Case ReportA de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension
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.
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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
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2023, Surgical Pathology ClinicsA novel mutation in TRMT5 associated with idiopathic non-cirrhotic portal hypertension and hepatopulmonary syndrome: Case report of two siblings
2022, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :A previous report identified rare homozygous p.N46S mutation in deoxyguanosine kinase (DGOUK) gene, which encodes an enzyme required for faithful replication of mitochondrial DNA, in three patients with INCPH [5]. Familial cluster of INCPH was also reported in a family with de novo mutation in KCNN3 which fits autosomal dominant inheritance [6]. Mitochondrial tRNA mutations (MTT) are associated with a wide phenotypic spectrum from isolated disorders affecting specific organs to multisystemic involvement and account for the majority of mitochondrial diseases.
Porto-sinusoidal vascular disorder
2022, Journal of HepatologyCitation Excerpt :In 4 families with more than 1 member with PSVD, Sarin et al. reported an association with HLA-DR 3 positivity.48 In a family with PSVD (idiopathic NCPH) a mutation in the KCNN3 gene was identified.55 This encodes for SK3 channels which are involved in the regulation of vascular tone and blood pressure.
Channelopathy-causing mutations in the S<inf>45</inf>A/S<inf>45</inf>B and HA/HB helices of K<inf>Ca</inf>2.3 and K<inf>Ca</inf>3.1 channels alter their apparent Ca<sup>2+</sup> sensitivity
2022, Cell CalciumCitation Excerpt :The KCa2.3_V450L mutant channel with an EC50 value for Ca2+ of 0.15 ± 0.013 μM (Table 1) is associated with INCPH. This patient with KCa2.3_V450L mutation was not classified as ZLS[3]. Among the ZLS-related mutant channels, KCa2.3_G350D is the least sensitive to Ca2+ with an EC50 value of 0.12 ± 0.013 μM (Table 1).