Novel Compound Heterozygote Variations in FADD Identified to Cause FAS-Associated Protein with Death Domain Deficiency
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LETTER TO EDITOR
Novel Compound Heterozygote Variations in FADD Identified to Cause FAS-Associated Protein with Death Domain Deficiency Lisa A. Kohn 1 & Joseph D. Long 1 & Edward C. Trope 1 & Caroline Y. Kuo 1 Received: 29 November 2019 / Accepted: 31 March 2020 # The Author(s) 2020
Keywords FADD deficiency . Autoimmune lymphoproliferative syndrome . Genetics . Apoptosis
To the Editor Autoimmune lymphoproliferative syndromes (ALPS and related disorders) are characterized by insufficient apoptosis due to defects in the FAS apoptosis pathway. FADD deficiency (OMIM: 602457; first described in Bolze et al. 2010 [1]) is an autosomal recessive disorder resulting from a pathogenic variation in FADD (FAS-associated protein with death domain), the adaptor protein involved in Fas signaling to caspases 8 and 10. Previously described FADD deficiency patients demonstrate a clinical phenotype partially overlapping with other ALPS disorders (decreased Fas-mediated lymphocyte apoptosis, increased circulating double negative T cells, elevated soluble Fas ligand, IL-10, and vitamin B12) but also recurrent febrile episodes with encephalopathy and seizures, variable degrees of lymphadenopathy or splenomegaly, cerebral atrophy, and structural cardiac abnormalities. Recurrent severe viral infections are thought to be mediated by FADD’s role in TLR-independent innate immune responses and induction of IRF7 and IFN-α [2]. There are very few cases in the literature of FADD deficiency patients (4 patients from a consanguineous family in the original report [1] and 2 patients in a second report [3]). These patients seem to have worse outcomes than classical ALPS patients. Three of four patients from the original report died prior to 5 years old from invasive pneumococcal infections or death during episodes of encephalopathy. In the second report, multiple Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00779-6) contains supplementary material, which is available to authorized users. * Lisa A. Kohn [email protected] 1
Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA
family members who were presumed to be affected had also died in early childhood, and both patients described in that report underwent hematopoietic stem cell transplantation. All prior reports of patients with FADD deficiency were homozygous for the pathogenic variation p.C105W. Here, we present a case of FADD deficiency identified by clinical exome sequencing with novel compound heterozygote genetic variations whose clinical presentation is consistent with prior described cases. At 14 months of age, our unvaccinated patient presented with fever, rash, vomiting, and status epilepticus with respiratory arrest that required intubation. He had enlarged cervical lymph nodes that regressed with antibiotics and steroids. He recovered from this initial episode but subsequently experienced a series of similar illnesses with fevers, altere
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