Sclerosing Cholangitis, Neonatal

A number sign (#) is used with this entry because of evidence that neonatal sclerosing cholangitis (NSC) is caused by homozygous or compound heterozygous mutation in the DCDC2 gene (605755) on chromosome 6p22.

Description

Neonatal sclerosing cholangitis is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (summary by Girard et al., 2016; Grammatikopoulos et al., 2016).

Clinical Features

Girard et al. (2016) reported 4 patients from 2 unrelated consanguineous families with neonatal sclerosing cholangitis. The patients presented with neonatal icterus, cholestasis, acholic stools, and portal hypertension. All were diagnosed with cirrhosis between 2 and 9 months of age. In family 1, the sibs needed liver transplantation at ages 25 and 14 years, respectively, whereas in family 2, 1 sib needed liver transplantation at age 6 years, and the other was on the waiting list at age 3.5 years. Cholangiograms showed patent bile ducts with thin and irregular intrahepatic biliary tree; the patients in family 2 also had extrahepatic bile duct irregularities. Liver biopsy showed cirrhosis and fibrosis. The patients had variable renal involvement: 1 patient had left vesicoureteral reflux with ureteral duplication and a small left kidney, and showed altered renal function after liver transplant associated with septic shock, whereas his sib had normal renal morphology and size, but also developed altered renal function after transplant. In the other family, 1 sib had a hyperechogenic kidney with normal renal function. One of the 4 patients had mild developmental delay; otherwise, none of the patients had additional features, including skin involvement or hearing loss.

Grammatikopoulos et al. (2016) reported 7 patients from 6 unrelated families, 4 of whom were of Greek descent, with neonatal sclerosing cholangitis. The patients presented in the first weeks or years of life (median age of 6 weeks) with jaundice, hepatomegaly, splenomegaly, pale stools, and/or abnormal liver function tests with increased serum GGT (see 612346). Cholangiography confirmed intrahepatic cholangiopathy in all patients. Liver biopsies showed ductular proliferation, portal tract inflammation, and bridging fibrosis, and most patients developed biliary cirrhosis. Other histologic findings included ductal bile plugs, variable ectasia of perihilar bile ducts, absence of bile ducts in areas of fibrosis, and chronic cholestasis. Five patients underwent liver transplantation between 10 and 15 years of age, 1 patient was lost to follow-up at age 6 years, and another died at age 16 years without liver transplantation. Two patients had renal involvement: the patient who died at age 16 without a liver transplant developed end-stage renal disease requiring dialysis before she died, and another patient developed hepatorenal syndrome that resolved after liver transplantation. None of the patients had neurologic involvement or hearing loss.

Inheritance

The transmission pattern of NSC in the families reported by Girard et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with NSC, Girard et al. (2016) identified 2 different homozygous mutations in the DCDC2 gene (605755.0005 and 605755.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. One was a missense mutation and the other was an in-frame deletion. Patient cells showed loss of DCDC2 immunostaining in the ciliary axoneme of liver cholangiocytes and fewer cilia on cholangiocytes, as well as abnormal accumulation of the mutant protein in the cytoplasm compared to controls.

In 7 patients from 6 unrelated families, many of Greek origin, with NSC, Grammatikopoulos et al. (2016) identified homozygous or compound heterozygous truncating mutations in the DCDC2 gene (see, e.g., 605755.0001; 605755.0002; 605755.0007; 605755.0008). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Parental DNA was only available for 1 patient, but it confirmed segregation of the mutations with the disorder within the family. Patient liver samples showed absence of DCDC2 expression, consistent with a complete loss of function, as well as absence of normally constituted primary cilia in cholangiocytes. The patients were part of a cohort of 12 families with the disorder who underwent whole-exome sequencing; direct sequencing of the DCDC2 gene in 10 patients from 8 additional families did not identify any mutations. Grammatikopoulos et al. (2016) concluded that this disease represents a novel liver-based nonmotile ciliopathy.