Elsevier

Journal of Hepatology

Volume 64, Issue 4, April 2016, Pages 974-977
Journal of Hepatology

Case Report
A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension

https://doi.org/10.1016/j.jhep.2015.11.027Get rights and content

Abstract

Non-cirrhotic portal hypertension is characterized by histopathological abnormalities in the liver, mostly affecting small intrahepatic portal veins that cause portal hypertension in the absence of cirrhosis. It can be secondary to coagulation disorders or toxic agents. However, most cases are idiopathic non-cirrhotic portal hypertension (INCPH) and familial cases are rare.

We report a family in which a father and three of his four children conceived with three different mothers are affected by INCPH. Whole exome and Sanger sequencing showed the father to have a de novo single nucleotide substitution c.1348G>C in the KCNN3 gene that was transmitted to all three of his affected offspring.

The KCNN3 gene encodes small conductance calcium-activated potassium (SK) channel 3. SK channels are involved in the regulation of arterial and venous vascular tone by causing smooth muscle relaxation on activation. No data exist on the expression and function of SK channels in portal veins.

The autosomal dominant inheritance in this unique pedigree and the single de novo mutation identified, strongly suggests that KCNN3 mutations have a pathogenetic role in INCPH.

Introduction

Idiopathic non-cirrhotic portal hypertension (INCPH; synonymous: hepatoportal sclerosis, idiopathic portal hypertension, obliterative portal venopathy, incomplete septal cirrhosis) is defined as the presence of portal hypertension in the absence of cirrhosis, known liver disease, extrahepatic portal vein thrombosis or Budd-Chiari syndrome [1]. The disorder encompasses a realm of liver histological abnormalities that cause a disturbed blood micro-circulation in the liver. One of the main histopathological hallmarks of this disorder is the obliteration of small intrahepatic branches of the portal vein. Established causes of obliteration can be coagulation disorders and drugs. Other suggested causes are infections, thrombophilia, toxins and immunological disorders. In most cases no cause can be established [1].

Twenty-five familial cases of INCPH have been reported in the literature [2]. The pattern of inheritance was suggestive of autosomal recessive mode of inheritance in most familial cases. Recently autosomal dominant inherited INCPH was reported [3]. Up until now no risk genes for INCPH have been identified.

Section snippets

Clinical report

A 37-year old male and three of his four children (presenting age: boy A, 10 years; girl B, 1 year; girl C, 2 years) conceived with three different mothers came to our attention at different time points with hepatosplenomegaly and liver abnormalities. The pedigree is depicted in Fig. 1. The guardians of all children and the affected father gave written informed consent for inclusion in this study and publication of the data.

First, the girl B was referred for hepatosplenomegaly at the age of 18 

Exome sequencing

Whole exome sequencing was performed using genomic DNA of boy A, girl C, their affected father and their unaffected paternal grandparents. Details of the sequencing and filtering of variants are described in the electronic Supplementary data.

Assuming a dominant inheritance model we searched for variants that occurred de novo in the father and were transmitted to both affected children (A and C). Only one such variant was found: a nucleotide substitution c.1348G>C, predicted to result in the

Discussion

The unique pedigree in the presented family is highly suggestive of autosomal dominant inherited INCPH, in accordance with another recently reported rare family with autosomal dominant INCPH [3). In two cases (father and girl B) the diagnosis of INCPH was definite as the findings were compatible with the criteria published by Schouten [1]. In the two other cases of this family (boy A and girl C) the diagnosis was probable, but not definite as liver histology was lacking to exclude cirrhosis.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contribution

BGPK the conception of the study, acquisition of data and drafting of the article. MA acquisition of data, drafting of the article and critical revision of the article for important intellectual content. JV acquisition of data, drafting of the article and critical revision of the article for important intellectual content. UB acquisition of data, critical revision of the article for important intellectual content. JMB the conception of the study, acquisition of data, drafting of the article and

References (10)

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