Salt-Losing Syndrome in a Girl with Type I and II Pseudohypoaldosteronism.

BACKGROUND Pseudohypoaldosteronism (PHA) is characterized by renal tubular resistance to aldosterone and leads to hyponatremia, hyperkalemia, and metabolic acidosis. PHA is divided into 2 types: PHAI and PHAII. PHAI can be dominant (systemic disease) or recessive (renal form). PHAII causes hypertension with hyperkalemia and is recognized mostly in adults. PHA can be a life-threatening disease due to salt-wasting syndrome and severe hypovolemia. CASE REPORT We describe the case of a 2-month-old girl who was admitted to our hospital with hypovolemic shock due to salt-wasting syndrome. Laboratory tests revealed severe electrolyte abnormalities: hyponatremia (Na-116 mmol/L), hyperkalemia (K-10 mmol/L) and metabolic acidosis (pH-7.27; HCO3-12 mmol/L). Serum aldosterone was >100 ng/dL. Genetic analysis confirmed mutations in SCNN1A and CUL3 gene responsible for PHAI and PHAII. Supplementation with NaCl, pharmacological treatment of hyperkalemia, and restriction of potassium in the diet resulted in the normalization of serum electrolytes and proper future development. CONCLUSIONS Pseudohypoaldosteronism should always be considered in the differential diagnosis of hyponatremia and hyperkalemia in children. Salt loss syndrome can lead to hypovolemic shock and, when unrecognized and untreated, to death of a child due to arrythmias and brain edema. The presence of 2 types of PHA in the same patient increases the risk of salt loss and at the same time significantly increases the risk of hypertension because of genetic predisposition and regular diet. Increased salt concentration in sweat and saliva may suggest pseudohypoaldosteronism.

TRANSIENT PSEUDOHYPOALDOSTERONISM SECONDARY TO URINARY TRACT INFECTION IN A MALE INFANT WITH UNILATERAL HYDRONEPHROSIS DUE TO PRIMARY OBSTRUCTIVE MEGAURETER: A CASE REPORT.

We present a case of transient form of type 1 pseudohypoaldosteronism (S-PHA) in a 1.5-month-old male infant who presented with lethargy, failure to thrive, severe hyponatremia (Na=118 mmol/L), hypochloremia (Cl=93 mmol/L) and fever due to urinary tract infection. Potassium levels were normal. Markedly elevated serum aldosterone level and elevated serum renin confirmed the diagnosis of pseudohypoaldosteronism. Renal ultrasound showed grade III hydronephrosis on the left kidney while contrast-enhanced voiding urosonography excluded the existence of vesicoureteral reflux, which raised suspicion of obstructive uropathy at the level of vesicoureteral junction. Serum sodium normalized after several days of intravenous fluids and antibiotic therapy, after which oral supplementation of sodium was introduced. The levels of 17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol and thyroid-stimulating hormone were normal. Functional magnetic resonance urography conducted at the age of 3 months confirmed the diagnosis of primary congenital obstructive megaureter and the infant was referred to a pediatric surgeon. Although a rare occurrence, S-PHA can be a potentially life-threatening condition in infants if not recognized and treated appropriately. Therefore, serum concentrations of electrolytes should be obtained in every child diagnosed with obstructive anomaly of the urinary tract and/or acute cystopyelonephritis. On the other hand, every child diagnosed with S-PHA should be evaluated for obstructive anomaly of the urinary tract.

Metabolic Acidosis, Hyperkalemia, and Renal Unresponsiveness to Aldosterone Syndrome: Response to Treatment with Low-Potassium Diet.

Gordon syndrome involves hyperkalemia, acidosis, and severe hypertension (HTN) with hypercalciuria, low renin and aldosterone levels. It is commonly observed in children and adolescents. Such patients respond successfully to sodium restriction and thiazide diuretics. In this article, we present three cases of metabolic acidosis, hyperkalemia, and renal unresponsiveness to aldosterone (MeHandRU Syndrome). All three patients did not have HTN or hypercalciuria and demonstrated normal renin and aldosterone levels. These patients did not respond to thiazide-type diuretic therapy and salt restriction. Two males (aged 55- and 62-year) and a female patient (aged 68-year) presented to the clinic with unexplained hyperkalemia (5.9 mEq/L, 5.9 mEq/L and 6.2 mEq/L, respectively). On physical examination, blood pressure (BP) was found to be normal (<140/90 mm Hg). Over the counter potassium supplement, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretic use, as well as hyporeninemic hypoaldosteronism states such as diabetes mellitus were excluded. Plasma renin and aldosterone levels were normal. All three patients had low transtubular potassium gradient, despite high serum potassium levels. None of the patients reported a family history of hyperkalemia or kidney failure. All failed to demonstrate a response to hydrochlorothiazide and salt restriction. After careful consideration, strict low potassium diet (<2 g/day) was initiated in consultation with the dietician. Diuretic therapy was discontinued while BP remained within normal range (<140/90 mm Hg). At eight weeks, all three patients demonstrated normalization of potassium and correction of acidosis. At follow-up of six months, all patients are maintaining a normal potassium level. We suggest that potassium restriction can be successful in patients presenting with MeHandRU syndrome.

Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout.

The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the αENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion of αENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa+)/low potassium (LK+) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the γENaC subunit in the PHA-I phenotype. Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking αENaC or ßΕΝaC, an HNa+/LK+ diet did not normalize plasma potassium (K+) concentration or increase NCC activation. However, when K+ was eliminated from the diet at the time that γENaC was deleted, plasma K+ concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced ßENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K+ concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na+ balance in γENaC-deficient mice.

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, potassium-lowering 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.

Clinical and molecular analysis of six Japanese patients with a renal form of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1.

Life threatening hyperkalemia in a neonate with pseudo-hypoaldosteronism.

Pseudohypoaldosteronism type 1 is a rare disorder characterized by renal resistance to aldosterone which may present with a salt wasting crisis in infancy. We report a neonate with hyponatremia, severe dehydration and refractory life threatening hyperkalemia who was treated with dietary sodium chloride supplementation, potassium binding resins and fluid replacement therapy which proved to be lifesaving.

[Pseudohypoaldosteronisme type I: a rare cause of failure to thrive]. / Une cause rare de stagnation pondérale à la naissance : le pseudohypoaldostéronisme de type I.

We report on a boy, born on term, presenting with a weight loss and a persistent failure to thrive after 10 days despite a normal behavior under bottle-feeding. The clinical examination was normal and biological assessment revealed hyponatremia with hyponatriuria, normal kaliemia and elevated aldosterone values, leading to type I pseudohypoaldosteronism diagnosis. Treatment with salt supplementation allowed growth improvement. The diagnosis was confirmed by the identification of a mutation in the mineralocorticoid receptor. This change was also found in several family members.

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.

Structural chromosome disruption of the NR3C2 gene causing pseudohypoaldosteronism type 1 presenting in infancy.

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Critical points in the management of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA-1, MIM #264350) is caused by defective transepithelial sodium transport. Affected patients develop life-threatening neonatal-onset salt loss, hyperkalemia, acidosis, and elevated aldosterone levels due to end-organ resistance to aldosterone. In this report, we present a patient diagnosed as PHA-1 who had clinical and laboratory findings compatible with the diagnosis and had genetically proven autosomal recessive PHA-1. The patient received high doses of sodium supplementation and potassium-lowering therapies; however, several difficulties were encountered in the management of this case. The aim of this presentation was to point out the potential pitfalls in the treatment of such patients in the clinical practice and to recommend solutions.

A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding α-subunit of ENaC (α-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt-losing nephropathy. In vitro expression of the αSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC.

Increased Na reabsorption via the Na-Cl cotransporter in autosomal recessive pseudohypoaldosteronism.

BACKGROUND: The autosomal recessive form of pseudohypoaldosteronism type 1 (AR-PHA1) is caused by loss-of-function mutations in the epithelial sodium channel subunit genes and is characterized by a multisystemic and lifelong severe salt-wasting tendency. However, we observed a male AR-PHA1 patient who exhibited less frequent salt wasting with advancing age, despite the cessation of daily salt supplementation. OBJECTIVE: To elucidate the mechanism for the above phenomenon. METHODS: We evaluated the sodium-reabsorption ability of his distal nephrons (from the distal convoluted tubules to the collecting ducts) and compared it to that of a patient with the dominant form of PHA1 (AD-PHA1) carrying a heterozygous NR3C2 (mineralocorticoid receptor) gene mutation. In addition, immunoblotting of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) protein was conducted using urine samples from the AR- and AD-PHA1 patients. RESULTS: The levels of sodium reabsorption that occurred via the distal nephrons were almost identical in the two PHA1 patients, despite their different molecular pathogeneses. Immunoblotting showed an increased urinary NCC protein level in the AR-PHA1 patient. CONCLUSION: Taken together, increased sodium reabsorption via the upregulation of the expression of NCC might have been responsible, at least in part, for the clinical improvement seen in an AR-PHA1 patient.

Case report: severe neonatal hyperkalemia due to pseudohypoaldosteronism type 1.

Hyponatremia and hyperkalemia in infancy can represent a variety of renal and genetic disorders with significant long-term health implications. We report a newborn with severe hyperkalemia and hyponatremia from autosomal recessive pseudohypoaldosteronism type 1 requiring aggressive therapy. The evaluation and treatment of children with disorders of mineralocorticoid action are discussed.

Shakuyaku-kanzo-to induces pseudoaldosteronism characterized by hypokalemia, rhabdomyolysis, metabolic alkalosis with respiratory compensation, and increased urinary cortisol levels.

BACKGROUND: Licorice, the primary ingredient of the Japanese herbal medicine shakuyaku-kanzo-to, can cause pseudoaldosteronism. Thus, shakuyaku-kanzo-to can cause this condition. CASE DESCRIPTION: A 79-year-old woman was brought to the emergency room. She had been experiencing general fatigue, numbness in the hands, and weakness in the lower limbs and could not stand up without assistance. She presented with hypokalemia (potassium level, 1.7 mEq/L), increased urinary excretion of potassium (fractional excretion of K, 21.2%), abnormalities on an electrocardiogram (flat T waves in II, III, AVF, and V1-6), rhabdomyolysis (creatine kinase level, 28,376 U/L), myopathy, metabolic alkalosis with respiratory compensation (O(2) flow rate, 2 L/min; pH, 7.473; pco(2), 61.0 mm Hg; po(2), 78.0 mm Hg; HCO(3), 44.1 mmol/L), hypertension (174/93 mm Hg), hyperglycemia (blood glucose level, 200-300 mg/dL), frequent urination, suppressed plasma renin activity (0.1 ng/mL/hour), decreased aldosterone levels (2.6 ng/dL), and increased urinary cortisol levels (600.6 microg/day; reference range, 26.0-187.0 microg/day). CONCLUSIONS: In this case, the observed reduction in the urinary cortisol levels, from 600.6 to 37.8 microg/day, led to a definitive diagnosis of pseudoaldosteronism instead of the apparent mineralocorticoid excess syndrome. Discontinuing shakuyaku-kanzo-to treatment and administering spironolactone and potassium proved effective in improving the patient's condition. Medical practitioners prescribing shakuyaku-kanzo-to should take into account the association between licorice, which is its main ingredient, and pseudoaldosteronism.

Pseudohypoaldosteronisms, report on a 10-patient series.

BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS: Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS: Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS: PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.

[Mineralocorticoid resistance: pseudohypoaldosteronism type 1]. / Resistência aos mineralocorticóides: pseudo-hipoaldosteronismo tipo 1.

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by neonatal renal salt wasting, vomiting, dehydration and failure to thrive. Affected patients present hyponatremia, hyperkalemia, associated with high levels of plasma renin and aldosterone resulting from a renal or systemic resistance to aldosterone. The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent. This form is associated with autosomal recessive transmission. Homozygous or compound heterozygous loss of function mutations in the genes coding for the epithelial sodium channel (ENaC) subunities are responsible for this disease. The renal form of PHA1 results in a mild phenotype. Low doses of salt supplementation are required and usually the symptoms remit at the end of the first year of life. Heterozygous loss-of-function mutations in the mineralocorticoid receptor (MR) gene are associated with the renal form of PHA1 in the majority of the affected families but sporadic cases have been reported. In this review the mechanisms of aldosterone action and its effects are discussed. Additionally, clinical and molecular findings of a Brazilian family with the renal form of PHA1 caused by a nonsense mutation (R947X) in the MR gene are presented.