Rapidly Progressing to ESRD in an Individual with Coexisting ADPKD and Masked Klinefelter and Gitelman Syndromes

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic hereditary renal disease, promoting end-stage renal disease (ESRD). Klinefelter syndrome (KS) is a consequence of an extra copy of the X chromosome in males. Main symptoms in KS include hypogonadism, tall stature, azoospermia, and a risk of cardiovascular diseases, among others. Gitelman syndrome (GS) is an autosomal recessive disorder caused by SLC12A3 variants, and is associated with hypokalemia, hypomagnesemia, hypocalciuria, normal or low blood pressure, and salt loss. The three disorders have distinct and well-delineated clinical, biochemical, and genetic findings. We here report a male patient with ADPKD who developed early chronic renal failure leading to ESRD, presenting with an intracranial aneurysm and infertility. NGS identified two de novo PKD1 variants, one known (likely pathogenic), and a previously unreported variant of uncertain significance, together with two SLC12A3 pathogenic variants. In addition, cytogenetic analysis showed a 47, XXY karyotype. We investigated the putative impact of this rare association by analyzing possible clinical, biochemical, and/or genetic interactions and by comparing the evolution of renal size and function in the proband with three age-matched ADPKD (by variants in PKD1) cohorts. We hypothesize that the coexistence of these three genetic disorders may act as modifiers with possible synergistic actions that could lead, in our patient, to a rapid ADPKD progression.

Keywords: ADPKD; Gitelman syndrome; Klinefelter syndrome; apoptosis; chronic kidney disease progression; fibrosis; intracranial aneurysm.

Figure 1

(A) Pedigree of the family. The proband (arrow). (B) Abdominal coronal T2 MRI of the proband at 36 years, showing a TKV of 726 mL (htTKV of 370 mL/m). (C) Cerebral angiography showing an aneurysm of the anterior communicating artery with hourglass image (arrow) (D) Cytogenetic analysis showing a 47, XXY karyotype, 50 metaphases are counted. (E) Molecular establishment of PKD1 variants in the proband: NM_001009944.3:c.9499A>T and NM_001009944.3:c.9756G>C, by NGS (top) and Sanger sequencing (bottom). (F) Molecular establishment of SLC12A3 variants in the proband: NM_0000339.3:c.1928C>T and NM_0000339.3:c.2891G>A, by NGS (top) and confirmed by Sanger sequencing (bottom). ADPKD, Autosomal dominant polycystic kidney disease; KS, Klinefelter syndrome; GS, Gitelman syndrome.

Figure 2

Hypothetical scheme for putative mechanisms on synergistic ADPKD pathogenesis and additional effects of KS and GS in our proband. Based in animal and human models of disease.