The patient presented at age 2 with left inguinal lymphadenopathy. The lymph node biopsy showed peri-cortical expansion with increase in S-100+ histiocytes, although classical emperipolesis was not identified in either hematoxylin and eosin (H and E) or immunostained sections (Figure 1).

He then developed pancytopenia, with hemoglobin 7.9 g/dl, platelet count 2 k/mcl, and absolute neutrophil count (ANC) 80 k/mcl. He required intravenous immune globulins as well as steroids for persistent thrombocytopenia. At age 4, he developed severe hemolytic anemia with hemoglobin of 2.1 g/dl. He had altered mental status, encephalopathy with electroencephalogram changes, and white matter ischemia on MRI, attributed to hypoxia secondary to severe anemia. He was found to have elevated IL-18 and DNTs, leading to a diagnosis of probable ALPS. After a prolonged course of steroids, he started mycophenolate mofetil (MMF) and his blood counts remained stable for several months.

The patient was lost to follow-up for about 6 months and discontinued MMF during this time. When he returned to care, he was found to have hepatosplenomegaly, increased DNTs (7%), and elevated soluble FAS ligand. He subsequently developed thrombocytopenia with mucosal bleeding, requiring intravenous methylprednisolone. After restarting MMF, he developed neutropenic gingivitis, requiring granulocyte-colony stimulating factor therapy. He was then switched from MMF to sirolimus. Blood counts normalized and laboratory testing after 6 months showed normalization of DNTs, B12, and IL-18 levels.

Genetic testing in unsorted blood cells was performed, and he was found to carry a heterozygous variant in FAS, Exon 9, c.857G>A (p.Gly286Glu). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the FAS protein (p.Gly286Glu).This variant is not present in population databases. Algorithms developed to predict the effect of this missense change on protein structure and function were inconclusive (SIFT: ”Not Available”; PolyPhen-2: ”Possibly Damaging”; Align-GVGD: ”Not Available”). A FAS-mediated apoptosis assay revealed significantly reduced apoptosis cell loss at 8% (normal:57-100%).