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Gitelman syndrome combined with growth hormone deficiency

Three cases report

Huang, Ke MDa; Dai, Yang-Li MDa; Zhang, Jian-Wei MDa,b; Zhang, Li MDa; Wu, Wei MDa; Dong, Guan-Ping MDa; Ullah, Rahim MDa; Fei, Yue MDa; Fu, Jun-Fen MDa,∗

Section Editor(s): NA.,

doi: 10.1097/MD.0000000000017244
Research Article: Clinical Case Report
Open

Rationale: Gitelman syndrome (GS) is a rare autosomal recessive hereditary salt-losing tubulopathy caused by loss-of-function mutations in the SLC12A3 gene. It is usually characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. There are only a few reports on GS combined with growth hormone deficiency (GHD).

Patient concerns: Three patients presented with weakness, spasm, and growth retardation, respectively.

Diagnoses: GS was diagnosed based on the clinical symptoms, laboratory test results, and genetic analysis. GH stimulation tests were performed when the magnesium level returned to normal under magnesium oxide (MgO) therapy.

Interventions: Initially, all patients received oral replacement of MgO and potassium chloride, and 2 of them received simultaneous spironolactone therapy. Recombinant human growth hormone (rhGH) therapy was initiated after they were diagnosed with GHD.

Outcomes: All 3 patients exhibited satisfactory growth velocity and normal serum magnesium level, although the potassium level was still slightly lower than normal.

Lessons: We suggest that all GS patients should undergo genetic evaluation, especially regarding SLC12A3 gene mutation. GHD should be considered if these patients have short stature. rhGH therapy is useful for stimulating the patients’ growth, and it may increase the serum magnesium level.

aDepartment of Endocrinology, The Children's Hospital, Zhejiang University School of Medicine

bDepartment of Pediatric, Shaoxing Women and Children's Hospital, China.

∗Correspondence: Jun-Fen Fu, The Children's Hospital, Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou 310052, China (e-mail: fjf68@zju.edu.cn).

Abbreviations: BS = Bartter syndrome, ClC-Kb = chloride voltage-gated channel Kb, FGF-23 = fibroblast growth factor-23, GHD = growth hormone deficiency, GHST = growth hormone stimulation test, GS = Gitelman syndrome, IGF-1 = insulin-like growth factor 1, NCCT = thiazide-sensitive sodium chloride cotransporter channel, rhGH = recombinant human growth hormone, SDS = standard deviation score.

How to cite this article: Huang K, Dai1 Yl, Zhang Jw, Zhang L, Wu W, Dong Gp, Ullah R, Fei Y, Fu Jf. Gitelman syndrome combined with growth hormone deficiency. Medicine. 2019;98:40(e17244).

This work was supported by the Research Council of the Science Technology Department of Zhejiang Province (2016C33130), Zhejiang Health and Family Planning Commission (2016KYA128), and National Natural Science Foundation of China (81371215).

Written informed consent was obtained from all parents of the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.

Written informed consent was obtained from the patients’ parents for their blood collection and genetic analysis. Genetic analyses were also approved by the ethics committee of our hospital.

The authors have no conflicts of interests to disclose.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0

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1 Introduction

Gitelman syndrome (GS) is a rare autosomal recessive hereditary salt-losing tubulopathy with a characteristic set of metabolic abnormalities, including hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria.[1] The GS phenotype is usually caused by loss-of-function mutations in the SLC12A3 gene which encodes the thiazide-sensitive sodium chloride cotransporter channel in the distal convoluted tubule of the kidney. Clinically, these patients may present with fatigue, tetany, cramps, muscle weakness, vomiting, diarrhea, and abdominal pain.[2] In addition, growth retardation was noted in some patients with GS.[3] Although potassium depletion may have some negative effects on growth, the pathogenesis of growth retardation in GS is still unclear. There are few reports on GS combined with growth hormone deficiency (GHD).[4–7] Herein, we describe 3 cases of patients with GS combined with GHD.

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2 Clinical case

2.1 Case 1

A 6-year, 2-month-old boy was admitted to our hospital complaining of a 4-day history of weakness. His birth weight was 3.00 kg. No family history of endocrine, renal, celiac, and cardiovascular diseases or history of diuretic use was noted. Blood pressure was normal (91/63 mmHg). Initial biochemical analysis revealed metabolic alkalosis with hypokalemia (Table 1) based on the following values: serum total calcium level was 2.40 mmol/L (normal range: 2.20–2.65 mmol/L), phosphorus was 1.25 mmol/L (normal range: 1.29–2.26 mmol/L), and serum magnesium level was very low compared to the normal range. Further investigations revealed high serum renin and aldosterone levels. The 24-hour urinalysis showed that calcium was 2.5 mg/24 hour, significantly lower than the normal range of 100–300 mg/24 hour. The patient had normal adrenal, hepatic, renal, parathyroid, and thyroid function. Abdominal ultrasound showed that the kidneys and liver were normal. Whole blood DNA sequencing revealed 2 heterozygous mutations in the SLC12A3 gene (c.473G>A p.R158Q and c.602-16G>A p. splicing) (Table 2). Administration of oral replacement of magnesium oxide (MgO, 1 g/day), potassium chloride (KCl, 2.0 g/day), and spironolactone (2 mg/kg·day−1) was done. Serum potassium and magnesium levels increased to 3.0 mmol/L and 0.85 mmol/L, respectively. The frequency of weakness significantly decreased. However, his growth rate was just 4.2 cm/year, slightly higher than that before MgO and KCl therapy, which was only 3.2 cm/year.

Table 1

Table 1

Table 2

Table 2

His height was 108 cm (−2.78 standard deviation score [SDS]) and his weight was 18.7 kg (−1.58 SDS) at 9.50 years. The pubertal stage was genitalia stage I and pubic hair stage I, and his bone age (BA), according to the Greulich-Pyle method, was 6 years old. Growth hormone stimulation tests (GHSTs) (L-dopa and arginine) for short stature identified GHD, the peak GH level was 6.00 ng/mL (see Table 1). Pituitary MRI revealed no remarkable findings. The patient was treated with 0.277 mg/kg/week of recombinant human growth hormone (rhGH), and he achieved a 10.6-cm height gain over 11 months.

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2.2 Case 2

A 9-year, 3-month-old girl came to the clinic with a chief complaint of a 7-year history of growth retardation. No complaints of weakness, nausea, or abdominal distension were observed. At full-term birth, the weight was 3.60 kg. No family history of cardiovascular, endocrine, or renal diseases was noted. Her height and weight were 120 cm (−2.27 SDS) and 19.5 kg (−2.26 SDS), respectively. The patient was Tanner stage 1 for breast and pubic hair, and the BA was 7 years old. Blood pressure was 113/71 mmHg. Moreover, laboratory test results revealed low potassium level with metabolic alkalosis, hypocalciuria, and hypomagnesemia (Table 1). The patient also had normal thyroid, adrenal, hepatic, parathyroid, and renal function. Abdominal ultrasound showed that the kidneys and liver were normal. Furthermore, whole blood DNA sequencing identified 2 heterozygous mutations in the SLC12A3 gene (c.1456 G>A p.D486N and c.965-1G>A p. splicing) (Table 2). She received oral replacement of 1.5 g/day MgO, 3.0 g/day KCl, and spironolactone (2 mg/kg·day−1). Within 3 months of treatment, serum potassium and magnesium levels increased to 3.1 mmol/L and 0.83 mmol/L, respectively. At that time, her growth velocity was 3.6 cm/year. Then, GHST was performed and GHD was identified, the peak GH level was 6.88 ng/mL (see Table 1). No remarkable findings were shown based on pituitary MRI. She was treated with 0.280 mg/kg/week of rhGH and achieved a 3.2-cm height gain over the first 3 months.

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2.3 Case 3

A 4-year, 8-month-old boy who complained weakness and spasm for 1 week were referred to our hospital. He reported no headache, nausea, vomiting, or abdominal distension. Birth weight was 3.45 kg. No medical history of cardiovascular, endocrine, or renal diseases was noted. His height and weight were 97 cm (−2.57 SDS) and 19.5 kg (−2.26 SDS), respectively. His Tanner stage was genitalia stage I and pubic hair stage I. Heart rate was 110 beats per minute, blood pressure was 87/66 mmHg, respiratory rate was 30 breaths per minute, and oxygen saturation was 98% on ambient air. The sodium level was 141 mmol/L, potassium level was 2.5 mmol/L, chloride level was 103 mmol/L, total calcium level was 2.40 mmol/L, phosphorus level was 0.73 mmol/L, magnesium level was 0.65 mmol/L, and 24-hour urine calcium was 17.8 mg/24 hour (normal range, 100–300 mg/24 hour) (Table 1). The patient also had normal thyroid, adrenal, hepatic, parathyroid, and renal function. No remarkable findings were noted on electroencephalogram and pituitary MRI. Likewise, abdominal ultrasound showed that the kidneys and liver were normal. He was treated with magnesium sulfate and his weakness and spasm diminished. Whole blood DNA sequencing also identified two heterozygous mutations in the SLC12A3 gene (c.911C>T p.T304 M and c.506-1G>A p. splicing) (Table 2). His medications included MgO (1.0 g/day) and KCl (2.0 g/day). Serum potassium and magnesium level back to 3.2 mmol/L and 0.93 mmol/L, respectively, after three months of treatment. At that time, his growth velocity was still 3.6 cm/year. Then, GHSTs were performed and GHD was identified, the peak GH level was 3.30 ng/mL (see Table 1). Hence, he was treated with 0.300 mg/kg/week of rhGH and achieved a 2.8-cm height gain over the first 3 months.

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3 Discussion

GS is an autosomal recessive salt-losing renal tubulopathy with a characteristic set of hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Epidemiologic studies showed that the prevalence of GS was approximately 1 per 40,000 among Europeans.[8] Patients were diagnosed with GS based on their clinical features and biochemical parameters. Symptoms of GS include spasm, weakness, and numbness. However, these symptoms are usually nonspecific and variable. Thus, the typical laboratory findings which include hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria are much more important. However, hypomagnesemia and hypocalciuria are not always present in patients with GS. Therefore, genetic testing is the optimal standard for the diagnosis of GS. It was reported that GS is usually caused by loss-of-function mutations in the SLC12A3 (solute carrier family 12 member 3) gene, encoding the thiazide-sensitive sodium chloride (NaCl) cotransporter protein. Inactivation of SLC12A3 gene mutation reduces NaCl reabsorption in the distal convoluted tubule and causes the symptoms of GS. To date, more than 400 mutations throughout the SLC12A3 gene have been identified in different ethnic groups. Recently, 2 studies on GS gene mutations among Chinese patients were reported. These results showed that the D486N mutation of the SLC12A3 gene appeared to be more frequent than the other mutations in Chinese patients with GS.[9,10] This study also found that 1 of the 3 patients had the same mutation. Although mutations have also been identified in the chloride voltage-gated channel Kb (CLCNKB) gene in a minority of patients with atypical GS phenotypes, we did not find any mutation of CLCNKB gene in our 3 patients. One research from China showed that nearly 30% of Chinese patients with GS carried 0 or just 1 mutant allele; they failed to have a genetic diagnosis of GS based on autosomal recessive inheritance. This might be attributed to undetected large genomic rearrangements and deep intronic mutations, which account for a considerable proportion of GS patients, by direct sequencing.[9] Although the gene analysis results are not the only criteria for GS diagnosis, genetic analysis is still recommended for all suspected patients.

A majority of GS patients may present with weakness, muscle cramps, paresthesias, and episodes of tetany or paralysis. Meanwhile, other symptoms, such as nocturia, polydipsia, diarrhea, dizziness, and salt craving are included. These symptoms are all related to electrolyte and acid-base abnormalities. GS is associated with less severe growth retardation, compared with Bartter syndrome (BS). There are some factors that may contribute to growth retardation in BS or GS. Significant salt loss in the antenatal–neonatal period, hypokalemia, or metabolic alkalosis may have some effect on growth. However, the precise causes of growth retardation remain unclear. Some cases investigating GS combined with GHD have been reported in the last 2 decades,[4–7] as shown in Table 3. Moreover, because classic BS and GS shared the laboratory finding of hypokalemic alkalosis, Adachi et al[11] conjectured that some of the older cases reported in the literature do not comply with the current definition and concept of BS and thus, should be recognized as GS.

Table 3

Table 3

Experimental studies suggested that potassium depletion could have a negative effect on growth by reducing the circulating levels of growth hormone and insulin-like growth factor 1 (IGF-1), which may blunt the GH response and lead to false-negative results in GHST.[12,13] However, another study showed there was abnormal chondrocyte maturation in rats which fed a potassium-free diet, and it was not normalized by a high dose of exogenous GH. This observation can easily explain why there is resistance to GH in hypokalemic rats.[13] The excellent response to GH therapy made us believe that GHD should be regarded as a complication in classic BS or GS, which is similar with the other study.[5,11,14] It has also been reported that higher urine magnesium excretion alters the GH/IGF-1 axis in a type 1 diabetes mellitus cohort.[15] Matsuzaki et al[16] reported that magnesium deficiency increases serum fibroblast growth factor 23 (FGF-23) levels in rats. Another research showed that FGF-23 altered the GH/IGF-1 axis, delayed puberty, malnutrition, and metabolic acidosis.[17] Additionally, these researches demonstrated that hypomagnesemia may play an important role in the GH/IGF-1 axis. However, our patients underwent GHST when the serum magnesium concentration return to normal range after therapy. Our result showed that there might be no direct relationship between hypomagnesemia and GHD. In summary, GHD should be regarded as a complication of GS in these three patients, although the exact cause of GS combined with GHD remains unclear.

In our study, all three patients received rhGh therapy and exhibited a growth velocity of 10.3–12.8 cm/year, significantly higher than before. No impaired glucose metabolism or other side effects were found in our three patients during the treatment. Our result was similar with some other researches which also reported that rhGH therapy markedly improved GS patients’ growth rate. Interestingly, rhGH treatment also seemed to be helpful for the correction of hypomagnesemia,[5] we suggest that rhGH therapy might be considered in short children with GS, even though they do not suffer from GHD.

In summary, we reported three cases of GS combined with GHD. GS should be diagnosed based on the clinical manifestations and laboratory results. We propose that all patients with GS should undergo genetic test. When these patients suffer from growth retardation, GHD should be considered and GHST should be performed. rhGH therapy is helpful for stimulating the patients’ growth and increasing the serum magnesium level.

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Acknowledgments

We acknowledge the nursing staff of our Endocrinology department for their dedicated care of these patients and collection of blood samples. We thank all the patients and parents who took part in this project.

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Author contributions

Methodology: Rahim Ullah.

Project administration: Yangli Dai.

Resources: Jianwei Zhang, Li Zhang, Wei Wu, Guanping Dong, Yue Fei.

Writing – original draft: Ke Huang.

Writing – review & editing: Ke Huang, Junfen Fu.

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References

[1]. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966;79:221–35.
[2]. Graziani G, Fedeli C, Moroni L, et al. Gitelman syndrome: pathophysiological and clinical aspects. QJM 2010;103:741–8.
[3]. Gaur A, Ambey R, Gaur BK. Gitelman's syndrome: rare presentation with growth retardation. Indian J Nephrol 2014;24:60–2.
[4]. Min SR, Cho HS, Hong J, et al. Gitelman syndrome combined with complete growth hormone deficiency. Ann Pediatr Endocrinol Metab 2013;18:36–9.
[5]. Ko CW, Koo JH. Recombinant human growth hormone and Gitelman's syndrome. Am J Kidney Dis 1999;33:778–81.
[6]. Bettinelli A, Rusconi R, Ciarmatori S, et al. Gitelman disease associated with growth hormone deficiency, disturbances in vasopressin secretion and empty sella: a new hereditary renal tubular-pituitary syndrome? Pediatr Res 1999;46:232–8.
[7]. Slyper AH. Growth, growth hormone testing and response to growth hormone treatment in Gitelman syndrome. J Pediatr Endocrinol Metab 2007;20:257–9.
[8]. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension 2000;36:389–94.
[9]. Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with Gitelman syndrome: Sixteen Novel SLC12A3 mutations identified in a new cohort. Am J Nephrol 2016;44:113–21.
[10]. Wang F, Shi C, Cui Y, et al. Mutation profile and treatment of Gitelman syndrome in Chinese patients. Clin Exp Nephrol 2016;21:293–9.
[11]. Adachi M, Tajima T, Muroya K, et al. Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report. J Med Case Rep 2013;7:283.
[12]. Flyvbjerg A, Dorup I, Everts ME, et al. Evidence that potassium deficiency induces growth retardation through reduced circulating levels of growth hormone and insulin-like growth factor I. Metabolism 1991;40:769–75.
[13]. Gil-Pena H, Garcia-Lopez E, Alvarez-Garcia O, et al. Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment. Am J Physiol Renal Physiol 2009;297:F639–45.
[14]. Buyukcelik M, Keskin M, Kilic BD, et al. Bartter syndrome and growth hormone deficiency: three cases. Pediatr Nephrol 2012;27:2145–8.
[15]. Moyer-Mileur LJ, Slater H, Jordan KC, et al. IGF-1 and IGF-binding proteins and bone mass, geometry, and strength: relation to metabolic control in adolescent girls with type 1 diabetes. J Bone Miner Res 2008;23:1884–91.
[16]. Matsuzaki H, Kajita Y, Miwa M. Magnesium deficiency increases serum fibroblast growth factor-23 levels in rats. Magnes Res 2013;26:18–23.
[17]. Sgambat K, Moudgil A. Optimization of bone health in children before and after renal transplantation: current perspectives and future directions. Front Pediatr 2014;2:13.
[18]. Jie YAN, Gui-chen NI, Yu-chuan L. Clinical analysis of Gitelman syndrome in children. J Appl Clin Pediatr 2007;22:1560–2.
    Keywords:

    genetic analysis; Gitelman syndrome; growth hormone deficiency; therapy

    Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.