ORPHA: 494348;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.1 | Portal hypertension, noncirrhotic, 1 | 617068 | Autosomal recessive | 3 | DGUOK | 601465 |
A number sign (#) is used with this entry because of evidence that noncirrhotic portal hypertension-1 (NCPH1) is caused by homozygous mutation in the DGUOK gene (601465) on chromosome 2p13.
Biallelic mutation in the DGUOK gene can also cause mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880), a more severe disorder that is sometimes associated with liver failure in infancy.
Noncirrhotic portal hypertension-1 (NCPH1) is an autosomal recessive disorder characterized by onset of portal hypertension associated with hepatosplenomegaly in the first or second decades of life, in the absence of cirrhosis, known extrahepatic diseases, or splanchnic venous thrombosis. Liver function is normal, and the disorder is relatively benign (Vilarinho et al., 2016).
Genetic Heterogeneity of NCPH
See also NCPH2 (619463), caused by mutation in the GIMAP5 gene (608086) on chromosome 7q36.
At the Baveno VI Consensus workshop on portal hypertension, it was stated that the terms idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), and idiopathic noncirrhotic portal hypertension (INCPH) indicate the same clinical entity, and include the histologic diagnosis of obliterative portal venopathy (OPV). Under these criteria, diagnosis requires the exclusion of cirrhosis and other causes of NCPH; liver biopsy is mandatory, and measurement of the hepatic venous pressure gradient is recommended; and screening for immunologic diseases and prothrombotic disorders should be performed (de Franchis, 2015).
Vilarinho et al. (2016) reported 3 patients from 2 unrelated consanguineous Turkish families with onset of noncirrhotic portal hypertension in childhood. In the first family, the patient presented at age 12 years with right upper quadrant pain associated with hepatosplenomegaly and no other liver-specific findings; liver enzymes were normal. Liver biopsy showed subtle vascular changes, including fibrosis and fibromuscular thickening of the portal venules, with increased muscle fibers in the wall and narrowed lumen. There was no significant fibrosis or cirrhosis. In the second family, the older sib was found to have hepatosplenomegaly and elevated liver enzymes at 5 months of age; his younger sister had similar features at age 5 years. Liver synthetic function was normal in both. At age 6, the brother had esophageal varices; the sister did not. Liver biopsy in both sibs showed portal venule changes similar to the first patient. Overall, the phenotype was benign; none of the patients had advanced fibrosis or cirrhosis, signs or symptoms of coagulopathy and/or cholestasis, or signs of mitochondrial disease such as myopathy or neurologic impairment. The patients remained clinically stable during 6 to 16 years of follow-up.
Reviews
Franchi-Abella et al. (2014) reviewed the clinical findings in 48 children who were diagnosed with obliterative portal venopathy (OPV), including 8 familial cases from 5 families. Diagnosis was based on strict histologic criteria, including portal fibrosis, phlebosclerosis or thickened smooth muscle wall of portal veins, presence of numerous dilated vascular channels in or around portal tracts, nodular/lobular regenerative activity, zonal atrophy, and/or sinusoidal dilation. Franchi-Abella et al. (2014) noted that hepatoportal sclerosis, nodular regenerative hyperplasia, idiopathic portal hypertension, idiopathic noncirrhotic portal hypertension, incomplete septal cirrhosis, partial nodular transformation, and noncirrhotic portal fibrosis were all thought to represent the common consequences of lesions of the intrahepatic branches of the portal vein and to correspond to various stages of OPV. Almost half of the patients presented due to enlarged spleen discovered on routine examination; the remainder presented with gastrointestinal bleeding, elevated serum alanine aminotransferase activity, thrombocytopenia, or liver anomalies. No signs of portal hypertension were recorded in 9 of the children, who were followed up to ages ranging from 1 to 26 years. At 20 years from first symptom, overall survival was 93%; 73% of survivors had experienced gastrointestinal bleeding and 23% had undergone liver transplantation.
Schouten et al. (2015) provided a review of idiopathic noncirrhotic portal hypertension, which they noted is a diagnosis of exclusion based on the presence of portal hypertension in the absence of cirrhosis, advanced fibrosis, or other causes of chronic liver disease, as well as the absence of thrombosis of the hepatic veins or portal vein at the time of diagnosis. A wide spectrum of nonspecific histologic features are observed in NCPH, which might reflect different stages of the disease or different nosologic entities sharing the same clinical presentation. The authors stated that the mechanisms responsible for obliteration of portal venules remained unknown, and noted that the overall prognosis in NCPH patients is generally better than in patients with cirrhosis and a similar degree of portal hypertension, likely because most NCPH patients have well-preserved liver function.
The transmission pattern of NCPH1 in the families reported by Vilarinho et al. (2016) was consistent with autosomal recessive inheritance.
In 3 patients from 2 unrelated consanguineous Turkish families with NCPH1, Vilarinho et al. (2016) identified a homozygous missense mutation in the DGUOK gene (N46S; 601465.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. No causative mutations in any genes were found in 4 additional families with portal hypertension. Functional studies of the variant were not performed, but Vilarinho et al. (2016) noted that the same mutation had been found in the compound heterozygous state with another DGUOK mutation in a patient with a mild form of MTDPS3; in vitro studies showed that the mutant protein has some residual activity (Mousson de Camaret et al., 2007). However, Sarzi et al. (2007) reported a patient (patient 9) who was homozygous for the N46S mutation who had onset of MTDPS3 at age 2 months and liver failure at age 10 months. Liver mtDNA was severely reduced at 8% of normal in that patient. The report of Vilarinho et al. (2016) thus significantly expands the phenotypes associated with DGUOK mutations and demonstrates pleiotropy. Vilarinho et al. (2016) also noted that the finding of portal hypertension resulting from genetic deficiency of purine nucleotide precursors for DNA replication and repair is reminiscent of the onset of noncirrhotic portal hypertension by exposure to pharmacologic inhibition of purine nucleotide biosynthesis. They suggested that the findings may enable identification of patients at increased risk for drug-induced noncirrhotic portal hypertension.
Associations Pending Confirmation
In a family in which a father and 3 children had NCPH, Koot et al. (2016) performed whole-exome sequencing and identified only 1 variant that occurred de novo in the father and was transmitted to all 3 affected children: a V450L missense mutation in the KCNN3 gene (602983). No functional studies were reported.
Noting that the V450L change detected by Koot et al. (2016) involves a highly conserved residue in the S(45)B helix of KCCN2, Bauer et al. (2019) performed functional analysis of the variant but observed only a slight increase in apparent Ca(2+) sensitivity with the mutant compared to wildtype channels, although the mutant channel showed a basal constitutive activity with very low Ca(2+) levels.
By genomewide linkage analysis and whole-exome sequencing in 2 unrelated families with NCPH that were previously studied by Franchi-Abella et al. (2014), Besmond et al. (2018) identified heterozygous missense variants in the LOC285556 gene (617881) that were not found in public variant databases. The authors observed variable expressivity of the phenotype as well as incomplete penetrance, with the putative causative variant being detected in an unaffected father in 1 of the families. No functional studies were reported.
Bauer, C. K., Schneeberger, P. E., Kortum, F., Altmuller, J., Santos-Simarro, F., Baker, L., Keller-Ramey, J., White, S. M., Campeau, P. M., Gripp, K. W., Kutsche, K. Gain-of-function mutations in KCNN3 encoding the small-conductance Ca(2+)-activated K+ channel SK3 cause Zimmermann-Laband syndrome. Am. J. Hum. Genet. 104: 1139-1157, 2019. [PubMed: 31155282] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.012]
Besmond, C., Valla, D., Hubert, L., Poirier, K., Grosse, B., Guettier, C., Bernard, O., Gonzales, E., Jacquemin, E. Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy. Liver Int. 38: 358-364, 2018. [PubMed: 28792652] [Full Text: https://doi.org/10.1111/liv.13547]
de Franchis, R. Expanding consensus in portal hypertension. Report of the Baveno VI consensus Workshop: stratifying risk and individualizing care for portal hypertension. J. Hepatol. 63: 743-752, 2015. [PubMed: 26047908] [Full Text: https://doi.org/10.1016/j.jhep.2015.05.022]
Franchi-Abella, S., Fabre, M., Mselati, E., De Marsillac, M. E., Bayari, M., Pariente, D., Jacquemin, E., Bernard, O. Obliterative portal venopathy: a study of 48 children. J. Pediat. 165: 190-193, 2014. [PubMed: 24768253] [Full Text: https://doi.org/10.1016/j.jpeds.2014.03.025]
Koot, B. G. P., Alders, M., Verheij, J., Beuers, U., Cobben, J. M. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension. J. Hepatol. 64: 974-977, 2016. [PubMed: 26658685] [Full Text: https://doi.org/10.1016/j.jhep.2015.11.027]
Mousson de Camaret, B., Taanman, J. W., Padet, S., Chassagne, M., Mayencon, M., Clerc-Renaud, P., Mandon, G., Zabot, M.-T., Lachaux, A., Bozon, D. Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. Biochem. J. 402: 377-385, 2007. [PubMed: 17073823] [Full Text: https://doi.org/10.1042/BJ20060705]
Sarzi, E., Bourdon, A., Chretien, D., Zarhrate, M., Corcos, J., Slama, A., Cormier-Daire, V., de Lonlay P., Munnich, A., Rotig, A. Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J. Pediat. 150: 531-534, 2007. [PubMed: 17452231] [Full Text: https://doi.org/10.1016/j.jpeds.2007.01.044]
Schouten, J. N. L., Verheij, J., Seijo, S. Idiopathic non-cirrhotic portal hypertension: a review. Orphanet J. Rare Dis. 10: 67, 2015. Note: Electronic Article. [PubMed: 26025214] [Full Text: https://doi.org/10.1186/s13023-015-0288-8]
Vilarinho, S., Sari, S., Yilmaz, G., Stiegler, A. L., Boggon, T. J., Jain, D., Akyol, G., Dalgic, B., Gunel, M., Lifton, R. P. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension. Hepatology 63: 1977-1986, 2016. [PubMed: 26874653] [Full Text: https://doi.org/10.1002/hep.28499]