title: Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings.
abstract: Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients.
authors: Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, USA.
authors: Julie
authors: J
authors: Niemela
authors: Hye Sun
authors: HS
authors: Kuehn
authors: Corin
authors: C
authors: Kelly
authors: Mingchang
authors: M
authors: Zhang
authors: Joie
authors: J
authors: Davies
authors: Jose
authors: J
authors: Melendez
authors: Jennifer
authors: J
authors: Dreiling
authors: David
authors: D
authors: Kleiner
authors: Katherine
authors: K
authors: Calvo
authors: João B
authors: JB
authors: Oliveira
authors: Sergio D
authors: SD
authors: Rosenzweig
mesh_terms: D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D001706:Biopsy; D053181:Caspase 8 / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D059472:Exome; D005260:Female; D006099:Granuloma / Q000473:pathology*; D006529:Hepatomegaly / Q000175:diagnosis; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D016130:Immunophenotyping; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation; D035781:Siblings; D013163:Splenomegaly / Q000175:diagnosis; D014057:Tomography, X-Ray Computed
chemical_list: D016207:Cytokines; D053181:Caspase 8