Prenatal diagnosis of MAGED2 gene mutation causing transient antenatal Bartter syndrome.

Transient antenatal Bartter syndrome due to melanoma-associated antigen D2 gene mutation is a newly reported type of Bartter syndrome. Its characteristics include an X-linked inheritance pattern, early-onset hydramnios, and spontaneous disappearance of symptoms after childbirth. To date, there have been no reports of prenatally diagnosed cases. We herein present the case of a preterm male born to a mother with early-onset hydramnios and a family history of X-linked idiopathic hydramnios. We suspected melanoma-associated antigen D2 gene mutation and performed direct sequencing. As a result, we were able to prenatally establish a diagnosis of transient Bartter syndrome due to a melanoma-associated antigen D2 gene mutation.

Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome.

BACKGROUND: Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. METHODS: We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. RESULTS: Median age at diagnosis was 0.9 months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. CONCLUSIONS: This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses.

Two neonates with Bartter syndrome.

Bartter syndrome is an autosomal recessive disorder caused by gene mutations that involve hypokalaemia, hypochloraemia and metabolic alkalosis along with raised serum renin, hyperaldosteronism and normal blood pressure. We report two cases of neonatal Bartter syndrome. Case 1 was a product of non-consanguineous marriage and mother had unexplained polyhydramnios in pregnancy while case 2 was a product of consanguineous marriage. Both cases were diagnosed based on hypokalaemia, hypochloraemia and metabolic alkalosis along with elevated serum renin and aldosterone levels. Case 1 positively responded to indomethacin while case 2 had Protein C and S deficiency and sepsis as coexisting diseases and thus could not be given indomethacin and expired. Regular antenatal visits can help in diagnosis of the syndrome particularly if unexplained poly hydramniosis investigated .

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Unusual case of failure to thrive: Type III Bartter syndrome.

Bartter syndrome Type III is a rare autosomal recessive disorder resulting from an inherited defect in the thick ascending limb of the loop of henle of the nephrons in kidney. The typical clinical manifestations in childhood are failure to thrive and recurrent episodes of vomiting. Typical laboratory findings which help in the diagnosis are hypokalemic metabolic alkalosis, hypomagnesemia and hypercalciuria. We report a case of Type III Bartter syndrome not responding to repeated conventional treatment of failure to thrive.

Increased level of p63RhoGEF and RhoA/Rho kinase activity in hypertensive patients.

OBJECTIVE: p63RhoGEF, a guanine nucleotide exchange factor, has been reported 'in vitro' as key mediator of the angiotensin II-induced RhoA/Rho kinase activation leading to vasoconstriction and cardiovascular remodeling. We assessed p63RhoGEF gene and protein expression and RhoA/Rho kinase activity in essential hypertensive and Bartter's and Gitelman's syndrome patients, a human model opposite to hypertension; the latter have, in fact, increased plasma angiotensin II, activation of the renin-angiotensin system, yet normotension/hypotension, reduced peripheral resistance and lack of cardiovascular remodeling due to an endogenously blunted angiotensin II type 1 receptor signaling. METHODS: Mononuclear cell p63RhoGEF gene and protein expression and the phosphorylation status of the myosin phosphatase target protein-1 (MYPT-1), marker of Rho kinase activity, were assessed in essential hypertensive patients, Bartter's/Gitelman's patients and healthy individuals by quantitative real-time PCR and western blot. RESULTS: p63RhoGEF mRNA and protein level and MYPT-1 phosphorylation status were higher in hypertensive patients and lower in Bartter's/Gitelman's patients compared with healthy individuals: p63RhoGEF mRNA level: 0.59 ± 0.17 ΔΔCt vs. 0.37 ± 0.17 vs. 0.20 ± 0.19, analysis of variance (ANOVA): P <0.016; p63RhoGEF protein level 1.35 ± 0.14 vs. 1.09 ± 0.05 vs. 0.90 ± 0.09 densitometric units, ANOVA: P <0.0001; MYPT-1: 1.39 ± 0.34 vs. 1.01 ± 0.12 vs. 0.81 ± 0.06, ANOVA: P < 0.0001. p63RhoGEF mRNA was significantly correlated with both SBP and DBP in both hypertensive patients (R = 0.79, P < 0.02 and R = 0.78, P < 0.02) and in Bartter's syndrome/Gitelman's syndrome patients (R = 0.87, P < 0.001 and R = 0.86, P < 0.001), respectively. CONCLUSION: Increased p63RhoGEF mRNA and protein level and Rho kinase activity are shown for the first time in essential hypertensive patients, whereas the opposite was found in Bartter's/Gitelman's patients, a human model opposite to hypertension. These results combined with other 'in-vitro' studies strongly support the crucial importance of p63RhoGEF in Ang II-mediated signaling involved in the regulation of blood pressure and its long-term complications in humans.

Expanding the spectrum of genetic mutations in antenatal Bartter syndrome type II.

Bartter syndrome (BS) is a group of genetic disorders characterized by hypokalemic metabolic alkalosis, hyponatremia and elevated renin and aldosterone plasma concentrations. BS type II is caused by mutations in the KCNJ1 gene and usually presents with transient hyperkalemia. We report here a novel KCNJ1 mutation in a male neonate, prematurely born after a pregnancy complicated by polyhydramnios. The infant presented with typical clinical and laboratory findings of BS type II, such as hyponatremia, hypochloremic metabolic alkalosis, severe weight loss, elevated renin and aldosterone levels and transient hyperkalemia in the early postnatal period, which were later normalized. Molecular analysis revealed a compound heterozygous mutation in the KCNJ1 gene, consisting of a novel K76E and an already described V315G mutation, both affecting functional domains of the channel protein. Typical manifestations of antenatal BS in combination with hyperkalemia should prompt the clinician to search for mutations in the KCNJ1 gene first.

QT and JT dispersion and cardiac performance in children with neonatal Bartter syndrome: a pilot study.

BACKGROUND: QT dispersion and JT dispersion are simple noninvasive arrhythmogenic markers that can be used to assess the homogeneity of cardiac repolarization. The aim of this study was to assess QT and JT dispersion and their relation with left ventricular systolic and diastolic functions in children with Bartter syndrome (BS). METHODS: Nine neonatal patients with BS (median age 9.7 years) and 20 controls (median age 8 years) were investigated at rest. Both study and control subjects underwent electrocardiography (ECG) in which the interval between two R waves and QT intervals, corrected QT, QT dispersion, corrected QT dispersion, JT, corrected JT, JT dispersion and corrected JT dispersion were measured with 12-lead ECG. Two-dimensional, Doppler echocardiographic examinations were performed. RESULTS: Patients and controls did not differ for gender and for serum levels of potassium, magnesium, and calcium (p > 0.05). Both study and control subjects had normal echocardiographic examination and baseline myocardial performance indexes. The QT dispersion and JT dispersion were significantly prolonged in patients with BS compared to those of the controls {37.5 ms [interquartile range (IQR) 32.5-40] vs. 25.5 ms (IQR 20-30), respectively, p = 0.014 and 37.5 ms (IQR 27.5-40) vs. 22.5 ms (IQR 20-30), respectively, p = 0.003}. CONCLUSIONS: Elevated QT and JT dispersion during asymptomatic and normokalemic periods may be risk factors for the development of cardiac complications and arrhythmias in children with BS. In these patients the need for systematic cardiac screening and management protocol is extremely important for effective prevention.

Bartter syndrome and growth hormone deficiency: three cases.

BACKGROUND: Bartter syndrome is a rare autosomal recessive disorder characterized by hypokalemia, salt loss, and metabolic alkalosis. Short stature is one of the clinical manifestations in these children. Although polyuria, polydipsia, hypokalemia, and salt loss may be responsible for growth retardation, the exact pathogenesis of short stature in Bartter syndrome is not known. CASE DIAGNOSIS AND TREATMENT: In this study, we present three children diagnosed as having Bartter syndrome with short stature and growth hormone (GH) deficiency. After recombinant human growth hormone therapy (rhGH), their growth velocities were improved. CONCLUSIONS: These results indicate that GH deficiency may contribute to short stature in children with Bartter syndrome, and rhGH therapy would be an excellent adjunctive treatment for short children with this syndrome whose condition is resistant to conventional therapies in terms of growth.

[An analysis of hyperinsulinemia in Bartter syndrome].

OBJECTIVE: To analyse hyperinsulinemia in Bartter syndrome. METHODS: Twenty-three cases of Bartter syndrome [age (27 ± 9) years; fasting serum potassium (2.8 ± 0.5) mmol/L], 20 patients of aldosterone-producing adenoma [APA, age (45 ± 11)years, fasting serum potassium (3.0 ± 0.4) mmol/L], 20 patients of idiopathic hyperaldosteronism [IHA, age (51 ± 11) years, fasting serum potassium (3.4 ± 0.2) mmol/L] were diagnosed in Peking Union Medical College Hospital from September 2003 to May 2008. All patients underwent 3-hours oral glucose tolerance test (3hOGTT), postural stimulation test and calculated HOMA-insulin resistance (HOMA-IR) and HOMA-insulin sensitivity (HOMA-IS) by Homeostasis model. RESULTS: The insulin area under curve[(229.0 ± 162.4) mIU×L(-1)×h] was significantly higher than APA group [(121.2 ± 81.1) mIU×L(-1)×h, P < 0.05] and were similar to the aged-matched patients with IHA [(227.7 ± 158.6) mIU×L(-1)×h]. But HOMA-IR in Bartter group were similar to APA group (1.96 ± 1.14 vs 1.41 ± 0.91), and HOMA-IR in APA group was lower than IHA group (1.96 ± 1.14 vs 2.40 ± 1.60, P < 0.05). There was no deference in HOMA-IS among three groups, but APA group had lower level. In all three groups, the peak of insulin secretion was delayed. CONCLUSION: Bartter syndrome patients commonly present with hyperinsulinemia.

ACE2 and angiotensin 1-7 are increased in a human model of cardiovascular hyporeactivity: pathophysiological implications.

BACKGROUND: ACE and ACE2 produce angiotensin II (Ang II), a vasopressor that induces cardiovascular remodeling, and Ang 1-7, a vasodilator with an antiremodeling effect. While Ang 1-7 has antiarrhythmic properties, at higher concentration it may induce ventricular tachycardia and sudden death. ACE2, therefore, may play an essential role in blood pressure homeostasis, in the long-term complications of hypertension (cardiovascular remodeling), and in the induction of cardiac electric abnormalities. This study evaluated the levels of ACE2 and Ang 1-7 in Bartter's/Gitelman's patients (BS/GS) who have elevated Ang II and endogenous blockade of Ang II type 1 receptor signaling compared with healthy subjects (C) and essential hypertensives (EH). BS/ GS patients were also considered because of their predisposition to cardiac arrhythmias, which has yet to be completely clarified. METHODS: Mononuclear cell ACE2 and Ang 1-7 were evaluated using western blot. RESULTS: One-way ANOVA showed that ACE2 and Ang 1-7 levels were significantly different between the three groups (p=0.0074 and p=0.0001, respectively). Post-hoc analysis (Tukey's HSD) showed that both ACE2 (1.59+/-0.63) and Ang1-7 (2.26+/-1.18) were significantly elevated in BS/GS compared with either C (0.98+/-0.45; p=0.008; 1.12+/-0.48, p=0.002, respectively) or EH (1.06+/-0.24; p=0.043; 0.72+/-0.28; p=0.0001, respectively). ACE2 and Ang 1-7 directly correlated only in BS/GS (r=0.91, p<0.0003). CONCLUSIONS: The elevated ACE2 and Ang 1-7 in BS/ GS patients mirror those in hypertensives and are in line with the clinical, hemodynamic and pathophysiological characteristics of BS/GS, likely contributing to them. In consideration of the clinical picture of these syndromes, the opposite of hypertension, the results of this study further strengthen the importance of the ACE2/Ang 1-7 system in the regulation of vascular tone and cardiovascular biology.

Inherited renal tubular defects with hypokalemia.

Bartter's and Gitelman's syndrome are two ends of a spectrum of inherited renal tubular disorders that present with hypokalemic metabolic alkalosis of varying severity. Clinical features and associated calcium and magnesium ion abnormalities are used to diagnose these cases after excluding other commoner causes. We report on two cases, the first being a young boy, born of pregnancy complicated by polyhydramnios, who had classical dysmorphic features, polyuria, hypokalemia and hypercalciuria and was diagnosed as having Bartter's syndrome. The second patient is a lady who had recurrent tetany as the only manifestation of Gitelman's syndrome, which is an unusual presentation. Potassium replacement with supplementation of other deficient ions led to satisfactory clinical and biochemical response.

Severe failure to thrive in infant.

Failure to thrive in an infant has multiple etiologies and at times, is only manifestation of underlying serious disease. Bartter syndrome is a rare disease that manifests as failure to thrive. It can be diagnosed by a careful history, physical examination, and abnormal electrolyte pattern. It can be alleviated by appropriate management, whereas failure to recognize early can be life threatening. A case of severe failure to thrive in an infant due to neonatal form of Bartter syndrome, its manifestations, management, and outcome is presented in this article.

Side-effects of long-term prostaglandin E(1) treatment in neonates.

BACKGROUND: In some neonates suffering from ductus arteriosus dependent congenital heart defect, a Prostaglandin E(1) (PGE1) therapy longer than 2 weeks may be needed. However, PGE1 analogue compounds may produce several adverse effects. METHODS: The authors retrospectively analyzed the data of nine patients who underwent a PGE1 treatment lasting longer than 14 days. RESULTS: The leukocyte count of the patients remained high throughout the treatment period, and the proportion of neutrophils was over 50%. Transient feeding difficulty and abdominal distension, and possible signs of gastric-outlet obstruction, were observed in two cases. In the case of three patients, cortical hyperostosis developed after different cumulative doses (1584, 3384 and 4320 microg). Significant correlations were found between the doses of PGE1 and serum K(+) levels (r=-0.770, P < 0.05) and between the blood standard bicarbonate levels and PGE1 doses (r= 0.889, P < 0.01). Bartter syndrome-like condition developed in those three patients who received the largest cumulative doses. CONCLUSIONS: Fluid-electrolyte parameters must be controlled frequently in the case of each patient treated with PGE1 for longer than 2 weeks. Although the dose, the length of the therapy and individual susceptibility may be equally important, fluid-electrolyte disturbances and the development of pseudo-Bartter syndrome seem to be more dose-dependent than cortical hyperostosis.

A novel mutation in KCNJ1 in a Bartter syndrome case diagnosed as pseudohypoaldosteronism.

Bartter syndrome (BS) is a genetic disorder with hypokalemic metabolic alkalosis and is classified into five types. One of these, type II BS (OMIM 241200), is classified as neonatal Bartter syndrome, which is caused by mutations in the KCNJ1 gene. Transient hyperkalemia and hyponatremia are usually noted in the early postnatal period, but as type II BS is a relatively rare disease, its exact clinical course and genetic background have not yet been thoroughly characterized. This report concerns a male type II BS patient with a novel mutation in the KCNJ1 gene. The unique clinical findings of this case are that hyperkalemia (8.9 mEq/l), hyponatremia, and metabolic acidosis detected in the early postnatal period led to a diagnosis of pseudohypoaldosteronism (PHA). As an adolescent, however, the patient currently shows normal potassium levels and normal renal function, although with hypercalciuria and nephrocalcinosis, without having received any treatment. In such cases, KCNJ1 mutations should be suspected. In our case, genetic analysis of the KCNJ1 gene identified a novel homozygous 1-bp deletion mutation (c.607 del. C in exon 5).