Balkan Journal of Medical Genetics

THE ROLE OF NEXT GENERATION SEQUENCING IN THE DIFFERENTIAL DIAGNOSIS OF CAROLI’S SYNDROME
Smolović B, Muhović D, Hodžić A, Bergant G, Peterlin B
*Corresponding Author: Professor Borut Peterlin, M.D., Ph.D., Department of Gynecology and Obstetrics, Institute of Medical Genetics, Department of Gynecology and Obstetrics, University Medical Centre Ljubljana, Šlajmerjeva Street 4, Ljubljana, Slovenia. Tel./Fax: +386-(0)1-540-1137. E-mail: borut.peterlin@guest.arnes.si
page: 49

DISCUSSION

In the presented patient, we discovered two pathogenic heterozygous variants in the PKHD1 gene (c.370C>T and c.4870C>T). Both variants have previously been reported as pathogenic in at least four patients with clinical presentation of ARPKD [26]. Furthermore, the rarity of the variants in the control population and the compatibility with clinical presentation, both favor the pathogenic nature of the identified variants. In accordance with guidelines for interpretation of sequence variants [27], these variants are classified as pathogenic, and present a likely cause for the clinical presentation of CD in the patient. Two types of CD have been described in the literature, based on the presence of congenital hepatic fibrosis and the severity of the liver impairment. In our patient, CD presented clinically with recurrent cholangitis, which is normally the most common clinical manifestation of the type 1 disease, simply referred to as CD. Other clinical presentation of CD are varied and include right upper quadrant pain, jaundice, recurrent chills and fevers, weight loss, anorexia, nausea and vomiting, most of which were common complaints during several hospitalizations of the patients. On the other hand, CS is a complex clinical syndrome that includes characteristics of CD and CHF, portal hypertension, liver cirrhosis, esophageal varices and ascites. Caroli’s syndrome is mostly comorbid with cystic kidney diseases, and rarely with pancreatic or lineal cysts. Caroli’s syndrome may progress to cholangiocarcinoma due to cirrhosis, chronic inflamation and prolonged exposure of the ductal epithelium to high concentration of un-conjugated secondary bile acids. Hepatobiliary malignant transformation occurs in approximately 7.0-14.0% of cases, and occurrence of cholangiocarcinoma in CD/CS is 100 times greater than that in the general population. However, the division may be arbitrary, as many investigators believe that the two conditions present a continuation of the same disease. Nevertheless, the diagnosis in this patient established after clinical exome sequencing was CD, due to the absence of the hepatic symptoms characteristic of CS. The mild clinical presentation bearing similarities to PSC, contributed to the difficulty of diagnosis in the presented patient as multiple MRCP and ERCP as well as liver biopsy, were insufficient to clearly diagnose CD. In selected groups of patients genetic analysis may thus be helpful to differentiate between genetic and non genetic etiologies, as in our example, where clinical exome sequencing enabled the diagnosis of CD in this patient after the detection of the pathogenic variants in the PKHD1 gene [11].

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