AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) or AUTOIMMUNE LYMPHOPROLIFERATIVE IMMUNODEFICIENCY (ALPID): THE ONGOING DIAGNOSTIC DILEMA: A CASE SERIES.

Background: Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of lymphocyte apoptosis characterized by chronic non-malignant lymphadenopathy, splenomegaly, autoimmune cytopenias, and an increased risk of lymphoma. The diagnostic hallmark is expansion of double-negative T cells (DNTs: CD3+ TCRαβ+ CD4– CD8–). Reports from low and middle-income countries remain limited, and diagnosis is often delayed or missed. We present six pediatric cases from a single center in Pakistan, highlighting their clinical and laboratory findings, management, therapeutic responses, diagnostic challenges, and outcomes. Materials & Methods : This descriptive study presents an observational case series from the pediatric Haematology Oncology department at The Children’s Hospital, University of Child Health Sciences, Lahore, Pakistan. The medical records of six patients with clinical and immunological features consistent with ALPS were reviewed. Demographic, clinical, laboratory, genetic, and treatment data were collected. Results : Six children (median age of onset 8 months) were included. Splenomegaly and autoimmune cytopenias were present in all cases, while lymphadenopathy was seen in four. All had raised double-negative T cells. Corticosteroids showed limited benefit, whereas sirolimus achieved sustained remission in most patients. One child required a splenectomy for refractory thrombocytopenia. Conclusion : ALPS should be considered in the differential diagnosis of children presenting with non-malignant lymphadenopathy and unexplained cytopenia. This case series highlights the variable clinical spectrum of ALPS in children and emphasizes the diagnostic utility of clinical and immunologic features, along with double-negative T cells, in diagnosing ALPS. Early recognition and targeted therapy are critical to improve outcomes, particularly in resource-limited settings where genetic testing is not readily available. INTRODUCTION; Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare primary immune dysregulation disorder caused by defective FAS-mediated lymphocyte apoptosis. Pathogenic variants are most commonly identified in FAS, FASL, and CAP10 , although many patients remain genetically unidentified 1 . Clinically, ALPS is characterized by non-malignant lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, and an increased lifetime risk of lymphoma 2 . The presentation often mimics other conditions, such as infections, malignancy, hemolytic anemia, immunodeficiency, or ALPS-like disorders, making diagnosis challenging. In low and middle-income countries (LMICs), recognition is further delayed due to limited awareness and restricted access to genetic testing. The true incidence, therefore, remains unknown as ALPS is rarely in the differential diagnosis of chronic cytopenias and lymphoproliferation. Here, we present a case series of six children with ALPS who experienced significant diagnostic challenges but demonstrated good clinical response to treatment.

& METHODS; This was a descriptive case series conducted in the Paediatric Haematology Oncology Department, at The Children’s Hospital, University of Child Health Sciences, Lahore, from January 2020 till September 2025. Medical records of Children diagnosed with ALPS were reviewed. Diagnosis was made based on the clinical features, together with immunological criteria, including elevated CD3⁺ TCRαβ⁺ CD4⁻CD8⁻ double-negative T (DNT) cells (>1.5% of total lymphocytes). Laboratory investigations reviewed included complete blood counts, renal and liver function tests, autoantibody screen (ANA), Direct Coombs test, immunoglobulin level, lymph node biopsy, and bone marrow aspiration biopsy, where indicated. Genetic testing was available in selected cases. Treatment modalities used included corticosteroids, Intravenous immunoglobulin, sirolimus, mycophenolate mofetil, and cyclosporine, tailored to clinical response. Patient outcomes were assessed based on resolution of cytopenias, regression of lymphadenopathy, and splenomegaly. Exemption was taken from the institutional review board (IRB) for publication as it’s an observational case series. Informed consent was taken from the parents of all patients. Descriptive statistics were used to summarize the findings. Continuous variables like age, hemoglobin, and laboratory parameters were expressed as means, medians, and ranges. Categorical variable such as gender, presence of lymphadenopathy, splenomegaly, and treatment response was presented as frequencies and percentages. Given the small sample size, no inferential statistical analysis was performed.

Six children were identified (four males, two females), with a median age of onset of 8 months (range 4months -6.5 years)(table 1). The most consistent finding was splenomegaly (100%), followed by autoimmune cytopenias (100%) and lymphadenopathy (66%). All patients had elevated double-negative T cells, while genetic confirmation was possible in one child with KRAS-associated ALPS. Corticosteroids were used as first-line therapy but showed poor sustained response. Sirolimus proved effective in most patients, leading to normalization of blood counts and regression of lymphadenopathy and splenomegaly, and was well tolerated. One child required a splenectomy due to refractory thrombocytopenia. CASE DESCRIPTION: The clinical and laboratory features of ALPS can easily mimic other autoimmune diseases, ITP, or immune dysregulation. We present six cases that were diagnosed as ALPS based on the 2010 International revised classification. Case 1 : A 3 year girl presented with 6 months history of intermittent fever and bilateral neck swelling. She has one elder sister who was healthy and one younger brother who presented later and was diagnosed with ALPS (case 2). On examination, her weight was 8.5 kg (<5 th centile), and a BCG scar was present. She had bilateral cervical and axillary lymphadenopathy, the largest being left cervical 4 × 3 cm, multiple discrete (pictures 1&2). Hepatomegaly (liver span 12 cm, palpable 3 cm below the right costal margin) and splenomegaly (8 cm below the left costal margin) were noted. Family history was significant; her maternal uncle had persistent cervical lymphadenopathy since childhood, was later diagnosed as non-Hodgkin lymphoma (T cell/histiocyte-rich large B cell lymphoma) at 15 years, and died of infection-related complications. ALPS was suspected in the patient. She had raised IgE (3896 IU/ml) and IgG levels, while IgA and IgM were normal. She was initially treated with Tab Deltacortil 2mg/kg/day for 7 weeks, without clinical improvement. Subsequently, tablet Sirolimus (0.2mg/kg/day) was commenced, leading to a marked clinical response with normalization of blood counts and regression of lymphadenopathy and splenomegaly. After two years, Sirolimus was discontinued; however, she experienced a recurrence of cytopenia and splenomegaly. Sirolimus was reinitiated with excellent disease control and no adverse effects to date. Case 2: Nine nine-month-old younger sibling of case 1 were brought by their mother with a one-week history of fever and multiple neck swellings about 0.5×0.7cm. On examination, he weighed 9 kg and was found to have bilateral cervical lymphadenopathy along with hepatosplenomegaly (liver 3cm, spleen 6 cm below the costal margins). His immunoglobulin levels were normal. He was initially treated with oral prednisolone (Deltacortil) but showed no clinical improvement . Subsequently, he was switched to oral Sirolimus, which resulted in a marked response with regression of lymphadenopathy and splenomegaly as well as normalization of blood counts. He continues to do well on sirolimus without adverse effects. Case 3 : An 8-month-old boy presented with pallor, fever, recurrent infections, generalized lymphadenopathy, and massive Hepatosplenomegaly. There was no family history of ALPS. He required repeated platelets and packed red cell transfusions and was treated sequentially with prednisolone, IVIG, sirolimus, and cyclosporine. During therapy, he developed jerky movements of the right hand along with poor feeding and irritability. Infectious causes such as meningoencephalitis and TORCH infections were excluded. MRI brain revealed diffuse abnormal signals and bilateral symmetrical diffusion restriction suggestive of drug-induced neurotoxicity secondary to Sirolimus /Cyclosporine. He was managed with Antiepileptics(phenytoin, Levetiracetam) and supportive care. Cyclosporine was discontinued, and the sirolimus dose was adjusted according to trough blood levels. The patient responded well with resolution of lymphadenopathy and splenomegaly, and normalization of blood counts. Treatment was continued for two years, after which sirolimus was withdrawn. However, he experienced recurrence of symptoms, necessitating reintroduction of sirolimus, to which he again showed a favorable response. Case 4: A 4-year-old boy was referred from another hospital for splenectomy. He had been diagnosed at 15 months of age with KRAS-associated ALPS on genetic testing. At presentation, his weight was 10 kg, and examination revealed hepatosplenomegaly (Liver palpable 2 cm below the right costal margin and spleen 15 cm below the left costal margin). He was diagnosed through genetic testing. He had previously been treated with various doses of oral prednisolone (Deltacortil) and mycophenolate mofetil for one year, followed by rituximab, and later Sirolimus. Initially, he responded to medical treatment with normalization of platelet counts and reduction in spleen size. However, over time, his platelet count dropped to 23,000, and he developed massive splenomegaly. Owing to worsening hypersplenism and cytopenias, he underwent splenectomy at the age of 4 years. Case 5 : A 6.5 years old boy was admitted with 3 months history of worsening pallor. In infancy, he had been diagnosed with immune thrombocytopenia purpura (ITP) following recurrent spontaneous bruising, epistaxis, and gum bleeding for 10 months. On current examination, he appeared pale with no lymphadenopathy. The liver was palpable 2cm below the right costal margin, and the spleen was 8 cm below the left costal margin. He had received multiple red cell and platelet transfusions, as well as several courses of oral and intravenous steroids without sustained benefit. Given the persistent cytopenia and organomegaly, he was reinvestigated and subsequently diagnosed with ALPS. Oral sirolimus therapy was initiated with marked clinical improvement, including recovery of blood counts and resolution of splenomegaly. Case 6: A 2-year-old girl presented in the outpatient clinic with a history of two episodes of epistaxis, first noted at 4 months of age, along with three episodes of grade 3 diarrhea, recurrent upper respiratory tract infection requiring treatment, and failure to thrive. At the time of diagnosis, she was found to have anemia, thrombocytopenia, and splenomegaly. She was initially labelled as having autoimmune hemolytic anemia. Her family history was notable for four siblings, two of whom had died, one due to congenital heart disease, and another with unexplained cytopenia and pneumonia. The patient required three red cell transfusions and received intravenous immunoglobulins. She was started on Mycophenolate Mofetil and oral steroids (in tapering doses), which she has been receiving for one year. She is currently doing well with normalized blood counts, no lymphadenopathy, and no splenomegaly.

A total of six children were included. The median current age was 6.2 years (range 1-8.5 years). The median age of disease onset was 9.5 months (4months to 6.5 years). Consanguinity was present in 1(16.7%) family. A positive or partial family history was present suggestive of ALPS was noted in 3(50%) cases. Lymphadenopathy was present in 3(50%) patients, and splenomegaly in all (100%) (Table 1 summarizes the key findings). All patients exhibited cytopenia to variable degrees. The mean hemoglobin levels were 8.2g/dl, and leucocyte counts ranged from 3.9-13×10 9 /L, and platelets ranged from 23,000-59,000, reflecting persistent thrombocytopenia in all. Elevated double negative T cells (DNT)cells (CD3⁺ TCRαβ⁺ CD4⁻CD8⁻) were observed in all tested patients, ranging from 8.4% to 42.3%. Antinuclear Antibody (ANA) was positive in 19(6.7%) patients. Direct Antiglobulin (DAT) was positive in 2(33.3%) patients. All patients received immunomodulatory therapy tailored to severity, including corticosteroids, IVIG, Sirolimus, or mycophenolate mofetil. Clinical improvement was assessed by resolution of symptoms (lymphadenopathy, splenomegaly) and cytopenia. At last, follow-up (median follow-up 2 years), all are alive, with normal blood counts and resolution of symptoms. Table 1: Patient Characteristics | Current age/Gender | 7 yrs/F | 1 yr/M | 8.5yrs/M | 4.5 yrs/M | 8yrs/M | 2yrs/F | | Age of onset | 6months | 9months | 8months | 15months | 6.5yrs | 4months | | Consanguinity | -ve | -ve | -ve | -ve | +ve | | | Family history | +/- | +/- | absent | absent | absent | +/- | | Lymphadenopathy | present | present | present | absent | absent | absent | | splenomegaly | present | present | present | present | present | present | | Hb(gm/dl) | 7.2 | 7.1 | 8 | 8.6 | 9 | 9.3 | | WBC× 10 9 | 4.5 | 8.1 | 10 | 7.2 | 13.0 | 3.9 | | Platelets | 59,000 | 33,000 | 45,000 | 33,000 | 23,000 | 41,000 | | Lymph node biopsy | normal | normal | granulomatous lymphadenitis | NA | NA | NA | | Bone Marrow Aspiration biopsy | normal | normal | normal | normal | normal | normal | | Serum B12 (93-1207ng/ml) | 149 | 279 ng/ml | NA | 1242 | 1282 | 457 | | ANA | negative | negative | NA | Positive | negative | negative | | DAT | negative | negative | positive | Negative | negative | positive | | IgG (610-1380mg/dl) | 2749 | 1470 | NA | NA | 1800 | 1380 | | CD4/CD8 Double negative T cells (DNT cell) % | 42.3 | 33.1 | 40 | not done, diagnosed on genetics | 17.2 | 8.4 | | Genetic test, next Generation Sequencing (NGS) | not done | not done | not done | Pathogenic variant in KRAS gene, autosomal dominant KRAS associated ALPS by somatic variants. | not done | normal | | Diagnosis | ALPS | ALPS | ALPS | KRAS-associated ALPS like disease | ALPS | ALPS-U/ ALPID | DISCUSSION; Autoimmune Lymphoproliferative Syndrome (ALPS) is an inborn error of immunity (IEI) and a rare genetic disorder associated with defective FAS-mediated apoptosis. It typically presents with non-malignant lymphoproliferation (splenomegaly, hepatomegaly, and /or chronic benign lymphadenopathy) and autoimmune cytopenias. Diagnosis relies on the revised international consensus criteria of 2010, requiring both major criteria and at least one primary accessory criterion for a definitive diagnosis or a secondary accessory criterion for probable diagnosis 3 . In our case series, all patients fulfilled criteria for probable ALPS with splenomegaly, elevated double-negative T cells, and autoimmune cytopenias as the most consistent findings. Family history was confirmed in two patients and suspected in one patient, suggesting a hereditary predisposition. Notably, one patient carried a somatic KRAS mutation, consistent with Ras-associated autoimmune lymphoproliferative Disease (RALD) 4, while another presented as ALPS-U, with an undefined genetic basis. The absence of genetic testing in four patients was a limitation, but their clinical and immunological features were typical of ALPS. The evolving molecular classification highlights its heterogeneity. Classical subtypes include ALPS-FAS, ALPS-FASLG, and ALPS-CAPS10, with type IV now redefined as RALD 5 . Increasingly, disorders once considered ALPS are recognized as distinct disorders, such as KRAS and NRAS-associated phenotypes, which mimic ALPS but are driven by dysregulated survival or increased cell proliferation rather than defects in apoptosis pathways alone. To address this gap, Magerus et al 6 proposed restricting the diagnosis of ALPS to proven FAS signaling defects, highlighting that ALPS represents only a small percentage of cases with an autoimmune lymphoproliferative phenotype. They proposed the umbrella term autoimmune lymphoproliferative immunodeficiencies (ALPID) for other disorders with autoimmune lymphoproliferation but without FAS abnormalities. Similarly, a large North American cohort of 802 patients at Cincinnati Children’s Hospital confirmed ALPS in 7.7%, mostly due to novel FAS variants, with diagnostic yield rising to 30% in those with abnormal immunology. Only 1.2% harbored ALPS-related variants (e.g, ADA2, CTLA4, KRAS, MAGT1, NRAS), highlighting the utility of next-generation sequencing in differentiating ALPS from overlapping immunodeficiencies 7 . ALPS usually presents in early childhood with non-infectious non-malignant fluctuant lymphadenopathy, splenomegaly, and autoimmune cytopenias, such as thrombocytopenia and hemolytic anemia. Lymphoproliferation is the most common finding. Seventy percent of ALPS patients develop immune-mediated cytopenias, which may mimic immune thrombocytopenia, autoimmune hemolytic anemia, or neutropenia. It can rarely cause uveitis, glomerulonephritis, hepatitis, and autoimmune pulmonary disease. Lymphoproliferation often resolves in adulthood, whereas cytopenias may persist 8 . Our findings are consistent with prior reports, where splenomegaly and cytopenias are the most frequent manifestations 9 . Importantly, ALPS carries a significantly increased risk of developing malignancies like Hodgkin Lymphoma and non-Hodgkin Lymphoma 10 . Two siblings in our series had a family history of childhood non-Hodgkin lymphoma, underscoring the importance of surveillance, genetic testing, and family screening. In our series, all six children fulfilled the clinical or immunological criteria for ALPS, highlighting the heterogeneity of presentation in a resource-limited setting. Double-negative T cells were observed in five of the six patients, underscoring their diagnostic value in the absence of advanced molecular testing. Diagnostic challenges include misclassification as ITP or autoimmune hemolytic anemia, delayed recognition of family clustering, and lack of early access to immunophenotyping or genetic confirmation in several cases. All patients in this series demonstrated elevated double-negative T cells, fulfilling a key required diagnostic criterion for ALPS. This, combined with clinical features and treatment responses, confirms the diagnosis in all cases. Diagnosing ALPS can be challenging due to its clinical overlap with Evans syndrome, Common variable immunodeficiency (CVID), Hemophagocytic Lymphohistiocytosis (HLH), and can mimic other IEI, like combined immunodeficiency (CID), cytotoxic T-lymphocyte–associated Protein-4 (CTLA4 deficiency, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, activated PI3-Kinase delta syndrome (APDS), or signal transducer and activation of transcription-3 (STAT3) gain-of-function (GOF), all of which can present with lymphoproliferation and autoimmune cytopenias 11,12,13,14 . In settings where genetic testing is limited, practical biomarkers such as double-negative T cells and high serum B12 levels remain useful for diagnosis. Histopathology can also provide supportive evidence, with follicular hyperplasia and paracortical expansion with double-negative T cells, a pattern that helps differentiate it from other lymphoproliferative disorders 15 . Worldwide, fewer than 1000 genetically confirmed cases of ALPS have been reported, with most cases in developed countries. However, large series from regions with a high rate of consanguinity, such as the review by Hafezi et al on 780 patients, of which 532 are genetically diagnosed cases of ALPS, highlight the substantial burden of ALPS and ALPS-like disorders in low—and middle-income countries. Our cohort reflects the challenges in resource-limited countries where reliance on clinical and immunological criteria is often required in the absence of genetic testing 16 . Seif et al demonstrated that the clinical features of Evans syndrome can overlap with those of ALPS. In their study of 45 children across 22 institutions, ALPS was diagnosed in 47% of patients using DNT testing and Fas-mediated apoptosis. Its recommended that all children with Evans syndrome and unexplained cytopenias should be screened for ALPS 17 . The clinical course of ALPS can be quite variable. Sometimes, the Patient may do well without any therapy, especially those with isolated lymphadenopathy. However, many patients require therapy mainly for autoimmune cytopenia 18 . Management of ALPS focuses primarily on controlling manifestations of the primary disease and complications. Corticosteroids with or without Intravenous immunoglobulin (IVIG) are standard first-line therapies. Increasingly, steroid-sparing agents such as Mycophenolate Mofetil (MMF) and Sirolimus (mTor inhibitor) are used, with sirolimus showing particular efficacy with FAS mutations by reducing lymphoproliferation and cytopenia 19 . Rituximab may be considered for refractory cases but carries risk, particularly of prolonged hypogammaglobulinemia 20 . Mycophenofenolate Mofetil is given orally at a dose of 60mg/m2/dose, twice daily. It has a steroid-sparing effect and is recommended for refractory cytopenias, massive splenomegaly, and hypersplenism 21 . Sirolimus is recommended in a dose of 3mg/m2 loading dose, then 2.5mg/m2/day maintenance (max 4 mg) dose, and helps reduce lymphoproliferation, cytopenia, and splenomegaly. Sirolimus levels are monitored initially weekly, then monthly to keep them between 5-15ng/ml 22,23 . Hematopoietic stem cell transplantation (HCT) remains the only curative treatment but is reserved for severe cases with severe disease with homozygous or compound heterozygous FAS defects or those with refractory severe cytopenia and a matched donor, given its potential complications 24 . Our study is limited by the small sample size and variable follow-up, which restricts generalizability. Lack of genetic testing in most patients prevented definitive molecular classification. Still, we believe that ALPS remains a neglected disease in low and middle-income countries, where it is rarely considered as a differential diagnosis for chronic cytopenias and lymphoproliferation. Our study contributes to the limited regional data on ALPS/ALPID and emphasizes the need for greater awareness, access to genetic testing, and long-term surveillance to guide management and improve outcomes.

ALPS and ALPS-like disorders represent a diagnostic and therapeutic challenge due to their clinical overlap with other immune dysregulation syndromes and the limited availability of genetic testing in many regions. Our case highlights the importance of combining clinical features with biomarkers such as double-negative T cells and vitamin B12 levels in resource-limited settings. Greater awareness, improved access to diagnostic tools, and long-term follow-up are essential to ensure timely recognition, appropriate management, and better outcomes for affected children. ACKNOWLEDGEMENTS; To all patients and families of ALPS patients who have been involved in the care of these children. FUNDING; No funding received from any source for data analysis, publication or for any other purpose for this article LIST OF ABBREVIATIONS; | ALPS | Autoimmune Lymphoproliferative Syndrome | | RALD | Ras-associated autoimmune lymphoproliferative Disease | | ALPID | auto immune Lymphoproliferative Immunodeficiency | | DNT | Double negative T cells | | LMIC’S | Low- and Middle-income countries | DECLARATION OF COMPETING INTEREST; There is no conflict of interest REFERENCES;

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Authors Metrics & Citations Metrics Article Usage 377views 137downloads Citations Download citation Mahwish Faizan, Saadia Anwar, Rahat Ul Ain, et al. AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) or AUTOIMMUNE LYMPHOPROLIFERATIVE IMMUNODEFICIENCY (ALPID): THE ONGOING DIAGNOSTIC DILEMA: A CASE SERIES.. Authorea. 17 October 2025. DOI: https://doi.org/10.22541/au.176068450.09169283/v1 DOI: https://doi.org/10.22541/au.176068450.09169283/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.