Genetic investigation confirmed the clinical phenotype of congenital chloride diarrhea in a Hungarian patient: a case report

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Abstract

Background

Congenital chloride diarrhea (CCD, OMIM 214700) is a rare autosomal recessively inherited condition characterized by watery diarrhea, hypochloremia and metabolic alkalosis. Mutations of the solute carrier family 26, member 3 ( SLC26A3, OMIM 126650) gene are responsible for the disease. The gene encodes a transmembrane protein, which is essential for intestinal chloride absorption.

Case presentation

Here we report a Hungarian boy, presenting the clinical phenotype of CCD. The patient born at 32 weeks of gestation and underwent surgery for abdominal distension and intestinal obstruction related to malrotation. After recovery, electrolyte replacement therapy was necessary due to several periods of diarrhea. After exclusion of other possible causes, increased chloride concentration in the feces supported the diagnosis of CCD. The diagnosis was confirmed by molecular genetic testing. Direct sequencing revealed compound-heterozygosity for a frameshift mutation c.1295delT (p.Leu432Argfs*11) and the known Polish founder mutation c.2024_2026dupTCA (p.Ile675_Arg676insLeu).

Conclusions

Here we present the clinical symptoms of the first patient in Hungary diagnosed with CCD. Based on the clinical symptoms, stool analysis and genetic testing, the diagnosis of CCD was established. Our study provides expansion for the mutation spectrum of the SLC26A3 gene and the genetic background of CCD.

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Most cited references 11

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Update on SLC26A3 mutations in congenital chloride diarrhea.

Pia Höglund, Satu Wedenoja, Hans-Christer Holmberg … (2011)

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl(-) /HCO 3- transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl(-) /HCO 3- exchange activity in vitro, and accordingly, evidence of genotype-phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. © 2011 Wiley-Liss, Inc.

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Long-term clinical outcome in patients with congenital chloride diarrhea.

Jorma O. Kokkonen, T Ormälä, Pia Höglund … (2006)

Congenital chloride diarrhea (CLD) is a rare, autosomal recessive disorder of intestinal Cl/HCO3 exchange caused by mutations in the SLC26A3 gene and characterized by persistent Cl rich diarrhea from birth. Treatment is symptomatic and replacement therapy with NaCl and KCl has been shown to be effective in children, but the long-term prognosis remains unclear. We studied the largest known cohort of patients to evaluate the long-term outcome of CLD and to search for extraintestinal manifestations. This is a cross-sectional clinical evaluation and retrospective analysis of medical history of 36 Finnish patients with CLD, born in the 1960s (n = 8), 1970s (n = 7) and 1980s (n = 21). Early diagnosis and aggressive salt replacement therapy were associated with normal growth and development, in addition to significantly reduced mortality rates among the groups of patients born in the different decades, respectively (P = 0.001). No deaths due to CLD were observed after 1972. Enuresis, slight soiling and hospitalizations for gastroenteritis were common, especially in childhood, but 92% of the patients found their health excellent or good. Complications documented were end-stage renal disease (n = 1) and hyperuricemia (n = 4), novel findings possibly associated with CLD being male subfertility (n = 3), spermatoceles (n = 3), intestinal inflammation (n = 2), inguinal hernias (n = 4) and increased concentrations of sweat Cl in 12% of the patients. When early diagnosed and adequately treated, the long-term prognosis of CLD is favorable. A putative role of a primary anion exchange defect of SLC26A3 in male subfertility and the decline of renal function due to chronic dehydration deserve further characterization.

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Review article: the clinical management of congenital chloride diarrhoea.

Jennie Holmberg, S Wedenoja, P Höglund (2010)

Congenital chloride diarrhoea in a newborn is a medical emergency, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. While most of the 250 cases reported arise from Finland, Poland and Arab countries, single cases with this autosomal recessive disorder appear worldwide. Such congenital chloride diarrhoea rarity makes diagnosis difficult. Life-long salt substitution with NaCl and KCl stabilizes fluid, electrolyte and acid-base balance diagnosis. When properly treated, the long-term outcome is favourable. To summarize data on congenital chloride diarrhoea diagnosis, pathophysiology and treatment, and to provide guidelines for both acute and long-term management of congenital chloride diarrhoea. Data are based on MEDLINE search for 'chloride diarrhoea', in addition to clinical experience in the treatment of the largest known series of patients. Treatment of congenital chloride diarrhoea involves (i) life-long salt substitution; (ii) management of acute dehydration and hypokalaemia during gastroenteritis or other infections; and (iii) recognition and treatment of other manifestations of the disease, such as intestinal inflammation, renal impairment and male subfertility. This review summarizes data on congenital chloride diarrhoea and provides guidelines for treatment. After being a mostly paediatric problem, adult patients constitute a rare challenge for gastroenterologists worldwide.

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Author and article information

Contributors

Éva Dávid: dr.davideva@gmail.com

Dóra Török: +36-62-545134 , torok.dora@med.u-szeged.hu

Katalin Farkas: farkas.katalin.1@med.u-szeged.hu

Nikoletta Nagy: nagy.nikoletta@med.u-szeged.hu

Emese Horváth: horvath.emese@med.u-szeged.hu

Zsuzsanna Kiss: titkarsag@markusovszky.hu

György Oroszlán: oroszlan.gyorgy@markusovszky.hu

Márta Balogh: balogh_marta@freemail.hu

Márta Széll: szell.marta@med.u-szeged.hu

Journal

Journal ID (nlm-ta): BMC Pediatr

Journal ID (iso-abbrev): BMC Pediatr

Title: BMC Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2431

Publication date (Electronic): 11 January 2019

Publication date PMC-release: 11 January 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 16

Affiliations

[1 ]GRID grid.416443.0, Department of Pediatrics, , Markusovszky Teaching Hospital, ; Szombathely, Hungary

[2 ]ISNI 0000 0001 1016 9625, GRID grid.9008.1, Department of Medical Genetics, , University of Szeged, ; Szeged, Hungary

[3 ]GRID grid.416443.0, Genetic Counseling Outpatient Clinic, , Markusovszky Teaching Hospital, ; Szombathely, Hungary

[4 ]ISNI 0000 0001 1016 9625, GRID grid.9008.1, MTA-SZTE Dermatological Research Group, , University of Szeged, ; Szeged, Hungary

Article

Publisher ID: 1390

DOI: 10.1186/s12887-019-1390-1

PMC ID: 6330408

PubMed ID: 30635044

SO-VID: f3ad42a6-017a-4e1d-a3ac-42b210017813

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 October 2018

Date accepted : 2 January 2019

Funding

Funded by: Gazdaságfejlesztési és Innovációs Operatív Program

Award ID: GINOP-2.3.2-15-2016-00039

Award Recipient : Márta Széll

Funded by: Emberi Erőforrás Fejlesztési Operatív Program

Award ID: EFOP-3.6.1-16-2016-00008

Award Recipient : Nikoletta Nagy

Custom metadata

ScienceOpen disciplines: Pediatrics

Keywords: congenital chloride diarrhea,slc26a3 gene,compound heterozygous state,novel mutation,recurrent mutation

Data availability:

ScienceOpen disciplines: Pediatrics

Keywords: congenital chloride diarrhea, slc26a3 gene, compound heterozygous state, novel mutation, recurrent mutation

Genetic investigation confirmed the clinical phenotype of congenital chloride diarrhea in a Hungarian patient: a case report

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Abstract

Background

Case presentation

Conclusions

Related collections

Estudio del peso al nacer

Most cited references 11

Update on SLC26A3 mutations in congenital chloride diarrhea.

Long-term clinical outcome in patients with congenital chloride diarrhea.

Review article: the clinical management of congenital chloride diarrhoea.

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