Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute's genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

Congenital Sodium Diarrhea by mutation of the SLC9A3 gene.

Congenital Sodium Diarrhea (CSD) due to SLC9A3 mutation is a rare cause of neonatal diarrhea explained by dysfunction of the Na+/H+ antiporter 3 in intestine. To date only 10 patients have been described. We report a male patient with typical antenatal symptoms (polyhydramnios and intestinal dilation) and neonatal diarrhea with fecal sodium and bicarbonates loss. Next generation sequencing revealed a missense homozygous mutation in exon 6 of the SLC9A3 gene (NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys). Oral electrolytes supplements (Sodium and Bicarbonates) allowed a normal growth to the child currently aged twenty months. CSD symptomatology usually begins during third trimester of pregnancy. Antenatal signs are polyhydramnios and diffuse intestinal dilation. Main differential diagnoses are intestinal obstruction and Congenital Chloride Diarrhea. Diarrhea begins from the first days of life and its severity is variable. Based on the report and on the literature we suggest that non syndromic CSD can be detected during third trimester of pregnancy. With adequate electrolytes supplementation good evolution is possible.

Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.