Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation

Abstract

Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic germline c.934-2A > G splice site mutation in MUTYH. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.

Gitelman syndrome: A first published clinical association with chronic pancreatitis, a case report and review of literature

“…Gitelman syndrome (GS) is a rare autosomal recessively inherited disease and salt-losing tubulopathy, also refers as familial hypokalemia-hypomagnesemia, characterized by hypokalemia, hypomagnesemia, hypocalcemia, hyperreninemia, and hyperaldosteronism, It is caused by mutations of genes encoding the sodium, chloride, and magnesium carriers in the apical membrane of the distal convoluted tubule. The mutations involve 1 - SLC12A3 gene which encodes the thiazide-sensitive sodium chloride cotransporter (NCCT) 2 - TRPM6 (Transient Receptor Potential Cation Channel Subfamily M Member 6) gene handles the distal tubular magnesium [1] , [2] , [3] , [4] , [5] . The impaired reabsorption of sodium and chloride at the thiazide-sensitive sodium chloride co-transporter (TSC) effectively leads to some degree of hypovolemia which in turn activates the renin-angiotensin system, ultimately increasing levels of aldosterone to maintain intravascular volume results in hypokalemia and metabolic alkalosis, as potassium and hydrogen ions are excreted in exchange for sodium, despite the up-regulation of the renin-angiotensin system, patients with GS have normal or low blood pressure [3] , [5] .…”

“…Shahzad et al in 2019 reported GS presented with seizure as the main complain [6] , out of 122 patients 5.7% presented with GI-related issues such as anorexia, vomiting, constipation, abdominal pain, and weight loss as the main complaint [6] . Chan et al in 2020 reported an unusual case of a patient with Gitelman syndrome carrying a germline monoallelic MUTYH c.934-2A>G variant, who subsequently developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomas, and a desmoid tumor [2] . GS was also found to be associated with pseudogout and CPPD crystal deposition in about 10% of patients.…”

“…Gitelman syndrome (GS) is a rare autosomal recessive, salt-losing tubulopathy, also referred to as familial hypokalemia-hypomagnesemia, characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism [1–] . Its prevalence is estimated to be 1:40,000 [2] , [3] caused by mutation of genes encoding the sodium chloride cotransporter(NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal convoluted tubule (DCT) of the nephron [1] , [2] , [3] . English literature review reveals that clinical manifestations of GS are highly variable [1] , [2] , [3] , [4] , [6] .…”

“…Its prevalence is estimated to be 1:40,000 [2] , [3] caused by mutation of genes encoding the sodium chloride cotransporter(NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal convoluted tubule (DCT) of the nephron [1] , [2] , [3] . English literature review reveals that clinical manifestations of GS are highly variable [1] , [2] , [3] , [4] , [6] . This work has been reported in line with the SCARE 2020 criteria [9] .…”