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X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency (X-SCID), also known as SCID-X1, is a rare, life-threatening primary immunodeficiency disorder caused by pathogenic variants in the IL2RG gene on the X chromosome, resulting in defective cytokine signaling essential for lymphocyte development and function.^[1]^[2] This X-linked recessive condition primarily affects males, who are hemizygous for the gene, while females are typically asymptomatic carriers, and it accounts for approximately 20-30% of all severe combined immunodeficiency (SCID) cases.^[3]^[1] The IL2RG gene encodes the common gamma chain (γc), a shared subunit of receptors for multiple interleukins including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, leading to the characteristic T^-B⁺NK^- immunophenotype with absent or profoundly reduced T cells and natural killer (NK) cells, alongside nonfunctional B cells despite normal numbers.^[2]^[3] Infants with typical X-SCID appear healthy at birth but develop recurrent, severe infections—such as pneumonia, diarrhea, sepsis, and opportunistic infections from viruses, bacteria, or fungi—within the first few months of life, often accompanied by failure to thrive, chronic rashes.^[1]^[3] Atypical forms may present later with milder symptoms, including autoimmunity or Omenn syndrome, a severe inflammatory condition mimicking graft-versus-host disease.^[1] Without intervention, X-SCID is fatal within the first two years of life, usually from overwhelming infection.^[2] Diagnosis is typically established through newborn screening programs that measure T-cell receptor excision circles (TRECs) to detect low T-cell production, followed by confirmatory flow cytometry showing the T^-B⁺NK^- profile and molecular genetic testing to identify IL2RG variants.^[1]^[3] Prenatal or preimplantation genetic diagnosis is available for families with known mutations.^[1] Management focuses on early hematopoietic stem cell transplantation (HSCT) from a matched donor, which offers over 90% long-term survival if performed before significant infections occur, or gene therapy using retroviral vectors to correct the IL2RG defect in autologous stem cells, as demonstrated in clinical trials with sustained immune reconstitution.^[3]^[1] Supportive care includes prophylactic antibiotics, immunoglobulin replacement, and avoidance of live vaccines and unirradiated blood products to prevent complications.^[1] Ongoing research emphasizes improving gene therapy safety and efficacy to address limitations like insertional mutagenesis risks observed in early trials.^[1]

Genetics

Molecular Basis

X-linked severe combined immunodeficiency (X-SCID) arises from mutations in the IL2RG gene, located on the long arm of the X chromosome at cytogenetic band Xq13.1.^[1] This gene encodes the common gamma chain (γc), a 64-kDa transmembrane protein that serves as a shared subunit in the receptor complexes for multiple interleukins, specifically IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.^[1]^[4] The γc protein belongs to the type I cytokine receptor family and is critical for signal transduction in immune cells, particularly lymphocytes.^[1] Mutations in IL2RG were first identified as the underlying cause of X-SCID in 1993, establishing the gene's role in the disease.^[4] More than 300 distinct pathogenic variants in IL2RG have been documented, encompassing a range of mutation types including missense, nonsense, frameshift (due to small insertions or deletions), and splice site alterations.^[1]^[5] Null mutations, which typically introduce premature stop codons or disrupt splicing to abolish γc protein expression entirely, predominate in typical X-SCID cases and lead to a complete loss of receptor function.^[1] In contrast, hypomorphic variants—often missense changes that permit reduced or altered γc expression—result in partial protein activity and are associated with milder or atypical phenotypes.^[1] These variants are distributed throughout the gene, with hotspots in the extracellular and intracellular domains affecting protein folding, stability, or signaling capability.^[5] Functionally, γc mutations impair the assembly and activation of cytokine receptors, thereby disrupting downstream Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways.^[1] Specifically, the absence or dysfunction of γc prevents phosphorylation and activation of associated JAK kinases (primarily JAK1 and JAK3), blocking STAT protein dimerization and nuclear translocation necessary for gene transcription in response to cytokine binding.^[1] This leads to defective signal transduction in developing and mature lymphocytes, profoundly affecting their proliferation, differentiation, and survival.^[1]^[4] Detection of IL2RG variants relies on targeted molecular testing, with sequence analysis of the coding regions and splice junctions identifying approximately 99% of pathogenic changes.^[1] The remaining ~1% involve larger deletions or duplications, which are detected through methods such as multiplex ligation-dependent probe amplification (MLPA) or array comparative genomic hybridization (aCGH).^[1]

Inheritance and Variants

X-linked severe combined immunodeficiency (X-SCID) follows an X-linked recessive inheritance pattern, primarily affecting males who inherit a pathogenic variant in the IL2RG gene on their single X chromosome, rendering them hemizygous and susceptible to severe immune dysfunction.^[1] Females, possessing two X chromosomes, are typically asymptomatic carriers if heterozygous, as random X-chromosome inactivation (Lyonization) favors expression of the normal allele in most cells, including immune cells.^[6] In carrier females, each son has a 50% risk of inheriting the variant and developing X-SCID, while each daughter has a 50% chance of becoming a carrier; conversely, affected males transmit the variant to all daughters (who become obligatory carriers) but to none of their sons due to the absence of a Y-linked counterpart.^[1] Carrier detection in females relies on assessing X-inactivation patterns, which can show non-random skewing in T lymphocytes due to selective survival of cells expressing the normal IL2RG allele, or through direct molecular testing such as sequencing of the IL2RG gene or deletion/duplication analysis.^[7] This approach is particularly useful in families without a clear history, as skewed inactivation in maternal T cells identifies carrier status with high sensitivity.^[8] Pathogenic variants in IL2RG exhibit genotype-phenotype correlations that influence disease severity. Null variants, including large deletions, nonsense mutations, and frameshift alterations, completely abolish function of the common gamma chain (γc) protein and result in typical X-SCID with profound T-, B+, and NK-cell deficiencies.^[1] Hypomorphic variants, such as certain missense mutations (e.g., p.Arg222Cys), preserve partial γc signaling and lead to atypical X-SCID, characterized by less severe or delayed-onset immunodeficiency, often with residual T-cell function.^[1] While a family history of affected males is common, indicating inherited transmission, de novo mutations in IL2RG account for a significant proportion of cases—up to one-third—particularly in sporadic presentations, underscoring the need for genetic testing regardless of pedigree.^[7]

Pathophysiology

Immune Defects

X-linked severe combined immunodeficiency (X-SCID) is characterized by a profound combined deficiency in adaptive and innate immunity, primarily manifesting as the T^-B⁺NK^- phenotype, where T cells and natural killer (NK) cells are markedly reduced or absent, while B cells are present in normal numbers but functionally impaired.^[1] This phenotype arises from mutations in the IL2RG gene, which encodes the common gamma chain (γc) essential for multiple cytokine receptors, leading to disrupted signaling that selectively affects lymphocyte development and function.^[9] The most severe defect in X-SCID is the profound T-cell deficiency, with circulating CD3⁺ T cells typically numbering less than 300/μL and often absent, particularly naïve CD45RA⁺ T cells. This results from blocked T-cell development in the thymus due to impaired interleukin-7 (IL-7) signaling, which is critical for early T-cell progenitor survival and proliferation.^[1] Consequently, patients exhibit a near-complete absence of adaptive cellular immunity, severely compromising the ability to mount T-cell-mediated responses against pathogens.^[9] NK-cell numbers are also drastically reduced, with CD16⁺CD56⁺ NK cells often below 100/μL in approximately 88% of affected infants, stemming from disrupted IL-15 signaling that is vital for NK-cell differentiation, survival, and cytotoxic activity.^[1] This innate immune defect impairs antiviral and antitumor surveillance, as NK cells fail to provide essential early cytotoxic responses independent of adaptive immunity.^[9] Although B-cell counts are typically within the normal range (300-2,000/μL), these cells are nonfunctional in X-SCID, unable to produce antibodies effectively due to the absence of T-helper cell support for antigen-driven responses and impaired IL-21 signaling, which is necessary for B-cell maturation, class-switch recombination, and immunoglobulin production.^[1] The resulting humoral immune deficiency further exacerbates vulnerability to infections.^[9] Collectively, these defects in T, NK, and B cells create a state of profound immunodeficiency affecting both adaptive and innate arms, rendering individuals highly susceptible to a broad spectrum of infections from birth, while the typical form of X-SCID does not feature autoimmunity.^[1]^[9]

Cytokine Signaling Disruption

X-linked severe combined immunodeficiency (X-SCID) arises from mutations in the IL2RG gene, which encodes the common gamma chain (γc), a shared subunit essential for the assembly and function of multiple cytokine receptors.^[10] These receptors include those for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21, where γc pairs with cytokine-specific subunits to form high-affinity complexes capable of ligand binding and signal transduction.90167-O) Mutations in IL2RG typically disrupt γc expression, folding, or stability, preventing proper receptor assembly and impairing ligand binding across these pathways.^[11] The primary signaling defect in X-SCID involves failure of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, as γc associates with JAK1 and JAK3 kinases upon cytokine engagement.^[11] For IL-7 and IL-15 receptors, which are critical for early T and natural killer (NK) cell progenitors, γc mutations block JAK1/JAK3 activation and subsequent phosphorylation of STAT5, halting downstream signals that drive progenitor proliferation and differentiation.^[10] Similarly, IL-2, IL-4, and IL-21 receptors rely on γc for JAK3-mediated STAT5 (and STAT3 for IL-21) activation, which is essential for B-cell maturation, class-switch recombination, and the development of regulatory T cells.^[12] This signaling disruption prevents transcription of key survival and proliferation genes, such as BCL2 (anti-apoptotic) and MYC (pro-proliferative), which are directly upregulated by STAT5 in response to IL-7 and other γc-dependent cytokines. In severe cases, complete loss of γc function abolishes these pathways, leading to profound developmental arrest.^[11] Hypomorphic IL2RG variants, however, permit residual receptor assembly and partial JAK-STAT activation, resulting in leaky signaling that allows limited immune cell function and milder disease presentations.^[10] Animal models have confirmed the centrality of γc in these pathways; Il2rg knockout mice exhibit disrupted cytokine signaling analogous to human X-SCID, with absent JAK3-STAT activation in response to IL-2, IL-7, and IL-15. These mice demonstrate that γc deficiency specifically impairs the shared signaling components without affecting cytokine-specific pathways, underscoring IL2RG's indispensable role.

Clinical Presentation

Symptoms and Signs

X-linked severe combined immunodeficiency (X-SCID) typically presents with symptoms emerging between 3 and 6 months of age, as maternal antibodies wane and the infant's defective immune system fails to protect against pathogens.^[1] Due to newborn screening programs, many cases of typical X-SCID are now identified presymptomatically in otherwise healthy-appearing male infants, preventing early-onset infections.^[1] In cases where live vaccines such as rotavirus or BCG are administered shortly after birth, symptoms may appear earlier due to disseminated vaccine-related infections.^[13] These manifestations stem from profound defects in T-cell and natural killer cell function, leading to an inability to mount effective immune responses.^[14] Patients experience recurrent and severe infections across multiple categories. Bacterial infections commonly include otitis media, pneumonia, and sepsis caused by organisms like Staphylococcus or Haemophilus.^[1] Viral infections are particularly persistent and life-threatening, involving pathogens such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, and respiratory syncytial virus (RSV).^[1] Fungal infections manifest as oral thrush from Candida species or Pneumocystis jirovecii pneumonia, often as opportunistic invaders in the absence of cellular immunity.^[1] Chronic diarrhea is a frequent gastrointestinal symptom, frequently resulting from persistent viral (e.g., rotavirus) or parasitic (e.g., Giardia) infections.^[13] Growth and development are markedly impaired, with failure to thrive evident as poor weight gain and stunted growth due to ongoing infections and malabsorption from protracted diarrhea.^[15] Physical examination and imaging reveal absent or hypoplastic lymphoid tissues, including no palpable tonsils and a small or absent thymus shadow on chest radiographs.^[16] Skin rashes may occur due to graft-versus-host disease from transplacental maternal lymphocytes in a significant proportion of typical cases, as maternal engraftment is observed in about 40% of patients.^[1]^[17] Untreated, there is no elevated risk of malignancy prior to immune reconstitution, as infections typically prove fatal in early infancy.^[1]

Variants: Typical vs. Atypical

X-linked severe combined immunodeficiency (X-SCID) is classified into typical and atypical variants based on the severity of IL2RG gene mutations and resulting clinical phenotypes. Typical X-SCID arises from null or severe loss-of-function mutations in IL2RG, leading to complete absence of functional T and natural killer (NK) cells while sparing B cells, resulting in the characteristic T–B+NK– immunophenotype.^[1] Clinically, it manifests with severe, early-onset infections starting in the first months of life, including opportunistic pathogens, persistent diarrhea, and failure to thrive, often proving fatal within 1-2 years without intervention such as hematopoietic stem cell transplantation.^[1] These mutations disrupt cytokine signaling essential for lymphocyte development, facilitating maternal T-cell engraftment due to the profound lack of host immunity.^[18] In contrast, atypical X-SCID results from hypomorphic IL2RG mutations that permit residual cytokine receptor function, allowing partial lymphocyte development and a Tlow–B+NKlow immunophenotype with low but detectable T and NK cell numbers.^[1] These cases typically present later, often after the first year of life, with milder or recurrent infections rather than overwhelming early sepsis, and may evade newborn screening due to less profound lymphopenia.^[1] A subset develops Omenn syndrome, characterized by erythroderma, eosinophilia, hepatosplenomegaly, and oligoclonal T-cell expansion, reflecting dysregulated immune activation.^[1] Immune dysregulation, including autoimmunity such as cytopenias, arthritis, or rashes, occurs in about 20-25% of atypical cases, driven by the imperfect immune reconstitution.^[18] Overlaps between variants include maternal T-cell engraftment, which occurs in up to 40% of typical X-SCID cases and can mimic graft-versus-host disease with a GVHD-like rash, though this is uncommon without partial host immunity.^[17] Leaky SCID phenotypes, akin to atypical forms, can emerge from hypomorphic mutations providing partial immunity, delaying severe complications but increasing risks of autoimmunity or malignancy.^[1] For example, the R222C hypomorphic variant in IL2RG has been associated with atypical presentations featuring residual T cells, oligoclonal repertoires, and autoimmunity, including skin eruptions from maternal engraftment.^[17] Atypical X-SCID represents a small proportion of overall X-SCID cases, highlighting the spectrum of IL2RG dysfunction.^[1]

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected X-linked severe combined immunodeficiency (X-SCID) begins with a detailed medical history and physical examination to identify patterns suggestive of this condition in male infants. A key aspect of the history is inquiring about family history, particularly prior unexplained deaths of male infants or siblings, which may indicate X-linked inheritance without male-to-male transmission.^[1] Recurrent or persistent severe infections emerging after the decline of maternal antibodies around 3-6 months of age are also critical, including respiratory tract infections, chronic diarrhea, sepsis, and skin infections; additionally, any history of avoidance or adverse reactions to live vaccines, such as rotavirus or bacillus Calmette-Guérin, raises concern due to the risk of disseminated disease or graft-versus-host reactions.^[19] These historical features often align with typical symptoms of early-onset immunodeficiency, such as failure to thrive and opportunistic infections.^[9] On physical examination, infants with suspected X-SCID typically exhibit absent or underdeveloped lymphoid tissues, including small or nonpalpable lymph nodes and tonsils, reflecting profound T-cell deficiency. Failure to thrive is evident in approximately 60% of cases, often accompanied by signs of chronic infection such as oral thrush (candidiasis) and persistent diarrhea leading to dehydration and poor weight gain. Chronic lung disease, manifesting as recurrent pneumonia or bronchiectasis, may be observed, while hepatosplenomegaly is notably absent in the typical form of X-SCID.^[9]^[19] Red flags during evaluation include infections with opportunistic pathogens, such as Pneumocystis jirovecii pneumonia presenting by 6 months of age, cytomegalovirus, or other viral/fungal agents, which fail to respond adequately to standard antibiotic therapy. These findings, particularly in a male infant with an X-linked family pattern, heighten suspicion for X-SCID over other immunodeficiencies.^[1]^[19] Differential considerations in the clinical assessment encompass other forms of severe combined immunodeficiency (e.g., autosomal recessive types like JAK3 or ADA deficiency), as well as acquired conditions such as pediatric HIV infection; however, the X-linked pattern in affected males, combined with early severe infections and absent lymphoid tissues, points specifically toward X-SCID.^[1]^[9]

Laboratory and Genetic Testing

Diagnosis of X-linked severe combined immunodeficiency (X-SCID) relies on a combination of laboratory assessments and genetic confirmation to identify characteristic immune defects and molecular variants. Initial laboratory evaluations typically reveal profound lymphopenia, with total lymphocyte counts often below 2,000/μL in affected infants, and specifically fewer than 300 autologous CD3+ T cells per μL (or <300/mm³) in typical cases.^[1] Proliferative responses to mitogens such as phytohemagglutinin (PHA) are absent or severely diminished, reflecting the functional impairment of T cells.^[1] Immunoglobulin levels are generally low, particularly IgA and IgM, with absent or poor antibody responses to vaccines and infections despite the presence of B cells, underscoring the dysfunction in humoral immunity.^[20] Flow cytometry plays a central role in immunophenotyping, demonstrating the classic T–B+NK– profile in typical X-SCID, characterized by markedly reduced or absent T cells and natural killer (NK) cells alongside normal or elevated B cells.^[1] In atypical variants, the phenotype may vary, with some residual T cells present but dysfunctional, and potentially altered NK cell numbers.^[1] Newborn screening (NBS) programs utilize quantitative polymerase chain reaction (qPCR) to measure T-cell receptor excision circles (TRECs), which are absent or markedly low in X-SCID due to impaired T-cell development; TRECs below established thresholds (typically <20-25 copies per 10^5 nucleated cells, varying by assay) prompt immediate referral for confirmatory testing.^[21] Genetic testing confirms the diagnosis through sequencing of the IL2RG gene on chromosome Xq13.1, identifying hemizygous pathogenic variants in over 99% of cases via targeted Sanger or next-generation sequencing; deletion/duplication analysis accounts for the remaining ~1%.^[1] More than 300 distinct IL2RG variants have been reported, including missense, nonsense, and frameshift mutations, with carrier testing for female relatives and prenatal diagnosis available using chorionic villus sampling or amniocentesis.^[1] Since the implementation of universal NBS for SCID in the United States starting in 2008 (with Wisconsin as the first state and all states by 2018), these programs have detected nearly all cases of typical SCID, including X-SCID, prior to symptom onset, enabling early intervention and improving outcomes.^[21]

Treatment

Supportive Care

Supportive care for patients with X-linked severe combined immunodeficiency (XSCID) focuses on preventing and managing infections, maintaining nutritional status, and minimizing exposure to pathogens until curative treatment can be administered.^[22] Infection prophylaxis is a cornerstone, with trimethoprim-sulfamethoxazole (TMP-SMX) administered at 2.5 mg/kg of the trimethoprim component twice daily, three days per week, to prevent Pneumocystis jirovecii pneumonia (PJP), a common opportunistic infection in these patients.^[23] Antifungal prophylaxis with itraconazole (5 mg/kg/day) or fluconazole (3-6 mg/kg/day, adjusted for age in neonates) is recommended to mitigate fungal risks, while antivirals such as acyclovir may be used prophylactically if caregivers have active herpes simplex infections.^[23]^[22] Intravenous immunoglobulin (IVIG) replacement therapy is essential for antibody deficiency, typically dosed at 400-600 mg/kg monthly to maintain trough IgG levels and reduce infection susceptibility, even if initial levels appear normal due to maternal transfer.^[24] Nutritional support addresses failure to thrive, which affects many XSCID infants due to recurrent infections and malabsorption.^[3] Multidisciplinary evaluation by gastroenterology and nutrition specialists is advised, with total parenteral nutrition (TPN) initiated for severe cases involving persistent diarrhea or inadequate oral intake to promote growth and prevent further immune compromise.^[23] Weekly monitoring of weight, height, and head circumference guides adjustments to feeding plans, including sterile formula if breastfeeding is suspended.^[22] Strict isolation protocols are implemented to limit pathogen exposure. In hospital settings, reverse isolation in single rooms with high-efficiency particulate air (HEPA) filtration and positive pressure is standard, restricting visitors and requiring personal protective equipment for staff.^[22] At home, families receive education on hygiene practices, such as frequent handwashing with antibacterial soap, limiting contact with young children or animals, and avoiding public spaces to reduce infection risk.^[23] Live vaccines, including BCG and rotavirus, are contraindicated for patients and household contacts due to the risk of disseminated disease, and all blood products must be irradiated and cytomegalovirus (CMV)-negative to prevent graft-versus-host disease (GVHD).^[25] Ongoing monitoring includes regular complete blood counts (CBC) to assess lymphopenia and immunoglobulin levels to guide IVIG dosing, alongside viral load testing for CMV, Epstein-Barr virus (EBV), and adenovirus every 1-2 weeks.^[26] Complications such as BCG dissemination, which can occur post-vaccination in undiagnosed cases, require prompt antimycobacterial therapy with a regimen including rifampicin, ethambutol, isoniazid, and clarithromycin until resolution.^[22] These measures bridge the gap to definitive therapy while addressing the heightened susceptibility to opportunistic infections characteristic of XSCID.^[3]

Curative Therapies

Hematopoietic stem cell transplantation (HSCT) remains the preferred curative therapy for X-linked severe combined immunodeficiency (X-SCID), aiming to restore functional immunity through donor-derived hematopoietic cells. When an HLA-matched sibling donor is available, HSCT achieves success rates exceeding 90%, with sustained T-cell engraftment in over 95% of cases and overall survival nearing 97% at five years. In infants under 3.5 months of age, this procedure can often be performed without myeloablative conditioning to minimize toxicity, leveraging the absence of host immunity for natural engraftment, particularly of T cells. For mismatched or unrelated donors, which are more common due to the rarity of matched siblings, busulfan-based reduced-intensity conditioning is standard to enhance multilineage engraftment, targeting a cumulative area under the curve (AUC) of approximately 80 mg×h/L to improve event-free survival while reducing risks like graft failure.^[27]^[28]^[29] Gene therapy offers an alternative curative approach by correcting the underlying IL2RG mutation in autologous hematopoietic stem cells, avoiding donor-related complications. Lentiviral vectors deliver a functional IL2RG cDNA to patient-derived CD34+ cells ex vivo, followed by reinfusion after mild conditioning; this targets the common gamma chain deficiency central to X-SCID pathogenesis. Clinical trials initiated between 2019 and 2024, including the LVXSCID-ND study (NCT01512888) and others like NCT03311503, have treated over 10 infants, demonstrating robust T-cell reconstitution in all participants, with 50-100% achieving normal-range CD3+ counts and independence from intravenous immunoglobulin in most cases within 1-2 years post-treatment. As of 2025, follow-up data from these trials confirm durable T- and B-cell function without malignancy, including emergence of innate-like memory T cells.^[30] No leukemia has been reported in these recent cohorts, contrasting with earlier retroviral trials, due to self-inactivating vector designs that minimize insertional mutagenesis. Preclinical advancements include CRISPR-Cas9 base editing of IL2RG in murine models, achieving up to 87% correction efficiency in hematopoietic stem cells and restoring T- and B-cell development without off-target effects or tumorigenesis.^[31]^[32]^[33] Unlike adenosine deaminase (ADA)-deficient SCID, no enzyme replacement therapy is available for X-SCID, as the defect involves a cytokine receptor subunit rather than a metabolic enzyme; any supportive enzymatic interventions apply only to atypical variants with residual function. Recent advances through the Primary Immunodeficiency Treatment Consortium (PIDTC) include ongoing optimization of HSCT conditioning regimens, with 2024 analyses emphasizing targeted busulfan dosing to balance engraftment and toxicity in SCID subtypes like X-SCID.^[3]^[29]

Prognosis and Outcomes

Survival Rates

Without treatment, infants with X-linked severe combined immunodeficiency (X-SCID) typically succumb to overwhelming infections within the first year of life, with nearly 100% mortality if untreated.^[34]^[35] Hematopoietic stem cell transplantation (HSCT) has dramatically improved survival, with 5-year overall survival rates exceeding 90% for patients diagnosed early through newborn screening and transplanted before significant infections develop.^[1] In cohorts from 2010 onward identified via newborn screening, 5-year survival rates range from approximately 87-94% depending on age at transplant and donor match.^[36]^[27] Outcomes are optimal with HLA-matched donors, achieving up to 95% survival, compared to 70-80% with mismatched or unrelated donors, though early intervention mitigates these differences.^[37]^[27] Gene therapy using lentiviral vectors targeting the IL2RG gene has shown promising results in small clinical cohorts, with 100% survival reported in patients followed for over 5 years and sustained T-cell reconstitution. In a phase 1/2 trial involving 12 infants, all patients were alive 16 to 33 months post-treatment, with no severe adverse events. Follow-up data as of 2025 from lentiviral trials show sustained immune reconstitution in over 30 patients with no treatment-related mortality, and as of July 2025, gene therapy trials have provided insights into early T-cell development.^[38]^[1] Patients with atypical X-SCID due to hypomorphic IL2RG mutations exhibit milder disease and may survive into adulthood without curative therapy, though they face recurrent infections and heightened autoimmunity risks.^[1]^[3] Unlike typical X-SCID, these variants allow partial immune function, enabling prolonged survival but necessitating vigilant management.^[39]

Long-term Complications

Survivors of X-linked severe combined immunodeficiency (X-SCID) who undergo hematopoietic stem cell transplantation (HSCT) face several chronic complications, primarily related to the procedure itself. Chronic graft-versus-host disease (cGVHD) affects approximately 15-20% of patients at two years post-HSCT, manifesting as skin, liver, or gastrointestinal involvement that can persist and require prolonged immunosuppression.^[27] Autoimmune disorders, such as cytopenias or thyroiditis, occur in about 10-11% of cases, often due to dysregulated immune reconstitution and are more frequent with mismatched donors.^[40] Growth delays are common, particularly in those receiving myeloablative conditioning, with catch-up growth possible if transplantation occurs before age two; infertility risks arise from gonadal toxicity of conditioning regimens like busulfan.^[41] Dental abnormalities, including delayed eruption or enamel defects, and thyroid dysfunction, such as hypothyroidism, also emerge in long-term follow-up, necessitating routine screening.^[41]^[42] Gene therapy for X-SCID, involving retroviral or lentiviral vectors to correct IL2RG mutations, carries risks of insertional mutagenesis. In early trials using gamma-retroviral vectors, leukemia developed in five of twenty patients due to proto-oncogene activation near integration sites, leading to T-cell acute lymphoblastic leukemia between 2.5 and 5.5 years post-therapy.^[43] Subsequent trials with self-inactivating lentiviral vectors have shown no leukemic events in over thirty patients followed for up to ten years, though lifelong monitoring for clonal expansion via vector integration site analysis remains essential.^[44] In atypical X-SCID caused by hypomorphic IL2RG mutations, long-term issues often stem from partial immune function, leading to persistent dysregulation. Patients may develop inflammatory bowel disease-like symptoms, including very early-onset IBD with chronic diarrhea and malabsorption, as well as increased allergy risks such as atopic dermatitis or food allergies, due to impaired regulatory T-cell function.^[45]^[46] Overall, more than 80% of X-SCID patients achieve long-term normal immunity following early HSCT or gene therapy, with robust T-cell function and reduced infection susceptibility. Neurodevelopment remains normal in those treated before six months of age, though mild delays can occur if transplantation is delayed beyond infancy due to pre-existing infections.^[1]^[47]

Epidemiology

Incidence and Prevalence

X-linked severe combined immunodeficiency (X-SCID) is a common form of severe combined immunodeficiency (SCID), accounting for approximately 20% of cases in recent newborn screening cohorts in low-consanguinity populations, though older estimates suggested up to 50%.^[48]^[49]^[1] The overall incidence of SCID is estimated at 1 in 50,000 to 60,000 live births, with X-SCID thus occurring in roughly 1 in 250,000 to 300,000 live births, though it exclusively affects males due to its X-linked inheritance pattern.^[49]^[2] More precisely, the prevalence of X-SCID is reported as 1 in 50,000 to 100,000 male births in various populations.^[50] In the United States, newborn screening (NBS) data from 11 programs screening over 3 million infants established the SCID incidence at 1 in 58,000 live births (95% CI: 1 in 46,000 to 1 in 80,000), with X-SCID comprising about 19% to 50% of cases depending on the cohort analyzed.^[49] Pre-NBS estimates suggested a higher underdiagnosis rate, with X-SCID incidence around 1 in 100,000 male births.^[34] Globally, incidence rates are similar but can be elevated in populations with high consanguinity due to increased autosomal recessive SCID forms, though X-SCID itself shows less variation from consanguinity.^[51] Recent 2024 estimates continue to cite 1 in 75,000 male births for X-SCID in diverse cohorts.^[35] Implementation of NBS has significantly impacted detection trends. In the US, where NBS for SCID began in 2008 and became nationwide by 2018, early identification has increased without altering underlying incidence rates, leading to diagnosis in asymptomatic infants.^[49] In Europe, NBS adoption varies by country, with programs in places like Italy and the UK showing similar stable incidence but improved timeliness of diagnosis since the early 2010s.^[52] As of 2024, global data indicate no significant changes in X-SCID prevalence, but NBS expansion has enhanced case ascertainment worldwide. As of September 2025, 23 countries have implemented TREC-based NBS for SCID.^[53]^[54] Ethnic variations in X-SCID are minimal, with no prominent founder mutations reported, unlike certain autosomal recessive SCID subtypes that show clusters in specific groups such as the Navajo population.^[49] Isolated reports note slightly higher detection in some non-consanguineous cohorts, but overall distribution remains uniform across racial and ethnic groups.^[55]

Risk Factors and Screening

X-linked severe combined immunodeficiency (X-SCID) primarily affects males due to its X-linked recessive inheritance pattern, where pathogenic variants in the IL2RG gene on the X chromosome lead to impaired immune cell development.^[15] A key genetic risk factor is having a carrier mother who harbors a heterozygous IL2RG variant, which confers a 50% chance of transmitting the variant to male offspring, resulting in the full phenotype.^[1] Family history also plays a significant role, particularly a pattern of early infant deaths in males due to recurrent or severe infections, which can prompt earlier clinical suspicion and testing in at-risk families.^[56] Environmental factors can exacerbate the condition in undiagnosed infants. Administration of live vaccines, such as the bacillus Calmette-Guérin (BCG) vaccine for tuberculosis prevention, shortly after birth poses a substantial risk, as it can lead to disseminated BCG infection (BCG-osis) due to the lack of adaptive immunity, potentially worsening prognosis before treatment.^[57] Additionally, consanguinity between parents increases the risk of autosomal recessive forms of severe combined immunodeficiency that mimic X-SCID phenotypically, such as those caused by variants in JAK3 or IL7R, by elevating the likelihood of homozygous pathogenic variants in offspring.^[25] Newborn screening (NBS) for X-SCID and other forms of severe combined immunodeficiency has become a cornerstone of early detection. This involves quantitative polymerase chain reaction (PCR) assays measuring T-cell receptor excision circles (TRECs) from dried blood spots collected on Guthrie cards, typically within the first 2-7 days of life, with high sensitivity approaching 100% for typical SCID cases including X-SCID.^[58] Positive screens trigger immediate referral for confirmatory testing, such as flow cytometry for lymphocyte subsets and genetic analysis of IL2RG, enabling prompt intervention.^[59] In the United States, universal NBS for SCID using TREC assays is implemented in all 50 states, significantly improving early diagnosis rates.^[60] Globally, the program continues to expand as of 2025, with over 20 countries adopting TREC-based screening and additional nations, including Portugal and France, initiating or planning rollout to enhance survival through presymptomatic identification.^[61]^[62] For families with a known history of X-SCID, prenatal diagnostic options are available to assess fetal status. Chorionic villus sampling (CVS), performed between 10-13 weeks of gestation, allows direct genetic testing of placental tissue for IL2RG variants in at-risk pregnancies.^[63] Preimplantation genetic diagnosis (PGD), conducted during in vitro fertilization, enables selection of embryos without the pathogenic variant, offering a preventive approach for carrier couples.^[64]

References

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X-linked severe combined immunodeficiency (XSCID) is a rare and potentially fatal disease caused by mutations of IL2RG, the gene encoding the interleukin-2 ...
[6]
X-linked severe combined immunodeficiency - Genetics - MedlinePlus
Mar 18, 2022 · Inheritance. Expand Section. This condition is inherited in an X-linked recessive pattern . The gene associated with this condition is located ...
[7]
Identification of X-linked severe combined immunodeficiency by ...
The most sensitive method for diagnosis of XSCID in the absence of X-linked inheritance pattern is by mutation analysis.<|control11|><|separator|>
[8]
Prenatal Test for X-Linked Severe Combined Immunodeficiency by ...
Apr 12, 1990 · An assay to determine whether the inactivation pattern of the X chromosomes in a woman's T cells is random or skewed by selection can thus be used to identify ...
[9]
Severe Combined Immunodeficiency - StatPearls - NCBI Bookshelf
T-B+NK- SCID can be X linked and due to absent IL receptor for a range of cytokines due to lack of common gamma chain. A similar phenotype named Jak 3 kinase ...
[10]
https://doi.org/10.1038/nri2580
[11]
Mutation of Jak3 in a Patient with SCID: Essential Role of ... - Science
These observations indicate that the functions of γ c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.
[12]
IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 ...
IL-2 signals by activating three principal signaling pathways, the SHC/RAS/MAP kinase pathway, JAK1/JAK3/STAT5 pathway, and PI 3-K/AKT/p70 S6 kinase pathway.
[13]
Severe Combined Immunodeficiency—Classification, Microbiology ...
Jun 15, 2023 · Clinical manifestations of SCID include gastrointestinal infections, chronic diarrhea, and failure to thrive. Gram-positive bacteria, such ...
[14]
Severe Combined Immunodeficiency (SCID) | NIAID
Apr 4, 2019 · Most often, SCID is inherited in an autosomal recessive pattern ... X-linked severe combined immunodeficiency. Content last reviewed on ...
[15]
X-linked severe combined immunodeficiency: MedlinePlus Genetics
### Symptoms and Signs of X-linked Severe Combined Immunodeficiency
[16]
Clinical and imaging considerations in primary immunodeficiency ...
A defining radiologic feature of SCID and other severe T cell deficiencies, such as complete DiGeorge anomaly, is the absence of thymus [17]. For example, chest ...
[17]
Clinical, Immunological, and Molecular Features of Typical and ...
Aug 13, 2019 · The most common manifestations of infections were: lobar and/or interstitial pneumonia (54%), otitis (18%), bronchiolitis (16%), and sepsis (9%) ...
[18]
Characterizing T Cells in SCID Patients Presenting with Reactive or ...
Partial T-cell development is found also in other SCID variants, such as the common γc-R222C hypomorphic mutation, enabling thymic epithelial cell maturation, ...
[19]
Severe Combined Immunodeficiency (SCID) Clinical Presentation
Nov 30, 2023 · The clinical hallmarks of severe combined immunodeficiency (SCID) are repetitive and frequent bacterial, viral, and fungal infections that persist despite ...History · X-Linked Immunodeficiency... · Physical
[20]
The diagnosis of severe combined immunodeficiency (SCID) - NIH
A pathognomonic finding in many genotypes of typical SCID is the presence of maternal T cells in peripheral blood, due to failure to reject transplacentally ...Missing: symptoms | Show results with:symptoms<|control11|><|separator|>
[21]
Newborn Screening for Severe Combined Immunodeficiency in the US
Jun 21, 2017 · Severe Combined Immunodeficiency (SCID) refers to a group of disorders characterized by profound impairment in T cell development and function ...
[22]
https://www.jacionline.org/article/S0091-6749(19)31040-1/fulltext
[23]
https://www.allergy.org.au/images/stories/pospapers/ASCIA_HP_Guidelines_SCID_2019.pdf
[24]
Pediatric Severe Combined Immunodeficiency Treatment ...
May 16, 2024 · The consensus among clinical immunologists is that an IVIg dose of 400-600 mg/kg each month or a dose that maintains trough serum immunoglobulin ...IVIg Replacement Therapy · Other Pharmacologic Therapy · Gene Therapy · Activity
[25]
How I treat severe combined immunodeficiency | Blood
One such regimen is detailed in the ESID/EBMT guidelines and involves the use of fludarabine and low-dose cyclophosphamide in combination with alemtuzumab.
[26]
Severe Combined Immunodeficiency (SCID) Workup
Nov 30, 2023 · Patients with suspected SCID require complete evaluation of specific humoral and cellular immunity, which includes measurement of immunoglobulin levels.Approach Considerations · Laboratory Studies · Imaging Studies · Other Tests
[27]
Transplantation Outcomes for Severe Combined Immunodeficiency ...
Jul 31, 2014 · Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection.
[28]
Immune Reconstitution After Gene Therapy Approaches in Patients ...
The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is ...
[29]
Association of busulfan exposure and outcomes after HCT for ...
Sep 27, 2024 · In patients with IEI, improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUC of 80 mg × h/L.
[30]
Immune Reconstitution After Gene Therapy Approaches in Patients ...
The genetic origin of SCID-X1 was identified in 1993 due to the presence of mutations in the interleukin 2 receptor γ chain (IL2RG) gene (8, 9). This gene is ...
[31]
LVXSCID-ND: Lentiviral Gene Therapy Combined with Low-Dose ...
This study is designed to help infants with X-SCID who lack matched donors. The study evaluated a treatment called lentiviral gene transfer.
[32]
https://www.stjude.org/care-treatment/clinical-trials/lvxscid-nd-scid-x1.html
[33]
X-Linked Severe Combined Immunodeficiency - ScienceDirect
If untreated, the prognosis of X-SCID remains poor and most patients die by the age of 1 year. Prophylaxis and aggressive treatment of bacterial, viral, and ...
[34]
X-Linked Severe Combined Immunodeficiency (X-SCID)
Jun 25, 2024 · X-SCID is a chromosomal disorder in which the immune system lacks multiple protective cells that defend the body from disease.<|control11|><|separator|>
[35]
Successful trials result in a commercial partner for XSCID treatment
Overall survival for the 10% of patients who have matched sibling donors is 95%; however, it falls to 60 to 75% with other types of transplant, with over 50% of ...Missing: rates | Show results with:rates
[36]
X-SCID gene therapy gives scientists rare glimpse into early ...
Jul 31, 2025 · X-SCID gene therapy gives scientists rare glimpse into early immune system. Scientists at St. Jude Children's Research Hospital verified the ...
[37]
X-linked SCID with a rare mutation
Oct 11, 2021 · A case of atypical X-SCID was reported in 1994 presented with a high rate of infections, decreased growth rate, and persistent diarrhea. His ...Abstract · Results · Discussion And Conclusion
[38]
Retrospective, Landmark Analysis of Long-term Adult Morbidity ...
May 17, 2022 · Nine patients (11% of total cohort) developed 10 de novo autoimmune events at a median of 10.5 years post-HSCT at a range of 3–17 years (P13 ...<|separator|>
[39]
SCID bone marrow transplant can result in chronic long-term health ...
Dec 15, 2022 · Growth disturbance – Growth delay may occur, though a child may catch up depending on their age at transplant and how long they received ...Missing: infertility | Show results with:infertility
[40]
[PDF] Immune-Mediated Complications after Hematopoietic Stem Cell ...
Thyroid dysfunction is a commonly reported complica- tion after HSCT from radiation and high-dose chemotherapy. [12,68,69]. Autoimmune thyroid disease (AITD) ...
[41]
Insertional oncogenesis in 4 patients after retrovirus-mediated gene ...
Aug 7, 2008 · Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor γ (IL2RG) ...
[42]
Gene therapy for severe combined immunodeficiencies and beyond
Dec 11, 2019 · This review describes how gene therapy of severe combined immunodeficiency became a reality, primarily based on the expected selective advantage conferred by ...
[43]
The Diagnostic Approach to Monogenic Very Early Onset ... - NIH
X-linked immune dysregulation, polyendocrinopathy, enteropathy (IPEX) syndrome is caused by mutations in the transcription factor FOXP3. Those mutations affect ...
[44]
A great disturbance in the force: IL-2 receptor defects disrupt ... - NIH
Although earlier diagnosis has improved clinical outcomes for X-SCID, atypical SCID or other IEI not detected on NBS may present with more limited infectious ...
[45]
Pre- and Post-Hematopoietic Stem Cell Transplant (HSCT) - PMC
Our study shows that SCID patients have decreased mental development 1 year post-HSCT, followed by a stabilization in test scores over time. However, when ...Missing: complications | Show results with:complications
[46]
X-Linked SCID - Immunodeficiency Search
T-cell Receptor Gene Rearrangement (TCR Spectratyping). Literature Resources. 1. Noguchi 1993. IL2RG mutations cause X-linked SCID. 2. Kovanen 2004. Cytokine ...
[47]
Clinical, Immunological, and Molecular Findings in 57 Patients ... - NIH
Feb 4, 2019 · The most common clinical manifestations were pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), oral ...
[48]
https://www.immunodeficiencysearch.com/x-linked-scid
[49]
X-linked severe combined immunodeficiency - Myriad Genetics
X-SCID is inherited in an X-linked manner. This means the condition is typically more severe in individuals assigned male at birth (XY).
[50]
Severe combined immunodeficiency - Orphanet
Gene therapy has been shown to be effective for patients with ADA deficiency (as well as enzyme replacement therapy) and X-linked SCID. Prognosis. Without ...<|separator|>
[51]
Comprehensive newborn screening for severe combined ...
Nov 5, 2024 · The positive predictive values (PPVs) of NBS for SCID, XLA, and SMA were 2.44%, 2.78%, and 100%, respectively. The estimated prevalence rates in ...<|control11|><|separator|>
[52]
[PDF] X-Linked Severe Combined Immunodeficiency (SCID) in a Newborn
Dec 23, 2024 · Worldwide roll-out has been slower, but it is now performed in some European countries and several states in Australia [5, 11]. Screening has ...
[53]
The Genetic Landscape of SCID in the US and Canada in the ...
Sep 5, 2018 · We therefore estimate that we captured approximately 49% (range, 39–67%) of SCID cases imputed from incidence data and birth rates. Knowing gene ...<|control11|><|separator|>
[54]
Family History of Early Infant Death Correlates with Earlier Age at ...
Family history of early infant death correlates with earlier age at diagnosis but not shorter time to diagnosis for severe combined immunodeficiency.
[55]
BCG vaccination in SCID patients: complications, risks and ...
SCID is a syndrome characterized by profound T cell deficiency. BCG vaccine is contraindicated in SCID patients. Because most countries encourage BCG ...
[56]
SCID Newborn Screening: What we've learned - PMC
Live attenuated rotavirus vaccine, an otherwise important public health measure for infants in the first six months of life, has caused severe diarrhea in ...<|control11|><|separator|>
[57]
Newborn screening for severe combined immunodeficiency - Frontiers
Sep 14, 2022 · In the patients with NBS, 100% sensitivity of TREC and KREC values were 2,000 copies per 106 cells (Table 4). TREC levels in patients with SCID ...
[58]
All 50 states now screening newborns for severe combined ...
At present, the estimated incidence of SCID has increased to 1 in every 40,000 newborns. About SCID. SCID is a potentially fatal primary immunodeficiency in ...Missing: TREC PCR rate
[59]
Current Status of Newborn Bloodspot Screening Worldwide 2024
By 2019, all states, almost all provinces, and at least 20 countries had included some version of SCID and other T-cell lymphocyte deficiencies (a secondary ...
[60]
implementation of neonatal screening programme
Jun 28, 2025 · Portugal introduced SCID in the country's national neonatal screening programme in April 2025, while in France the screening will begin as of ...
[61]
Pregnancy, child bearing and prevention of giving birth to the ...
Jul 11, 2018 · Couples at risk could benefit from prenatal diagnosis via chorionic villus sampling (CVS) and amniocentesis (12-16w) early in pregnancy.
[62]
Case Report: Preimplantation Genetic Testing for X-Linked Severe ...
May 31, 2022 · In this study, we report a case where PGT was used to prevent the transmission of disease-caused variant in a SCID-X1 (OMIM:300400) family.Missing: CVS | Show results with:CVS