Hodgkin lymphoma in a child with biallelic FASL variant (ALPS‐FASL): Case report and review of literature

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory disorder characterized by mutations in the apoptotic signaling pathway, particularly involving the FS-7-associated surface antigen (FAS) gene.1-3 Common features include benign chronic lymphoproliferation, splenomegaly, autoimmune cytopenias, elevated double negative T cells (DNTs) (α/βTCR CD3+CD4−CD8−), increased serum vitamin B12 levels, and impaired lymphocyte apoptosis.1 Most cases are attributed to germline or somatic mutations in the FAS gene (ALPS-FAS), with FAS ligand (ALPS-FASL) gene mutations being rare. Patients with ALPS are predisposed to developing malignancies, with the highest risk observed in those with ALPS-FAS.1 Here, we present a unique case of ALPS-FASL in a young girl harboring a biallelic FASL mutation, who subsequently developed Hodgkin's disease. She underwent a successful haploidentical hematopoietic stem cell transplant (HSCT) as part of her treatment. The index patient, born to second-degree consanguineous parents, had been symptomatic since 3 months of age. She had recurrent episodes of pallor, abdominal distention, and petechiae necessitating frequent red cell and platelet transfusions. She also had generalized lymphadenopathy and splenomegaly (Figure 1). Investigations revealed anemia, leucocytosis, thrombocytopenia, elevated serum vitamin-B12 levels, hypergammaglobulinemia, and increased DNTs (Table 1 and Figure 2). A diagnosis of ALPS was proffered, and treatment with oral prednisolone was initiated. Test – 9.8%; Control – 41.2% Reduced apoptosis Genetic analysis revealed a novel pathogenic homozygous nonsense mutation in exon 1 (c.343C>T; p.Arg115Ter) of the FASL gene. Both parents were found to be heterozygous carrier for the same. Flow cytometric Annexin V assay indicated reduced apoptosis (9.8%) compared to healthy controls (41.2%).4 Mycophenolate mofetil (MMF) was added to the treatment regimen. At 3 years of age, she developed a deep-seated abscess in the left lower limb, requiring incision, drainage, and intravenous antibiotics (Figure 1). Regular follow-up included serial DNT level monitoring, with MMF dosage adjusted accordingly (Figure 2). At 8 years, she presented with high-grade fever, right supraclavicular lymphadenopathy, sternal tenderness, and hepatosplenomegaly. Lymph node biopsy confirmed mixed cellularity Hodgkin lymphoma stage IV and Epstein–Barr encoding region in situ hybridization (EBER-ISH) was negative. Serum Epstein–Barr virus (EBV) viral load was elevated (2900 copies/mL). She underwent 6 cycles of vincristine sulfate, etoposide, prednisone, and doxorubicin hydrochloride chemotherapy, achieving complete remission. Serum EBV viral load at the end of chemotherapy was negative. Post-remission, sirolimus therapy was initiated. After a year, she again developed fever, generalized bone pain, and a retro-peritoneal paravertebral mass causing paraparesis. Biopsy indicated a relapse of Hodgkin lymphoma stage IVB. Serum EBV viral load was again elevated (Table 1). However, the EBER-ISH stain in para-aortic lymph node mass was negative. Treatment involved dexamethasone, high-dose cytarabine, and cisplatin, and plans were made for HSCT. One-year post-relapse, she underwent haploidentical HSCT with her elder sister as the donor (8/12 HLA matched). She tolerated HSCT well and had 100% donor chimerism. Post-transplant, her DNT cells and serum vitamin-B12 levels normalized, and EBV viral load became negative. She is currently stable at 2 years of follow-up post-transplant. Germline or somatic variants causing defective Fas-mediated apoptosis (FAS, FASL, FADD) lead to clinical and laboratory manifestations of ALPS.2, 3 To date, less than 1000 cases of genetically confirmed ALPS have been documented, with 95% attributed to FAS gene mutations.1 Homozygous FASL mutations are extremely rare, only a handful cases have been reported so far (Table 2). Our patient is the first case report of a novel homozygous FASL to develop Hodgkin's disease and successfully managed by HSCT. Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly Autoimmune cytopenias: AIHA, ITP [5]/2006 [6]/2015 Lymphoproliferation: Massive hepatosplenomegaly, lymphadenopathy Autoimmune cytopenia: Absent Others: repeated episodes of fever, growth retardation Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly Autoimmune cytopenias: absent Others: NA Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly Autoimmune cytopenias: AIHA, ITP Others: Repeated episodes of fever, diarrhea; Pancytopenia, failure to thrive Lymphoproliferation: Massive hepatosplenomegaly Autoimmune cytopenias: Pancytopenia Others: respiratory insufficiency; failure to thrive; elevated ferritin and immunoglobulin levels Lymphoproliferation: Generalized lymphadenopathy, hepatosplenomegaly Autoimmune cytopenia: AIHA (Coombs positive), ITP Others: fever, rash Lymphoproliferation: Hepatosplenomegaly Autoimmune cytopenias: AIHA, ITP Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly: present Autoimmune cytopenias: severe Evans syndrome Others: Intermittent urticarial rashes Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly Autoimmune cytopenias: NA Others: Generalized erythema, short stature Lymphoproliferation: Lymphadenopathy, hepatosplenomegaly Autoimmune cytopenias: NA Others: short stature, developmental delay Warts, recurrent candida infection, recurrent pneumonia, EBV reactivation Lymphoproliferation: present Autoimmune cytopenias: present Hodgkin lymphoma (8 years) Early relapse (9 years) FASL, through its intracellular domain, facilitates retrograde FASL-mediated signaling, crucial for regulating the proliferation of activated T cells. Mutations in FASL disrupt this reverse-signaling pathway, resulting in impaired apoptosis, which underlies the clinical features observed in ALPS-FASL.10 Lymphoma development is frequently observed in ALPS-FAS, with a significantly increased relative risk of 51 times for Hodgkin lymphoma and 14 times for non-Hodgkin lymphoma. These patients typically respond favorably to standard chemotherapy, although monitoring is complicated by ongoing lymphoproliferation.11 In ALPS-FASL, only one instance of T-cell lymphoma development has been reported to date.5 Notably, there are no documented cases of Hodgkin disease relapse associated with FASL mutation in the existing English literature. Our patient represents the first reported case of Hodgkin lymphoma relapse in a child with a novel FASL mutation. Our patient experienced EBV viremia, which may have triggered the development of lymphoma. There are documented cases of individuals with FAS mutations developing EBV-associated lymphomas, managed successfully with chemotherapy.1 In our patient, onset and recurrence of lymphoma was preceded by increasing EBV viremia. Treatment for ALPS typically involves immunosuppressive agents such as corticosteroids, alongside steroid-sparing medications like sirolimus, MMF, azathioprine, and sirolimus. HSCT remains the only known cure for ALPS, reserved for severe cases that do not respond to immunosuppressive therapy or in cases complicated by lymphomas.1 The index case, despite being compliant with treatment and regular follow-ups, developed Hodgkin lymphoma, indicating an aggressive disease phenotype. Her underlying primary immune dysregulatory condition, ALPS, as well as an aggressive malignant complication, Hodgkin lymphoma, both responded well to allogeneic haploidentical HSCT. Suprit Basu: Conceptualization; investigation; writing – review and editing; writing – original draft. Pallavi L. Nadig: Data curation; project administration; validation. Urmimala Bhattacharjee: Investigation; methodology. Aaqib Zaffar Banday: Investigation; methodology. Ankur Kumar Jindal: Writing – review and editing; formal analysis. Rakesh Kumar Pilania: Supervision; software. Pandiarajan Vignesh: Formal analysis; supervision. Amit Rawat: Investigation; methodology. Alka Khadwal: Writing – review and editing; supervision. Deepti Suri: Supervision; resources; project administration; writing – review and editing; conceptualization. The authors have nothing to report. The authors have nothing to report. All authors declare that there are no conflicts of interest. This study was performed in line with the principles of the Declaration of Helsinki. Departmental Review Board approved the manuscript (vide Memo No.- APC DRB 58-24). Informed consent was obtained from the participant and her parents in this report. Participants consented to the publication of the clinical details in an academic journal. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.