Neonatal systemic pseudohypoaldosteronism type I / 中国当代儿科杂志

An 18-day-old male infant was admitted to the hospital due to recurrent hyperkalemia for more than 10 days. The neonate had milk refusal and dyspnea. The blood gas analysis revealed recurrent hyperkalemia, hyponatremia and metabolic acidosis. Adrenocortical hormone replacement therapy was ineffective. Additional tests showed a significant increase in aldosterone levels. Family whole exome sequencing revealed that the infant had compound heterozygous in the SCNNIA gene, inherited from both parents. The infant was diagnosed with neonatal systemic pseudohypoaldosteronism type I. The infant's electrolyte levels were stabilized through treatment with sodium polystyrene sulfonate and sodium supplement. The infant was discharged upon clinical recovery. This study provides a focused description of differential diagnosis of salt-losing syndrome in infants and introduces the multidisciplinary management of neonatal systemic pseudohypoaldosteronism type I.

Clinical features and genetic results of 6 cases with pseudohypoaldosteronism type 1 and literature review / 中华实用儿科临床杂志

Objective:To summarize clinical features, diagnosis, treatment, and follow-up of children with pseudohypoaldosteronism type 1 (PHA1) and review relevant literatures to improve the understanding of the disease and reduce misdiagnosis.Methods:Six children with the main performance of salt losing treated in the Shanghai Children′s Hospital from January 2015 to December 2018, who were diagnosed as PHA1 after relevant auxiliary examinations and genetic tests.They were classified and analyzed for their treatment courses and follow-up prognosis.Results:Six children with PHA1 had varying degrees of salt losing, dehydration and infection.After the examination, 3 cases with urinary system malformations were diagnosed as secondary PHA1.Genetic testing of 2 cases revealed 2 hete-rozygous mutations c. 1439+ 1G>C and c. 875+ 1G>A in the intron region of the SCNN1A gene, and they were diagnosed as multiple target organ defect/systemic PHA1 according to American College of Medical Genetics and Genomics(ACMG) guidelines.The other case failed to be examined by genetic testing due to the refusal of parents, and was finally diagnosed as renal PHA1 according to clinical diagnosis and treatment.Conclusions:PHA1 is a rare cause of infant salt-losing syndrome, renal and secondary PHA1 children can recover quickly after sodium supplementation and the secondary factors are removed; while multiple target organ defect/systemic PHA1 has severe clinical manifestations, electrolyte imbalance is not easy to correct, and fatal arrhythmia is prone to occur, the mortality rate is high.It is easy to be misdiagnosed in clinical practice.Auxiliary examination and genetic testing can help to diagnose and classify PHA1, as well as individualized treatment.

Transient Pseudohypoaldosteronism in a 5-Month-old Infant Manifested as a Failure to Thrive / 이화의대지

Pseudohypoaldosteronism (PHA) in infants is manifested by presence of hyperkalemia, hyponatremia, and metabolic acidosis. At initial stages, PAH is generally suspected as congenital adrenal hyperplasia. Transient PHA has been reported in infants with urinary tract infection and urinary tract malformation. We report a case of 5-month-old infant with failure to thrive and finally diagnosed with transient PHA due to urinary tract infection with vesicoureteral reflux.

Pseudohipoaldosteronismo y aparente exceso de mineralocorticoides: cara y ceca en dos pacientes pediátricos / Pseudohypoaldosteronism and apparent mineralocorticoid excess: two faces, two pediatric patients

Los síndromes endocrinológicos con hipofunción o hiperfunción con niveles paradójicos de dosajes hormonales han sido bien caracterizados en los últimos años del siglo XX, a partir del desarrollo de técnicas genéticas y moleculares. Presentamos dos pacientes con pseudohipoaldosteronismo y aparente exceso de mineralocorticoides como síndromes en espejo, con la intención de alertar al médico clínico respecto de su consideración como entidad diagnóstica en niños con alteraciones hidroelectrolíticas. (AU)

Endocrinological syndromes with underactive or overactive hormonal levels with paradoxical dosages have been well characterized over the years of the twentieth century, from the development of genetic and molecular techniques. We present two patients with pseudohypoaldosteronism and apparent mineralocorticoid excess as mirror syndromes, with the aim to alert the clinician regarding their consideration as a diagnostic entity in children with fluid and electrolyte disturbances. (AU)

Pseudohypoaldosteronism in a newborn male with functional polymorphisms in the mineralocorticoid receptor genes

Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.

Pseudohypoaldosteronism Type 1: Management Issues.

We report a newborn girl with life-threatening hyperkalemia and salt wasting crisis due to severe autosomal recessive multiple target organ dysfunction pseudohypoaldosteronism type 1 (MTOD PHA1). She was aggressively managed with intravenous fluids, potassiumlowering agents, high-dose sodium chloride supplementation and peritoneal dialysis. Genetic analysis revealed a homozygous mutation of the α- ENaC (epithelial Na+ channel) gene. She had a stormy clinical course with refractory hyperkalemia and prolonged hospitalization. Eventually, she succumbed to pneumonia and septicemia at 4 months of age. This is probably the first case of PHA1 confirmed by genetic analysis from India.

A Case of Autosomal Recessive Pseudohypoaldosteronism Type 1 with a Novel Mutation in the SCNN1A Gene

Pseudohypoaldosteronism (PHA) is a condition characterized by renal salt wasting, hyperkalemia, and metabolic acidosis due to renal tubular resistance to aldosterone. Systemic PHA1 is a more severe condition caused by defective transepithelial sodium transport due to mutations in the genes encoding the alpha (SCNN1A), beta (SCNN1B), or gamma (SCNN1G) subunits of the epithelial sodium channel at the collecting duct, and involves the sweat glands, salivary glands, colon, and lung. Although systemic PHA1 is a rare disease, we believe that genetic studies should be performed in patients with normal renal function but with high plasma renin and aldosterone levels, without a history of potassium-sparing diuretic use or obstructive uropathy. In the present report, we describe a case of autosomal recessive PHA1 that was genetically diagnosed in a newborn after severe hyperkalemia was noted.

A Case of Autosomal Recessive Pseudohypoaldosteronism Type 1 with a Novel Mutation in the SCNN1A Gene

Pseudohypoaldosteronism (PHA) is a condition characterized by renal salt wasting, hyperkalemia, and metabolic acidosis due to renal tubular resistance to aldosterone. Systemic PHA1 is a more severe condition caused by defective transepithelial sodium transport due to mutations in the genes encoding the alpha (SCNN1A), beta (SCNN1B), or gamma (SCNN1G) subunits of the epithelial sodium channel at the collecting duct, and involves the sweat glands, salivary glands, colon, and lung. Although systemic PHA1 is a rare disease, we believe that genetic studies should be performed in patients with normal renal function but with high plasma renin and aldosterone levels, without a history of potassium-sparing diuretic use or obstructive uropathy. In the present report, we describe a case of autosomal recessive PHA1 that was genetically diagnosed in a newborn after severe hyperkalemia was noted.

Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism (PHA), a rare syndrome of systemic or renal mineralocorticoid resistance, is clinically characterized by hyperkalemia, metabolic acidosis, and elevated plasma aldosterone levels with either renal salt wasting or hypertension. PHA is a heterogeneous disorder both clinically and genetically and can be divided into three subgroups; PHA type 1 (PHA1), type 2 (PHA2) and type 3 (PHA3). PHA1 and PHA2 are genetic disorders, and PHA3 is a secondary disease of transient mineralocorticoid resistance mostly associated with urinary tract infections and obstructive uropathies. PHA1 includes two different forms with different severity of the disease and phenotype: a systemic type of disease with autosomal recessive inheritance (caused by mutations of the amiloride-sensitive epithelial sodium channel, ENaC) and a renal form with autosomal dominant inheritance (caused by mutations of the mineralocorticoid receptor, MR). In the kidneys, the distal nephron takes charge of the fine regulation of water absorption and ion handling under the control of aldosterone. Two major intracellular actors necessary for the action of aldosterone are the MR and the ENaC. Impairment of the intracellular aldosterone signal transduction pathway results in resistance to the action of mineralocorticoids, which leads to PHA. Herein, ion handling the distal nephron and the clinico-genetic findings of PHA are reviewed with special emphasis on PHA type 1.

Transient Pseudohypoaldosteronism in an Infant with Vesicoureteral Reflux

A 6-month-old boy with vesicoureteral reflux exhibited features of transient type 1 pseudohypoaldosteronism (PHA) in the course of urinary tract infection. PHA presents hyponatremia, hyperkalemia, and metabolic acidosis, accompanying with high urinary sodium, low potassium excretion, and high plasma aldosterone concentration. Severe electrolyte disturbance can occur in an infant with vesicoureteral reflux because of secondary PHA. Appropriate treatment of dehydration and sodium supplementation induces rapid improvement of electrolyte imbalance and metabolic acidosis resulting from secondary PHA associated with vesicoureteral reflux.

WNK4 kinase-mediated inhibitory effect on expression of BK channel via lysosomal pathway / 中华肾脏病杂志

Objective To investigate the mechanism underlying the WNK4 kinasemediated inhibitory effect on BK channel. Methods Cos-7 cells were cotransfected with BK in combination with either CD4 (control group) or wild type WNK4 (WNK4-WT).Immunostaining and confocal microscopy,chemiluminescence,Western blotting analysis were then employed to determine the BK localization in cells,BK surface expression and total protein level,respectively.To further investigate whether the reduction of BK protein expression is due to an increase in degradation through a lysosomal pathway,BK protein level was determined after treated with bafilomycin A1(Baf A1),a proton pump inhibitor affecting lysosomal degradation. Results Immunostaining and confocal microscopic study showed that BK was localized both in plasma membrane and cytosol in the control group.After cells transfected with WNK4-WT,BK expression was markedly reduced.Chemiluminescent assay found that BK surface expression level was 299.9±18.6 in the control group,whereas it was significantly reduced (148.4±13.7,P＜0.01) in the WNK4-WT group.Western blotting analysis showed that total BK protein level was markedly reduced in the presence of WNK4-WT compared to the control group.WNK4-WT was shown to significantly reduce the BK total protein level (42.3％±15.2％) compared to the control group (100％) (P＜0.01).When the cells was treated with Bafilomycin A1 (Baf A1,0.5 μmol/L),WNK4-mediated reduction in BK protein was reversed (82.2％±12.1％,P＜0.05). Conclusions WNK4 inhibits total and surface protein expression of BK in Cos-7 cells whick is likely due to an increase in BK degradation through a lysosomal pathway.

Presentación de casos clínicos Seudohipoaldosteronismo de tipo 1: una emergencia hidroelectrolítica infrecuente. Comunicación de cuatro casos / Pseudohypoaldosteronism type 1: an uncommon electrolyte emergency. Report of four cases

El seudohipoaldosteronismo de tipo 1 es un síndrome infrecuente de resistencia a la aldosterona que se manifiesta con pérdida salina, hiponatremia, hiperpotasemia, acidosis metabólica hiperclorémica e hiperaldosteronismo hiperreninémico. El síndrome puede ser genético; secundario a uropatías e infección urinaria entre otras causas o presentarse esporádicamente. La pérdida salina puede ser sistémica y grave o localizada a nivel renal, por lo general, con mejor pronóstico. El cuadro clínico se manifiesta predominantemente en los primeros siete meses de vida; un marcado retraso pondoestatural y vómitos recurrentes suelen ser los signos clínicos habituales, rara vez se presenta como una emergencia hidroelectrolítica en forma de shock hipovolémico, arritmias cardíacas hiperpotasémicas y crisis convulsiva por hiponatremia. Se presentan cuatro pacientes que debutaron como una emergencia hidroelectrolítica.

Pseudohypoaldosteronism type 1 is a rare syndrome of resistance to aldosterone manifested by salt wasting, hyponatremia, hyperkalemia, hyperchloremic metabolic acidosis, and hiperreninemic hyperaldosteronism. The syndrome may be genetic, secondary to uropathies and urinary tract infection among other causes or it may occur sporadically. The salt wasting may be systemic and severe or localized to the kidney usually with better prognosis. The clinical picture is prevalent in the first seven months of life, failure to thrive and recurrent vomiting are usually the common clinical signs, an electrolyte emergency in the form of hypovolemic shock, hyperkalemic cardiac arrhythmias and hyponatremic seizures is rare. Four patients presenting with an electrolyte emergency are reported.

A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene / 소아과

Pseudohypoaldosteronism type 1 (PHA1) is a rare form of mineralocorticoid resistance characterized in newborns by salt wasting with dehydration, hyperkalemia and failure to thrive. This disease is heterogeneous in etiology and includes autosomal dominant PHA1 owing to mutations of the NR3C2 gene encoding the mineralocorticoid receptor, autosomal recessive PHA1 due to mutations of the epithelial sodium channel (ENaC) gene, and secondary PHA1 associated with urinary tract diseases. Amongst these diseases, autosomal dominant PHA1 shows has manifestations restricted to renal tubules including a mild salt loss during infancy and that shows a gradual improvement with advancing age. Here, we report a neonatal case of PHA1 with a NR3C2 gene mutation (a heterozygous c.2146_2147insG in exon 5), in which the patient showed failure to thrive, hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone levels. This is the first case of pseudohypoaldosteronism type 1 confirmed by genetic analysis in Korea.

Pseudohypoaldosteronism in a premature neonate with severe polyhydramnios in utero / 소아과

We report a case of a premature newborn baby who presented with hyponatremia, hyperkalemia, and metabolic acidosis accompanied by severe polyhydramnios in utero. The baby was diagnosed with pseudohypoaldosteronism on the basis of normal 17-hydroxyprogesterone levels, elevated aldosterone, and clinical symptoms. His serum electrolyte levels were corrected with sodium chloride supplementation. Sodium supplementation was reduced gradually and discontinued at 5 months of age. At 5 months, the child was able to maintain normal serum electrolyte levels without oral sodium chloride supplementation, and showed normal physical and neurological development. This case illustrates that pseudohypoaldosteronism must be considered if a newborn infant with an antenatal history of severe polyhydramnios shows excessive salt loss with normal levels of 17-hydroxyprogesterone.

A Case of Pseudohypoaldosteronism Type l Diagnosed after Infancy / 대한소아내분비학회지

Pseudohypoaldosteronism (PHA) type l is a rare neonatal disease characterized by salt wasting, dehydration, hyperkalemia and metabolic acidosis. It is unresponsive to mineralocorticoid treatment with elevated aldosterone concentration. The three different modes of inheritance has been described. The autosomal dominant form has a mild clinical course and gradually improves with age. In this form, resistance to aldosterone seems to be restricted to the kidney. The autosomal recessive form displays generalized aldosterone resistance including kidney, colon, lung, sweat and salivary gland system. This form is more severe and requires life-long supplement with high-dose salt. The sporadic form is mild and resembles the autosomal dominant form. In this paper, we describe a male patient diagnosed as PHA type l at the age of 19 months. He presented with recurrent vomiting, diaphoresis accompanying hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin activity and aldosterone level. Ultimately he has improved with treatment by oral sodium bicarbonate.

A case of idiopathic renal hypouricemia / 소아과

Idiopathic renal hypouricemia is a disorder characterized by impaired urate handling in the renal tubules. This disease usually produces no symptoms, but hematuria, uric acid nephrolithiasis or acute renal failure may develop. A defect in the SLC22A12 gene, which encodes the human urate transporter, is the known major cause of this disorder. We describe a 10-month-old boy with idiopathic renal hypouricemia. He was diagnosed with transient pseudohypoaldosteronism at admission, but hypouricemia was accidentally found through follow-up study. By gene analysis, his diagnosis was confirmed to idiopathic renal hypouricemia. In addition, we report a mutation in the human urate transporter 1 (hURAT1) gene identified in his family.

Pseudohipoaldosteronismo transitorio secundario a pielonefritis con reflujo vesicoureteral severo en un lactante

Resumen El pseudohipoaldosteronismo (PHA) secundario transitorio aparece como consecuencia de la resistencia del túbulo renal a la acción de la aldosterona en niños con infecciones del tránsito urinario y/o uropatía obstructiva. Presentamos el caso clínico de un lactante de 4 meses, que se presenta con un segundo episodio de deshidratación, hiperkalemia, hiponatremia y acidosis metabólica habiéndose descartado una hiperplasia suprarrenal congénita mediante valores plasmáticos de ACTH, 17-OH progesterona y cortisol normales. El urocultivo confirmó una infección del tracto urinario (ITU) a enterobacter, y los estudios anatómicos mostraron una ureterohidronefrosis izquierda con reflujo vesicoureteral (RVU) grado V. El centellograma con DMSA mostró un riñón izquierdo hipoplásico, con aporte de 13% a la funcionalidad renal total. El PHA secundario fue confirmado con niveles de renina y aldosterona plasmática elevados. Se realizó tratamiento médico-quirúrgico, con nefrectomía izquierda cursando con buena evolución clínica y normalización de los exámenes de laboratorio.

Summary Secondary transitory pseudohypoaldosteronism (PHA) appears as a consequence of a tubular renal resistance to aldosterone in children with urinary infections and/or obstructive uropathy. The story of a 4 month-old child who had its second episode of dehydration, hyperkalemia, hyponatremia and metabolic acidosis without congenital suprarenal hyperplasia with normal ACTH, 17-hydroxiprogesterone and cortisol is presented. Urine culture showed Enterobacter and the studies revealed a grade V reflux. The DMSA renal scan showed a hypoplasic left kidney with an overall function of 13%. The secondary PHA was confirmed with elevated levels of renin and aldosterone. Medical and surgical treatment was realized with left nephrectomy with good evolution afterwards and normalization of lab studies.

Meconium Ileus Combined with Pseudohypoaldosteronism Type Ⅰ in 1 Child / 实用儿科临床杂志

Objective To improve the recognition of meconium ileus and pseudohypoaldosteronism type Ⅰ and to explore the relationship between neonatal meconium ileus and cystic fibrosis.Methods The clinical and follow-up data of a premature infant with meconium ileus and pseudohypoaldosteronism type Ⅰ was analyzed.Relevant literature was reviewed.Results The child was a very low-birth weight premature infant who didn′t pass meconuim within 24 hours of birth and persistent abdominal distention was noted.Laparotomy was performed on day 4.Thick and inspissated meconium was found in the ileum with perforation.The atretic intestine was resected,and a double-barreled enterostomies was performed.On day 30,the child presented hyponatremia,hyperkalemia,high levels of plasma renin and aldosterone and was given 9 g/L salt supplementation.At 6-month age,9 g/L salt supplementation was discontinued.Anastomosis was performed at 8-month age.The child recovered with a good prognosis whose catch-up growth was obtained at 18-month age and didn′t pre-sent manifestations of cystic fibrosis.Conclusions This case could be diagnosed as meconium ileus and pseudohypoaldosteronism type Ⅰ.The relationship between neonatal meconium ileus and cystic fibrosis is different in China and the regions of Caucasian.

A Case of Transient Pseudohypoaldosteronism Secondary to Ureteropelvic Junction Obstruction

We report a 2-month-old boy who presented with severe hyponatremia and hyperkalemia secondary to ureteropelvic junction(UPJ) obstruction. By prenatal ultrasonography at 19 weeks of gestation, severe hydronephrosis was found which was confirmed postnatally. Pyeloplasty was done on the 45th day of life, and fifteen days after pyeloplasty, non-bilious vomiting, decreased activity and dehydration developed. Severe hyponatremia and hyperkalemia were observed, as a result of elevated serum aldosterone and plasma renin activity. The anterior posterior pelvic diameter(APPD) and Society for Fetal Urology(SFU) grade measured showed no interval change before and after pyeloplasty. Pseudohypoaldosteronism was diagnosed, and 2M NaCl was administrated orally for 7 days. The electrolyte imbalance was corrected, and 8 weeks later, the elevated levels of aldosterone and plasma renin activity were normalized. The left hydronephrosis was improved at 5 months of age. We hereby report a transient pseudohypoaldosteronism secondary to UPJ obstruction with a review of the literature.

Heterozygous Mutations of The Gene for Kir 1.1 (ROMK) in Antenatal Bartter Syndrome Presenting with Transient Hyperkalemia, Evolving to a Benign Course

Bartter-like syndrome encompasses a set of inherited renal tubular disorders associated with hypokalemic metabolic alkalosis, renal salt wasting, hyperreninemic hyperaldosteronism, and normal blood pressure. Antenatal Bartter syndrome, a subtype of Bartter-like syndrome, is characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. Mutations in the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and ATP-sensitive inwardly rectifying potassium channel (ROMK) of the thick ascending limb of Henle's loop have been identified in the antenatal Bartter syndrome. We report the identification of two heterozygous mutations of the gene for Kir 1.1 (ROMK) from an antenatal Bartter syndrome patient who presented at birth with mild salt wasting and a biochemical findings that mimicked primary peudohypoaldosteronism type 1, such as hyperkalemia and hyponatremia, and evolved to a relatively benign course. We have identified amino acid exchanges Arg338Stop and Met357Thr in the gene exon 5 for ROMK by PCR and direct sequencing. Both mutations alter the C-terminus of the ROMK protein, and can affect channel function.