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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.

SUBMITTER: Chan JY

PROVIDER: S-EPMC7501863 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic <i>MUTYH</i> mutation.

Chan Jason Yongsheng JY Toh Ming Ren MR Chong Siao Ting ST Ishak Nur Diana Binte NDB Kolinjivadi Arun Mouli AM Chan Sock Hoai SH Lee Elizabeth E Boot Arnoud A Shao-Tzu Li L Chew Min-Hoe MH Ngeow Joanne J

NPJ genomic medicine 20200918

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 hete ...[more]

PMID: 33024574

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Project description:Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.

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

Publications

Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic <i>MUTYH</i> mutation.

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

Publications

Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic &lt;i&gt;MUTYH&lt;/i&gt; mutation.

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OmicsDI is part of the ELIXIR infrastructure

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Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic <i>MUTYH</i> mutation.