Congenital chloride diarrhea explained

Congenital chloride diarrhea
Synonyms:Darrow Gamble syndrome
Symptoms:High volume diarrheaHigh chloride concentration in stool (>90mmol/L)Low chloride excretion in the urineHypochloremic alkalosis and hypokalemia

Congenital chloride diarrhea (CCD, also congenital chloridorrhea or Darrow Gamble syndrome) is a genetic disorder due to an autosomal recessive mutation on chromosome 7. The mutation is in downregulated-in-adenoma (DRA), a gene that encodes a membrane protein of intestinal cells. The protein belongs to the solute carrier 26 family of membrane transport proteins.[1] More than 20 mutations in the gene are known to date. A rare disease, CCD occurs in all parts of the world but is more common in some populations with genetic founder effects,[2] most notably in Finland.

Symptoms and signs

Chronic diarrhoea starting from early neonatal period. Failure to thrive is usually accompanying diarrhea.

Pathophysiology

CCD causes persistent secretory diarrhea. In a fetus, it leads to polyhydramnios and premature birth. Immediately after birth, it leads to dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive.[3]

Diagnosis

CCD may be detectable on prenatal ultrasound.[4] [5] After birth, signs in affected babies typically are abdominal distension, visible peristalsis, and watery stools persistent from birth that show chloride loss of more than 90 mmol/L.[5] An important feature in this diarrhea that helps in the diagnosis, is that it is the only type of diarrhea that causes metabolic alkalosis rather than metabolic acidosis.[6]

Treatment

Available treatments address the symptoms of CCD, not the underlying defect. Early diagnosis and aggressive salt replacement therapy result in normal growth and development, and generally good outcomes. Replacement of NaCl and KCl has been shown to be effective in children.[7]

History

Observations leading to the characterization of the SLC26 family were based on research on rare human diseases. Three rare recessive diseases in humans have been shown to be caused by genes of this family. Diastrophic dysplasia, congenital chloride diarrhea, and Pendred syndrome are caused by the highly related genes SLC26A2 (first called DTDST), SLC26A3 (first called CLD or DRA), and SLC26A4 (first called PDS), respectively.[8] Two of these diseases, diastrophic dysplasia and congenital chloride diarrhea, are Finnish heritage diseases.[9]

Notes and References

  1. Dorwart MR, Shcheynikov N, Yang D, Muallem S. The solute carrier 26 family of proteins in epithelial ion transport. Physiology. 23. 2. 104–14. April 2008. 18400693. 10.1152/physiol.00037.2007.
  2. Kere J, Lohi H, Höglund P. Genetic Disorders of Membrane Transport III. Congenital chloride diarrhea. The American Journal of Physiology. 276. 1 Pt 1. G7–G13. January 1999. 9886972. 10.1152/ajpgi.1999.276.1.G7.
  3. Mäkelä S, Kere J, Holmberg C, Höglund P. SLC26A3 mutations in congenital chloride diarrhea. Human Mutation. 20. 6. 425–38. December 2002. 12442266. 10.1002/humu.10139. 2450225. free.
  4. Rose NC, Kaplan P, Scott S, Kousoulis A, Librizzi R. Prenatal presentation of congenital chloride diarrhea: clinical report and review of the literature. American Journal of Perinatology. 9. 5–6. 398–400. 1992. 1418143. 10.1055/s-2007-999274.
  5. Abdullah AM, Shaheed MM, Katugampola SM, Patel PJ. Congenital chloride diarrhoea: case report and review of the literature. Annals of Tropical Paediatrics. 10. 1. 71–4. March 1990. 1694648. 10.1080/02724936.1990.11747412.
  6. Hirakawa. M.. Hidaka. N.. Kido. S.. Fukushima. K.. Kato. K.. Congenital Chloride Diarrhea: Accurate Prenatal Diagnosis Using Color Doppler Sonography to Show the Passage of Diarrhea. Journal of Ultrasound in Medicine. 34. 11. 2015. 2113–2115. 0278-4297. 10.7863/ultra.15.01011. 26446821.
  7. Hihnala S, Höglund P, Lammi L, Kokkonen J, Ormälä T, Holmberg C. Long-term clinical outcome in patients with congenital chloride diarrhea. Journal of Pediatric Gastroenterology and Nutrition. 42. 4. 369–75. April 2006. 16641574. 10.1097/01.mpg.0000214161.37574.9a. 12078505. free.
  8. Book: Kere J. Overview of the SLC26 Family and Associated Diseases. Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Novartis Foundation Symposium. Novartis Foundation Symposia. 273. 2–11; discussion 11–8, 261–4. 2006. 17120758. 10.1002/0470029579.ch2. 9780470016244.
  9. Uusimaa . Johanna . Kettunen . Johannes . Varilo . Teppo . Järvelä . Irma . Kallijärvi . Jukka . Kääriäinen . Helena . Laine . Minna . Lapatto . Risto . Myllynen . Päivi . Niinikoski . Harri . Rahikkala . Elisa . Suomalainen . Anu . Tikkanen . Ritva . Tyynismaa . Henna . Vieira . Päivi . Zarybnicky . Tomas . Sipilä . Petra . Kuure . Satu . Hinttala . Reetta . The Finnish genetic heritage in 2022 – from diagnosis to translational research . Disease Models & Mechanisms . The Company of Biologists . 15 . 10 . 2022-10-01 . 1754-8403 . 10.1242/dmm.049490 .

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