A novel MAGED2 variant in a Chinese preterm newborn with transient antenatal Bartter’s syndrome with 4 years follow-up

Background Transient antenatal Bartter’s syndrome caused by MAGED2 mutation is a rare X-linked recessive renal tubular disorder. Cases reported are mostly infants, and the long-term prognosis of the disease is still under investigation. Case presentation We encountered a preterm male infant with polyhydramnios, polyuria, salt loss, hypercalciuria, nephrocalcinosis and alkalosis. Antenatal Bartter’s syndrome was suspected, but these clinical symptoms surprisingly disappeared after about 2 months. This led to the clinical diagnosis of transient antenatal Bartter’s syndrome. Gene analysis in this patient disclosed a novel variant (c.1598C > T, p.Ala533Val) in exon 12 of MAGED2 gene, and his mother was a heterozygous carrier. This patient was followed up in clinic for 4 years without recurrence of imbalance of potassium, sodium and chloride. His height and weight were in normal range, and all laboratory examinations and nephrotic ultrasound were also normal. Conclusions We reported the first Chinese case of transient antenatal Bartter’s syndrome caused by MAGED2 mutation. The 4-year follow-up of our case further demonstrates the benign prognosis of the disease and indicates that early recognition of this phenotype could avoid unnecessary treatments.

EXPRESS: A Rare Case of Persistent Hyperkalaemia

Hyperkalaemia is a common biochemical finding that can allude to pre-analytical or truly pathological causes. Here, we present a case of a 41-year-old female patient who has regularly presented with incidences of isolated hyperkalaemia since 2012, with otherwise normal renal function and no other associated symptoms. Investigations into the patient’s family history revealed similar biochemical findings in her brother and eldest son. Familial causes of hyperkalaemia were investigated and an eventual diagnosis of pseudo-hypoaldosteronism type 2C was established. This is a rare congenital renal tubular disorder, also known as Gordon syndrome, that can cause a characteristic triad of symptoms that include hyperkalaemia, metabolic acidosis and hypertension. The presence and severity of each of these symptoms is dependent upon the disease-causing mutation that occurs in WNK4, WNK1, CUL3 or KLHL3 genes. These mutations alter the regulation of sodium/chloride co-transporter (NCC) expression on the luminal membrane of the principal cells of the distal convoluted tubule, disrupting normal homeostatic regulation of electrolyte reabsorption and excretion. The resolution for treating this condition is the administration of a thiazide diuretic, which directly counteracts the effects of NCC co-transporter overexpression and consequently aims to resolve the symptoms that arise as a result of this aberrant signalling. The case described here uniquely presents an extremely rare pathogenic variant in the conserved acidic motif of WNK1 resulting in a clear electrolyte phenotype with no hypertension.

Gitelman syndrome and ectopic calcification in the retina and joints

ABSTRACT Gitelman syndrome is a rare inherited renal tubular disorder with features that resemble thiazide use, including a hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria, a low or normal blood pressure, and hyperreninemia and hyperaldosteronism. Treatment is primarily correction of the K and Mg levels. The diagnosis is confirmed with genetic testing but Gitelman syndrome is often not suspected. However the association with ectopic calcification in the retina, blood vessels and chondrocalcinosis in the joints is a useful pointer to this diagnosis. Bilateral symmetrical whitish deposits of calcium pyrophosphate are visible superotemporally on ophthalmoscopy and retinal photography but are actually located beneath the retina in the sclerochoroid. Optical coherence tomography is even more sensitive for their detection. These deposits increase in size with time, but the rate of progression slows with long-term correction of the hypomagnesemia. Calcification may be complicated by atrophy of the overlying retina and visual loss. The deposits often correlate with ectopic calcification in the aorta, coronary and cerebral vessels. Chondrocalcinosis occurs in the large joints such as the knees. Ectopic calcification in Gitelman syndrome indicates the need for more aggressive management of Ca and Mg levels. Calcification is much less common in Bartter syndrome which itself is rarer and associated less often with hypomagnesemia.

Bartter Syndrome in Children; A Cause of Severe Hypokalemic Metabolic Alkalosis: Clinical Case Report and Literature Review

Bartter syndrome is an inherited renal tubular disorder caused by a defective salt reabsorption in the thick ascending limb of loop of Henle. It characterized by urinary loss of sodium, potassium, and chloride; hypokalemic metabolic alkalosis; normal blood pressure, high plasma levels of renin and aldosterone. There is phenotypical and genetic variability of Bartter syndrome since were identified five genes responsible for five different forms of Bartter syndrome. The objective of this work is to report a clinical case to study the pathophysiological, clinical, biological and therapeutic features of this syndrome. Materials and Methods: We reported a case of 04-month-old male infant admitted for acute dehydration secondary to polyuro-polydipsia syndrome and vomiting. In clinical presentation the patient had a dysmorphic syndrome with triangular face, protruding ears and flattened nasal root. Laboratory tests revealed hypokalemia, hyponatremia, metabolic alkalosis and hypercalciuria. Treatment with indomethacin was started at 1 mg/kg per day with favorable outcome.

A highly unusual case of osmotic demyelination syndrome and extrapontine myelinolysis in a 3-month-old infant with Bartter syndrome

Bartter syndrome (BS) is a rare autosomal recessive renal tubular disorder characterized by acute electrolyte imbalance, and similarly, osmotic demyelination syndrome (ODS) is a rather rare complication occurring during electrolyte imbalance. The pathological features of ODS include central pontine myelinolysis and extrapontine myelinolysis (EPM), which consist of severe damage to the myelin sheath of neurons. ODS is very rare in children. We describe a case of a 3-month-old infant with ODS and EPM associated with undiagnosed BS. ODS developed because of a sudden change in electrolyte levels and osmolality caused by acute dehydration during a gastrointestinal infection episode. Undiagnosed, untreated, and non-balanced BS was the cause of the neurological complication. Our patient represents the first case of ODS in BS, the ninth case of ODS in an infant less than one year old, and the third case of isolated EPM in such a young patient. This case report reminds us that in rare diseases, young patients tend to have genetic components.

Severe Polyhydramnios with Consistent Fetal Full Bladder: A Novel Sign of Antenatal Bartter's Disease

Bartter's disease, an inherited renal tubular disorder is due to a defect in ion transport across the ascending limb of the loop of Henle leading to failure of the ability of kidneys to concentrate urine and hence polyuria. We present three fetuses of mothers with severe polyhydramnios with normal maternal blood sugar profile, routine Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) serology. The ultrasound showed no structural anomaly in the fetus, but consistent overdistended bladder with severe polyhydramnios was observed without any evidence of obstructive uropathy. The biochemical test on amniotic fluid was suggestive of Bartter's disease in case 1 and borderline in case 2, and next-generation sequencing confirmed a mutation of KCNJ1 associated with Bartter's disease Type II in case 1 and a mutation in SLC21A1 in case 2. Amniotic fluid biochemistry was inconclusive in case 3. A consistent full bladder with severe polyhydramnios with onset around 24 to 25 weeks was a novel finding which was observed due to fetal polyuria and can be used as a clue to investigate cases with severe polyhydramnios with no structural anomaly. Antenatal diagnosis will help in the proper management of child and genetic counseling for the next pregnancy.

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

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

Bartter Syndrome Type 1 Presenting as Nephrogenic Diabetes Insipidus

Bartter syndrome (BS) type 1 (OMIM #601678) is a hereditary salt-losing renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, polyuria, recurrent vomiting, and growth retardation. It is caused by loss-of-function mutations of the SLC12A1 gene, encoding the furosemide-sensitive Na-K-Cl cotransporter. Recently, a phenotypic variability has been observed in patients with genetically determined BS, including absence of nephrocalcinosis, hypokalemia, and/or metabolic alkalosis in the first year of life as well as persistent metabolic acidosis mimicking distal renal tubular acidosis. We report the case of a child with a genetically determined diagnosis of Bartter syndrome type 1 who presented with a phenotype of nephrogenic diabetes insipidus, with severe hypernatremia and urinary concentrating defect. In these atypical cases, molecular analysis is mandatory to define the diagnosis, in order to establish the correct clinical and therapeutic management.