| CFTR 3 (cystic fibrosis) | Childhood/
adolescence | Diagnosis requires ≥2 of following findings:
↑ AST/ALT & GGTP for >6 mos HSM, confirmed on ultrasound Coarseness, nodularity, ↑ echogenicity or portal HTN on ultrasound Liver biopsy w/biliary or multilobular cirrhosis 4
Synthetic dysfunction is usually minimal. | Cystic fibrosis liver disease is diagnosed in 10%-15% of persons w/CF & is cause of mortality in 2%-3% of persons w/CF. 4 Cirrhosis & portal HTN are most clinically significant manifestations. Neonatal cholestasis is possible presenting feature. |
| CLDN1 5 (neonatal ichthyosis-sclerosing cholangitis) (OMIM 607626) | Neonatal | ↑ ALT & GGTP | Portal HTN; ichthyosis & alopecia |
| DCDC2 6 (neonatal sclerosing cholangitis) (OMIM 617394) | Neonatal | ↑ ALT & GGTP | Acholic stools, HSM, coagulopathy, ascites (variable presentation), renal disease |
| HNF1B 7 (HNF1B deficiency) (OMIM 137920) | Neonatal to adulthood | ↑ AST/ALT; ↑ GGTP | Spectrum of hepatic involvement ranges from severe neonatal cholestasis to asymptomatic increase of transaminases in adulthood; clinical manifestations incl paucity of intralobular bile ducts sometimes assoc in newborns w/IUGR. HCC has been reported. Other findings can incl kidney involvement (CAKUT, tubulopathy, &/or interstitial kidney disease), MODY5, &/or pancreatic insufficiency. |
JAG1; NOTCH2 8
(Alagille syndrome) | Infancy | ↑↑↑ GGTP | Cholestasis, progressing to ESLD in some; butterfly vertebrae, xanthomas, CHD, posterior embryotoxon, vascular abnormalities |
| NPC1; NPC2 (Niemann-Pick disease type C) | Neonatal to adulthood | | Neonatal features incl cholestasis, HSM, & in some cases ALF; neurodegenerative findings in older groups |
| PEX genes (Zellweger spectrum disorder) | Neonatal | Abnormal VLCFA | Cholestasis + hepatomegaly; neurologic deficits |
| PKHD1 9 (polycystic kidney disease, autosomal recessive) | Infancy to adulthood | Abnormal lab findings may be absent in newborns w/ARPKD. | Congenital hepatic fibrosis; variable dilatation of intrahepatic bile ducts (Caroli syndrome) & dilatation of common bile duct; nephromegaly, HTN, & varying degrees of renal dysfunction |
| SCYL1 10 (cholestasis, acute liver failure, & neurodegeneration) (OMIM 616719) | Infancy | Low GGTP | Cholestasis, fibrosis, & recurrent ALF; DD, neuropathy, cerebellar atrophy, ataxia, chronic anemia, skeletal dysplasia |
| SERPINA1 (alpha-1 antitrypsin deficiency) | Infancy to adulthood | ↑ AST/ALT & GGTP in 20% | Neonatal onset in severe phenotype w/cholestasis & progressive liver disease. HCC possible; chronic obstructive lung disease, panniculitis, & vasculitis; rare in Asian populations |
| SLC25A13 (neonatal intrahepatic cholestasis caused by citrin deficiency) (See Citrin Deficiency.) | Age <1 yr | Hypoproteinemia, synthetic liver dysfunction; ↑ NH3; ↓ glucose | ↓ birth weight, growth restriction; transient cholestasis; resolves by age 1 yr in most |
| SLC51A 11 (SLC51A deficiency) | Neonatal | ↑ AST/ALT/ALP | Diarrhea & malabsorption, poor weight gain & bleeding; early fibrosis & cirrhosis w/cholestasis |
| SLC51B 12 (primary bile acid malabsorption 2) (OMIM 619481) | Neonatal | ↑ AST/ALT & GGTP; ↑ INR, normal albumin; ↓ fat-soluble vitamins | Congenital diarrhea; prolonged jaundice in neonatal period |
| TALDO1 13 (transadolase 1 deficiency) | Neonatal | ↑ AST/ALT/ALP; normal GGTP | Hepatomegaly, pancytopenia, renal defects, cardiac defects, fetal hydrops, & dysmorphic features; ↑ HCC risk |
| TTC26 14 (biliary, renal, neurologic & skeletal syndrome) (OMIM 619534) | Neonatal | ↑ liver enzymes; ↑ bilirubin; ↑ GGTP in some cases | Cardiac defects, renal abnormalities (small/echogenic kidneys, hydronephrosis), DD, pituitary stalk interruption syndrome |
| VIPAS39 (VIPAR); VPS33B (arthrogryposis, renal dysfunction, & cholestasis) (OMIM PS208085) | Neonatal | ↑ AST/ALT & bilirubin; ↓ or normal GGTP | Arthrogryposis, renal tubular acidosis, & ichthyosis; poor growth; largely fatal in 1st yr of life |
| ZFYVE19 15 (ciliopathy of bile duct epithelia) (OMIM 619849) | Neonatal | ↑ GGTP & bile acids; hyperlipidemia | Fibrosis/cirrhosis w/o effect on synthetic function; HSM |
