H. von Bernuth

X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3δ subunit of the complex, which is essential for both forms. In contrast, the AP3β3A subunit, affected in HPS2 patients, is substituted by AP3β3B in the neuron-specific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.

Severe macrophage activation syndrome. Is there a causative role for a homozygous A91V mutation in the perforin gene

A 16 year old lebanese girl with consanguinous parents presented with a severe “abdominal” sepsis supposedly resulting from an infected vaginal tampon (ESBL E.coli). She had been healthy before. She developed severe hepatic functional disorder, infarction of the spleen, cardiovascular and renal insufficiency, as well as anemia and thrombocytopenia. Macrophage activation syndrome was diagnosed subsequently and systemic glucocorticoid treatment initiated. The girl recovered clinically. Of note, she developed severe cushingoid syndrome. Due to limited compliance she discontinued all anti-inflammatory medication (nsaids, gc and ciclosporin) 4 weeks later. The following 18 months inflammatory parameters were persistantly elevated (ESR>100mm/h). Familial mediteranean fever was excluded. Genetic analysis revealed a homozygous perforin I gene mutation 91 (GCG) -> Valin (GTG)/.pAla91Val-/A91V in exon 2. Familial hemophagocytic lymphohistiocytosis type II was discussed as a potential diagnosis. Perforin expression was diminshed to about 50% in NK-cells, however functional NK-cell cytotoxicity was in the lower normal range, considered not impaired. On the basis of these findings, we want to discuss the role of the homozygous A91V perforin mutation for the initiation or perpetuation of a life-threatening macrophage activation syndrome, in addition to the further management of the patient.

FRI0515 Neutrophil-Specific S100A12 Phenotype Correlates to Genotype in Familial Mediterranean Fever

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disorder associated with MEFV pyrin-encoding gene mutations. S100A12 is a pro-inflammatory “damage associated molecular pattern” molecule and is strongly elevated in active FMF Objectives To investigate the association between genotype and S100A12 secretion in clinically active, inactive and subclinical disease in vitro and ex vivo. Methods Serum S100A12 concentration was retrospectively analysed for 125 patients in the German Auto-Inflammatory Diseases Network (AID-Net) Registry according to disease activity and genotype. In vitro, secretion of S100A12, IL-18, IL-1beta and caspase-1 was measured after stimulation of neutrophils from six M694V-positive patients and four healthy controls (HC). Results S100A12 hypersecretion correlated significantly with clinical disease activity and also with genotype in a “gene-dosing” way, being highest in homozygotes > compound heterozygotes > heterozygotes. M694V-positive heterozygous, compound heterozygous or homozygous patients h had higher S100A12 concentration during inactive and subclinical disease than M694V-negative heterozygous, compound heterozygous or homozygous patients respectively. In vitro, unstimulated neutrophils from M694V-positive patient spontaneously secreted higher S100A12, IL-8 and caspase-1 compared to healthy controls. Colchicine significantly inhibited secretion of S100A12 from stimulated and unstimulated patient neutrophils. Conclusions FMF phenotype is known to be more severe in patients with M694V mutations. We describe for the first time a biomarker that correlates with clinical disease activity and FMF genotype both ex vivo and in vitro, which has implications for clinical management. References Wittkowski H. et al. Pediatr Rheumatol 2008. Kallinich T. et al. ARD 2010. Jeske M et al. Klin Pädiatrie 2013. Disclosure of Interest None declared

PW01-008 – The inflammasome and secretory pathways in FMF.

Aberrant inflammasome priming and dysregulated secretory pathways contribute to parallel IL-18 and S100A12 hypersecretion from neutrophils in instable FMF.

Angeborene Immundefekte@@@Congenital immune defects

DOI 10.1007/s00112-009-2063-1 Online publiziert: 2. September 2009