is extensive lymphoproliferation – for example, Sharfe et al. noted lymphocytic infiltrates in lung, liver, gut, and other tissues of their patient (10). Our patients also had significant hepatosplenomegaly and lymph node enlargement, consistent with lymphoproliferation. The immunopathology likely reflects uncontrolled activation and expansion of autoreactive T cells that lack regulation by Tregs (11, 12). In line with previous reports, we found that both patients had no detectable CD25 on their T cells, confirming the diagnosis at a protein level. This was also true in all other published cases of IL2RA mutations. To date, all reported patients showed absent CD25 expression on flow cytometry (Table 3) (10–18). This immunophenotypic hallmark can be invaluable for diagnosis: in an infant or young child with unexplained polyautoimmunity and infections, flow cytometric analysis of CD25 on T cells can provide an immediate clue to IL2RA deficiency, even before genetic results are available.

The genetic findings in our patients expand the known mutational spectrum of IL2RA. Prior to this report, approximately 15 cases from various ethnic backgrounds had been documented in the literature (10–18). The majority of reported mutations are either missense substitutions that disrupt protein expression/folding or nonsense/frameshift mutations leading to truncated proteins (10–15, 17). For example, Sharfe et al. reported a frameshift (4-bp deletion) in IL2RA that produced a nonfunctional receptor (10). Vignoli et al. described a conformational missense mutation that prevented IL-2Rα from reaching the cell surface (17). Our Case 1 has a splice-site mutation (c.65-2A>G) which is predicted to cause abnormal mRNA splicing and likely results in an out-of-frame transcript or nonsense-mediated decay. Notably, this splice mutation is novel and had not been recorded in any variant databases, emphasizing the uniqueness of each family’s mutation in this ultra-rare disease. Our Case 2 harbors a large deletion spanning multiple exons of IL2RA. The multi-exon deletion c.557_795-1625del identified in patient 2 represents, to our knowledge, the first reported structural null allele of IL2RA. This deletion results in the complete loss of several essential exons, accounting for the observed absence of CD25 expression. Its identification highlights the importance of actively investigating copy number variations in patients with IPEX-like phenotypes, particularly when conventional sequencing fails to detect point mutations. This finding underscores the role of multi-exon deletions as an underlying genetic mechanism of IL2RA deficiency and enhances our understanding of CD25 loss in these patients. Large deletions can be challenging to detect by standard gene panel sequencing, but in our targeted NGS approach we were able to infer the deletion from read-depth analysis. These two mutations underscore that IL2RA pathogenic variants can be diverse (point mutations, indels, splice defects, large deletions), and comprehensive genetic testing is often required to identify them.

Clinically, both patients reinforce certain patterns noted in CD25 deficiency. First, the onset of disease is in early infancy. Patient 1 and patient 2 both showed symptoms within the first year of life. This is consistent with the notion that IL-2Rα is critical from the neonatal period for immune regulation. Second, consanguinity was present in both families. Given the autosomal recessive inheritance, CD25 deficiency is more likely to appear in settings of parental consanguinity or endogamous communities. This is an important epidemiological clue; indeed, most previously reported cases were from consanguineous families, including reports from communities in the Middle East and South Asia (16, 17). Our report highlights that this disorder, while exceedingly rare, can also occur in North Africa, and underscores the need to consider IL2RA mutations in patients from this region presenting with IPEX-like features. Third, while both our patients had multiple autoimmune diseases, the exact spectrum can vary. Case 1 had severe autoimmune hepatitis, whereas Case 2 had autoimmune thyroiditis. In the literature, autoimmune enteropathy is the most common feature (16), and both of our patients indeed had enteropathy, with biopsy-proven celiac-like disease. Other reported autoimmune manifestations include type 1 diabetes mellitus, which can be an early presenting feature in up to ~60% of cases, autoimmune skin conditions (eczema or psoriasis), and autoimmune cytopenias (11, 16, 27, 28). Neither of our patients has developed diabetes to date, although they remain at risk given the breakdown of tolerance (regular monitoring is in place). Unlike FOXP3 deficiency, IL2RA deficiency does not involve mutations in FOXP3 but results from impaired IL-2 signaling required to sustain FOXP3 expression in Tregs (11, 12, 16). Despite some clinical differences, including occasionally more pronounced lymphoproliferation, the strong phenotypic overlap supports classifying CD25 deficiency among IPEX-like syndromes, alongside STAT5b, CTLA4, and LRBA deficiencies (17). Although hyperleukocytosis and elevated IgG levels were observed in both patients, these findings alone do not constitute a specific biological profile that would allow a definitive diagnosis of CD25 deficiency. In contrast, the absence of CD25⁺ cells represents the key element in the diagnostic reasoning.

From a management standpoint, the definitive treatment for CD25 deficiency is hematopoietic stem cell transplantation (HSCT). Restoring a functional immune system via HSCT, ideally from an HLA-matched sibling or suitable donor, has been shown to cure the immune dysregulation in at least one reported case (16). Al-Sukaiti et al. documented an infant with CD25 deficiency who underwent a successful bone marrow transplant, resulting in resolution of his autoimmune diabetes and other manifestations (16). HSCT provides donor-derived T cells that express CD25, thereby re-establishing IL-2 responsive regulatory T cells and normalizing immune homeostasis. Both of our patients are being evaluated for potential HSCT while receiving supportive therapy. In the interim, meticulous multidisciplinary care is required: management includes aggressive treatment of infections (prophylactic antibiotics, antifungals and antivirals as needed) and immunosuppressive therapy to control autoimmunity, for example, Case 2’s hypothyroidism is managed with hormone replacement and her enteropathy with immunosuppressants. The use of therapies like rapamycin (sirolimus) that expand regulatory T cells by exploiting IL-2 signaling could be considered, although paradoxically in CD25 deficiency the Tregs cannot respond normally to IL-2 (27). Low-dose IL-2 therapy, which has shown promise in boosting Tregs in some autoimmune conditions (29), would presumably be ineffective in CD25 absence. Therefore, immune reconstitution by transplantation remains the only curative option. Early diagnosis is essential to enable timely HSCT before irreversible organ damage from ongoing autoimmunity. Our cases highlight that CD25 deficiency should be considered in infants with unexplained multisystem autoimmunity particularly enteropathy and endocrinopathy associated with recurrent infections, especially in the context of consanguinity or affected siblings. Flow cytometric assessment of CD25 expression on T cells provides a simple initial screening tool.

These two Moroccan cases expand the geographic and genetic spectrum of IL2RA deficiency. They are, to the best of our knowledge, the first reported patients from Morocco. Prior to this, fewer than 20 cases had been recorded globally, with the largest series noting only about eight families worldwide as of a few years ago (17). Our report adds novel mutations to the literature, including a unique large deletion, and reinforces the genotype-phenotype correlation that any null mutation in IL2RA will lead to the characteristic severe autoimmune immunodeficiency syndrome. The rarity of CD25 deficiency means it is often not immediately recognized. Many patients, like the brother of Case 2, may succumb before a diagnosis is made. Increasing awareness among immunologists and pediatricians is therefore vital. In settings where infantile IPEX-like symptoms are present but FOXP3 is normal (or the patient is female, ruling out X-linked IPEX), testing for IL2RA mutations is indicated.

This study has some limitations that should be acknowledged. First, it is based on two patients from a single center, which does not allow firm conclusions about the prevalence, full phenotypic spectrum or long-term prognosis of IL2RA deficiency, particularly in North African populations. Second, although we documented a complete absence of CD25 surface expression and used several in silico tools to support the pathogenicity of the identified variants, we did not perform functional assays of IL-2 signaling (such as STAT5 phosphorylation or regulatory T-cell suppressive function) or transcript-level studies to directly confirm the splicing consequences of the c.65-2A>G variant and the impact of the multi-exon deletion at RNA and protein level. Third, genetic testing was restricted to the two index cases, and we were therefore unable to formally confirm carrier status in all relatives or to document the molecular defect in the deceased sibling of Case 2. Finally, follow-up remains relatively short, especially for the younger child, so later-onset complications cannot be excluded. These limitations do not weaken the diagnostic attribution of IL-2Rα deficiency in our patients, but they highlight the need for additional functional work and longitudinal data in larger cohorts.

We report the first two molecularly confirmed cases of IL2RA (CD25) deficiency in Morocco, each due to a novel homozygous variant, including a previously undescribed multi-exonic deletion. Both children developed disease in early life with recurrent infections, severe enteropathy and multi-organ autoimmunity, giving an IPEX-like picture typical of complete CD25 loss. The combination of absent CD25 expression on CD4⁺ T cells and biallelic IL2RA variants allowed a precise diagnosis in both cases. These observations extend the geographic and genetic spectrum of IL2RA deficiency and underline that this disorder should be considered in infants and children from consanguineous families who present with unexplained polyautoimmunity and infections, even outside previously described populations. Simple flow cytometric assessment of CD25 on T cells provides a rapid and accessible screening tool, while early genetic confirmation is essential to guide timely hematopoietic stem cell transplantation and genetic counselling. Larger collaborative series with detailed functional studies will be needed to refine genotype–phenotype correlations and to optimize management strategies for this ultra-rare but life-threatening inborn error of immunity.