Phenotypic and genetic heterogeneity of familial hyperkalaemic hypertension (Gordon syndrome)

1. Familial hyperkalaemic hypertension (FHH), also called pseudohypoaldosteronism type II (PHA2) or Gordon syndrome, is a rare Mendelian-form of low-renin hypertension. The first cases of FHH were reported approximately 30 years ago and they described the peculiar biochemical abnormalities (i.e. hyperkalaemia and hyperchloraemic acidosis despite a normal glomerular filtration rate). 2. Since then, more than 90 single cases and families have been reported in the literature. These various reports show marked differences in phenotype. 3. Our group has now collected 14 unrelated pedigrees originating from different parts of France and Europe. We confirm the large variations in the age of discovery and in the severity of the biochemical abnormalities from one individual to another and from one family to another one. 4. Blood pressure levels have no significant relationship with hyperkalaemia or hyperchloraemia, but there is a positive relationship with age, as in the normal population. 5. Analyses of clinical features and Mendelian segregation in our families demonstrate autosomal-dominant inheritance, as expected from the literature. 6. Efforts have been made in the past years to unravel the gene responsible for the disease. Until now, a primary responsibility of the gene encoding the thiazide-sensitive Na-Cl cotransporter (SLC12A3) has been excluded in PHA2 families. Three loci have been identified on chromosomes 1 (PHA2A), 17 (PHA2B) and 12 (PHA2C). 7. More recently, analysis of three additional pedigrees, including 10 affected subjects, with over 25 members allowed us to demonstrate further genetic heterogeneity and the existence of at least a fourth locus. 8. The genetic heterogeneity of this syndrome, and thus the variety of molecular defects, suggests the role of either several new components of the same pathway, multiple aldosterone- regulated effectors or direct or indirect partners of the Na-Cl cotransporter.     

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??Objective To analyze thecauses ofinfantsalt losing syndrome and theapplication value of gene detection inthe diagnosis of the cause. Methods Four cases ofsalt losingsyndrome withlow sodium and highpotassium admitted from 2010 to 2014in Shanghai Children’s Medical Center?? Affiliated to Shanghai Jiaotong University School of Medicine wereincluded and clinicaldata??therapy and follow-up were collected. DNA of childrenandtheir parentsin thefour cases were detected. Results There were different degrees ofsalt losingsituation in the fourcases. It found that the patients had different gene mutations through genetic testing??mutations of splicing site??c.293-13A??G??heterozygous???? andsmallduplication??c.923dupT?? p.Leu308Phefs*6??heterozygous???? were detected in CYP21A2?? mutation of small deletion??c.1334delC?? p.Ala445Valfs*17??hemizygous???? was detected in DAX1?? mutation of splicing site??c.del1311G?? p.Arg438Glyfs*43??heterozygous???? and point mutation??c.1439+1G??C??heterozygous???? were detected in SCNN1A and mutation of splicing site??c.240-1G??A??heterozygous???? and nonsensemutation??c.1009C??T??p.Gln337*??heterozygous???? were detected in CYP11B2?? respectively. The four cases werediagnosed asfour differentdiseases??congenitaladrenal hyperplasia??21-hydroxylase deficiency????congenital adrenal hypoplasia??pseudohypoaldosteronismtype I and hypoaldosteronism. Conclusion The cause of infant salt losing syndrome is complex and is misdiagnosed easily. Gene analysismay be helpful for early diagnosis and treatment.     

Sodium transport deficiency and sodium balance in gene‐targeted mice

Animals with induced or natural null mutations in renal NaCl and water transporter genes provide a powerful tool to study the physiological mechanisms that enable the kidney to optimize the match between glomerular filtration rate and tubular reabsorption. Deficiencies in the Na/H exchanger NHE3 and in the water channel aquaporin 1 (AQP1) cause reductions in proximal fluid absorption which are accompanied by proportionate decrements in glomerular filtration rate (GFR). Compensation of the transport defect by a reduction in filtered load is so efficient that clinically symptomatic Na losses are not observed in either NHE3 or AQP1 deficient animals. On the other hand, severe syndromes of salt wasting are caused by loss of function of the Na,K,2Cl‐cotransporter (NKCC2) in the thick ascending limb, or of the epithelial Na channel (ENaC) the collecting duct indicating that the severity of Na dysregulation is unrelated to the basal absorption of NaCl in a given nephron segment. In these states, the increased delivery of Na to downstream segments is not monitored by a sensor linked to the site of filtrate formation. In the absence of adaptations in the filtered load intrarenal compensation of a circumscribed NaCl malabsorption by adjustment of NaCl transport in other nephron segments is sometimes insufficient, particularly in the immature kidney of the newborn.     

Two Japanese patients with the renal form of pseudohypoaldosteronism type 1 caused by mutations of NR3C2

Pseudohypoaldosteronism type 1 (PHA1) is a disease characterized by neonatal salt loss due to aldosterone resistance. Two types of PHA1 are known: an autosomal recessive systemic form and an autosomal dominant renal form. The cause of the renal form of PHA1 is heterozygous mutations in NR3C2, which encodes the mineralocorticoid receptor (MR). We encountered two female Japanese infants with the renal form of PHA1 and analyzed NR3C2. The two patients had poor weight gain, and one was developmentally delayed. Genetic analysis identified one novel mutation (c.492_493insTT, p.Met166LeufsX8) and one previously reported mutation (p.R861X). The two produced a premature stop codon, resulting in haploinsufficiency of the MR. In conclusion, genetic analysis of NR3C2 is useful for diagnosis and planning therapeutic strategies.     

Familial Pseudohypoaldosteronism

ABSTRACT. The clinical course of two siblings with a severe form of pseudohypoaldosteronism was followed over a period of seven and five years respectively. Both children persistently had a high sodium-potassium excretion ratio in the urine, sweat, saliva, and stools as well as high serum concentrations of aldosterone and renin and an increased urinary excretion of tetrahydroaldosterone. Despite sustained treatment with sodium chloride (10–40 mmol/kg/d) and cation exchange resin (sodium polystyrole sulfonate 0.5–2 g/kg/d) they repeatedly developed episodes of salt wasting and hyperkalemia which occurred mainly during uncomplicated respiratory tract infections. Aldosterone receptor characteristics were studied in the cytosol of the rectal mucosa at ages 2.5 years and 6 months respectively. Compared to age matched controls there was a decreased affinity for aldosterone at the low affinity binding site. Among the members of the family, the father and one of his sisters had high concentrations of sodium in the sweat and an increased urinary excretion of tetrahydroaldosterone.     

Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review

Systemic pseudohypoaldosteronism (PHA) is a rare, salt-wasting syndrome that is caused by inactivating variants in genes encoding epithelial sodium channel subunits. Hyponatremia, hyperkalemia, metabolic acidosis, increased aldosterone and renin levels are expected findings in PHA. Clinical management is challenging due to high dose oral replacement therapy. Furthermore, patients with systemic PHA require life-long therapy. Here we report a patient with systemic PHA due to SCNN1B variant whose hyponatremia and hyperkalemia was detected at the 24^th hour of life. Hyperkalemia did not improve with conventional treatments and dialysis was required. He also developed myocarditis and hypertension in follow-up. Challenges for diagnosis and treatment in this patient are discussed herein. In addition, published evidence concerning common features of patients with SCNN1B variant are reviewed.