Autoimmune lymphoproliferative syndrome (ALPS) is a rare inborn error of immunity caused by defective FAS-mediated apoptosis, resulting in chronic nonmalignant lymphoproliferation, autoimmune cytopenias, and an increased lifetime risk of lymphoma.

Because its manifestations overlap with hematologic malignancies and other immune dysregulation disorders, diagnosis is frequently delayed. We report a 21-month-old girl who presented with recurrent viral illnesses, normocytic anemia, transient thrombocytopenia, monocytosis, and massive splenomegaly. Initial evaluation focused on excluding acute leukemia, lymphoma, juvenile myelomonocytic leukemia, hemolytic anemia, and other causes of pediatric splenomegaly. Bone marrow biopsy, flow cytometry, cytogenetic analysis, and fluorescence in situ hybridization demonstrated no evidence of malignancy or myelodysplasia. Persistent reticulocytosis and splenomegaly prompted evaluation for an underlying immune dysregulation syndrome. Next-generation sequencing identified a pathogenic FAS variant, establishing the diagnosis of ALPS, with supporting findings of elevated vitamin B12, interleukin-18, borderline expansion of TCRαβ? double-negative T cells, and persistent splenomegaly. A concurrent TNFRSF13B variant of uncertain significance was also identified. The patient’s father was subsequently found to carry the same FAS variant but remained asymptomatic, illustrating the incomplete penetrance and variable clinical expressivity characteristic of haploinsufficient FAS mutations. The patient was treated with mycophenolate mofetil as a steroid-sparing agent, resulting in reduction of splenomegaly and stable hematologic parameters over six months of follow-up. This case highlights the importance of considering ALPS in young children with unexplained cytopenias and splenomegaly after malignancy has been excluded and emphasizes the role of early genomic testing in establishing the diagnosis, guiding therapy, facilitating genetic counseling, and informing long-term surveillance.

• Anemia

• Splenomegaly

• ALPS

• Monocytosis

• CVID

• Lymphoproliferation

Sorial M, Gaál Z, Suhet P, Walter JE, Chang S. (2026) An Uncommon Cause of Cytopenias and Splenomegaly in a Toddler: Autoimmune Lymphoproliferative Syndrome. Pediatr Child Health 14(1): 1365.

ALPS: Autoimmune Lymphoproliferative Syndrome CVID: Common Variable Immunodeficiency

Autoimmune lymphoproliferative syndrome (ALPS) is a rare inborn error of immunity characterized by defective FAS-mediated apoptosis, resulting in chronic nonmalignant lymphoproliferation, autoimmune cytopenias, and an increased lifetime risk of lymphoma [1-4]. Most cases are caused by pathogenic variants in the FAS gene, which impair activation-induced lymphocyte apoptosis and lead to the accumulation of autoreactive lymphocytes,particularly T-cell receptor αβ-positive CD4?CD8? double negative T (DNT) cells [1-4]. Clinically, patients most commonly present with chronic lymphadenopathy, splenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, or autoimmune neutropenia, although the severity and age of presentation are highly variable depending on the underlying genetic defect and its effect on FAS signaling [1-4].

Diagnosing ALPS remains challenging because its initial manifestations frequently overlap with more common pediatric conditions, including hematologic malignancies, infectious diseases, hemophagocytic syndromes, autoimmune cytopenias, and other inborn errors of immunity [1-6]. In particular, the combination of persistent cytopenias and splenomegaly often prompts an extensive evaluation for leukemia or lymphoma before immune dysregulation is considered. Recent advances in next-generation sequencing have substantially improved the recognition of monogenic immune dysregulation disorders while simultaneously identifying additional variants that may modify disease expression, emphasizing the importance of integrating molecular findings with the clinical phenotype [6].

We report a 21-month-old girl who presented with recurrent viral infections, anemia, thrombocytopenia, monocytosis, and massive splenomegaly, initially raising concern for hematologic malignancy. Comprehensive evaluation ultimately identified a pathogenic FAS nonsense variant, establishing the diagnosis of ALPS. This case highlights the diagnostic challenges of distinguishing ALPS from malignant and inflammatory disorders in young children and underscores the growing role of genomic testing in the evaluation of unexplained cytopenias and lymphoproliferation.

A previously healthy 21-month-old girl was referred to the pediatric hematology clinic for evaluation of anemia, thrombocytopenia, monocytosis, and newly identified splenomegaly. Four months before presentation, she developed intermittent febrile illnesses (>38°C) associated with frequent viral upper respiratory infections occurring approximately monthly. She had no history of recurrent bacterial infections, including sinusitis, pneumonia, otitis media, osteomyelitis, or skin and soft tissue infections. Her parents denied weight loss, poor appetite, night sweats, abdominal distention, easy bruising, bleeding, or constitutional symptoms.

Approximately three months before hematology referral, a point-of-care hemoglobin obtained by her primary care physician measured 7.6 g/dL, and she was started on oral iron supplementation for presumed iron deficiency anemia. Repeat laboratory studies demonstrated improvement in hemoglobin, and iron supplementation was discontinued. Three months later, while experiencing another viral illness, repeat laboratory evaluation demonstrated recurrent anemia (hemoglobin 9.4g/dL) and thrombocytopenia (platelet count 94 × 10?/L), prompting reinstitution of iron therapy.

One week later, persistent splenomegaly was noted on physical examination, and she was referred to pediatric hematology for further evaluation.

On presentation, growth and developmental milestones were appropriate for age. Physical examination was notable for massive splenomegaly, with the spleen palpable approximately 3.5 cm below the left costal margin. No hepatomegaly, peripheral lymphadenopathy, dysmorphic features, or skeletal abnormalities were appreciated (Figure 1).

Figure 1: Splenomegaly to 13.1 cm in coronal plane

Initial laboratory evaluation demonstrated normocytic, normochromic anemia (hemoglobin 9.4 g/dL) with reticulocytosis, thrombocytopenia (94 × 10?/L), and mild monocytosis. White blood cell count and differential were otherwise within normal limits. Iron studies revealed an elevated ferritin level (292 ng/mL) with low transferrin saturation (9%), consistent with a mixed picture of iron deficiency and inflammation. Direct antiglobulin testing (DAT) was negative, and serum bilirubin, lactate dehydrogenase (LDH), haptoglobin, and uric acid were within normal limits. Serologic testing for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was negative. Quantitative immunoglobulin concentrations were normal for age.

Abdominal ultrasonography confirmed splenomegaly exceeding the upper limit of normal for age without focal splenic lesions. Because of persistent splenomegaly, cytopenias, and transient monocytosis, an extensive evaluation for hematologic malignancy was pursued. Bone marrow aspiration and biopsy, including cytogenetic analysis and fluorescence in situ hybridization (FISH), demonstrated no evidence of leukemia, lymphoma, myelodysplastic syndrome, or juvenile myelomonocytic leukemia. Flow cytometric immunophenotyping similarly showed no evidence of an abnormal lymphoid or myeloid population. Computed tomography of the chest, abdomen, and pelvis demonstrated marked splenomegaly with mildly enlarged cervical and pelvic lymph nodes interpreted as reactive.

Although conventional laboratory markers of hemolysis remained normal, persistent reticulocytosis raised concern for an underlying hemolytic process. DAT negative hemolytic anemia panel was sent but was cancelled at the laboratory. Hemoglobin electrophoresis was normal, making an inherited hemoglobinopathy unlikely. Because the combination of splenomegaly, cytopenias, recurrent viral infections, and exclusion of malignancy suggested an underlying immune dysregulation syndrome, next generation sequencing using a primary immunodeficiency/ immune dysregulation panel was obtained. This identified a pathogenic FAS variant (*NM_000043.6:c.133G>T [p.Glu45]**), establishing the diagnosis of autoimmune lymphoproliferative syndrome (ALPS). A concurrent variant of uncertain significance in TNFRSF13B was also identified. Additional immunologic evaluation demonstrated markedly elevated serum biomarkers supportive of ALPS, including vitamin B12 >2,000 pg/mL (reference range: 200-900 pg/mL), interleukin-18 (IL-18) 1,738 pg/mL (elevated), interleukin-10 (IL-10) 136.1pg/ mL (reference ≤2.8 pg/mL), and soluble Fas ligand (sFasL) 4,464 pg/mL (reference 69–493 pg/mL). F l o w cytometric immunophenotyping expansion of demonstrated TCRαβ?CD3?CD4?CD8?double-negative T cells comprising 60% of the reference interval (institutional reference range 5–25%), further supporting the diagnosis of ALPS according to established diagnostic criteria [4].

Family history was notable for the patient’s mother, who required intravenous immunoglobulin replacement during childhood. Maternal genetic testing demonstrated the same germline TNFRSF13B variant but did not identify the pathogenic FAS mutation. Paternal genetic testing confirmed the same germline FAS pathogenic variant despite the absence of lymphadenopathy, autoimmune disease, cytopenias, or recurrent infections, illustrating the incomplete penetrance and variable clinical expressivity characteristic of haploinsufficient FAS mutations. Following multidisciplinary discussion involving pediatric hematology and clinical immunology, treatment with mycophenolate mofetil (MMF) was initiated as a steroid sparing immunosuppressive strategy because the patient had significant lymphoproliferation without severe autoimmune cytopenias. Cytopenias were attributed to hypersplenism. Baseline vaccine responses demonstrated protective antibody titers to diphtheria and tetanus but inadequate pneumococcal serotype-specific antibody responses despite normal quantitative immunoglobulin levels. Intravenous immunoglobulin replacement was deferred because she had not experienced recurrent or severe bacterial infections.

Quantitative immunoglobulin concentrations remained largely preserved throughout follow-up. Initial evaluation in June 2024 demonstrated normal IgG and IgA concentrations. Repeat testing in March 2025 showed a transient decrease in IgA to 35 mg/dL while IgG remained within the normal range; however, subsequent testing demonstrated normalization of both IgG and IgA concentrations. Given the absence of recurrent bacterial infections, preserved responses to diphtheria and tetanus vaccination, and normalization of immunoglobulin levels, these findings were insufficient to establish a diagnosis of common variable immunodeficiency at that time, although continued longitudinal monitoring was recommended given the concurrent TNFRSF13B variant.

At six-month follow-up, the patient remained clinically well. Serial laboratory studies demonstrated stable blood counts without progression of cytopenias. Repeat abdominal ultrasonography showed a mild reduction in splenic size but it still remains enlarged for age. During follow-up, she experienced two episodes of hand-foot and-mouth disease and one episode of herpes simplex virus labialis that responded to oral acyclovir. She had no episodes of pneumonia, sinusitis, otitis media, invasive bacterial infection, or hospitalization. Ongoing follow-up with pediatric hematology and immunology was planned to monitor for autoimmune cytopenias, progressive lymphoproliferation, evolving  humoral immune dysfunction, and lymphoma.

Autoimmune  lymphoproliferative syndrome (ALPS) is a rare inborn error of immunity caused by defective FAS-mediated apoptosis, resulting in impaired elimination of activated lymphocytes and accumulation of autoreactive T cells [1-4].This dysregulation produces chronic nonmalignant lymphoproliferation, autoimmune cytopenias, splenomegaly, lymphadenopathy, and a markedly increased lifetime risk of lymphoma [1,3,7]. Although ALPS is classically associated with autoimmune hemolytic anemia and immune thrombocytopenia, the initial presentation is highly variable, often delaying diagnosis and leading clinicians to pursue more common hematologic or oncologic disorders first [1-5].

Our patient’s presentation illustrates this diagnostic challenge. The combination of anemia, thrombocytopenia, transient monocytosis, recurrent febrile viral illnesses, and massive splenomegaly appropriately prompted an extensive evaluation for hematologic malignancy. Acute leukemia, lymphoma, and juvenile myelomonocytic leukemia were initially considered because each may present with cytopenias and splenomegaly during early childhood [5,8]. However, normal lactate dehydrogenase and uric acid levels, absence of blasts on peripheral smear, and negative bone marrow examination, cytogenetic analysis, and flow cytometry effectively excluded these diagnoses. Similarly, Evans syndrome and autoimmune hemolytic anemia remained considerations because of the coexistence of anemia, thrombocytopenia, and reticulocytosis.

Although the direct antiglobulin test was negative and conventional markers of hemolysis remained within normal limits, DAT-negative autoimmune hemolytic anemia has been described in patients with low-affinity antibodies or antibodies below the detection threshold of routine testing [5]. Nonetheless, spontaneous resolution of thrombocytopenia and the absence of convincing biochemical evidence of hemolysis made isolated autoimmune cytopenias less likely. The persistence of splenomegaly despite exclusion of malignancy prompted consideration of an underlying immune dysregulation syndrome. Over the past decade, advances in next generation sequencing have substantially changed the diagnostic evaluation of children with unexplained cytopenias and lymphoproliferation by allowing earlier recognition of monogenic inborn errors of immunity [6]. This approach proved particularly valuable in our patient, in whom targeted sequencing identified a pathogenic FAS variant (NM_000043.6:c.133G>T; p.Glu45*), establishing the diagnosis of ALPS [5]. The diagnosis was further supported by persistent splenomegaly together with markedly elevated ALPS biomarkers, including vitamin B12 (>2,000 pg/mL), IL-18 (1,738 pg/mL), IL-10 (136.1 pg/mL), and soluble Fas ligand (4,464 pg/mL), in addition to expansion of TCRαβ? CD3?CD4?CD8? double-negative T cells. Elevated vitamin B12, IL-10, IL-18, soluble Fas ligand, and DNT cells are well-established biomarkers incorporated into the revised diagnostic criteria for ALPS and substantially increase diagnostic confidence when interpreted alongside molecular testing [4]. Elevated TCRαβ? CD3?CD4?CD8? double-negative T cells remain one of the hallmark immunologic findings of ALPS. Our patient’s DNT-cell percentage was elevated at 60% (institutional reference interval 5–25%). Interpretation in infants and toddlers should nevertheless be approached cautiously because validated age-specific reference ranges for children younger than 24 months remain limited [4]. Consequently, integration of molecular findings with clinical manifestations and additional biomarkers including vitamin B12, IL-10, IL-18, and soluble Fas ligand, is particularly valuable when evaluating suspected ALPS in very young children [2-5].

The identified FAS variant represents an extracellular nonsense mutation predicted to produce disease through haploinsufficiency, resulting in reduced expression of functional FAS receptors and impaired activation induced apoptosis [1,2,7].This mechanism differs from the dominant-negative effect observed with many intracellular death-domain missense mutations.

Haploinsufficient FAS variants have been associated with incomplete penetrance and variable clinical expressivity, findings that may explain this patient’s relatively mild autoimmune phenotype despite significant lymphoproliferation [1,7]. This was illustrated in our family, as the patient’s father carried the identical pathogenic germline variant but remained clinically asymptomatic, whereas the patient developed significant lymphoproliferation early in childhood. Although additional somatic “second-hit” events have been described in some patients with haploinsufficient FAS mutations, further molecular characterization was not available in this case [1,3].

An additional finding in our patient was a variant of uncertain significance in TNFRSF13B, which encodes the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). Variants in TNFRSF13B are enriched among patients with common variable immunodeficiency (CVID) but are also present in healthy populations, suggesting that many function as susceptibility alleles rather than independently disease causing mutations [8]. Although our patient currently demonstrates normal quantitative immunoglobulin levels and has not experienced recurrent bacterial infections, the coexistence of variants affecting both FAS-mediated T-cell apoptosis and TACI-mediated B-cell regulation raises the possibility of multilocus immune dysregulation [6]. Rather than establishing a diagnosis of concurrent CVID, this finding supports continued longitudinal immunologic follow-up as additional clinical manifestations may emerge over time and variant interpretation continues to evolve.

The differential diagnosis of chronic lymphoproliferation has likewise expanded considerably with the recognition of autoimmune lymphoproliferative immunodeficiencies (ALPID), including Activated PI3K-δ Syndrome (APDS), RAS-associated autoimmune leukoproliferative disease (RALD), CTLA4 haploinsufficiency, and LRBA deficiency. These disorders share overlapping features of splenomegaly, cytopenias, and immune dysregulation, making comprehensive molecular evaluation increasingly important. Although our patient’s clinical phenotype was ultimately most consistent with ALPS, awareness of these phenocopies is essential because targeted therapies continue to emerge. In particular, selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitors such as leniolisib have demonstrated significant benefit in APDS and are being investigated as potential therapeutic strategies for other immune dysregulation disorders involving aberrant PI3K/AKT/mTOR signaling [10].

Management of ALPS is individualized according to disease severity. Current treatment strategies emphasize corticosteroid-sparing immunosuppression, with sirolimus increasingly considered first-line therapy for patients with significant lymphoproliferation or refractory autoimmune cytopenias [5,9]. Because our patient had clinically significant splenomegaly without severe autoimmune cytopenias, a multidisciplinary decision was made to initiate mycophenolate mofetil as a steroid-sparing alternative [5,9]. This approach resulted in normalization of splenic size, stable hematologic parameters, and no serious infectious complications during follow-up, supporting the effectiveness of less intensive immunosuppression in selected patients.

This case emphasizes the importance of considering ALPS in young children with persistent splenomegaly and unexplained cytopenias after malignancy has been excluded. Early recognition of immune dysregulation disorders and timely use of next-generation sequencing can substantially shorten the diagnostic journey, facilitate targeted therapy, provide appropriate genetic counseling, and establish long-term surveillance for autoimmune complications and lymphoma. As genomic testing becomes increasingly integrated into pediatric practice, careful interpretation of both pathogenic variants and variants of uncertain significance will become essential for delivering precision medicine to children with complex immune dysregulation syndromes.

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