Abstract
Gitelman syndrome is a rare, autosomal recessively inherited tubulopathy manifesting with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Common symptoms include fatigue, myalgia, reduced performance capacity, tetany, paresthesia, and delayed growth. However, as reported in the literature, diagnosis in some patients is prompted by an incidental finding of hypokalemia. GS develops due to mutations in the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter. Many variants in the SLC12A3 gene causing GS have been reported in literature. A new pathogenic homozygous mutation (c.2612G > T), absence of hypomagnesemia, and accompanying autoimmune thyroiditis are remarkable in our patient. There are a few Gitelman syndrome cases that are complicated with autoimmune thyroiditis in the literature. In this study, we present a case of Gitelman syndrome with a novel homozygous mutation and accompanying autoimmune thyroiditis and review of the literature.
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Introduction
Gitelman syndrome (GS) is a rare, autosomal recessively inherited tubulopathy manifesting with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis [1]. Studies have reported a prevalence of approximately 1/40,000 in Caucasians, and a higher prevalence in Asia [2]. GS generally affects adolescents and adults, whereas symptoms rarely appear during the neonatal period and childhood. Common symptoms include muscle weakness, fatigue, reduced performance capacity, fainting episodes, cramps, tetany, paresthesia, carpopedal spasm, delayed growth and puberty, short stature, thirst, vertigo, polyuria, joint pain, and vision problems. However, as reported in the literature, diagnosis in some patients is prompted by incidental detection of hypokalemia. Unlike Bartter syndrome (BS) which is often considered in the differential diagnosis, GS is accompanied by hypocalciuria, generally has a milder course and is diagnosed at a later age. However, it is not always easy to discriminate GS from Bartter syndrome type 3, in which mutations in the CLCNKB gene are observed in terms of clinical and laboratory features. Definitive discrimination, however, can be achieved using genetic tests.
GS is caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter. Many variants of the SLC12A3 gene causing GS and autoimmune thyroid diseases accompanying cases with different genotypes have been reported in the literature [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. However, reflection of these different pathogenic variants in the clinical phenotype remains unclear. In this study, we present a case of concomitant GS and autoimmune thyroiditis with novel variant and an extensive literature review.
Case report
A 32-year-old female patient applied to the outpatient clinic with a 1-year history of fatigue. Systemic inquiry revealed no remarkable features and physical examination was normal. There was no diarrhea, nausea, or vomiting. The patient’s mother and father had a third-degree consanguineous marriage.
Hypokalemic alkalosis was detected in laboratory investigations. Consistent with renal potassium excretion, increased transtubular potassium gradient (10), hypocalciuria (72.8 mg/day), and increased chloride fractional excretion (1493 mmol/day) and plasma renin activity were observed. Spot urinary calcium/creatinine ratio was 0.05 and 0.09 (< 0.15) (Table 1). Hypomagnesemia was absent. Urea, creatinine, and 24 h creatinine clearance in the urine were in the normal range according to age and weight (Table 1). There was no use of diuretics, laxatives or any other medications, and no history of vitamin B12 replacement therapy. There was no history of use of alcohol or herbal product(s). She was normotensive according to 24 h ambulatory blood pressure monitoring (24 h average blood pressure, 117/72 mmHg). Aldosterone level was normal, plasma renin activity was increased, and cortisol was suppressed in the 1 mg dexamethasone test (Table 1). Abdomen MRI revealed normal renal parenchymal thickness, contour, and size.
GS was primarily considered in this hypokalemic normotensive patient with metabolic alkalosis who had renal potassium loss, hypocalciuria, increased renin activity, and increased chloride fractional excretion. Normal serum potassium levels could be maintained with oral potassium supplements (40 mEq/day). A tubulopathy screening panel was requested. Next-generation sequencing analysis revealed a homozygous c.2612G > T (p.Arg871Leu) variant in the SLC12A3 (NM_000339.3) gene. Laboratory investigations further revealed subclinical hypothyroidism, with anti-thyroid peroxidase and anti-thyroglobulin autoantibody positivity and the patient was also diagnosed with Hashimoto’s thyroiditis (Table 1).
Whole exome sequencing
The concentration and quality of genomic DNA (gDNA) extracted from peripheral blood were examined with the Qubit™ dsDNA BR Assay Kit (Thermo Scientific, USA). For WES analysis, 3 μg of genomic DNA (gDNA) was sheared to yield 100–450 bp fragments. Insolution whole-exome capture, circularization, and high-throughput sequencing were performed using the Twist Human Core Exome EF Multiplex Complete Kit (Twist Bioscience, South San Francisco), MGIEasy Circularization Kit (MGI, China), and DNBSEQ-G400RS High-throughput Sequencing Kit (FCL PE100) (MGI, China), respectively. Enriched DNA fragments were sequenced on the DNBSEQ-G400 platform as paired-end 100–125 base-pair reads. Total number of reads in target was 301 million, the mean coverage was 100 and the sequencing depth of the regions was 129.11. Targeted panel data analysis identified 15,691 variants. Among these variants with an effect on coding/splice site regions, the variant filtering strategy was based on allele frequency with MAF ≤ 1% variants and according to the phenotypic and clinic findings by Human Phenotype Ontology. The variants found were checked with the IGV (Integrative Genomics Viewer) program. The variants were extracted from candidate genes with the annotations of frameshift, stop gained, splice acceptor, splice donor, missense, and splice site region (within the terminal 1–5 bases of the exon or terminal 3–8 bases of the intron). Next-generation sequencing analysis revealed a novel homozygous c.2612G > T (p.Arg871Leu) variant in the SLC12A3 (NM_000339.3) gene (shown in Fig. 1). The variant affects hotspot regions of the gene (PM1) and in silico tools evaluation results were compatible with the high pathogenicity scores (PP3) (shown in Figs. 2, 3). Previously, different pathogenic alteration was reported in same amino acid (PM5). The variant was not previously reported in gnomAD, 1000 genomes and ESP 6500 (PM2). The c.2612G > T variant was also detected in both father and mother in heterozygous state. Therefore, the variation in our patient evaluated as a pathogenic according to ACMG guidelines (PM1, PM2, PM5, PP3) [20].
Discussion
To date, more than 50 hereditary tubulopathy syndromes have been reported [21]. GS is the most common salt-losing tubulopathy syndrome caused by mutations in the SLC12A3 gene encoding for the thiazide-sensitive Na-Cl cotransporter [22]. When GS is suspected in a patient, it is recommended that a next-generation sequencing panel is performed. The genes in these panels should include SLC12A3, CLCNKB, and HNF1B. We initially requested a next-generation sequencing-based tubulopathy panel (Table 2).
To our knowledge, the homozygous c.2612G > T (p.Arg871Leu) variation detected in the SLC12A3 (NM_00339.3) gene in our case has not been reported in the literature. Because the pathogenicity score was high and consistent with the clinical evaluation, it was considered to be a novel pathogenic variant. Additionally, the presence of an autoimmune thyroiditis i.e., (Hashimoto’s thyroiditis) diagnosed along with GS was remarkable. There are a few reported cases of concomitant autoimmune thyroiditis and GS in the literature (Table 3) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. Nevertheless, studies have not been able to establish an association between autoimmune thyroid disease and GS.
A literature review revealed 23 cases of GS in total, including ours, that reported a SLC12A3 gene mutation and accompanying autoimmune thyroid disease. Apart from our case, there were two patients diagnosed with Hashimoto’s thyroiditis among the cases harboring a SLC12A3 mutation. Including our case, 17 of 23 patients described in the literature had Graves’ disease, three had Hashimoto’s thyroiditis, and two had antibody-positive autoimmune thyroid disease (Table 3). Because thyrotoxicosis contributes to the deterioration of hypokalemia in patients diagnosed with Graves’ disease, it is possible that these patients were diagnosed with GS, more commonly, by presenting with hypokalemia. When patients with GS accompanying Graves’ disease are reviewed, the fact that some present with thyrotoxic hypokalemic paralysis supports this finding [7, 11, 19]. It is not known whether Hashimoto’s thyroiditis in three cases was related to a genotype or was coincidental because Hashimoto’s thyroiditis is already a common disorder in the population. Also a definitive association between Graves’ disease and GS has not been demonstrated yet but there is some weak evidence reveals that some variants in SLC12A3 coexist with autoimmune thyroiditis. Previously, some studies reported that there could be some relationship between clinical presentation and genotype of GS [23,24,25]. Some mutations (p.(T60M)) may be associated with earlier manifestation and lower calciuria [24], some (intronic or nonframeshift mutations) may be associated with severe hypokalemia [25].
The absence of hypomagnesemia can be considered to be due to the genotype. In a review published in 2019, 185 patients with GS in Japan were studied in terms of clinical and genetic characteristics, and that review revealed that patients with some genotypes have milder hypomagnesemia [26]. It has been reported that patients with c.2573T > A (p.Leu858His) and/or c.1924C > T (p.Arg642Cys) pathogenic variants, more commonly observed in the Japanese population, exhibit higher serum magnesium levels compared to those without these variants (1.76 mg/dL versus 1.43 mg/dL; p < 0.001). Apart from our case, there were only four cases (Case 1, 9, 10, 14) with normal magnesium levels and two of these cases (Case 9 and 14) had heterozygous c.2573T > A (p.Leu858His) pathogenic variants. Case 9 and 14 were the only cases that had c.2573T > A (p.Leu858His) pathogenic variant in the review and there was no case that had c.1924C > T (p.Arg642Cys) pathogenic variant. The homozygous c.2612G > T (p.Arg871Leu) variant in our case, which to our knowledge is reported here for the first time, can also be related to normal magnesium levels in our patient.
In our case, Arginine (Arg) at the 871st position was the aminoacid that changed (to Leucine). There are various reports documenting mutations at the 871st Arg position that cause different aminoacids [18, 27,28,29,30]. In an article examining DNA samples of 163 patients with a suspicion of GS, 114 different mutations were identified, 31 of which have not been reported before [27]. There is a case (out of 163 cases) that reported an aminoacid change of p.Arg871Cys (c.2611C > T) but no additional information was included about the phenotype [27].
In another article examined 20 patients with hypokalemia (16 patients with GS, 4 patients with BS), 12 NCC mutations, including six novel mutations were identified and one of the novel heterozygous mutations was p.Arg871His [28]. The patient with p.Arg871His variant had hypokalemia and hypomagnesemia at the presentation, unlike our patient. Like our patient, he was also admitted in early adulthood (age 28). His symptomatology at the presentation was paralysis, muscle weakness, cramps, nocturia, palpitation, and paresthesias; our patient did not have that rich symptomatology. Thyroiditis was not reported in that case [28].
p.Arg871His variant has been reported in three other articles [18, 29, 30]. In a study to understand the role of deep intronic mutations on GS with uniallelic or undetectable SLC12A3 mutations, 29 patients with GS were evaluated and besides the deep intronic mutations, one patient with p.Arg871His variant was detected [29]. The patient had hypokalemia and hypomagnesemia and age at diagnosis in early adulthood (age 32), thyroiditis was not reported.
A larger study from Taiwan was performed on 117 Taiwanese GS patients to evaluate the genotype and phenotype correlation [30]. In this study, 40 different SLC12A3 mutations were identified and the authors concluded that patients with homozygous and deep mutations in intron 13 had more severe phenotypes. On the follow-up, out of 117 patients, 7 patients developed stage III or IV chronic kidney disease (CKD), 6 of the patients with CKD underwent renal biopsy, and revealed chronic tubulointerstitial nephritis in favor of hypokalemic nephropathy. The average age of CKD was 37 ± 3. In this GS patients with CKD, three patients were found to have Arg871His variant heterozygously. The age of disease onset was 15, 18, and 12 and the age of CKD were 38, 37, and 36 in patients with Arg871His variant. All three patients are male and had hypokalemia and hypomagnesemia, thyroiditis was not mentioned [30]. In this study, 42% (3/7) of patients with GS and CKD were shown to have one heterozygous p.Arg871His variant is also remarkable.
Another case with p.Arg871His variant is included in Table 3 because of the coexistence of autoimmune thyroiditis in the patient [18]. The patient with heterozygous p.Arg871His variant in this report had hypomagnesemia, unlike our patient; like our patient, she was admitted in early adulthood (age 29), and her symptom of presentation was bilateral lower limb weakness. Like our patient, she was diagnosed with autoimmune thyroiditis (Graves’ disease) [18].
Also, a literature review was performed on the genotype of autoimmune thyroiditis, there were a limited number of cases with autoimmune thyroiditis examined by WES [31,32,33]. In a recent original article that performed exome sequencing to understand the genetic susceptibility to the coexistence of Hashimoto’s thyroiditis and PCOS; 142 patients had Hashimoto’s thyroiditis performed WES and SLC12A3 mutation was not reported [31]. In another article, four patients with Hashimoto’s thyroiditis (four members of a family) were selected for WES and they found a missense mutation in PTPN22; a variant is not reported in the SLC12A3 gene [32]. A family with an autosomal dominant inheritance of Hashimoto thyroiditis is also described in the literature and proband’s WES identified a splice site variant in the thyroglobulin gene; the SLC12A3 variant was not reported in this case either [33].
In conclusion, GS should be suspected in adult patients with hypokalemia. Different genotypes have been reported in the SLC12A3 gene causing GS. The homozygous variant detected in our case is a new pathogenic variant and accompanying autoimmune thyroiditis and the absence of hypomagnesemia should be underlined with this variant. It may be appropriate to screen patients for autoimmune thyroiditis who are diagnosed with GS in adulthood. Further studies are needed to characterize the relationship between different genotypes and clinical features in patients with GS.
Abbreviations
- GS:
-
Gitelman syndrome
- BS:
-
Bartter syndrome
- NCC:
-
Na-Cl cotransporter
- CKD:
-
Chronic kidney disease
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Koca, O., Alay, M.T., Murt, A. et al. A novel homozygous SLC12A3 mutation causing Gitelman syndrome with co-existent autoimmune thyroiditis: a case report and review of the literature. CEN Case Rep (2024). https://doi.org/10.1007/s13730-023-00845-z
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DOI: https://doi.org/10.1007/s13730-023-00845-z