This scenario may be an increasingly frequent challenge for clinicians given the use of broad-range genetic tests, such as WES

This scenario may be an increasingly frequent challenge for clinicians given the use of broad-range genetic tests, such as WES. The optimal immunomodulatory treatment for autoinflammatory/lymphoproliferative conditions often need to be searched and optimised in each individual patient. The differentiation between infectious, inflammatory and malignant diseases may be complex and difficult and require extensive analysis of histopathology, functional immunological assay and cell biological assay as well as sequencing of the entire exome or, alternatively, a more targeted sequencing approach. Acknowledgments The authors wish to thank the patient and his family for participation and for permission to publication of Rabbit Polyclonal to MMP17 (Cleaved-Gln129) the medical story. Footnotes Contributors: THM identified and cared for the patient. in an autosomal recessive manner, many patients have characteristic symptoms despite being heterozygous for mutations in the MEFV gene, and for around 30% of patients no disease-causing mutations are identified.4C6 Mutations in XIAP were first described in 2006 to cause X linked lymphoproliferative syndrome.7 However, more recent studies have revealed that patients with XIAP deficiency may present with a wide clinical spectrum, including periodic fevers, splenomegaly hypogammaglobulinaemia and inflammatory bowel disease, and carriers may be asymptomatic.8 XIAP mediates its effects by limiting apoptosis through inhibition of apoptotic caspases and is also involved in innate immune signalling pathways downstream of the cytosolic pattern recognition receptors NOD1 and NOD2.9C12 Structurally, XIAP consists of three regulatory baculovirus inhibitor of apoptosis protein repeat (BIR) domains, a ubiquitin-associated (UBA) domain and finally a C-terminal RING domain with Ub ligase activity.10 NOD2 activation by the peptidoglycan degradation product muramyl dipeptide (MDP) leads to recruitment of receptor interacting protein kinase 2 and the Ub ligases XIAP, cellular inhibitor of apoptosis 1 and 2.10 13 This event triggers ubiquitination of RIPK2 by XIAP and subsequent downstream activation of mitogen-activated protein kinases as well as the TAK1-TAB1/2/3 and downstream IB kinase (IKK) complex.14 15 NF-B activation ultimately results in synthesis of proinflammatory cytokines and chemokines.16 The curative treatment for XIAP deficiency is haematopoietic stem cell transplantation (HSCT). Although the outcome of HSCT has been poor17 recent advances in the treatment regime by reduced conditioning have improved clinical outcome and survival.8 18 19 Case presentation A 16-year-old boy of Caucasian Danish ethnicity was admitted to the department of infectious diseases, Aarhus University Hospital, for evaluation of recurrent febrile episodes during most of his life but with increasing severity and duration over the past year. The patient was born to healthy non-consanguineous parents and had one healthy brother. His medical history included pituitary insufficiency treated with eltroxin and growth hormone for several years. He had been admitted to other hospitals several times during the past 10?years with episodes of elevated temperatures and evaluated for meningitis, urinary tract infection, appendicitis other viral and bacterial infections without any specific diagnosis and with no positive microbial cultures, serology or PCR indicating infection. During admission to our department, he had a particularly severe and long-lasting inflammatory febrile episode. During this febrile episode lasting almost 2?months, he developed extensive splenomegaly, lymphadenopathy, anaemia, Mitiglinide calcium severe intermittent abdominal and thoracic pain (requiring morphine administration), general malaise, fatigue and weight loss. Investigations The patient was extensively evaluated, including blood tests, histopathology on enlarged lymph nodes, liver and Mitiglinide calcium bone marrow, as well as genetic testing by whole exome sequencing (WES). Blood tests revealed elevated C reactive protein (CRP) to 400?mg/L in the setting of a largely normal leucocyte count, although with fluctuating lymphopenia normalising between fever episodes). Sedimentation rate was normal. Liver and renal tests were normal. A profound normocytic anaemia developed with haemoglobin levels as low as 4.2?mmol/L. During some periods, he experienced elevated ferritin levels but triglycerides and IL-2 R remained normal. Computerised axial tomography scan demonstrated hepatosplenomegaly with multiple enlarged lymph nodes in relation to the great vessels in the abdomen. Pathology from an enlarged lymph node demonstrated inflammation and extensive sinus histiocytosis (Langerhans histiocytosis was ruled out by histological stain for CD207 and CD1a, which were negative) and no malignancy or granuloma was found. Biopsy from the liver demonstrated lymphocytic infiltration but no malignancy. A bone marrow aspirate was found to be without malignancy, myelodysplastic syndrome, haemophagocytosis or granuloma. Microbiological testing was negative for HIV, hepatitis A, B and C, cytomegalovirus, Epstein-Barr virus (EBV), influenza virus, toxoplasmosis, cause amino acid changes P369S and R408Q, of which the P369S variant is predicted to belong to the 10% most Mitiglinide calcium damaging variants with a combined annotation dependent depletion (CADD) score of 15.6. However, the variants are frequent ( 1%, table 1) and both were present in the mother, but not in the father or healthy brother. Table?1 Variants and genotypes detected mutations were detected by WES (figure 1A) and confirmed by Sanger sequencing (figure 1B). The mutations include a frameshift.