Congenital chloride diarrhea and Pendred syndrome: case report of siblings with two rare recessive disorders of SLC26 family genes

Abstract

Background: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness.

Case presentation: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD.

Conclusions: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.

Keywords: Case report; Congenital chloride diarrhea; Deafness; Neonatal diarrhea; Pendred syndrome.

Fig. 1

SLC26A3 (purple arrow) and SLC26A4 (green arrow) genes on chromosome 7q22.3-q31.1 (marked with red bar) are shown. The promoters of these genes are marked with arrows and the SLC26A3 deletion causative for CLD with a red square bracket. The two nearest enhancer elements are shown, of which one is 17.8 kb upstream of SLC26A3; none is near SLC26A4. The 8.6 kb deletion responsible for CLD extends upstream only about half-way to the nearest enhancer element. The image is a screen capture from the FANTOM5 database (http://fantom.gsc.riken.jp/zenbu)