Discussion:
We present a patient who meets clinical diagnostic criteria for ALPS9 and has a heterozygous germline FAS variant of previously unknown significance. His clinical phenotype was severe and included lymphadenopathy, recurrent autoimmune cytopenias, elevated levels of DNTs, and defective lymphocyte apoptosis. He also met several secondary accessory criteria, including elevation of soluble FAS ligand, IL-18, and B12 levels, and typical immunohistological findings. While he had severe autoimmune cytopenias, he has never had elevation of IgG. Lymph node biopsy showed S100+ histiocytosis, characteristic of ALPS.10
The FAS variant found in our patient is not known to be pathogenic. The variant is on Exon 9 of the FAS receptor gene, which generally encodes the death domain of the receptor.6,11 This is consistent with the finding of impaired FAS-mediated apoptosis. There has been one prior report of a similar phenotype with this genetic variant,12 which combined with our patient’s presentation, provides evidence that this variant is pathogenic and is associated with severe ALPS-FAS phenotype.
The variation in ALPS phenotypes likely relates to the range of genetic variants associated with the disease. Our patient and the previously reported patient with the same mutation share many features: both presented in toddlerhood with lymphadenopathy followed by recurrent cytopenias.12 The severity of our patient’s cytopenias, with acute, life-threatening drops in hemoglobin and platelets, is remarkable and is consistent with prior work identifying severity and frequency of cytopenias as predictors of defects in FAS-mediated apoptosis. 13 Unlike the case reported by Gu et al., our patient did have short-term response to steroids. Both had good response to sirolimus, with stabilization of blood counts and normalization of DNTs. It is not clear whether severity of cytopenias is predictive of lymphoma risk or whether disease control with sirolimus mitigates this risk. 14 Continued identification of genetic variants and associated disease course is needed to help with future risk stratification.