What is the diagnosis for a young patient with hyperalkalinephosphatasemia, lymphocytopenia, monocytosis, splenomegaly, axillary lymphadenopathy, and thymic hyperplasia?

Autoimmune Lymphoproliferative Syndrome (ALPS)

The clinical presentation of enlarged axillary lymph nodes, splenomegaly, and thymic hyperplasia in a young patient strongly suggests Autoimmune Lymphoproliferative Syndrome (ALPS), which requires confirmation by measuring double-negative T cells (DNT) and assessing for lymphocytopenia as a critical diagnostic step. 1, 2

Diagnostic Approach

Required Criteria Assessment

Both of the following must be present for ALPS diagnosis:

• Chronic lymphadenopathy and/or splenomegaly (≥6 months duration): The patient has enlarged axillary lymph nodes and splenomegaly, meeting this criterion. The lymphadenopathy must affect at least 2 nodal chains if isolated, and neoplastic/infectious causes must be excluded. 1

• Elevated TCRαβ+ CD3+ CD4-CD8- double-negative T cells (DNT): Must be ≥1.5% of total lymphocytes or ≥2.5% of CD3+ lymphocytes, but only in the setting of normal or elevated lymphocyte counts. 1, 2

Critical Pitfall: Lymphocytopenia Invalidates DNT Criteria

The presence of lymphocytopenia in this patient is a major diagnostic challenge because it invalidates the DNT cell criterion—the relative distribution of DNT cells becomes unreliable when total lymphocyte counts are low. 1 This means you cannot use the standard DNT percentage cutoffs to diagnose ALPS in this patient without first understanding the cause of the lymphocytopenia.

Addressing the Lymphocytopenia

The lymphocytopenia must be evaluated separately:

• If lymphocytopenia is reactive or secondary (e.g., from acute illness, medications, or nutritional deficiency), repeat testing after resolution may show normal lymphocyte counts with elevated DNT cells. 1

• If lymphocytopenia is chronic and intrinsic to the disease process, ALPS becomes less likely as the diagnostic criteria cannot be properly applied. 1, 2

Accessory Criteria for Definitive vs. Probable Diagnosis

For definitive ALPS diagnosis, one primary accessory criterion is required: 1

• Defective lymphocyte apoptosis (in 2 separate assays), OR
• Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10

For probable ALPS diagnosis, one secondary accessory criterion suffices: 1

• Elevated plasma sFASL (≥200 pg/mL), IL-10 (≥20 pg/mL), vitamin B12 (≥1500 ng/L), or IL-18 (≥500 pg/mL)
• Typical immunohistological findings on lymph node biopsy
• Autoimmune cytopenias with polyclonal hypergammaglobulinemia
• Compatible family history

Evaluating Other Laboratory Abnormalities

Elevated Alkaline Phosphatase

The elevated alkaline phosphatase requires separate evaluation and is not a feature of ALPS. In young patients, extremely high ALP can indicate: 3, 4

• Bone involvement from malignancy or metastases (most common cause of extreme ALP elevation in adults, but consider in context of lymphoproliferation) 3, 4
• Transient hyperphosphatasemia of infancy/childhood (benign, self-limited condition in previously healthy children) 5
• Sepsis (can cause extreme ALP elevation even with normal bilirubin) 3
• Infiltrative liver disease (less common) 3, 4

Order ALP isoenzymes or fractionation to determine if the elevation is from bone or liver origin. 5 Given the patient's lymphoproliferation, bone marrow involvement or hepatic infiltration should be excluded.

Monocytosis

Monocytosis is not a typical feature of ALPS and suggests alternative or concurrent pathology: 1

• Consider infectious mononucleosis-like syndromes
• Evaluate for hemophagocytic lymphohistiocytosis (HLH) if fever, hepatosplenomegaly, or cytopenias are prominent 1
• Assess for chronic infections or inflammatory conditions

Thymic Hyperplasia

True thymic parenchymal hyperplasia in young patients with lymphoproliferation can occur but is more commonly associated with autoimmune conditions or can be a reactive phenomenon. 6, 7 In the context of ALPS, mediastinal lymphadenopathy is recognized, though thymic hyperplasia specifically is not a diagnostic criterion. 1 The thymic enlargement warrants imaging (CT chest) to characterize the mass and exclude thymoma or lymphoma. 6, 7

Recommended Diagnostic Workup

1. Repeat complete blood count with differential to reassess lymphocyte count and confirm lymphocytopenia is persistent 1

2. Flow cytometry for DNT cells (TCRαβ+ CD3+ CD4-CD8-) with absolute counts and percentages, but interpret cautiously given lymphocytopenia 1, 2

3. Lymphocyte apoptosis assay (Fas-mediated apoptosis testing) 1

4. Genetic testing for FAS, FASLG, and CASP10 mutations 1, 2

5. Biomarker panel: sFASL, IL-10, IL-18, vitamin B12 1

6. ALP fractionation to determine bone vs. liver origin 5

7. Lymph node biopsy for immunohistology if diagnosis remains uncertain 1

8. CT chest/abdomen/pelvis to fully characterize lymphadenopathy, splenomegaly, and thymic mass 6

9. Exclude infections: EBV, CMV, HIV, and other causes of lymphoproliferation 1

10. Bone marrow biopsy if concern for infiltrative process or HLH 1, 8

Management Considerations

Patients with probable ALPS should be treated and monitored identically to those with definitive diagnosis while pursuing complete diagnostic workup. 1 The lymphocytopenia complicates diagnosis but does not preclude empiric management if clinical suspicion is high and other causes are excluded. 1, 2