Combined Mutations of Canalicular Transporter Proteins Causing Low Phospholipid-Associated Cholelithiasis and Transient Neonatal Cholestasis in an Infant

Abstract

Low phospholipid-associated cholelithiasis syndrome is characterized by the development of cholelithiasis in early adulthood (<40 years of age) but is rarely diagnosed in childhood. It is associated with gene sequence variants in the ABCB4 gene encoding the multidrug resistance protein 3 which are mostly heterozygous. Transient neonatal cholestasis has been reported with heterozygous mutations in both ABCB4 and ABCB11 (Bile Salt Exporter Protein). We report a 3-month-old male with cholelithiasis and transient neonatal cholestasis in the setting of combined pathogenic heterozygous mutations in the genes ABCB4 and ABCB11. Initiation of ursodeoxycholic acid therapy led to a resolution of the cholestasis and gall stones. Our case highlights the complex nature of the genetics of cholestatic disorders.

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

“…With reference to the previously mentioned patient in Section 5.1.1 who had both a single heterozygous pathogenic change in ABCB11 and a possibly pathogenic change in ABCB4, it is worth noting that the role of digenic heterozygosity has been discussed in the context of several other diseases [76][77][78][79]. In the context of genetic cholestasis, a recent case report described the finding of heterozygous digenic mutations in ABCB4 and ABCB11 in an infant with low phospholipid-associated cholelithiasis (LPAC) and TNC, where ursodeoxycholic acid led to resolution of symptoms [80]. However, without further large-scale studies, the broader importance of digenic heterozygosity in genetically determined cholestatic conditions is unclear.…”