RARE DISEASE
X-linked lymphoproliferative disease due to SAP deficiency
X-linked lymphoproliferative disease due to SAP deficiency
X-linked lymphoproliferative disease due to SAP deficiency
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Drug discovery
0
drugs
With orphan designations
Overview
X-linked lymphoproliferative disease due to SAP deficiency (XLP1) is a rare X-linked recessive immunodeficiency caused by SH2D1A mutations, impairing cytotoxic lymphocyte regulation and EBV response. Key manifestations include EBV-triggered hemophagocytic lymphohistiocytosis (HLH), lymphoma, hypogammaglobulinemia, and vasculitis. Untreated, mortality exceeds 70% by age 10. Hematopoietic stem cell transplantation (HSCT) remains curative if performed early, while pre-transplant strategies focus on controlling HLH and preventing EBV complications [1][4][9][14].
Therapies
Curative: Allogeneic HSCT (80% survival; reduced to 50% with pre-transplant HLH) [4][5]
Pre-transplant management: Rituximab (anti-CD20) for EBV suppression, IVIG for hypogammaglobulinemia, and HLH-directed therapy (dexamethasone/etoposide) [5][7][14]
Monitoring: Avoid live vaccines; EBV PCR surveillance [9][10]
Categories: rare genetic diseases, rare immunological diseases, rare neoplastic diseases
Research Papers
118 drug discovery papers about X-linked lymphoproliferative disease due to SAP deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
118 drug discovery papers about X-linked lymphoproliferative disease due to SAP deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-11-03 | Hemophagocytic lymphohistiocytosis of the ocular adnexal mimicking orbital cellulitis in a patient with unknown X-linked lymphoproliferative syndrome type 1 (XLP1): Case report and literature review.
A 5-year-old boy presented with severe acute bilateral periorbital edema. Initial misdiagnosis was made as preseptal orbital cellulitis, and he failed to respond to conventional antibiotic therapy. Magnetic resonance imaging revealed thickening of the anterior orbital adipose tissue bilaterally, with hyperintensity on T2-weighted imaging. The biopsy unveiled lymphoma-associated hemophagocytic syndrome, specifically Epstein-Barr virus related. The patient was administered rituximab, resulting in a significant amelioration. A family history, coupled with genetic investigation, ultimately led to the diagnosis of X-linked lymphoproliferative syndrome type 1 due to a large deletion of exons 2-4 of *SH2D. Reported ocular manifestation of XLP1 includes retinal hemorrhages, disc edema, acute posterior multifocal placoid pigment epitheliopathy, and macular edema. No ocular adnexal involvement has been previously reported. This case documents a case of XLP1 syndrome affecting the ocular adnexa and emphasizes the critical need to consider underlying immunodeficiencies in patients who do not respond to conventional therapies.
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals. The online version contains supplementary material available at 10.1186/s13023-025-04057-9.
2025-10-08 | Image 2_X-linked lymphoproliferative disease with initial onset of neurological symptoms: a case and literature review.jpg
X-linked lymphoproliferative syndrome type 1 (XLP-1) is a life-threatening X-linked recessive immunodeficiency classically characterized by susceptibility to Epstein–Barr virus (EBV), hypogammaglobulinemia, and lymphoma. While neurological involvement can occur, it is exceptionally rare as the initial and predominant manifestation. This case report details a novel presentation of XLP-1 in a 4-year-old boy who presented with acute, initial neurological symptoms (sudden fever, headache, and vomiting) in the absence of typical immune dysregulation features. Whole-exome sequencing (WES) identified a hemizygous variant in the SH2D1A gene (c.1A>G, p. Met1Val), predicted as damaging/disease-causing by MutationTaster (probability = 0.993) and PolyPhen-2 (probability = 0.992). Meanwhile, according to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, this variant met four evidence criteria (PVS1_Moderate+ +PM2_Moderate+PP3+PP5) and was classified as pathogenic. Structural analysis leveraging the AlphaFold protein structure database demonstrated that this variant disrupts the Kozak consensus sequence and splice site, critically impairing start codon recognition and translation initiation, thereby explaining the loss of functional SLAM-associated protein (SAP) protein expression. This case, along with a focused review of the literature, underscores that XLP-1 rarely presents primarily with neurological symptoms, broadening the clinical phenotype spectrum and emphasizing the need for early genetic evaluation in children with unexplained acute neurological presentations, even in the absence of overt immunodeficiency signs. This finding provides crucial clinical data for a more comprehensive understanding of XLP-1.
2025-09-05 | Severe Oral Lichen Planus Masking a Primary Immunodeficiency: X-Linked Lymphoproliferative Disease Type 1 (XLP-1).
A 14-year-old boy was initially diagnosed with erosive oral lichen planus based on clinical and histopathological findings. However, the atypical clinical course and resistance to immunosuppressive therapy raised suspicion for an autoinflammatory disorder or inborn error of immunity. Genetic testing revealed a pathogenic SH2D1A mutation, confirming X-linked lymphoproliferative disease type 1 (XLP-1) in the absence of Epstein-Barr virus exposure. This case highlights oral mucosal lesions as a potential early, EBV-independent manifestation of XLP-1 and emphasizes the importance of considering monogenic immune disorders in persistent, treatment-refractory mucosal disease.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
2025-11-03 | Hemophagocytic lymphohistiocytosis of the ocular adnexal mimicking orbital cellulitis in a patient with unknown X-linked lymphoproliferative syndrome type 1 (XLP1): Case report and literature review.
A 5-year-old boy presented with severe acute bilateral periorbital edema. Initial misdiagnosis was made as preseptal orbital cellulitis, and he failed to respond to conventional antibiotic therapy. Magnetic resonance imaging revealed thickening of the anterior orbital adipose tissue bilaterally, with hyperintensity on T2-weighted imaging. The biopsy unveiled lymphoma-associated hemophagocytic syndrome, specifically Epstein-Barr virus related. The patient was administered rituximab, resulting in a significant amelioration. A family history, coupled with genetic investigation, ultimately led to the diagnosis of X-linked lymphoproliferative syndrome type 1 due to a large deletion of exons 2-4 of *SH2D. Reported ocular manifestation of XLP1 includes retinal hemorrhages, disc edema, acute posterior multifocal placoid pigment epitheliopathy, and macular edema. No ocular adnexal involvement has been previously reported. This case documents a case of XLP1 syndrome affecting the ocular adnexa and emphasizes the critical need to consider underlying immunodeficiencies in patients who do not respond to conventional therapies.
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals. The online version contains supplementary material available at 10.1186/s13023-025-04057-9.
2025-10-08 | Image 2_X-linked lymphoproliferative disease with initial onset of neurological symptoms: a case and literature review.jpg
X-linked lymphoproliferative syndrome type 1 (XLP-1) is a life-threatening X-linked recessive immunodeficiency classically characterized by susceptibility to Epstein–Barr virus (EBV), hypogammaglobulinemia, and lymphoma. While neurological involvement can occur, it is exceptionally rare as the initial and predominant manifestation. This case report details a novel presentation of XLP-1 in a 4-year-old boy who presented with acute, initial neurological symptoms (sudden fever, headache, and vomiting) in the absence of typical immune dysregulation features. Whole-exome sequencing (WES) identified a hemizygous variant in the SH2D1A gene (c.1A>G, p. Met1Val), predicted as damaging/disease-causing by MutationTaster (probability = 0.993) and PolyPhen-2 (probability = 0.992). Meanwhile, according to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, this variant met four evidence criteria (PVS1_Moderate+ +PM2_Moderate+PP3+PP5) and was classified as pathogenic. Structural analysis leveraging the AlphaFold protein structure database demonstrated that this variant disrupts the Kozak consensus sequence and splice site, critically impairing start codon recognition and translation initiation, thereby explaining the loss of functional SLAM-associated protein (SAP) protein expression. This case, along with a focused review of the literature, underscores that XLP-1 rarely presents primarily with neurological symptoms, broadening the clinical phenotype spectrum and emphasizing the need for early genetic evaluation in children with unexplained acute neurological presentations, even in the absence of overt immunodeficiency signs. This finding provides crucial clinical data for a more comprehensive understanding of XLP-1.
2025-09-05 | Severe Oral Lichen Planus Masking a Primary Immunodeficiency: X-Linked Lymphoproliferative Disease Type 1 (XLP-1).
A 14-year-old boy was initially diagnosed with erosive oral lichen planus based on clinical and histopathological findings. However, the atypical clinical course and resistance to immunosuppressive therapy raised suspicion for an autoinflammatory disorder or inborn error of immunity. Genetic testing revealed a pathogenic SH2D1A mutation, confirming X-linked lymphoproliferative disease type 1 (XLP-1) in the absence of Epstein-Barr virus exposure. This case highlights oral mucosal lesions as a potential early, EBV-independent manifestation of XLP-1 and emphasizes the importance of considering monogenic immune disorders in persistent, treatment-refractory mucosal disease.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
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