Gitelman's syndrome (GS) is an inherited condition that features low levels of magnesium and potassium in the serum and low levels of calcium in the urine. The inheritance pattern is autosomal recessive.
Presentation
Gitelman syndrome is a genetic condition that affects the renal tubules, leading to hypomagnesemia, hypokalemia and hypocalciuria, as well as acid-base imbalance (metabolic alkalosis). Although Gitelman syndrome was previously thought to be a milder form of a tubular transport disorder ascribed to Bartter syndrome, it is now recognized as a distinct medical entity that should not be confused with Bartter's syndrome [1] [2] [3] [4].
Gitelman syndrome is characterized by a wide variety of symptoms; not all patients experience the full spectrum. Diarrhea, vomiting and tetany, as a result of significant hypomagnesemia related to fluid loss, are some of the reported symptoms. Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity. However, there have been cases reported that do not display serious symptoms; a young adult has been described in the literature as exhibiting only leg cramps, weakness, vomiting, and malaise [5]. Growth is hindered only in cases of profound hypomagnesemia and hypokalemia [6].
Some Gitelman syndrome patients may also report swollen, burning and tender joints; this is attributed to the chondrocalcinosis that may accompany the rest of the symptoms. Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well. As for the cardiovascular system, although Gitelman syndrome causes ventricular arrhythmias, they only rarely result in any considerable symptomatology, with only a few patients experiencing cardiac arrest [7] [8]. Patients are usually hypotensive.
Entire Body System
- Weakness
Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity. [symptoma.com]
Differential diagnosis for muscle weakness and tetany is large. [sjkdt.org]
In our patient, the symptoms started at the age of two years in the form of recurrent episodes of muscle weakness. [jmedicalcasereports.biomedcentral.com]
His mother had more slight symptoms of weakness than him with mild hypokalemia and hypocalciuria. Mild hypomagnesemia was also observed in his sister with occasional weakness. [ncbi.nlm.nih.gov]
Volume depletion is not as severe as in true Bartter syndrome, but patients can suffer from weakness, fatigue, dizziness, ataxia, and blurred vision. [wohproject.org]
- Fatigue
Paresthesias may be described, as well as weakness and fatigue that discourages the individuals from engaging in physical activity. [symptoma.com]
Clinical signs are mostly secondary to chronic hypokalemia and include dizziness, fatigue, constipation and weakness. Patients can also present with muscle cramps, tetany, fatigue and convulsions due to severe metabolic alkalosis or hypomagnesemia. [ncbi.nlm.nih.gov]
Volume depletion is not as severe as in true Bartter syndrome, but patients can suffer from weakness, fatigue, dizziness, ataxia, and blurred vision. [wohproject.org]
Case presentation A 17-year-old South Asian man with recurrent episodes of generalized muscle weakness, fatigue and cramps from the age of two years was admitted for further workup. [jmedicalcasereports.biomedcentral.com]
Clinical findings are brief episodes of fatigue, syncope, vertigo, ataxia and blurred vision; sudden cardiac death might occur. This review aims to give insight into cardiovascular implications and management of GS. [imrpress.com]
- Anorexia
He had no history of diuretic, laxative and licorice intake, no episode of anorexia, vomiting and diarrhea. [springerplus.springeropen.com]
She had no obvious clinical symptoms such as palpitations, shortness of breath, muscle weakness of the lower limbs, vomiting, nausea, anorexia, diarrhea, polyphagia and emaciation and denied a history of chronic kidney disease. [dovepress.com]
Medical findings in outpatients with anorexia nervosa. Arch Intern Med. 2005 Mar 14. 165(5):561-6. [Medline]. Perazella MA, Brown E. Electrolyte and acid-base disorders associated with AIDS: an etiologic review. [medscape.com]
[…] abnormalities found in Gitelman syndrome, include: [4] Low levels of potassium in the blood (hypokalemia) Metabolic alkalosis (too much base in the body) Low magnesium in the blood (hypomagnesemia) Low levels of calcium in the urine (hypocalciuria) Anorexia [rarediseases.info.nih.gov]
[…] ordered by the treating nephrologist or pediatrician because of persistent metabolic alkalosis and/or hypokalemia, after the exclusion of secondary causes of the clinical phenotype (e.g., diuretics, laxative consumption, surreptitious drugs assumption, anorexia [mdpi.com]
Gastrointestinal
- Abdominal Pain
Patients usually present with muscle weakness, salt craving, thirst, nocturia, facial paresthesia, tetany, and abdominal pain. Gitelman Syndrome is an autosomal recessive disorder. [clinlabnavigator.com]
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. [ncbi.nlm.nih.gov]
Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis.[8] Other features include: Short stature. [patient.info]
pain vomiting Physical exam growth is often normal but can be delayed Studies Labs hypokalemia (lower than in Bartter’s) hypomagnesemia metabolic alkalosis genetic testing most definitive diagnosis Urine studies ↓ Ca2+ Differential Bartter’s syndrome [step1.medbullets.com]
- Failure to Thrive
We present an 18-month-old boy who presented with psychomotor retardation and failure to thrive. Investigations revealed hypokalemia at 2.7 mmol/L, metabolic alkalosis, hypocalciuria and normal serum magnesium level. [ncbi.nlm.nih.gov]
Signs in infants include dehydration, weakness, and failure to thrive but the relative mildness of this condition often does not lead to the diagnosis until the 2nd or 3rd decades. [wohproject.org]
In Bartter syndrome, affected individuals may present in infancy or early childhood with severe volume depletion and failure to thrive. Prematurity and maternal polyhydramnios are common. [doi.org]
History Part I: Pattern Recognition: Bartter and Gitelman syndromes Unexplained hypokalemia, metabolic alkalosis Normotension or mild hypotension Bartter syndrome Polyuria Polydipsia Fatigue Failure to thrive Salt cravings Muscle weakness Impaired urinary [clinicaladvisor.com]
Urogenital
- Renal Insufficiency
Progressive renal insufficiency is extremely rare. [8] Renal function is usually maintained despite long-term hypokalemia (low potassium), but progression to chronic renal insufficiency has rarely been reported. [2] [8] Some people with Gitelman syndrome [rarediseases.info.nih.gov]
In general, neither Bartter syndrome nor Gitelman syndrome typically leads to chronic renal insufficiency. [merckmanuals.com]
Progression to renal insufficiency is extremely rare in GS. As yet, only one patient who developed chronic renal insufficiency and subsequent progression to end-stage renal disease has been reported [ 19 ]. [ncbi.nlm.nih.gov]
- Urinary Retention
He did not complain of difficulty in breathing or urinary retention. There was no history of any antecedent respiratory infection, fever, diarrhoea, vomiting or any drug intake. [jpma.org.pk]
Neurologic
- Vertigo
Some isolated reports have described neurological symptoms such as ataxia, visual impairment and vertigo as well. [symptoma.com]
Clinical findings are brief episodes of fatigue, syncope, vertigo, ataxia and blurred vision; sudden cardiac death might occur. This review aims to give insight into cardiovascular implications and management of GS. [imrpress.com]
Although Gitelman's syndrome is described as an asymptomatic or benign disorder with characteristic electrolyte abnormalities, most reports of clinical series document presyncope, vertigo, ataxia, and blurred vision. [nejm.org]
- Agitation
Under this condition, hypokalemia might recover spontaneously following agitation remission. At first, we considered his electrolyte disturbance was only caused by agitation. [springerplus.springeropen.com]
Workup
A detailed medical history, clinical examination and symptomatology, as well as laboratory testing are all used to diagnose Gitelman syndrome. Laboratory blood abnormalities include:
- Hypomagnesemia: less than 0.65 mmol/L
- Hypokalemia: between 2.3 and 3.1 mmol/L
- Hypocalciuria: less than 0.5 mg/kg/day
Although low serum magnesium and urine calcium had been regarded as a necessary part of the Gitelman syndrome diagnosis, a 2004 study reported two families with a valid diagnosis of Gitelman syndrome (corroborated by genetic tests), with women presenting with hypokalemia but normal urine calcium and serum magnesium [9]. The female patients of these families were also found to exhibit less severe hypokalemia and were generally asymptomatic. Patients with Gitelman syndrome tend to respond to diuretics, which suggests that the syndrome mainly affects the distal tubules. Genetic testing to confirm a diagnosis can be performed, if indicated. The gene involved is the SLC12A3 gene, encoding for the thiazide-sensitive NaCl cotransporter (NCC); the majority of patients affected by Gitelman syndrome exhibit SLC12A3 mutations. Genetic counseling is available for families affected by Gitelman syndrome.
Differential diagnosis should include Bartter's syndrome, laxative abuse and chronic vomiting. Other diagnostic modalities, such as electrocardiography or joint magnetic resonance imaging scans (MRI) can be employed depending on the symptoms reported by each individual.
Serum
- Hyponatremia
This tubulopathy is associated with disorders of water-electrolyte homeostasis, such as metabolic alkalosis, hypokalemia, hyponatremia, hypomagnesemia and hypocalciuria. GS has an autosomal recessive inheritance. [imrpress.com]
Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. [ncbi.nlm.nih.gov]
We present the clinical case an 82-year-old female with pulmonary and digestive tract morbidities, in which the hydroelectrolitic status control was difficult due to persistently negative water balances associated with metabolic alkalosis, hyponatremia [medigraphic.com]
Gitelman syndrome : a closely associated disorder, milder than both subtypes of Bartter's syndrome Schwartz-Bartter's syndrome : a separate entity characterized by hypertonicity of urine, hyponatremia and inability to excrete water load Promoted articles [radiopaedia.org]
- Hypophosphatemia
Additionally, increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance have been reported. [ncbi.nlm.nih.gov]
A rare case of Gitelman’s syndrome with hypophosphatemia. J Coll Physicians Surg Pak. 2009;19:257-9. Lau P, Yap H. Treatment of magnesium deficiency. In: Yap HK, Liu ID, Tay WC, editors. Pediatric nephrology on-the-go. [paediatricaindonesiana.org]
- Hypouricemia
A 6-year-old Caucasian girl was admitted via the Emergency department for vomiting, and initial laboratory investigations found hyponatremia, hypokalemia, metabolic acidosis with normal anion gap, hypophosphatemia, and hypouricemia. [ncbi.nlm.nih.gov]
Treatment
Therefore, the recommended treatment has been based on potassium supplementation and a prostaglandin inhibitor; spironolactone1 is also an option, but with transient effect, and ACE inhibitors have been used in some studies.[15]The treatment is similar [patient.info]
Male patients tend to experience more severe symptoms and poor treatment effect. [ncbi.nlm.nih.gov]
Treatment: Vigorous treatment with potassium replacement is sufficient to alleviate most symptoms. Prognosis: Excellent. Ancillary treatments and support: Electrolyte monitoring. [wohproject.org]
We report a case of GS presenting in early childhood years and the consequences of delayed diagnosis and lack of treatment. [jmedicalcasereports.biomedcentral.com]
Prognosis
In general, the long-term prognosis of GS is excellent. [ncbi.nlm.nih.gov]
Prognosis To date, there is no evidence that GS affects life expectancy. The documents contained in this web site are presented for information purposes only. [orpha.net]
Prognosis - Gitelman syndrome Not supplied. Treatment - Gitelman syndrome Not supplied. Resources - Gitelman syndrome Not supplied. [checkorphan.org]
Etiology
Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria. [ncbi.nlm.nih.gov]
Etiology GS is caused by biallelic inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter NCC expressed in the apical membrane of cells lining the distal convoluted tubule. [orpha.net]
Celiac disease is an enteropathy for which the etiology is not known and where environmental, immunologic and genetic factors may all contribute to the disease. Celiac disease may lead to hypokalemia. [turkjnephrol.org]
Epidemiology
Epidemiology Gitelman's syndrome is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some can present in childhood.[8] Bartter's syndrome is rare. [patient.info]
Introduction Clinical definition a renal tubular defect affecting the distal convoluted tubules characterized by mild hypokalemia mild metabolic alkalosis significant hypomagnesemia normal blood pressure Epidemiology incidence rare 1:40,000 demographics [step1.medbullets.com]
Summary Epidemiology Gitelman syndrome (GS) prevalence is estimated at 1 to 10 per 40,000 and potentially higher in Asia. GS is arguably the most frequent inherited tubulopathy. [orpha.net]
Pathophysiology
KEYWORDS: Acid–base; Electrolytes; Gitelman syndrome; Pathophysiology; Potassium [ncbi.nlm.nih.gov]
We review the molecular pathophysiology of Gitelman syndrome and related tubular disorders and discuss management in pregnancy. [scholars.northwestern.edu]
A pathophysiological and clinical uptodate. Endocrine 2012;41:53– [clinlabnavigator.com]
By taking the quite heterogeneous presentations and the apparently different pathophysiologies as the basis, the applicability of the physiologic classification has been tested. [journals.lww.com]
Prevention
Hypomagnesemia is corrected with magnesium chloride (magnesium sulfate or oxide are avoided to prevent diarrhea) [ 7, 11 ]. Conclusion GS can present as early as two years of age. [jmedicalcasereports.biomedcentral.com]
Prevention - Gitelman syndrome Not supplied. Diagnosis - Gitelman syndrome Not supplied. Prognosis - Gitelman syndrome Not supplied. Treatment - Gitelman syndrome Not supplied. Resources - Gitelman syndrome Not supplied. [checkorphan.org]
Genetics), Clinical DNA Testing and DNA Banking - Marshfield, WI, USA TAT : 3-5 weeks price : $990.00 Gitelman Syndrome via the SLC12A3 Gene method(s): ◦ Sequencing, Next Gen PreventionGenetics (Prevention Genetics), Clinical DNA Testing and DNA Banking [genetests.org]
References
- Geven WB, Willem JL, Schroder CH. Study of the path physiology of Bartter/Gitelman's syndrome. Attempt of classification-role of renal magnesium depletion. Magnesium B. 1994;16:29–36.
- Bettinelli A, Bianchetti MG, Girardin E. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. Pediatr J. 1992;120:38–43.
- Simon DB, Nelson-Williams C, Bia MJ. Gitelman's variant of Bartters syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 1996;12:24–30.
- Gladziwa U, Schwarz R, Gitter AH. Chronic hypokalaemia of adults: Gitelman's syndrome is frequent but classical Bartter's syndrome is rare. Nephrol Dial Transplant. 1995;10:1607–1613.
- M Gjata, M Tase, A Gjata, and Zh Gjergji. Gitelman's Syndrome (Familial hypokalemia-hypomagnesemia). Hippokratia. 2007 Jul-Sep; 11(3): 150–153.
- Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O. Belgian network for study of gitelman syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007;1:1271–1283.
- Foglia PEG, Bettineli A, Tosetto C, Cortesi C, Crosazzo L, Edefonti A, Bianchetti MG. Cardiac work up in primary hypokalemia-hypomagnesemia (Gitelman syndrome) Nephrol Dial Transplant. 2004;19:1398–1402.
- Scognamiglio R, Negut C, Calò LA. Aborted sudden cardiac death in two patients with Bartter's/Gitelman's syndromes. Clin Nephrol. 2007;67:193–197.
- Lin SH, Cheng NL, Hsu YJ, Halperin ML. Intrafamiliar phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis. 2004;43:304–312.