CBAS1 is a progressive liver disorder caused by a defect in the synthesis of bile acid. This defect results in intrahepatic cholestasis, jaundice, hepatomegaly, splenomegaly, cirrhosis, diarrhea, steatorrhea, malabsorption of lipids and lipid-soluble vitamins and a failure to thrive. The condition has a neonatal onset and often presents as neonatal cholestasis. However, in some cases it may only be identified later in life, when the disease has progressed further, often resulting in liver failure or death. The disorder is rare, with 1-9 affected individuals per one million live births.
Diagnosis is made based on liver function tests, laboratory analysis revealing increased serum bilirubin with decreased serum cholesterol and liver biopsy studies identifying giant cell hepatitis, nonspecific inflammation and fibrosis. The condition is treated with oral bile acid therapy.
The disorder follows an autosomal recessive pattern of inheritance and is caused by homozygous or compound heterozygous mutations in the HSD3B7 gene. This gene encodes the 3 beta-hydroxysteroid dehydrogenase type 7 enzyme, which is essential for the biosynthesis of bile acid from cholesterol. Specifically, it is responsible for catalyzing the second step in the production of bile acid, the conversion of 7alpha-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one. At least 17 HSD3B7 gene mutations have been identified in CBAS1 patients, including deletions and missense variants that hamper enzyme activity.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 10-year-old female from a consanguineous family, had suffered from high gamma-glutamyl transferase (GGT) cholestasis in infancy. At the time of presentation, her GGT and serum bilirubin were normal but she had elevated levels of transaminases suggestive of chronic compensated liver disease. She also had mild osteopenia, mild splenomegaly and a few gall stones. A liver biopsy indicated a diagnosis of progressive familial intrahepatic cholestasis type 3. Using a multigene panel for gastrointestinal disorders, a homozygous mutation (c.694+2T>-) was identified in exon 6 of the patient’s HSD3B7 gene, associated with congenital bile acid synthesis defect 1. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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