Journal of Human Hypertension (2004) 18, 677–679 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh CASE REPORT Hypertension in a patient with Gitelman’s syndrome

T Ogihara1, T Katsuya1, K Ishikawa1, A Matsuo1, H Rakugi1, M Shoji2 and M Yasujima2 1Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan; 2Department of Laboratory Medicine, Hirosaki University School of Medicine, Japan

Gitelman’s syndrome is an autosomal recessive dis- despite supplementation. This case demon- order characterized by wasting and hypoten- strates that hypertension could result in spite of the sion. A middle-aged woman was diagnosed with extremely decreased sodium reabsorption in Gitelman’s Gitelman’s syndrome because of typical clinical mani- syndrome and that essential hypertension is genetically festations in the youth and homozygous mutations of heterogeneous, and abnormality of all genes may not be 18-base-pair insertion in exon 6 of -sensitive necessarily required to cause blood pressure rise. NaCl- gene. It was unusual that she Journal of Human Hypertension (2004) 18, 677–679. showed hypertension with advancing age. Her serum doi:10.1038/sj.jhh.1001699 potassium levels remained low at around 3.5 mEq/l Published online 4 March 2004

Keywords: Gitelman’s syndrome; hypertension; ; thiazide-sensitive NaCl-cotransporter gene

Introduction syndrome (one of sisters with , hyper- reninemia, normal blood pressure, and decreased Gitelman’s syndrome is an autosomal recessive pressor response to angiotensin II).5 She was disorder characterized by sodium wasting and low 1–3 reevaluated recently and concluded to have Gitel- blood pressure. Recently, we have experienced an man’s syndrome by gene analysis. unusual case of Gitelman’s syndrome which mani- To detect the genetic mutation, direct sequencing fested as hypertension in middle age. analysis was conducted for all 26 exons of the TSC Gitelman’s syndrome is caused by homozygous or gene. In exon 6, an 18-base insertion was found compound heterozygous inactivating mutations in homozygously, which was the repeated sequence the thiazide-sensitive NaCl-cotransporter (TSC) just before the 18 bp insertion. This mutation has gene, leading to a reduction in renal sodium already been reported in a compound heterozygous reabsorption. To date, several compound heterozy- case;6 however, this is the first reported case of gous mutations in the TSC gene such as Gly439Ser, homozygous type. Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAG- She was followed up with potassium supple- CA, have been reported, and these mutations mentation (slow-Ks 6–12 tablets: 48–96 mEq/day) cause loss of function of the thiazide-sensitive for 19 years. At the age of 55 years, she under- NaCl-cotransporter (TSC) and reduce its capability 4 went surgery for breast cancer and received oral to reabsorb salt in the distal renal tubules. anticancer treatment for 2 years (5-fluorouracil and Here we describe a case of typical Gitelman’s tamoxifen) until her death from metastatic breast syndrome, caused by homozygous mutation of the cancer. During the follow-up course, her blood TSC gene, who developed hypertension during pressure increased gradually with advancing age. middle age. Her blood pressure was relatively low, around 100/ 60 mmHg, when she was initially diagnosed with familial Bartter’s syndrome at the age of 38 years.5 Case report Blood pressure was 120–135/70–84 mmHg at the age of 40–52 years and increased to 138–148/75– A 38-year-old woman was firstly diagnosed and 84 mmHg at 53–55 years, and further increased to reported in 1982 as a case of familial Bartter’s 150–174/76–90 mmHg at 56–57 years. The renal function had been normal and plasma renin activity Correspondence: Prof. T Ogihara, MD, PhD, Department of had been high all her life after diagnosed with Geriatric Medicine, Osaka University Graduate School of Medi- familial Bartter’s syndrome; ‘creatinine level was cine, 2-2 Yamadaoka, #B6, Suita 565-0871, Japan. 0.5–0.7 mg/dl, creatinine clearance was 90 ml/min/ E-mail: [email protected] 2 2 Received 7 November 2003; revised 22 December 2003; accepted m at 38 years old and 89 ml/min/m at 57 years old’ 12 January 2004; published online 4 March 2004 (Figure 1). A case of Gitelman’s syndrome with hypertension T Ogihara et al 678

Figure 1 Changes in blood pressure, plasma renin activity, and levels during the course. PRA: plasma renin activity (ng/ml/h); PAC: plasma aldosterone concentration (ng/dl).

Her serum potassium levels remained low at with significant differences in the polymorphisms of around 3.5 mEq/ l despite potassium supplementa- these genes.10 tion. Body weight did not change at about 60 kg The TSC gene is also a candidate gene for (body mass index ¼ 26.7 kg/m2), and it seemed essential hypertension.4,11 However, the present case unlikely that the chemotherapy had any effect on demonstrates that hypertension is able to be caused the tendency for increasing blood pressure. despite loss of TSC gene function and a sodium- losing state, thus indicating that essential hyperten- sion is genetically heterogeneous, and abnormality Discussion of all genes may not be necessarily required to cause the blood pressure rise. Further studies are needed Gitelman’s syndrome is an inherited disease to confirm this concept. characterized by hypokalemia, hypocalciuria, and caused by compound heterozygous or homo- zygous TSC gene mutations. The blood pressure References of this disease is normal or low (90–110/60– 1 Gitelman HJ, Graham JB, Welt LG. A new familial 6,7 70 mmHg). Moreover, subjects with heterozygous disorder characterized by hypokalemia and hypo- mutation have lower blood pressure (À8.7 mmHg in magnesemia. Trans Assoc Am Physicians 1996; 79: diastolic blood pressure) compared to those without 221–235. mutation.8 2 Bettinelli A et al. Use of excretion values to The present case was caused by TSC gene distinguish two forms of primary renal tubular hypo- homozygous mutations, which is consistent with kalemic alkalosis: Bartter and Gitelman syndromes. the disease and has already been reported in a J Pediatr 1992; 120: 38–43. compound heterozygous case,4 suggesting that this 3 Simon DB et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused mutation is functionally critical. by mutations in the thiazide-sensitive Na–Cl cotran- Interestingly, this case of typical Gitelman’s syn- sporter. Nat Genet 1996; 12: 24–30. drome showed hypertension during middle age. The 4 Melander O et al. Genetic variants of thiazide-sensi- patient was obese and her mother had essential tive NaCl-cotransporter in Gitelman’s syndrome hypertension, so it is presumed that her blood and primary hypertension. Hypertension 2000; 36: pressure rise was caused by essential hypertension. 389–394. Low blood pressure in patients with Gitelman’s 5 Ogihara T et al. Familial Bartter’s syndrome. Arch Int syndrome is relatively mild compared to that in Med 1982; 142: 906–908. Bartter’s syndrome, and the decrease of sodium 6 Tajima T et al. Two novel mutations of thiazide- reabsorption in Gitelman’s syndrome is not so severe. sensitive Na–Cl cotransporter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome. This may be the reason why hypertension occurred Endocrinol J 2002; 49: 91–96. in the present patient with Gitelman’s syndrome. 7 Reissinger A et al. Novel NCCT gene mutations as a Essential hypertension is a multifactorial poly- cause of Gitelman’s syndrome and a systematic review genic disease caused by gene–environmental inter- of mutant and polymorphic NCCT alleles. actions.9 Many candidate genes have been reported, Blood Press Res 2002; 25: 354–362.

Journal of Human Hypertension A case of Gitelman’s syndrome with hypertension T Ogihara et al 679 8 Cruz DN et al. Mutations in the Na–Cl cotransporter 10 Staessen JA, Wang J, Bianchi G, Birkenhager reduce blood pressure in humans. Hypertension 2001; WH. Essential hypertension. Lancet 2003; 361: 37: 1458–1464. 1629–1641. 9 Katsuya T et al. Salt sensitivity of Japanese from the 11 Matsuo A et al. Arg904Gln variant of thiazide sensitive viewpoint of gene polymorphism. Hypertens Res 2003; Na–Cl cotransporter gene predisposes to hypertension 26: 521–525. in young women, submitted for publication.

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