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.