Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the ...hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications.
One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant.
Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.
Objective
To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so ...far been identified, and to assess the functional consequences of the identified missense variation.
Methods
NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF‐κB activation.
Results
A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide‐binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF‐κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12‐associated disorders (NLRP12AD).
Conclusion
Given the rarity of known NLRP12‐associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.
Congenital esophageal stenosis (CES) is a rare condition frequently associated with esophageal atresia (EA). There are limited data from small series about the presentation, treatment, and outcomes ...of CES.
Medical records of all patients with CES included in the French Network on Esophageal Malformations and Congenital Diseases were reviewed retrospectively with regard to diagnosis, treatment, and outcome.
Over 18 years, 61 patients (30 boys) had CES, and 29 (47%) of these patients also had EA. The mean age at diagnosis was 24 months (1 day to 14 years) and was younger in patients with CES and EA than in those with isolated CES (7 vs. 126 months, p < 0.05). Twenty-one of the 61 patients with CES had no clinical symptoms: in three patients, the findings were incidental, and in 18 of the 29 patients with associated EA, CES was diagnosed at the time of surgical repair of EA or during a postoperative systematic esophageal barium study. In the 40 other patients, at diagnosis, 50% presented with dysphasia, 40% with vomiting, 50% with food impaction, and 42% with respiratory symptoms. Diagnosis of CES was confirmed by esophageal barium study (56/61) and/or esophageal endoscopy (50/61). Sixteen patients had tracheobronchial remnants (TBR), 40 had fibromuscular stenosis (FMS), and five had membrane stenosis (MS). Thirty-four patients (56%) were treated by dilation only (13/34 remained asymptomatic at follow-up); 15 patients were treated by dilation but required later surgery because of failure (4/15 remained asymptomatic at follow-up); and nine patients had a primary surgical intervention (4/9 were asymptomatic at follow-up). Dilation was complicated by esophageal perforation in two patients (3.4%). At follow-up, dysphagia remained in 36% (21/58) of patients, but the incidence did not differ between the EA and the isolated CS groups (10/29 vs. 7/32, p = 0.27).
CS diagnosis can be delayed when associated with EA. Dilation may be effective for treating patients with FMS and MS, but surgical repair is often required for those with TBR. Our results show clearly that, regardless of the therapeutic option, dysphagia occurs frequently, and patients with CES should be followed over the long term.
Anderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the SAR1B gene and to evaluate the ...expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease.
The SAR1B, SAR1A and PCSK9 genes were sequenced. The expression of the SAR1B and SAR1A genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies.
Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17). The third patient, who had a previously described SAR1B mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the PCSK9 gene. The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects.
Although the proteins encoded by the SAR1A and SAR1B genes are 90% identical, the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD.
Background & Aims: Oral rehydration therapy is the only treatment recommended by the World Health Organization in acute diarrhea in children. Antisecretory drugs available could not be used because ...of their side effects, except for racecadotril, which is efficient in acute diarrhea in adults. Methods: The efficacy and tolerability of racecadotril (1.5 mg/kg administered orally 3 times daily) as adjuvant therapy to oral rehydration were compared with those of placebo in 172 infants aged 3 months to 4 years (mean age, 12.8 months) who had acute diarrhea. The treatment groups were comparable in terms of age, duration of diarrhea, number of stools, and causative microorganism at inclusion. Results: During the first 48 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The 95% confidence interval was 43%–88% for the full data set (n = 166; P = 0.009) and 33%–75% for the per-protocol population (n = 116; P = 0.001). There was no difference between treatments depending on rotavirus status. Significant differences between treatment groups were also found after 24 hours of treatment: full data set (n = 167; P = 0.026) and per-protocol population (n = 121; P = 0.015). Tolerability was good in both groups of patients. Conclusions: This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as adjuvant therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.
GASTROENTEROLOGY 2001;120:799-805
Zinc Therapy for Wilson Disease in Children in French Pediatric Centers Santiago, Raoul; Gottrand, Frédéric; Debray, Dominique ...
Journal of pediatric gastroenterology and nutrition,
December 2015, 2015-December, 2015-Dec, 2015-12-00, 20151201, 2015-12, Letnik:
61, Številka:
6
Journal Article
Recenzirano
ABSTRACT
Background and Aims:
Zinc therapy is considered a good option in Wilson disease (WD), as a first‐line treatment in presymptomatic children and a maintenance therapy after the initial ...chelator therapy. The aim of the study was to determine the practical use of zinc treatment in French pediatric centers.
Methods:
A national survey was conducted in the 6 French centers using zinc acetate to treat WD. Clinical and biological parameters, dosage, and outcome were recorded.
Results:
A total of 26 children were reported to be treated with zinc acetate, alone or in association with chelators. Of the 9 children (35%) who received zinc alone as a first‐line therapy, 2 were switched to D‐penicillamine because of inefficacy and 7 remained on zinc alone, but serum transaminase levels normalized in only 4 of them. Five children (19%) were initially treated with zinc in association with D‐penicillamine (n = 4) or Trientine (n = 1) with good efficacy. Among the 12 children (46%) who received zinc as a maintenance therapy after D‐penicillamine, no relapse of hepatic cytolysis occurred during a median follow‐up of 5.2 years, but 2 of them were switched to Trientine because of zinc‐related adverse effects. Epigastric pain was observed in 4 children, and a gastric perforation occurred in 1 child.
Conclusions:
The present study demonstrates poor efficacy of zinc as first‐line therapy to control liver disease in half presymptomatic children and a high incidence of related gastrointestinal adverse effects in children with WD.
Early onset inflammatory bowel diseases (EO-IBD) developing during the first year of life are likely to reflect inherited defects in key mechanism(s) controlling intestinal homeostasis, as recently ...suggested for interleukin 10 (IL10). Thus, we aimed to further elaborate the hypothesis of defective anti-inflammatory responses in patients with IBD.
The capacities of transforming growth factor β (TGFβ) and IL10 to inhibit proinflammatory cytokine production by monocyte-derived dendritic cells (MoDC) or peripheral blood cells (PBMC) was analyzed in 75 children with IBD, including 13 infants with EO-IBD (in whom autoimmune diseases or classical immunodeficiencies were ruled out). IL10 receptor-A/-B expression, STAT3 activation in response to IL6, IL10, IL21, IL22 were analyzed by FACS and western blotting. IL10RA and B genes were sequenced. The response to IL22 was tested in ileal/colonic tissue cultures. Tissue gene expression was analyzed by Taqman real-time polymerase chain reaction.
Production of IL10 in response to bacterial motifs was normal in all IBD patients. In contrast to our original hypothesis, no defect of the anti-inflammatory potential of TGFβ and IL10 was observed in children with IBD or EO-IBD except two infants who presented with granuloma-positive colitis at 3 months of life: no response to IL10 was observed secondary to mutations in the α (p.R262C) or β (p.E141X) chain of IL10R, respectively, although a fully functional Jak-STAT3 pathway was present in both patients. When analyzing the regulation of intestinal bacterial clearance, we detected a defect in the patient with absent IL10 RB to upregulate protective transcripts in response to IL22, whereas all other EO-IBD patients, including the patient with an abnormal α chain, responded normally.
Impaired IL10 signaling characterizes a subgroup of IBD patients, whereas the majority of children with severe IBD including EO forms normally produces and responds to IL10. Defective IL22 signaling may additionally impair intestinal epithelial clearance. Our data point out the complexity of IBD, which represent a group of distinct diseases with several pathogenetic abnormalities.
Mouse splenic marginal zone precursors (MZPs) differentiate into marginal zone B (MZB) cells under a signaling pathway involving Notch2 and its ligand, delta-like 1 ligand (Dll1). We report the ...identification of an MZP subset in the spleen of young children. These MZPs differentiate into MZ-like B cells in vitro in the presence of OP9 cells expressing human DLL1, as demonstrated by the up-regulation of classical MZB cell markers. A set of diagnostic genes discriminating IgM(+)IgD(+)CD27(+) blood and splenic MZB cells from switched B cells was identified (up-regulation of SOX7, down-regulation of TOX, COCH, and HOPX), and their expression during the induction assay mirrored the one of MZB cells. Moreover, Alagille patients with a NOTCH2 haploinsufficiency display a marked reduction of IgM(+)IgD(+)CD27(+) B cells in blood, whereas their switched memory B cells are not affected. Altogether, these results argue in favor of the existence of a rodent-like MZB cell lineage in humans.
ABSTRACT
Objective:
Anastomotic ulceration (AU) is a rare complication after intestinal resection and anastomosis, described mostly in children. The main symptom is occult bleeding, leading to ...iron‐deficiency anemia, which is life threatening.
Methods:
The present survey reports a series of patients with AU after intestinal resection in infancy, focusing on predictive factors, medical and surgical treatment options, and long‐term outcomes. Eleven patients (7 boys) born between 1983 and 2005 with AU after an intestinal resection and anastomosis in infancy were included in this retrospective review.
Results:
The diagnosis of AU was often delayed for several years. No predictive factor (including the primary disease, the length of the remnant bowel, and the loss of the ileocaecal valve) could be identified. Numerous treatment options, including antibiotics and anti‐inflammatory drugs, proved to be ineffective to induce prolonged remission. Even after surgical resection, relapses were observed in 5/7 children.
Conclusions:
The mechanism leading to AU remains unknown. Contrary to previous reports with limited follow‐up, no medical or surgical treatment could prevent recurrences. Because relapses may occur several years after treatment, long‐term follow‐up is needed.
Objective. Ulcerative colitis (UC) is a chronic inflammatory condition. Previous reports suggested that UC may have a worse prognosis when associated with auto-immune diseases. We compared ...characteristics at diagnosis and natural history of the disease between classical ulcerative colitis (CUC) and UC associated with auto-immune diseases (CAI) in children. Material and methods. In this study, 67 children followed for UC at Nancy University Hospital between 1993 and 2012 were included: 45 patients in the CUC group and 22 in the CAI group. Results. Median follow-up was 4.8 years. Median age at diagnosis was 11.6 years in the CAI group and 9.8 years in the CUC group. Time between symptoms onset and diagnosis was broadly similar in the two groups (<3 months) and there were no significant differences regarding biological and histological findings. At 5 years, the need for corticosteroids and azathioprine did not differ between the CAI and the CUC groups. There was also no significant difference between the two groups regarding infliximab use at 1 and 5 years. Conclusions. In this pediatric study, CAI had similar characteristics at baseline as CUC. The course of CAI does not seem to be influenced by the presence of concomitant auto-immune diseases.
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