A diagnostic dilemma in AL(L)PS

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Dear Editor, An 18-month-old female infant presented to the paediatric haematology service in 1985 with lymphadenopathy, hepatosplenomegaly, anaemia (Hb 6.3 g/dL, range 11.7– 14 g/dL) and thrombocytopenia (17×10, range 150– 400×10). Bone marrow and lymph node examinations were reported as ‘reactive’. Karyotyping was normal. Viral, autoimmune and metabolic screens were negative. Following a period of observation and external review, during which time her marrow blast count rose to 9 %, the decision was made to proceed with Medical Research Council protocol for acute lymphoblastic leukaemia, with complete normalisation of peripheral blood counts and regression of spleen size for the duration of treatment (1986–1988). Her subsequent disease course included recurrent sinus and respiratory tract infections, fluctuating cytopenias, chronic lymphadenopathy and an elective splenectomy in the setting of massive splenomegaly. She developed severe autoimmune haemolytic anaemia, requiring intense immunosuppression and ultimately plasma exchange followed by recurrent invasive pneumococcal septicaemia on ages 14, 16 and 18 years. She was referred for immunological assessment in 2009 when a biopsy of an epitrochlear lymph node revealed paracortical T cell zone expansion with evidence of clonal T cell rearrangements, subsequently confirmed on bone marrow biopsy. CT images of thorax, abdomen and pelvis showed no evidence of lymphoma. On review, it emerged that her father, paternal aunt and first cousin all had a previous diagnosis of lymphoma. Screening for autoimmune lymphoproliferative syndrome (ALPS) confirmed the presence of double negative (DN) αβT cells (18 %, normal<1.5%) andFasL 1.5 ng/mL (normal range<0.2 ng/mL). Genetic testing demonstrated heterozygous nonsense mutation in exon 9 of the Fas gene confirming the diagnosis. Her father was found to have the same mutation. She failed to respond to the meningococcal vaccine and to both conjugated and unconjugated pneumococcal vaccines. She had a low IgG (IgG 4.6, range 6–15 g/L) and absent IgG2 with an elevated IgA (IgA 5.65, range 0.7–4.0 g/L) and normal IgM (IgM 1.0, range 0.5–2.3 g/L). Hypogammaglobulinaemia, recurring infection and failure to respond to vaccination is consistent with common variable immune deficiency which has been reported in association with ALPS [1]. At age 28, she presented with left hand and forearm swelling following minor trauma. C4 was undetectable (<0.0167 g/L, range 0.14–0.54 g/L). Both C3 and C1 inhibitor levels were reduced at 0.55 g/L (range 0.75–1.65 g/L) and 0.38 mg/L (range 150–350 mg/L), respectively. C1q levels were 44 mg/L (normal range 50– 250 mg/L). Based on the history, reduced C4, C1 inhibitor and C1q levels, a diagnosis of acquired C1 inhibitor deficiency was made. The diagnostic criteria for ALPS are elevated CD3 TCRαβ CD4 CD8 DNT cells ≥1.5 % of the total lymphocytes along with chronic non-malignant, non-infectious C. Lee-Brennan :M. Keogan Department of Immunology, Beaumont Hospital, Beaumont, Dublin 9, Ireland