RARE DISEASE
X-linked hyper-IgM syndrome
X-linked hyper-IgM syndrome
X-linked hyper-IgM syndrome
Synonyms: HIGM1, Hyper-IgM syndrome due to CD40 ligand deficiency, Hyper-IgM syndrome due to CD40L deficiency, Hyper-IgM syndrome type 1, XHIGM
Synonyms: HIGM1, Hyper-IgM syndrome due to CD40 ligand deficiency, Hyper-IgM syndrome due to CD40L deficiency, Hyper-IgM syndrome type 1, XHIGM
Synonyms: HIGM1, Hyper-IgM syndrome due to CD40 ligand deficiency, Hyper-IgM syndrome due to CD40L deficiency, Hyper-IgM syndrome type 1, XHIGM
Drug discovery
1
drug
With orphan designation
Overview
X-linked hyper-IgM syndrome (XHIGM) is a rare, X-linked recessive immunodeficiency caused by CD40LG mutations, disrupting CD40L-CD40 interactions critical for B-cell class switching and T-cell activation. Affected males exhibit low IgG, IgA, and IgE with normal/elevated IgM, leading to severe bacterial (e.g., Pneumocystis jirovecii pneumonia) and opportunistic infections, chronic neutropenia, and complications like sclerosing cholangitis and lymphoma. Prognosis is poor without hematopoietic stem cell transplantation (HSCT) [1][2][6][15].
Categories: rare genetic diseases, rare immunological diseases, rare transplant-related disorders
Research Papers
191 drug discovery papers about X-linked hyper-IgM syndrome, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
191 drug discovery papers about X-linked hyper-IgM syndrome, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report
Background Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. Case presentation We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii . An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient’s immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Conclusions Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-07-14 | Relevance of a Computational Deep-Dive to Characterize the Molecular Biology of a Novel Cd40l Variant
CD40L deficiency is a well-described inborn error of immunity (IEI). The disease is characterized immunologically by impaired class-switching and T cell costimulation. A male infant presented at 8 months of age with recurrent cellulitis. At 11 months, he was admitted for prolonged fever and leukopenia with vomiting and watery diarrhea, periorbital edema, back abscess, increased sIL2R at 50,598 pg/mL (<14,491), and normal CXCL9 at 22 pg/mL with mild to modest increases in IL-18 at 694 pg/mL (<185.4), IL-6 at 226.4 pg/mL (<10), serum amyloid A (SAA) at 1,413 mcg/mL (<373.8), IL-8 at 196 (<10), and IL-10 at 101pg/mL (<10). His IgG and IgA were low at <30 and <10 mg/dL, respectively. He developed Pseudomonas sepsis, palatal ulceration, jejunal perforation requiring repair, Candida peritonitis, persistent neutropenia, CMV, and Parechovirus viremia. Along with the hypogammaglobulinemia, class-switched memory B cells were decreased for age. Flow cytometry was performed for CD40L expression on activated CD4+ T cells along with functional evaluation of ligand binding to a soluble form of the receptor (CD40), using CD40-muIg. There was significantly diminished CD40L expression with essentially absent binding to the receptor. Genetic testing confirmed a diagnosis of CD40L deficiency due to a hemizygous variant in CD40LG, c.674T>C; p.Leu225Ser (NM_000074.2). We had previously evaluated a 4-year-old male with intermittent, non-bloody diarrhea, pneumonia, hypogammaglobulinemia, and significant neutropenia, and identified this novel variant, now also observed in this infant. We utilized advanced computational tools to evaluate the molecular impact of this variant on the structure and function of CD40L. The Leu225Ser variant is located within the trimerization interface of CD40L. Molecular modeling, mutagenesis alanine scanning, and molecular dynamic simulations revealed that the variant causes loss of critical intramolecular time-dependent interactions between hydrophobic molecules that would typically facilitate trimerization of wild-type CD40L for optimal interaction with the CD40 receptor. This analysis of the Leu225Ser variant revealed the molecular basis of the decreased CD40L protein expression (loss of contact to form trimers) and impaired CD40 binding (loss of intramolecular bonds affecting folding and impaired interaction at the trimerization interface). The patient also had immune paralysis due to decreased MHC class II (HLA-DR) expression on CD14+ monocytes, a result of a compensatory anti-inflammatory response syndrome (CARS). Assessment of neutrophil activation and granule markers (CD66b, lactoferrin, myeloperoxidase [MPO], and elastase) revealed low-normal CD66b and lactoferrin with slightly increased MPO and elastase, suggesting a complex and dysfunctional neutrophil response rather than simple activation or deactivation. This phenotype is consistent with the known pathology of CD40L deficiency, in which neutrophils are defective in their ability to respond effectively to infection, leading to chronic inflammation and tissue damage despite persistent signs of granule release. Treatment with rIFNg has been shown to reverse neutrophil dysfunction in X-linked hyper-IgM syndrome (XHIGM) but also restore HLA-DR expression on monocytes and reverse immune paralysis. He is currently being evaluated for hematopoietic cell transplantation (HCT). This case exemplifies the relevance of utilizing a variety of strategies to evaluate novel variants in IEI genes. Further, molecular and computational studies permitted an improved understanding of the impact of the Leu225Ser variant on CD40L protein expression and function.
2026-07-07 | Allogeneic hematopoietic cell transplantation with reduced-toxicity conditioning for X-linked hyper-IgM syndrome.
X-linked hyper-IgM syndrome (XHIGM) is an inborn error of immunity caused by variants in the CD40LG gene, leading to disrupted T-cell function and impaired immunoglobulin class-switch recombination. Supportive care alone is linked to unfavorable outcomes, necessitating allogeneic hematopoietic cell transplantation (HCT) as a curative option. Although myeloablative conditioning is recommended for HCT, concerns remain regarding its toxicity. We reviewed ten patients with XHIGM who underwent HCT using reduced-toxicity conditioning (RTC) at our institution between 2010 and 2024. All patients underwent HCT by 5 years of age (range: 2-5 years; median: 3 years). Donor sources included unrelated bone marrow, unrelated cord blood, and haploidentical-related donors. Conditioning primarily consisted of fludarabine and busulfan (target area under the curve: 60-65 mg/L·h), with low-dose total body irradiation (TBI) administered in five patients. Two patients experienced graft failure, requiring a second transplantation, and one died from post-transplant complications. The remaining nine patients survived. The 5-year overall survival rate was 88.9%; the 5-year graft-versus-host disease-free, relapse-free, and second transplantation-free survival rate was 67.5%. The addition of low-dose TBI to fludarabine/busulfan was associated with favorable long-term donor chimerism, although this finding should be considered hypothesis-generating. RTC may represent a feasible conditioning strategy for XHIGM.
2026-05-05 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in X-Linked Hyper IgM Syndrome: A Multicenter Chinese Cohort Study from CCBMT.
X-linked hyper-IgM syndrome (XHIGM) is a rare immunodeficiency for which allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option, yet large pediatric Chinese datasets are scarce. We retrospectively analyzed 71 boys with genetically confirmed CD40L deficiency who underwent allogeneic HSCT between 2009 and 2020 at eight centers in China. Median age at HSCT was 3 yr (range, 0.6 to 17), with 74.6% transplanted before age 5. Donors were mismatched unrelated (42.3%), matched unrelated (33.8%), matched sibling (18.3%), and haploidentical (5.6%). Peripheral blood was the predominant stem cell source (67.6%), followed by cord blood (31.0%). Myeloablative conditioning was used in 95.8%. Median times to neutrophil and platelet engraftment were 12 and 14 d, respectively. Primary graft failure occurred in 5.6%. Acute GVHD developed in 60.6% (grade III to IV, 11.3%), and chronic GVHD in 25.4% (none-severe). Cytomegalovirus and EBV-DNAemia occurred in 56.3% and 39.4%, respectively; post-transplant lymphoproliferative disorder developed in 4.2%. Other complications included sinusoidal obstruction syndrome and hemorrhagic cystitis (7.0% each). At last follow-up, 9 patients (12.1%) had died, mainly from infections (8.5%). At a median follow-up of 7.8 yr, the estimated 10-yr overall, disease-free, and GVHD-free survival rates were 85.91%, 64.79%, and 77.14%, respectively. Survival was superior in younger patients, those with lower body weight, and well-matched related or unrelated donors. Immune reconstitution showed early NK recovery with progressive T and B cell restoration over 1 yr. These data support HSCT as effective long-term therapy for XHIGM and highlight benefits of early timing and optimal HLA matching.
2026-05-01 | Thriving Without Transplant: A Case of X-Linked Hyper-IgM Syndrome with Near-Normal Quality of Life on IVIG
Introduction Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency characterized by impaired immunoglobulin class-switch recombination, most commonly due to mutations in the CD40 ligand (CD40L) gene. Affected patients typically present in early childhood with recurrent sinopulmonary infections and are at risk for opportunistic infections, chronic lung disease, and immune dysregulation. Hematopoietic stem cell transplantation (HSCT) is considered curative but carries significant risks. Long-term outcomes with immunoglobulin replacement therapy alone in selected patients remain an area of clinical interest. Case Report We present a male patient with X-linked HIGM (CD40L Thr254Met mutation) diagnosed at age 6 years. He initially developed recurrent otitis media by 1 year of age, followed by recurrent bacterial pneumonias and chronic sinusitis. Notably, he had no history of opportunistic infections. Initial immunologic evaluation revealed elevated IgM (431 mg/dL), markedly low IgG and IgA, and undetectable IgE levels. He was started on intravenous immunoglobulin (IVIG) replacement therapy in 2011, resulting in significant clinical improvement and resolution of recurrent infections. He is currently 21 years of age, his immunoglobulin levels demonstrated therapeutic IgG (1,542 mg/dL), persistently low IgA (<5 mg/dL), and improved IgM (170 mg/dL). Over the subsequent years, he experienced only two mild, self-limited upper respiratory infections and was described by his family as healthier than most peers. He remained compliant with IVIG therapy (30 g every 3 weeks) and reported excellent quality of life. A minor gastrointestinal concern consisting of intermittent passage of small amounts of mucus-like stool with flatus was reported but was infrequent, nonprogressive, and without systemic symptoms. Physical examination was unremarkable. Given his stable clinical course, lack of opportunistic infections, and excellent response to IVIG, HSCT was previously discussed but deferred in favor of continued immunoglobulin replacement. Discussion This case highlights the potential for excellent long-term clinical stability in selected patients with X-linked HIGM managed with IVIG alone. While HSCT remains the definitive therapy, careful patient selection is critical, particularly in those with mild phenotypes and excellent infection control. This case supports an individualized approach to management, emphasizing quality of life, treatment response, and shared decision-making in rare primary immunodeficiencies.
2026-08-11 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report
Background Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. Case presentation We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii . An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient’s immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Conclusions Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-07-14 | Relevance of a Computational Deep-Dive to Characterize the Molecular Biology of a Novel Cd40l Variant
CD40L deficiency is a well-described inborn error of immunity (IEI). The disease is characterized immunologically by impaired class-switching and T cell costimulation. A male infant presented at 8 months of age with recurrent cellulitis. At 11 months, he was admitted for prolonged fever and leukopenia with vomiting and watery diarrhea, periorbital edema, back abscess, increased sIL2R at 50,598 pg/mL (<14,491), and normal CXCL9 at 22 pg/mL with mild to modest increases in IL-18 at 694 pg/mL (<185.4), IL-6 at 226.4 pg/mL (<10), serum amyloid A (SAA) at 1,413 mcg/mL (<373.8), IL-8 at 196 (<10), and IL-10 at 101pg/mL (<10). His IgG and IgA were low at <30 and <10 mg/dL, respectively. He developed Pseudomonas sepsis, palatal ulceration, jejunal perforation requiring repair, Candida peritonitis, persistent neutropenia, CMV, and Parechovirus viremia. Along with the hypogammaglobulinemia, class-switched memory B cells were decreased for age. Flow cytometry was performed for CD40L expression on activated CD4+ T cells along with functional evaluation of ligand binding to a soluble form of the receptor (CD40), using CD40-muIg. There was significantly diminished CD40L expression with essentially absent binding to the receptor. Genetic testing confirmed a diagnosis of CD40L deficiency due to a hemizygous variant in CD40LG, c.674T>C; p.Leu225Ser (NM_000074.2). We had previously evaluated a 4-year-old male with intermittent, non-bloody diarrhea, pneumonia, hypogammaglobulinemia, and significant neutropenia, and identified this novel variant, now also observed in this infant. We utilized advanced computational tools to evaluate the molecular impact of this variant on the structure and function of CD40L. The Leu225Ser variant is located within the trimerization interface of CD40L. Molecular modeling, mutagenesis alanine scanning, and molecular dynamic simulations revealed that the variant causes loss of critical intramolecular time-dependent interactions between hydrophobic molecules that would typically facilitate trimerization of wild-type CD40L for optimal interaction with the CD40 receptor. This analysis of the Leu225Ser variant revealed the molecular basis of the decreased CD40L protein expression (loss of contact to form trimers) and impaired CD40 binding (loss of intramolecular bonds affecting folding and impaired interaction at the trimerization interface). The patient also had immune paralysis due to decreased MHC class II (HLA-DR) expression on CD14+ monocytes, a result of a compensatory anti-inflammatory response syndrome (CARS). Assessment of neutrophil activation and granule markers (CD66b, lactoferrin, myeloperoxidase [MPO], and elastase) revealed low-normal CD66b and lactoferrin with slightly increased MPO and elastase, suggesting a complex and dysfunctional neutrophil response rather than simple activation or deactivation. This phenotype is consistent with the known pathology of CD40L deficiency, in which neutrophils are defective in their ability to respond effectively to infection, leading to chronic inflammation and tissue damage despite persistent signs of granule release. Treatment with rIFNg has been shown to reverse neutrophil dysfunction in X-linked hyper-IgM syndrome (XHIGM) but also restore HLA-DR expression on monocytes and reverse immune paralysis. He is currently being evaluated for hematopoietic cell transplantation (HCT). This case exemplifies the relevance of utilizing a variety of strategies to evaluate novel variants in IEI genes. Further, molecular and computational studies permitted an improved understanding of the impact of the Leu225Ser variant on CD40L protein expression and function.
2026-07-07 | Allogeneic hematopoietic cell transplantation with reduced-toxicity conditioning for X-linked hyper-IgM syndrome.
X-linked hyper-IgM syndrome (XHIGM) is an inborn error of immunity caused by variants in the CD40LG gene, leading to disrupted T-cell function and impaired immunoglobulin class-switch recombination. Supportive care alone is linked to unfavorable outcomes, necessitating allogeneic hematopoietic cell transplantation (HCT) as a curative option. Although myeloablative conditioning is recommended for HCT, concerns remain regarding its toxicity. We reviewed ten patients with XHIGM who underwent HCT using reduced-toxicity conditioning (RTC) at our institution between 2010 and 2024. All patients underwent HCT by 5 years of age (range: 2-5 years; median: 3 years). Donor sources included unrelated bone marrow, unrelated cord blood, and haploidentical-related donors. Conditioning primarily consisted of fludarabine and busulfan (target area under the curve: 60-65 mg/L·h), with low-dose total body irradiation (TBI) administered in five patients. Two patients experienced graft failure, requiring a second transplantation, and one died from post-transplant complications. The remaining nine patients survived. The 5-year overall survival rate was 88.9%; the 5-year graft-versus-host disease-free, relapse-free, and second transplantation-free survival rate was 67.5%. The addition of low-dose TBI to fludarabine/busulfan was associated with favorable long-term donor chimerism, although this finding should be considered hypothesis-generating. RTC may represent a feasible conditioning strategy for XHIGM.
2026-05-05 | Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in X-Linked Hyper IgM Syndrome: A Multicenter Chinese Cohort Study from CCBMT.
X-linked hyper-IgM syndrome (XHIGM) is a rare immunodeficiency for which allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option, yet large pediatric Chinese datasets are scarce. We retrospectively analyzed 71 boys with genetically confirmed CD40L deficiency who underwent allogeneic HSCT between 2009 and 2020 at eight centers in China. Median age at HSCT was 3 yr (range, 0.6 to 17), with 74.6% transplanted before age 5. Donors were mismatched unrelated (42.3%), matched unrelated (33.8%), matched sibling (18.3%), and haploidentical (5.6%). Peripheral blood was the predominant stem cell source (67.6%), followed by cord blood (31.0%). Myeloablative conditioning was used in 95.8%. Median times to neutrophil and platelet engraftment were 12 and 14 d, respectively. Primary graft failure occurred in 5.6%. Acute GVHD developed in 60.6% (grade III to IV, 11.3%), and chronic GVHD in 25.4% (none-severe). Cytomegalovirus and EBV-DNAemia occurred in 56.3% and 39.4%, respectively; post-transplant lymphoproliferative disorder developed in 4.2%. Other complications included sinusoidal obstruction syndrome and hemorrhagic cystitis (7.0% each). At last follow-up, 9 patients (12.1%) had died, mainly from infections (8.5%). At a median follow-up of 7.8 yr, the estimated 10-yr overall, disease-free, and GVHD-free survival rates were 85.91%, 64.79%, and 77.14%, respectively. Survival was superior in younger patients, those with lower body weight, and well-matched related or unrelated donors. Immune reconstitution showed early NK recovery with progressive T and B cell restoration over 1 yr. These data support HSCT as effective long-term therapy for XHIGM and highlight benefits of early timing and optimal HLA matching.
2026-05-01 | Thriving Without Transplant: A Case of X-Linked Hyper-IgM Syndrome with Near-Normal Quality of Life on IVIG
Introduction Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency characterized by impaired immunoglobulin class-switch recombination, most commonly due to mutations in the CD40 ligand (CD40L) gene. Affected patients typically present in early childhood with recurrent sinopulmonary infections and are at risk for opportunistic infections, chronic lung disease, and immune dysregulation. Hematopoietic stem cell transplantation (HSCT) is considered curative but carries significant risks. Long-term outcomes with immunoglobulin replacement therapy alone in selected patients remain an area of clinical interest. Case Report We present a male patient with X-linked HIGM (CD40L Thr254Met mutation) diagnosed at age 6 years. He initially developed recurrent otitis media by 1 year of age, followed by recurrent bacterial pneumonias and chronic sinusitis. Notably, he had no history of opportunistic infections. Initial immunologic evaluation revealed elevated IgM (431 mg/dL), markedly low IgG and IgA, and undetectable IgE levels. He was started on intravenous immunoglobulin (IVIG) replacement therapy in 2011, resulting in significant clinical improvement and resolution of recurrent infections. He is currently 21 years of age, his immunoglobulin levels demonstrated therapeutic IgG (1,542 mg/dL), persistently low IgA (<5 mg/dL), and improved IgM (170 mg/dL). Over the subsequent years, he experienced only two mild, self-limited upper respiratory infections and was described by his family as healthier than most peers. He remained compliant with IVIG therapy (30 g every 3 weeks) and reported excellent quality of life. A minor gastrointestinal concern consisting of intermittent passage of small amounts of mucus-like stool with flatus was reported but was infrequent, nonprogressive, and without systemic symptoms. Physical examination was unremarkable. Given his stable clinical course, lack of opportunistic infections, and excellent response to IVIG, HSCT was previously discussed but deferred in favor of continued immunoglobulin replacement. Discussion This case highlights the potential for excellent long-term clinical stability in selected patients with X-linked HIGM managed with IVIG alone. While HSCT remains the definitive therapy, careful patient selection is critical, particularly in those with mild phenotypes and excellent infection control. This case supports an individualized approach to management, emphasizing quality of life, treatment response, and shared decision-making in rare primary immunodeficiencies.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for X-linked hyper-IgM syndrome.
1 orphan drug designation for X-linked hyper-IgM syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous peripheral blood-derived CD4 T-cells CRISPR-edited at the CD40LG locus | gene editing enzymes | EMA | 2022-05-16 | — | Fondazione Telethon Ets |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.