Familial chronic cholestasis associated with renal insufficiency and a TTC21B Gene Mutation: A family case report

Introduction: Familial chronic cholestases associated with renal involvement are rare and may reveal a genetic disease such as a ciliopathy. The TTC21B gene, involved in intraflagellar transport, is mainly associated with tubulointerstitial and glomerulocystic nephropathies, although hepatobiliary manifestations have also been described.
Observation: We report the case of a 48-year-old female patient followed for chronic cholestatic liver disease, initially considered to be seronegative primary biliary cholangitis in view of the familial context. The course was marked by edematous-ascitic decompensation with refractory ascites, persistent cholestasis despite ursodeoxycholic acid, chronic pruritus, and chronic renal insufficiency followed in nephrology. Viral, autoimmune, overload, and biliary MRI investigations did not support a classic etiology. Family investigation found several relatives affected by chronic cholestasis and/or renal involvement. Familial genetic testing identified a recurrent mutation in exon 6 of the TTC21B gene in two sisters.
Discussion: This observation underlines the diagnostic difficulty in distinguishing seronegative primary biliary cholangitis from familial genetic cholestasis, particularly when hepatobiliary involvement is associated with renal insufficiency. The presence of a TTC21B mutation points toward a ciliopathy, an entity that may combine renal and extra-renal involvement.
Conclusion: In the presence of seronegative familial chronic cholestasis associated with renal insufficiency, a genetic origin should be investigated. Identification of a TTC21B mutation has diagnostic, prognostic, therapeutic, and familial implications.