Case Presentation:
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%).