#3593 COEXISTENCE OF 2 (DE NOVO) MUTATIONS IN 2 DIVERSE GENES (PKD1, LRP5) IN A PATIENT WITH RENAL AND LIVER POLYCYSTIC DISEASE
Authors: Tsirpanlis George , Palaiologou Danai , Lazaros Leandros , Louka Michaela , Evangelou Eirini , Gkalitsiou Dimitra , Kanavakis Emmanouil 
Published: June 2023

Introduction

In Autosomal Dominant Polycystic Kidney Disease (ADPKD) the phenotype is variable. The most common extrarenal manifestation of the disease is the presence of hepatic cysts. Parallel cysts appearance in two different organs is possibly related to the genetic injury. We present in this report the case of a patient without family history of ADPKD and 2 different mutations related to cyst formation.

Case report

A 53 year old woman came to our outpatient ADPKD clinic with known multiple hepatic and renal cysts, diagnosed 11 years ago. She had no family history of ADPKD, both her parents aged 89 years old, had no renal or liver cysts on recent ultrasound scans. The patient had a background of recurrent UTIs, nephrolithiasis and hypertension diagnosed at 40 years old. Currently she was found to have e-GFR 49ml/min and liver function tests within normal range. Genetic testing and Magnetic Resonance Imaging (MRI) for estimating Total Kidney Volume (TKV) and hepatic imaging were conducted. In the genetic testing with a second generation sequencing, two heterozygous mutations in two different genes were depicted. The first was found in PKD1 gene: c.1396G&gt;A (p.Val466Met) and causes the amino acid valine to be replaced by methionine at position 466 of the produced protein (Polycystin 1). It is reported as a variant of uncertain clinical significance because while it has been described in the literature in individuals with ADPKD, no functional studies have been performed to confirm its pathogenetic role. The second mutation concerned the LRP5 gene: c.3586G&gt;A (p.Ala1196Thr) and causes the replacement of the amino acid alanine by threonine at position 1196 of the produced protein (Low density lipoprotein Receptor-related Protein-5). It is also referred as a variant of uncertain clinical significance, and exhibits autosomal dominant inheritance also. The MRI shows a particularly high cystic load in the liver (innumerable cysts) and multiple renal cysts in the two large kidneys, in a quite atypical form (not innumerable but many large cysts). The TKV was 1842 ml (1071 ml/m) and classified her in the class 1C (or possibly 2C because of the atypical form) according to the Mayo Clinic imaging classification system for ADPKD. The estimated prediction of the End-Stage Chronic Kidney Disease (ESCKD) (as long as the disease is not atypical) was according to the Mayo Clinic formula, 11 years.

Discussion

In a recent publication, pathological nucleotide variants of the LRP5 gene were associated with hepatic cystogenesis. Coexistence of PKD1 and LRP5 mutations was also identified in 2 families with polycystic kidney and liver disease. The underlying pathogenetic mechanism appears to be related to the connection between Polycystin-1 (the product of PKD1 involved in the pathogenesis of ADPKD) and the Wnt signaling pathway (affected by LRP5 gene mutations and linked to hepatic cystogenesis). The coexistence of the two mutations possibly means synergistic action. Unique facts and important phenotypic characteristics in this particular patient, is the de novo simultaneous appearance of the two mutations (the parents were not genetically tested but do not have cysts in very old age), the particularly large cystic liver load (which is also observed in typical ADPKD, especially in women), the atypical renal cyst imaging and the moderate to severe renal disease (expected ESCKD at 64 years, which it is more than expected in a PKD1 mutation only, but less than in a solitary PKD2 mutation). In conclusion, genetic complexity appears to go hand in hand with phenotype diversity in ADPKD and polycystic liver disease.