Abstract: TH-PO521
Unraveling the Mystery: McCune-Albright Syndrome as a Rare Cause of Fanconi Syndrome and Kidney Failure
Session Information
- Genetic Kidney Diseases: Genotypes and Phenotypes in Cases
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Boh, Geraldine, Tan Tock Seng Hospital, Singapore, Singapore
- Chin, Hui-Lin L., National University Hospital, Singapore, Singapore, Singapore
- Lim, Ru Sin, Tan Tock Seng Hospital, Singapore, Singapore
Introduction
McCune Albright Syndrome (MAS) is a rare sporadic genetic disorder caused by post-zygotic somatic missense mutations of the GNAS1 gene characterized by polyostotic fibrous dysplasia, café au lait skin pigmentation, and precocious puberty. Here we present a proband with MAS manifesting with Fanconi syndrome (FS) and eventual kidney failure (KF).
Case Description
A 44-year-old female was referred to Nephrology in 2007 for impaired renal function (Creatinine 136 umol/L, eGFR 42ml/min/1.73m2). Her medical history included right femur osteoid osteoma, hypophosphatemia, osteoporosis, Grave’s disease, and congenital primary amenorrhea. Further work up revealed FS with hypophosphatemia, hypokalemia, hyperchloraemic metabolic acidosis, aminoaciduria (24hr urine total protein 1.3g/day), euglycaemic glucosuria, and a low tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) ratio implying impaired tubular phosphate reabsorption. Ultrasound kidneys and secondary work up were unremarkable. Renal biopsy was unyielding with non-specific interstitial fibrosis and tubular atrophy. Her kidney function continued to deteriorate necessitating peritoneal dialysis in 2022. In view of idiopathic KF with FS, primary bone marrow failure of unclear cause and endocrinopathies (thyrotoxicosis and primary ovarian failure), genetic testing (whole exome sequencing) was performed. This identified that the proband was mosaic for pathogenic GNAS variant (NM:_000516:c.[602G>A];[=],p.(Arg201His)), diagnostic of MAS.
Discussion
This case marks the first instance of MAS presenting with FS and KF to our knowledge. While renal phosphate wasting due to increased FGF-23 level and proteinuria have been reported in MAS, FS and KF are unprecedented, likely mediated by factors apart from FGF-23. We hypothesize that dysfunction of proximal tubule (PT) transporters in MAS relate to elevated circulating cyclic adenosine monophosphate (cAMP) and selective expression of G protein-coupled receptors (GPCRs) in the PT via a gain-of-function in G-protein alpha subunit (Gαs), induced by the GNAS pathogenic variant. Raised cAMP level following chronic Gαs activation may lead to mesangial cell proliferation and hyperfiltration, potentially contributing to KF in MAS. The role of cAMP leading to FS and KF in MAS requires further investigations.