Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.

Keywords: ALPS; HLH; apoptosis; cytopenias; lymphadenopathy; splenomegaly.

FIGURE 1

Biomarkers in patients with ALPS-FAS and ALPS-sFAS. A, Data collected from 142 unique ALPS-FAS/ALPS-sFAS patients aged ≤26 years old were used to generate box plots for ferritin, sIL-2Rα, and vitamin B-12 values. Boxes represent the 25th–75th percentile of values; the median is indicated by a solid dark line within each box; whiskers represent the 2.5th–97.5th percentile of values; and outlier data points are shown as dark circles. B, Specific numerical data for the median, 25th percentile, 75th percentile, minimum-maximum range, and number of observations for each biomarker. Not all patients had all biomarker values available for this analysis. Within-person median values were analyzed when >1 data point was available for any individual. Vitamin B-12 levels were capped at an upper range of 4000 pg/mL because serial dilutions of plasma in our laboratory had shown vitamin B-12 values as high as 40 000 pg/mL in several patients with ALPS-FAS. Max, maximum; Min, minimum.