P7 Familial cryptogenic porto-sinusoidal vascular disease associated with arterial aneurysmal disease

Introduction

Porto-sinusoidal vascular disease (PSVD) comprises a disease-spectrum, including idiopathic non-cirrhotic portal hypertension (PH). Liver biopsy (LB) shows portal tract and sinusoidal abnormalities, without established fibrosis. Novel genetic variants associated with familial PSVD include FCHSD1, KCNN3, FOPV (dominant) and DGUOK (recessive). Telomeropathies have also been implicated. Bone morphogenetic protein receptor type-2 (BMPR2) gene variants are associated with vascular disorders, but there are no known associations with PSVD. We present a case of familial PSVD, associated with arterial aneurysms, inherited in a dominant fashion with variable penetrance.

Case

The proband, II-2 (figure 1), presented with lethargy age 40 (1999). Ultrasound demonstrated splenomegaly. Her non-invasive liver and vasculitis screen were negative, as with all members of this family. LB showed cirrhosis –precluding a diagnosis of PSVD- with nuclear atypia. Subsequent explant histology from orthotropic liver transplant (2003) showed atypical hepatocellular carcinoma, steatosis, cirrhosis and nodular regenerative hyperplasia. Post-transplant angiography (2020) demonstrated splanchnic and cerebral arterial aneurysms. She died following SARS-COV-2 infection (2021). II-1 had splenomegaly and oesophageal varices on screening age 49 (2002). Liver histology demonstrated distorted porto-central relationships and macronodules, without fibrosis. She died from cerebral haemorrhage (2010), suspected to be aneurysmal. III-6 underwent a LB age 10 demonstrating non-cirrhotic PH, without fibrosis. By age 20 (2013), he had splenomegaly and oesophageal varices. Liver stiffness measurement was 10.9kPa. MR angiography demonstrated left subclavian artery aneurysm and coeliac-axis dilatation. III-7 was diagnosed with PSVD in a similar course. III-4's liver MRI age 16 (2004) showed several enhancing liver nodules. LB demonstrated mild lymphocytic infiltrate in portal tracts. Subsequent imaging showed complete, spontaneous resolution of these findings. III-1 and III-2 had diffusely echogenic livers on ultrasound without signs of PH. In III-9, splenomegaly was identified at age 15 (2022). Members of this family underwent genetic testing (2008). A gene panel approach identified a variant of uncertain significance on BMPR2 (c.797G>C,p.Arg266Thr) in II-2, III-6 and III-7, but not II-1 or her children. Further testing as part of the 100,000 Genomes Project did not identify significant variants in the primary analysis of gene panels applied. Re-visiting the data in the South-West Genomic Laboratory confirmed the BMPR2 variant as before.

Summary

This familial PSVD associated with arterial aneurysms adds to growing literature establishing PSVD as a genetic entity. The novel BMPR2 variant we identified is interesting but currently unresolved as it does not clearly segregate the disease phenotype across the extended family. Further genomic analysis is underway.