JPGN Reports · 3 authors, 2 centres
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A 3-month-old infant with jaundice and gallstones was found to have mutations in both ABCB4 and ABCB11 genes, causing low phospholipid-associated cholelithiasis (LPAC) syndrome and transient neonatal cholestasis. Treatment with ursodeoxycholic acid resolved the cholestasis and gallstones. This case highlights the complex genetics of cholestatic disorders and reports LPAC in infancy for the first time.
**Background:** Low phospholipid-associated cholelithiasis (LPAC) syndrome is characterized by early-onset cholelithiasis (<40 years) and is associated with heterozygous mutations in the ABCB4 gene, which encodes multidrug resistance protein 3 (MDR3). Transient neonatal cholestasis (TNC) has been linked to heterozygous mutations in both ABCB4 and ABCB11 (bile salt export protein, BSEP). Combined mutations in these genes are rare, especially in infancy. This case report describes a 3-month-old male with cholelithiasis and TNC due to digenic heterozygous mutations in ABCB4 and ABCB11.
**Methods:** A 3-month-old male infant presented with jaundice since day 3 of life. He was born at term (weight 2.4 kg) to nonconsanguineous parents; his mother had undergone cholecystectomy at age 27. Examination showed icterus and hepatomegaly (liver 4 cm below costal margin). Laboratory tests revealed conjugated hyperbilirubinemia (total/direct bilirubin 6.94/4.67 mg/dl), elevated liver enzymes (AST 107 U/L, ALT 64.9 U/L, ALP 919 U/L, GGT 83 U/L), normal albumin (3.5 mg/dl) and INR (0.98). Abdominal ultrasound showed mild hepatomegaly and two gallstones (7.5 mm and 6.2 mm). Hemolytic workup was negative. Percutaneous liver biopsy showed marked intrahepatic and canalicular cholestasis with prominent bile ducts. Genetic testing identified digenic variations: c.1769G>A (p.Arg590Gln) in ABCB4 (heterozygous) and c.1772A>G (p.Asn591Ser) in ABCB11 (heterozygous). Treatment with ursodeoxycholic acid (UDCA) and fat-soluble vitamins was initiated.
**Key Results:** At 2-week follow-up, jaundice had decreased. At 6 months of age, jaundice had completely resolved, liver enzymes improved, and repeat ultrasound showed resolution of gallstones. The patient continues on UDCA and remains under follow-up.
**Clinical Implications:** This case demonstrates that combined heterozygous mutations in ABCB4 and ABCB11 can present as TNC and LPAC in infancy. The ABCB4 mutation (c.1769G>A) has been previously reported in a compound heterozygous state in PFIC3, and the ABCB11 mutation (c.1772A>G) has been observed in intrahepatic cholestasis of pregnancy. The patient did not meet classic LPAC criteria (age <40 years, recurrence after cholecystectomy, intrahepatic hyperechogenic foci), but these criteria are seldom applicable in children. Family history of biliary lithiasis and response to UDCA support the LPAC diagnosis. This is the first reported case of LPAC in infancy. The favorable response to UDCA suggests that long-term therapy may be beneficial, though the normal GGT at presentation raises the possibility of PFIC/BRIC type 2, which may also transiently respond to UDCA. Limitations include short follow-up and lack of parental genetic testing due to financial constraints. This case underscores the complex genetics of cholestatic disorders and the need for genetic evaluation in infants with unexplained cholestasis and cholelithiasis.