Severe Early-Onset Colitis Revealing Mevalonate Kinase Deficiency

Abstract

Hyperimmunoglobulinemia D is the less severe form of mevalonate kinase deficiency (MKD) caused by recessive inherited mutation in the mevalonate kinase gene. Hyperimmunoglobulinemia D is characterized by febrile attacks, often associated with transient digestive manifestations, such as abdominal pain, diarrhea, and vomiting. Here we report for the first time 2 patients with MKD revealed by severe neonatal colitis. Both patients had chronic bloody diarrhea and failure to thrive; 1 patient since the age of 1 month and the other since the age of 12 days. Total parenteral nutrition was required. A marked elevation of acute phase reactants was present, and no evidence of infection was found. In patient 1, ileocolonoscopy revealed ulcerative colitis at the age of 5 months. Patient 2 suffered from enterocolitis and shock, associated with multiple bowel adhesions at age 5 weeks; the rectosigmoidoscopy showed aphtoid lesions of the sigmoid colon. Pathologic findings of colonic biopsies revealed a dense polymorph inflammatory infiltrate associated with deep ulcerations. Febrile attacks occurred 2 months after the onset of digestive symptoms in patient 1, and at onset of disease in patient 2. Genomic sequencing of the mevalonate kinase gene revealed compound heterozygous mutations in both patients. Anti-interleukin-1 agent produced longterm remission of all digestive features and laboratory parameters. This report emphasizes that MKD may be the cause of severe earlyonset inflammatory colitis, and must be considered by physicians, even in the absence of fever, after ruling out infections. Antiinterleukin-1 therapy may result in a dramatic improvement of MKD-related inflammatory bowel disease. Pediatrics 2013;132:e779-e783 AUTHORS:

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

“…To assess the effects of thiopurine treatment, some CD patients were recruited immediately prior to commencing AZA therapy, and longitudinal blood sampling was conducted over a followup period of 6 months. The analyses of Vδ2 T cell subset distribution in peripheral blood were conducted in a subgroup of pediatric CD patients (mean age, 13 years [range [7][8][9][10][11][12][13][14][15][16][17][18][19]; 50% male; CRP, mean 12.5 mg/l [range 5-39 mg/l]) and sex/age/ethnicity-matched IBS controls (mean age, 13 years [range [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]; 50% male; CRP, <5 mg/l) in order to limit the effects of demography, historical pathogen exposure, and concomitant therapies.…”

“…PAg are produced by a wide range of bacteria that can colonize the gut (1) and can also accumulate in host cells due to dysregulation of the mevalonate kinase metabolic pathway during malignant transformation or microbial infection (5,6). Intriguingly, human patients with mutations in the mevalonate kinase gene exhibit a severe neonatal colitis that can be successfully treated with bisphosphonate drugs, which modulate PAg synthesis and alter Vδ2 T cell function in vivo (7)(8)(9)(10). We recently reported that PAg exposure stimulates human blood Vδ2 T cells to upregulate the gut-homing integrin α4β7, and we identified Vδ2 T cells in human colonic biopsies that produced proinflammatory cytokines and enhanced IFNγ synthesis by intestinal CD4 + T cells (11).…”

Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience

“…On the other hand, abdominal symptoms may arise from potentially lifethreatening complications of HIDS, such as the bowel strangulation with subsequent necrosis that occurred in one of our patients. Severe inflammatory colitis has been reported in two neonates as the presenting feature of HIDS [27]. Moreover, genetic variants associated with inflammatory bowel disease were recently found in a series of MKD patients [3].…”

“…These include the anti-tumor necrosis factor alpha (TNFα) agents infliximab [24,27], etanercept [53,54], and adalimumab [15], the anti-interleukin (IL)-1 agents anakinra [5,7,15,27] and canakinumab [15], and the IL-6 antagonist tocilizumab [41].…”

Mevalonate kinase deficiency and IBD: shared genetic background

“…In this regard, we wish to focus the attention on six patients suffering from mevalonate kinase deficiency (MKD, OMIM #260920), diagnosed during the first year of life and followed-up at the Institute for Maternal and Child Health—IRCCS ‘Burlo Garofolo’ (Trieste, Italy). MKD, caused by inherited recessive mutations in the mevalonate kinase gene ( MVK ), is characterised by febrile attacks, often associated with abdominal pain, diarrhoea and vomiting; it can be considered as an auto-inflammatory defect predisposing to IBD-like intestinal inflammation 3 4. The six MKD patients were homozygous and/or heterozygous for missense mutations on the MVK gene (table 1).…”