Alain Lachaux

GPIHBP1 C89F Neomutation and Hydrophobic C-Terminal Domain G175R Mutation in Two Pedigrees with Severe Hyperchylomicronemia

CONTEXTnGPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene.nnnOBJECTIVEnPhenotypic expression and functional consequences of these two mutations were studied.nnnDESIGNnWe performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells.nnnRESULTSnProbands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect.nnnCONCLUSIONSnThe emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting.

Isolated Deficient α6β4 Integrin Expression in the Gut Associated with Intractable Diarrhea

Background: An infant born with pyloric atresia had development of intractable diarrhea and was found to have total epithelial detachment of gastric and small and large bowel mucosa. She had no skin abnormalities. Parental consanguinity and pyloric atresia in a sibling who died without autopsy suggest an inherited origin for this disorder. The purpose of this study was to examine defects in intestinal and skin cell adhesion. Methods: Histologic, immunohistochemical, and ultrastructural characteristics of the skin and gut of the patient were compared with that of normal control subjects. Distribution of adhesion molecules was determined. Results: Immunofluorescent analysis of the digestive mucosa showed α6β4 integrin expression deficiency at the epithelial cell-lamina propria junction. Ultrastructural examination of the digestive mucosa revealed a complete epithelial detachment with a cleavage plane lying between the lamina densa and the basal pole of the enterocytes. Consistent with the absence of skin blistering, integrin α6β4 was expressed at the dermal-epidermal junction. Electron micrographs of skin biopsy specimens showed the presence of normal hemidesmosomes and the absence of dermal-epidermal dysadhesion. Conclusion: It was postulated that this patient had protracted diarrhea related to epithelial detachment of the digestive mucosa as a consequence of a deficiency of an integrin α6β4 isoform specific to the gut.

Familial autoimmune enteropathy with circulating anti-bullous pemphigoid antibodies and chronic autoimmune hepatitis

In a family of four children (two boys and two girls), the two brothers had severe, protracted watery diarrhea beginning at 2 and 3 weeks of life, respectively. Duodenal mucosa in both patients showed total villous atrophy and severe inflammatory infiltration of the entire bowel. The first patient also had lymphoid cell infiltration of the pancreas and died at 6 weeks of age. The second boy is alive at 2 years of age and is immunocompetent, but still receives total parenteral nutrition. Indirect immunofluorescence studies revealed circulating antibodies to enterocytes, smooth muscle, thyroid, and islet cells. Bullous pemphigoid antibodies (230 and 180 kd), specific for hemidesmosomal proteins and usually associated with a subepidermal blistering skin disease, were detected by direct and indirect immunofluorescence studies and by Western immunoblot. A diagnosis of autoimmune hepatitis was made, based on evidence of chronic active hepatitis and circulating anti-smooth muscle antibody. Immunosuppressive treatments induced partial clinical remission of the diarrhea but no resolution of the small bowel injury. At 16 months of age, remission of the diarrhea occurred, but persistent autoimmune hepatitis led us to maintain treatment with prednisone and azathioprine, and later with cyclosporine. In this child, as in other patients with autoimmune disease, the link between autoantibodies and organ damage remains uncertain but immunosuppressive treatment is indicated.

Autoimmune enteropathy in infants

Abstractu2002In two brothers with autoimmune enteropathy there was total villous atrophy in the small intestine and marked lymphoid cell infiltration in the lamina propria of the entire digestive tract, discovered at autopsy in one of these patients. In addition, the pancreas showed diffuse interstitial infiltration by lymphocytes. The liver was enlarged, with extensive haematopoiesis and cholestasis. Similar lesions in the digestive tract were noticed in the second boy, but on immunosuppressive therapy his diarrhoea gradually disappeared. When he was 16 months of age, percutaneous biopsies showed moderately aggressive chronic hepatitis and a focal interstitial lymphoid infiltrate in the kidney. After 3 years of immunosuppressive therapy (prednisone, cyclosporin), the child ate well and total parenteral nutrition was discontinued. The intestinal lesions had regressed but fibrotic lesions of the liver persisted.

Effects of Liver Transplantation on Long-chain Polyunsaturated Fatty Acid Status in Infants with Biliary Atresia

BACKGROUNDnThe long-chain polyunsaturated fatty acid (LC-PUFA) status of infants with untreated biliary atresia (BA) is known to be poor and is correlated to the severity of the liver disease. Liver transplantation (LT) markedly increases survival of patients with BA but the extent to which this reverses poor LC-PUFA status is not known.nnnMETHODSnTo explore this question, the erythrocyte (red blood cell, RBC) phospholipid content of eight infants with BA who underwent LT was determined 2 months after an initial portoenterostomy, immediately before LT, and 6 and 12 months after LT. Before LT, all infants were fed a protein hydrolysate formula containing medium-chain triglycerides and essential fatty acids. Afterward, they were fed a normal diet for age. The RBC phospholipid content at each time point was compared with that of 28 age-matched control infants.nnnRESULTSnJust before LT, median RBC phospholipid content of C20:4n-6, C20:5n-3, and C22:6n-3 was 25%, 48%, and 30% lower, respectively, than that observed in age-matched control infants. After LT, the RBC phospholipid content of most fatty acids reached normal values by 6 months. However, that of C20:4n-6 and C22:6n-3 contents remained 5% and 15% lower, respectively, than in normal control infants. Twelve months after LT, C20:4n-6 content remained lower than in normal children, but that of C22:6n-3 did not differ. The ratio of C20:3n-6/C20:4n-6, a reflection of delta-5 desaturase activity, was abnormal compared with normal children before LT (0.17 vs. 0.10, P < 0.009) but normalized by 6 months after LT (0.11 vs. 0.10, not significant).nnnCONCLUSIONSnThese data show that the abnormal LC-PUFA status of children with BA improves after LT but is not entirely reversed within a year after surgery. They suggest that the abnormal status before LT may be secondary, in part, to low delta-5 desaturase activity. The extent to which a different pre- and/or post-LT diet can prevent PUFA deficiency and/or hasten recovery of PUFA status remains to be determined.

Benign recurrent cholestasis with normal gamma-glutamyl-transpeptidase activity

We report two observations of intrahepatic cholestasis with normal serum levels of gamma-glutamyl-transpeptidase. These cases fit the diagnostic criteria of benign recurrent cholestasis and show that it, like Byler disease, is another form of pediatric intrahepatic cholestasis with a normal gamma-glutamyl-transpeptidase level in the infant.

DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.

Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight‐junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in‐frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.

Influence of measles vaccination on the progression of atopic dermatitis in infants

Atopic dermatitis (AD) is a chronic inflammatory skin disease, affecting 10–20% of children. Measles vaccination has been reported to have contradictory effects on incidence of AD in children. Therefore, we performed the first prospective, double‐blind, placebo‐controlled study to analyze the evolution of AD in infants after measles vaccination. The study included 12 infants (10–14u2003months old) with AD, randomly assigned to two groups: while the first group received a single dose of a standard measles vaccine ROUVAX, the second was treated with placebo (vehicle). Infants were followed‐up for 6u2003months after administration of ROUVAX/placebo for the clinical signs associated with AD, by determination of SCORAD index. In addition, serum was taken before vaccination and 1u2003month later to determine the presence of seroconversion and to analyze the progression of serum levels of CCL18 (PARC) and E‐selectin, known to be distinct serum markers that reflect clinical features of AD. In the vaccinated group, five of six children seroconverted 1u2003month after treatment and one infant showed a 50% improvement of SCORAD. Serum levels of CCL18 were significantly decreased in two treated infants (of four analyzed for this group) and E‐selectin slightly decreased in one infant (of three analyzed by this test). In placebo‐treated group the SCORAD improved in one patient and serum levels of CCL18 and E‐selectin did not change. These data suggest that measles vaccination not only does not aggravate AD, but may also improve some of the immunological parameters of this allergic disease. Inclusion of a higher number of patients in a similar study should give a more comprehensive overview of the benefit of measles vaccination on the clinical evolution of AD patients, and potentially open new avenues to the clinical application of the anti‐inflammatory effect of measles virus proteins.

Long-term treatment reduction and steroids withdrawal in children with autoimmune hepatitis: a single centre experience on 55 children.

Background The combination of corticosteroids and azathioprine is the standard therapy for autoimmune hepatitis. The aim of this study was to describe our experience on long-term corticosteroid doses reducing and withdrawal in a large cohort of children with autoimmune hepatitis (AIH). Methods All children presenting with AIH in our institution, from 1990 to 2006, were retrospectively included. Results The study population included 55 children [38 females, 17 males, median age 8 years (ranging from 0.8 to 15)] with type 1 (74.5%), type 2 (20%) or seronegative (5.5%) AIH. The diagnosis was made in 41 of them at the time of acute hepatitis (75%); the other 14 were diagnosed as chronic liver disease (25%). Treatment consisted of corticosteroids and azathioprine in 45 patients or corticosteroids alone in five patients. Complete remission was obtained within 1 year in 31 (69%) patients. The median initial dose of corticosteroids was 1.6u2009mg/kg/day, and the dose was progressively reduced to 0.32u2009mg/kg/day at 1 year, 0.24u2009mg/kg/day at 3 years, 0.11u2009mg/kg/day at 5 years and 0.05u2009mg/kg/day at 10 years. Corticosteroids withdrawal was possible in 0% of patients at 1 year, 75% at 3 years, 78% at 5 years and 90% at 10 years. At the end of follow-up, azathioprine was maintained in 36 patients (80%). Total treatment withdrawal was obtained in four patients. Conclusion Our results strongly confirm that long-term corticosteroids withdrawal is possible in a large majority of children with autoimmune hepatitis.

Quels traitements pour les coliques du nourrisson

BACKGROUNDnInfantile colics or excessive crying represent a source of stress for parents and a frequent reason for encounter in primary care.nnnOBJECTIVEnTo assess the effectiveness of treatments of this syndrome from a systematic review.nnnINFORMATION SOURCESnMedline, Cochrane and Embase databases.nnnSELECTION OF STUDIESnWe used the following inclusion criteria: therapeutic assessment of infant colics or excessive crying, randomized controlled trials or meta-analyses, published in English or French language. Thirty-one randomized controlled trials and one meta-analysis have been included.nnnRESULTSnAllopathic drugs have not proved effectiveness (simethicone, lactase) and some of them can cause potentially serious adverse reactions (dicyclomine). Protein hydrolysate or soy formulas seem to be effective, but soy milk can induce allergies. Sucrose solutions provide some benefit in studies with low level of evidence. Effectiveness is likely for a probiotics (Lactobacillus reuteri) and for herbal mixtures containing fennel extracts. Evidence is lacking for manual (osteopathy, acupuncture) and behavioural therapies (decreased stimulations, reassurance of parents).nnnLIMITATIONSnThe definition of infantile colics and the methods used for crying measurement changed across trials. The included trials were of variable quality, especially with no double-blind procedure in 17 trials.nnnCONCLUSIONnThe most validated treatments for infantile colics are the substitution of cows milk by a hydrolysed formula, the use of L.xa0reuteri and of fennel extracts.