Genetic Analysis of Gitelman Syndrome Co-Existent with Hyperthyroidism in a 2 Years Old Boy

2020 ◽  
Vol 20 ◽  
Author(s):  
Shufeng Yu ◽  
Caixia Wang
Keyword(s):  
Metabolic Alkalosis ◽  
Final Diagnosis ◽  
Gitelman Syndrome ◽  
Heterozygous Mutation ◽  
Slc12a3 Gene ◽  
Serum Aldosterone ◽  
Urinary Potassium ◽  
Blood Potassium ◽  
Urine Potassium ◽  
The Relationship

: A two-year-old boy went to the doctor for hypokalemia and metabolic alkalosis. Laboratory examination revealed that urinary potassium excretion and serum aldosterone level increased, at the same time with hyperthyroidism and thyroid related antibodies positive.Genetic testing showed that there was a complex heterozygous mutation in SLC12A3 gene ,c.1077C>G(p.N359K) and c.1567G>A(p.A523?)，the final diagnosis was Gitelman syndrome and autoimmune hyperthyroidism.Gitelman syndrome is an autosomal recessive genetic disease caused by the inactivation mutation of SLC12A3 gene. The onset age is more than 6 years old, mainly manifested as low blood potassium, low blood sodium, low blood chlorine, metabolic alkalosis, increased urine potassium and urine chlorine excretion and low urine calcium.Autoimmune hyperthyroidism due to the autoimmune disorders. The highest incidence rate in children is Graves' disease, followed by chronic lymphocytic thyroiditis.Several cases of Gitelman syndrome with autoimmune hyperthyroidism had been identified, most of which were Asian adults, and the case we identified is the first reported case of children under 14 years old with both Gitelman syndrome and autoimmune hyperthyroidism.At the same time, we carried out high-precision clinical exosome analysis of the gene of this case, and further explored the relationship between Gitelman syndrome and autoimmune hyperthyroidism from the perspective of gene.

Novel SLC12A3 mutation in Gitelman syndrome

2021 ◽  
Vol 14 (1) ◽  
pp. e238097
Author(s):  
Rita Veríssimo ◽  
Luís Leite de Sousa ◽  
Tiago J Carvalho ◽  
Pedro Fidalgo
Keyword(s):  
Metabolic Alkalosis ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Urinary Calcium ◽  
Gitelman Syndrome ◽  
Renal Ultrasound ◽  
Calcium Excretion ◽  
Slc12a3 Gene ◽  
Specific Symptoms

Gitelman syndrome (GS) is an autosomal recessive disease characterised by the presence of hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria. The prevalence of this disease is 1–10/40 000. GS is usually associated with mild and non-specific symptoms and many patients are only diagnosed in adulthood. The disease is caused by mutations in the SLC12A3 gene. We present the case of a 49-year-old man referred to a nephrology appointment due to persistent hypokalaemia and hypomagnesaemia. Complementary evaluation revealed hypokalaemia, hypomagnesaemia, metabolic alkalosis, hyperreninaemia, increased chloride and sodium urinary excretion, and reduced urinary calcium excretion. Renal function, remainder serum and urinary ionogram, and renal ultrasound were normal. A diagnosis of GS was established and confirmed with genetic testing which revealed a novel mutation in SLC12A3 (c.1072del, p.(Ala358Profs*12)). This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS.

A novel compound heterozygous mutation of SLC12A3 gene in a pedigree with Gitelman syndrome and literature review

2020 ◽  
Vol 42 (9) ◽  
pp. 1035-1040
Author(s):  
Minglan Yang ◽  
Ying Dong ◽  
Jianqing Tian ◽  
Li Yan ◽  
Yawen Chen ◽  
...  
Keyword(s):  
Literature Review ◽  
Gitelman Syndrome ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Slc12a3 Gene

P0084DIGENIC INHERITANCE: TWO RARE CASES OF GITELMAN SYNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Franca Anglani ◽  
Elisa Pagnin ◽  
Giovanni Bertoldi ◽  
Lisa Gianesello ◽  
Matteo Rigato ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Metabolic Alkalosis ◽  
Clinical Phenotype ◽  
Gitelman Syndrome ◽  
Molecular Diagnostic ◽  
Complex Spectrum ◽  
Type I ◽  
Disease Phenotypes ◽  
Pathogenic Variants ◽  
Slc12a3 Gene

Abstract Background and Aims The clinical implementation of whole-exome sequencing (WES) as molecular diagnostic tool allows investigation of the pathogenic variants interplay in multiple genes resulting in complex spectrum of phenotypes in a same patient. The phenotypic complexity of genetic disease in patients with multiple molecular diagnoses is a challenge. The blending of two distinct disease phenotypes in a same patient may suggest an apparently new clinical phenotype, while molecular diagnoses with two overlapping disease phenotypes may result in phenotypic expansion of a single disease. We present two autosomal recessive Gitelman syndrome (GS) patients whose pathogenic variants in two different genes challenged us for clinical interpretation and therapeutic intervention. Method Case 1: GS diagnosis at 4 years of age, severe clinical phenotype (appearance at unusual early age, hypochloremia, borderline hypomagnesemia resembling Bartter syndrome (BS), need of more complex therapy. Case 2: The diagnosis of GS was made at the age of 45 years. The patient presented classical signs of GS, with less marked metabolic alkalosis and unusual chronic renal insufficiency (CRI). Exome sequencing panel was used for mutational screening of Bartter (BS) and GS genes. Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were also applied. Results Case 1: We detected in the SLC12A3 gene the frameshift p.(Thr7Arfs) and the missense p.(Gly264Ala) variants, the first a known disease-causing mutation, the second associated with a severe form of GS in a patient. Another known disease-causing mutation p.(Met357Thr) was detected in the KCNJ1 gene encoding renal outer medullary K+ channel, ROMK1. It is one BS gene and was never associated with GS. The SLC12A3 p.(Gly264Ala) variant’s high frequency makes it uncommon polymorphism although functional because it alters NCC activity but makes questionable its causative effect on GS phenotype. Our patient severe GS phenotype may be determined by the mutations in either SLC12A3 and KCNJ1 genes inherited respectively from mother and father. If the hypomorphic SLC12A3 variant is causative, hence the heterozygous KCNJ1 pathogenic variant might be a modifier allele responsible of the GS severe presentation. Case 2: We detected two novel variants in the SLC12A3 gene [p.(Lys894fs):p.(Pro331Leu)]. Both are pathogenic according to ACMG guidelines. Another very rare missense variant p.(Val245Met) was identified in the SLC4A1 gene, whose mutations cause distal tubular acidosis type I (dRTA). The missense mutation, never associated with dRTA, is predicted pathogenic by in silico tools. Its presence questions on phenotype interpretation: blended phenotype due to a concomitant presence of a dual molecular diagnosis? Or an expansion of a single phenotype (GS) due to the presence of a modifier gene variant? dRTA and GS have overlapping features such as hypokalemia, hypercalciuria. In the patient the less marked metabolic alkalosis, and the presence of CRF points to the latter. Conclusion Digenic inheritance in GS was reported in only one other instance. These two cases demonstrate how our understanding of the complexity of genetic heterogeneity of rare diseases is far to be completed. It becomes essential to shed light on how combinations of variants in different genes are responsible for a disease phenotype

scholarly journals Gitelman Syndrome: A Rare Case of Hypokalaemia and a Novel Mutation

2021 ◽  
Author(s):  
Maria Clara Novais de Matos ◽  
Fábio Correia ◽  
Maria Inês Silva ◽  
Sofia Carola ◽  
Ana Órfão ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Sodium Chloride ◽  
Metabolic Alkalosis ◽  
Rare Case ◽  
Novel Mutation ◽  
Gitelman Syndrome ◽  
Clinical Approach ◽  
Slc12a3 Gene ◽  
Sodium Chloride Cotransporter ◽  
Renal Tubulopathy

Gitelman syndrome (GS) is a hereditary renal tubulopathy caused by mutations in the SLC12A3 gene which encodes the thiazide-sensitive apical sodium-chloride cotransporter. GS is characterized by hypokalaemia, hypomagnesaemia and metabolic alkalosis. Treatment is based on potassium and magnesium replacement ad eternum. We present the case of a young man with palpitations and persistent hypokalaemia, who was diagnosed with GS. Genetic testing revealed 2 mutations in the gene SLC12A3 of combined heterozygosity, both considered pathological. Interestingly, 1 of these mutations was not yet described in the literature or in the reviewed databases. We also discuss the clinical approach and the specificities of managing this rare hereditary renal tubulopathy.

scholarly journals Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene

Reumatismo ◽  
2020 ◽  
Vol 72 (1) ◽  
pp. 67-70
Author(s):  
E. Conticini ◽  
A. Negro ◽  
L. Magnani ◽  
R. Ugolini ◽  
B. Atienza-Mateo ◽  
...  
Keyword(s):  
Late Onset ◽  
Close Correlation ◽  
Gitelman Syndrome ◽  
Neurological Involvement ◽  
Heterozygous Mutation ◽  
Supporting Evidence ◽  
Salt Wasting ◽  
Slc12a3 Gene ◽  
First Case ◽  
Patient Reported

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

scholarly journals Novel heterozygous mutation of SLC12A3 gene in Gitelman syndrome

QJM ◽  
2021 ◽  
Author(s):  
T Wang ◽  
Y Chen ◽  
X Yin ◽  
H Qiu
Keyword(s):  
Gitelman Syndrome ◽  
Heterozygous Mutation ◽  
Slc12a3 Gene

scholarly journals A Case Report: Gitelman Syndrome or Bartter Syndrome?

2020 ◽  
Author(s):  
YuanBin WU ◽  
Jingjing Hu ◽  
Bo Wang ◽  
Dongxin Yang ◽  
Han Zheng ◽  
...  
Keyword(s):  
Bartter Syndrome ◽  
Gitelman Syndrome ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Slc12a3 Gene ◽  
Hypokalemic Alkalosis ◽  
Chinese Girl ◽  
History Of ◽  
Laboratory Examinations

Abstract Background: Gitelman syndrome (GS) is a rare autosomal recessive inherited tubular disease which is caused by mutation in the SLC12A3 gene. It is characterized by hypokalemic alkalosis with hypomagnesemia and hypocalciuria, and can cause serious complications such as arrhythmia, syncope, sudden death, etc. Bartter syndrome (BS) is similar to Gitelman syndrome in clinical and laboratory examinations. If lack of sufficient understanding of the disease, it is easy to cause misdiagnosis and missed diagnosis. Case presentation: A 6-year-old Chinese girl presented with history of hand and foot spasms and was diagnosed with hypokalemia. Although multiple symptomatic treatments of potassium supplementation was given, is the concentration of potassium was still at a low level. Gene analysis revealed that the presence of two heterozygous mutations, i.e. a missense mutation c.248G> A and a frameshift mutation c.2875_2876del, in the SLC12A3 gene.The child was diagnosed with Gitelman syndrome(GS) due to SLC12A3 compound heterozygous mutation. Through treatment, the level of ion metabolism in children remains stable. Conclusions: By reviewing its clinical characteristics and diagnosis and treatment ideas, we can help improve clinicians' understanding of children's GS.

scholarly journals SUN-LB133 Analysis of Clinical Characteristics and Gene Mutation in Four Cases of Gitelman Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bin Yao
Keyword(s):  
Gene Mutation ◽  
Metabolic Alkalosis ◽  
Clinical Characteristics ◽  
Gene Mutations ◽  
Gitelman Syndrome ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Slc12a3 Gene ◽  
Renal Tubular Disorder ◽  
Renal Tubular

Abstract Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by renal salt wasting with secondary hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria. GS was found to be caused by mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter (NCCT) on the apical membrane of distal convoluted tubule. The prevalence worldwide is estimated at approximately 1:40,000, making it one of the most frequent inherited renal tubular disorders. To date, over 400 mutations scattered throughout SLC12A3 have been identified in GS patients. The majority of patients are compound heterozygous for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation. The type of the SLC12A3 mutation may be a determinant factor in the severity of GS. The purpose of this study is to analyze clinical characteristics and gene mutation in four cases of GS. Methods: Four patients with closely resembling Gitelman syndrome was selected. Results: Six SLCl2A3 gene mutations were found in these four patients. There were one SLCl2A3 homozygous mutation in case 1 and case 3, and two SLCl2A3 heterozygous mutations in case 2 and case 4, respectively. This six gene mutations include missense mutations, frameshift mutations, and nonsense mutations. Four patients were diagnosed with Gitelman syndrome. Case 4 is the most severe with severe hypokalemia, accompanied by ventricular arrhythmias, which may be related to the presence of two SLC12A3 gene mutations in the patient. Conclusions: Four patients in this study were diagnosed with Gitelman syndrome based on their clinical characteristics and genetic testing results. For patients with hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria need to exclude Gitelman syndrome. Key words: Gitelmen Syndrome, Mutations, SlC12A3 gene

The association of lumbosacral transitional vertebral anomalies with acetabular dysplasia in adult patients with hip-spine syndrome

2021 ◽  
Vol 103-B (8) ◽  
pp. 1351-1357
Author(s):  
Joshua Sun ◽  
Avneesh Chhabra ◽  
Uma Thakur ◽  
Louis Vazquez ◽  
Yin Xi ◽  
...  
Keyword(s):  
Acetabular Dysplasia ◽  
Intraclass Correlation ◽  
Final Diagnosis ◽  
Hip Pain ◽  
Pars Interarticularis ◽  
Vertebral Anomalies ◽  
Lumbosacral Transitional Vertebra ◽  
Standard Radiographs ◽  
Time Of Presentation ◽  
The Relationship

Aims Some patients presenting with hip pain and instability and underlying acetabular dysplasia (AD) do not experience resolution of symptoms after surgical management. Hip-spine syndrome is a possible underlying cause. We hypothesized that there is a higher frequency of radiological spine anomalies in patients with AD. We also assessed the relationship between radiological severity of AD and frequency of spine anomalies. Methods In a retrospective analysis of registry data, 122 hips in 122 patients who presented with hip pain and and a final diagnosis of AD were studied. Two observers analyzed hip and spine variables using standard radiographs to assess AD. The frequency of lumbosacral transitional vertebra (LSTV), along with associated Castellvi grade, pars interarticularis defect, and spinal morphological measurements were recorded and correlated with radiological severity of AD. Results Out of 122 patients, 110 (90.2%) were female and 12 (9.8%) were male. We analyzed the radiographs of 122 hips (59 (48.4%) symptomatic left hips, and 63 (51.6%) symptomatic right hips). Average age at time of presentation was 34.2 years (SD 11.2). Frequency of LSTV was high (39% to 43%), compared to historic records from the general population, with Castellvi type 3b being the most common (60% to 63%). Patients with AD have increased L4 and L5 interpedicular distance compared to published values. Frequency of pars interarticularis defect was 4%. Intraclass correlation coefficient for hip and spine variables assessed ranged from good (0.60 to 0.75) to excellent (0.75 to 1.00). Severity of AD did not demonstrate significant correlation with frequency of radiological spine anomalies. Conclusion Patients with AD have increased frequency of spinal anomalies seen on standard hip radiographs. However, there exists no correlation between radiological severity of AD and frequency of spine anomalies. In managing AD patients, clinicians should also assess spinal anomalies that are easily found on standard hip radiographs. Cite this article: Bone Joint J 2021;103-B(8):1351–1357.

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