Alternative titles; symbols
ORPHA: 171876, 756; DO: 0060854;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | Pseudohypoaldosteronism, type IB1, autosomal recessive | 264350 | Autosomal recessive | 3 | SCNN1A | 600228 |
A number sign (#) is used with this entry because of evidence that autosomal recessive pseudohypoaldosteronism type IB1 (PHA1B1) is caused by homozygous or compound heterozygous mutation in the alpha subunit of the epithelial sodium channel (ENaC), SCNN1A (600228), on chromosome 12p13.
Mutation in the beta (SCNN1B; 600760) and gamma (SCNN1G; 600761) subunits of ENaC also cause autosomal recessive pseudohypoaldosteronism type I; see PHA1B2 (620125) and PHA1B3 (620126), respectively.
Autosomal recessive pseudohypoaldosteronism type I, including PHA1B1, is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; 219700). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by Scheinman et al., 1999).
A milder, autosomal dominant form of type I pseudohypoaldosteronism (PHA1A; 177735) is caused by mutations in the mineralocorticoid receptor gene (MCR, NR3C2; 600983).
Gitelman syndrome (263800), another example of primary renal tubular salt wasting, is due to mutation in the thiazide-sensitive sodium-chloride cotransporter (SLC12A3; 600968).
Hanukoglu and Hanukoglu (2016) provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases.
Pseudohypoaldosteronism is characterized by salt wasting in infancy that is responsive to supplementary sodium but not to mineralocorticoids. Marked aldosterone excess is present in all reported cases and the renin level is increased in most. Sweat and salivary glands, the distal renal tubule, and colonic mucosa are unresponsive to mineralocorticoids (Oberfield et al., 1979; Rosler, 1984, Speiser et al., 1986).
Barakat et al. (1974) described American black sister and brother with hyponatremia, hyperkalemia, and normal excretion of 17-ketosteroids. Increased urinary excretion of aldosterone was documented in the girl. She differed from other reported cases of pseudohypoaldosteronism in having persistent hyperkalemia and acidemia which failed to respond to sodium chloride replacement. A defect in cell membrane transport was postulated. The girl was brought to hospital at age 6 days because of vomiting and refusal to feed. She died on the 28th hospital day. Two years later, the boy, then aged 1 week, was admitted and died after only a few hours despite intensive therapy. The patients resembled those described by Shackleton et al. (1973).
Bosson et al. (1986) described 2 offspring of a first-cousin marriage who presented with severe salt wasting. Generalized pseudohypoaldosteronism was diagnosed on the basis of markedly elevated sodium concentration in urine, sweat, saliva, and stool, hyponatremia, and hyperkalemia in the presence of increased plasma aldosterone, increased plasma renin activity, and increased urinary aldosterone. Both parents, investigated under basal conditions and under sodium restricted diet, appeared to be normal.
Hanukoglu (1991) reported 2 sibs, born of consanguineous parents, with severe PHA type I. The proband developed severe renal salt wasting at age 9 days. She had also increased salivary and sweat electrolytes consistent with PHA resulting from multiple organ unresponsiveness to mineralocorticoids. Life-threatening episodes of salt wasting recurred beyond the age of 2 years; at 5 years, she still required high amounts of salt supplements. A sister died at 9 days of age with PHA symptoms. Six close relatives, including parents, 3 sibs, and a maternal uncle, showed no biochemical abnormalities.
Hanukoglu et al. (1994) pointed out the simulation of cystic fibrosis in patients with type I PHA. In 4 patients with the disorder in severe form, they observed recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values. They suggested that increased saliva electrolyte values affect normal mucociliary function in the respiratory tract and facilitate the occurrence of frequent lower respiratory tract involvement.
Chang et al. (1996) reported 5 unrelated consanguineous families with autosomal recessive PHA type I. One of the families had been reported by Hanukoglu (1991). Most affected individuals were diagnosed in the neonatal period, and all had severe dehydration, hypotension, hyponatremia, hyperkalemia, and metabolic acidosis, despite a normal glomerular filtration rate. Plasma renin activity and aldosterone levels were markedly elevated. Several had affected sibs who died in the first days of life. Dietary sodium supplementation resulted in clinical improvement; none of these patients showed amelioration of the dependence on supplemental dietary salt.
Schaedel et al. (1999) reported 4 Swedish patients from 3 families with pseudohypoaldosteronism type I. All of the patients had pulmonary symptoms to various degrees. The bacterial findings somewhat resembled those in cystic fibrosis, but development of chronic lung disease and progressive decline in lung function were not observed.
Gopal-Kothandapani et al. (2019) described 12 patients with genetic confirmation of PHA1, including 6 with PHA1B1 (patients 5-10). All 6 were born to consanguineous parents. Patients with PHA1B1 presented earlier than patients with PHA1A (177735) at a median age of 8 days (range, 1-17 days), with 2 patients presenting on day 1 of life. Patients presented with symptoms ranging from vomiting, weight loss, and poor feeding to severe dehydration, vomiting, and hypovolemic shock. All patients presented with significant hyponatremia (110-129 mmol/L) and hyperkalemia (6-10 mmol/L). Despite the severity of presentation, aldosterone levels in 2 patients were not markedly elevated. Patient 6 and patient 8 presented with modestly elevated aldosterone of 2000 and 3885 pmol/L, respectively (normal range, 1000-3500). Complications were more frequent in patients with PHA1B1 than in patients with PHA1A. The complications included more infections including recurrent tonsillitis and recurrent chest infections. Three patients (patients 6, 8, and 9) had cardiac arrest, likely secondary to electrolyte imbalance precipitated by intercurrent infection, leading to death in patient 6 at 30 days of age and patient 8 at 2.25 years. Given the challenge in differentiating autosomal dominant PHA1A and autosomal recessive PHA1B because of the similarity of clinical presentation in the acute and early phase of the disease, Gopal-Kothandapani et al. (2019) recommended early genetic analysis to determine and guide future management and counseling.
Hanukoglu (1991) reported 2 sibs, born of consanguineous parents, with severe systemic PHA type I. The transmission pattern was consistent with autosomal recessive inheritance.
All the affected families with PHA type I reported by Chang et al. (1996) were consanguineous, indicating autosomal recessive inheritance.
Strautnieks et al. (1996) found linkage of autosomal recessive PHA I to the region either of 12p or of 16p containing the SCNN1A and SCNN1B loci, respectively. The SCNN1G gene is also located on 16p.
In 5 families with PHA type I, Chang et al. (1996) identified homozygous mutations in either the SCNN1A gene (600228.0001-600228.0002) or the SCNN1B gene (600760.0003). These mutations cosegregated with the disease, and introduced frameshift, premature termination, or missense mutations that resulted in loss of channel activity. Since the epithelial sodium channel plays a major role in the removal of salt and water from the alveolar space in lung, it was of note that some PHA I patients had recurrent respiratory problems. Chang et al. (1996) studied these genes because mutations resulting in constitutive activation of ENaC activity were demonstrated to cause Liddle syndrome (177200), an autosomal dominant form of hypertension characterized by volume expansion, hypokalemia, and alkalosis. This finding in pseudoaldosteronism raised the possibility that mutations causing loss of function of ENaC activity could cause the converse phenotype of volume depletion, hyperkalemia, and acidosis characteristic of patients with PHA I.
Arai et al. (1999) studied the SCNN1A, SCNN1B, and SCNN1G cDNAs in 5 sporadic cases of PHA, all of whom had nonconservative homozygous and/or conservative heterozygous substitutions in their mineralocorticoid receptor (MCR; 600983) cDNAs that were also present at high frequencies in a control population with apparently normal salt conservation. The authors identified a nonconservative substitution (thr663 to ala) in the SCNN1A cDNAs of all 5 patients (2 were homozygous, and 3 were heterozygous) that was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively; they concluded that this substitution is a polymorphism. Arai et al. (1999) also identified a nonconservative homozygous substitution in the SCNN1B cDNAs and 3 nonconservative and conservative homozygous substitutions in the SCNN1G cDNAs of all patients and control subjects examined. They hypothesized that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MCR gene or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA.
In 4 patients from 3 Swedish families with PHA1B1, Schaedel et al. (1999) identified homozygous or compound heterozygous mutations in the SCNN1A gene (600228.0003-600228.0005).
Several early reports suggested that autosomal recessive pseudohypoaldosteronism may result from defects in the mineralocorticoid receptor (MCR; 600983). In an affected brother and sister, born of first-cousin parents, Armanini et al. (1985) found absent or greatly reduced high-affinity receptor binding sites for aldosterone on monocytes. The unaffected parents of the sib pair had normal binding. These findings suggested that the basic defect resides in the aldosterone receptor. Similarly, Bosson et al. (1986) found no high-affinity aldosterone receptors on mononuclear leukocytes from a child with recessive PHA I, whereas low levels were found in both unaffected parents. However, Chung et al. (1995) presented compelling evidence that the site of the mutations causing PHA I in the majority of autosomal recessive families is not the aldosterone/mineralocorticoid receptor. Studying 10 inbred families by homozygosity mapping with 3 simple sequence length (SSL) polymorphisms spanning the MCR gene region, they obtained lod scores of less than -2 over the whole region from D4S192 to D4S413 encompassing MCR.
Arai, K., Zachman, K., Shibasaki, T., Chrousos, G. P. Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential? J. Clin. Endocr. Metab. 84: 2434-2437, 1999. [PubMed: 10404817] [Full Text: https://doi.org/10.1210/jcem.84.7.5857]
Armanini, D., Kuhnle, U., Strasser, T., Dorr, H., Butenandt, I., Weber, P. C., Stockigt, J. R., Pearce, P., Funder, J. W. Aldosterone-receptor deficiency in pseudohypoaldosteronism. New Eng. J. Med. 313: 1178-1181, 1985. [PubMed: 2932642] [Full Text: https://doi.org/10.1056/NEJM198511073131902]
Barakat, A. Y., Papadopoulou, Z. L., August, G. P. A familial hyperkalemic, salt wasting syndrome in infancy. Clin. Proc. Children's Hosp. Nat. Med. Center 30(7): 163-168, 1974.
Bonnici, F. Pseudohypoaldosteronisme familial a transmission autosomique recessive. (Letter) Arch. Franc. Pediat. 34: 915-916, 1977. [PubMed: 606192]
Bosson, D., Kuhnle, U., Mees, N., Ramet, J., Vamos, E., Vertongen, F., Wolter, R., Armanini, D. Generalized unresponsiveness to mineralocorticoid hormones: familial recessive pseudohypoaldosteronism due to aldosterone-receptor deficiency. Acta Endocr. Suppl. 279: 376-380, 1986. [PubMed: 2946135] [Full Text: https://doi.org/10.1530/acta.0.112s376]
Chang, S. S., Grunder, S., Hanukoglu, A., Rosler, A., Mathew, P. M., Hanukoglu, I., Schild, L., Lu, Y., Shimkets, R. A., Nelson-Williams, C., Rossier, B. C., Lifton, R. P. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nature Genet. 12: 248-253, 1996. [PubMed: 8589714] [Full Text: https://doi.org/10.1038/ng0396-248]
Chung, E., Hanukoglu, A., Rees, M., Thompson, R., Dillon, M., Hanukoglu, I., Bistritzer, T., Kuhnle, U., Seckl, J., Gardiner, R. M. Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis. J. Clin. Endocr. Metab. 80: 3341-3345, 1995. [PubMed: 7593448] [Full Text: https://doi.org/10.1210/jcem.80.11.7593448]
Dillon, M. J., Leonard, J. V., Buckler, J. M., Ogilvie, D., Lillystone, D., Honour, J. W., Shackleton, C. H. L. Pseudohypoaldosteronism. Arch. Dis. Child. 55: 427-434, 1980. [PubMed: 7002056] [Full Text: https://doi.org/10.1136/adc.55.6.427]
Gopal-Kothandapani, J. S., Doshi, A. B., Smith, K., Christian, M., Mushtaq, T., Banerjee, I., Padidela, R., Ramakrishnan, R., Owen, C., Cheetham, T., Dimitri, P. Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1. J. Pediat. Endocr. Metab. 32: 959-967, 2019. [PubMed: 31301676] [Full Text: https://doi.org/10.1515/jpem-2018-0538]
Hanukoglu, A., Bistritzer, T., Rakover, Y., Mandelberg, A. Pseudohypoaldosteronism with increased sweat and saliva electrolyte values and frequent lower respiratory tract infections mimicking cystic fibrosis. J. Pediat. 125: 752-755, 1994. [PubMed: 7965429] [Full Text: https://doi.org/10.1016/s0022-3476(94)70071-0]
Hanukoglu, A. Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects. J. Clin. Endocr. Metab. 73: 936-944, 1991. [PubMed: 1939532] [Full Text: https://doi.org/10.1210/jcem-73-5-936]
Hanukoglu, I., Hanukoglu, A. Epithelial sodium channel (ENaC) family: phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene 579: 95-132, 2016. [PubMed: 26772908] [Full Text: https://doi.org/10.1016/j.gene.2015.12.061]
Kuhnle, U., Nielsen, M. D., Tietze, H.-U., Schroeter, C. H., Schlamp, D., Bosson, D., Knorr, D., Armanini, D. Pseudohypoaldosteronism in eight families: different forms of inheritance are evidence for various genetic defects. J. Clin. Endocr. Metab. 70: 638-641, 1990. [PubMed: 2137831] [Full Text: https://doi.org/10.1210/jcem-70-3-638]
Lauras, B., Ravussin, J.-J., David, M., Freycon, F., Jeune, M. Pseudo-hypoaldosteronisme chez l'enfant: apropos de quatre observations dont deux concernant des freres. Pediatrie 33: 119-135, 1978. [PubMed: 643461]
Lelong, M., Alagille, D., Philippe, A., Gentil, C., Gabilan, J. C. Diabete salin par insensibilite congenitale du tubule a l'aldosterone: pseudohypoadrenocorticisme. Rev. Franc. Etud. Clin. Biol. 5: 558-565, 1960. [PubMed: 13760685]
Oberfield, S. E., Levine, L. S., Carey, R. M., Bejar, R., New, M. I. Pseudohypoaldosteronism: multiple target organ unresponsiveness to mineralocorticoid hormones. J. Clin. Endocr. Metab. 48: 228-234, 1979. [PubMed: 218983] [Full Text: https://doi.org/10.1210/jcem-48-2-228]
Pham-Huu-Trung, Piussan, C., Rodary, C., Legrand, S., Attal, C., Mozziconacci, P. Etude du taux de secretion de l'aldosterone et de l'activite de la renine plasmatique d'un cas de pseudo-hypoaldosteronism. Arch. Franc. Pediat. 27: 603-615, 1970. [PubMed: 5433048]
Rosler, A. The natural history of salt-wasting disorders of adrenal and renal origin. J. Clin. Endocr. Metab. 59: 689-700, 1984. [PubMed: 6384251] [Full Text: https://doi.org/10.1210/jcem-59-4-689]
Roy, C. Pseudohypoaldosteronisme familial (apropos de 5 cas). Arch. Franc. Pediat. 34: 37-54, 1977. [PubMed: 851368]
Royer, P., Bonnette, J., Mathieu, H., Gabilan, J. C., Klutchko, G., Zittoun, R. Pseudo-hypoaldosteronisme. Ann. Pediat. 10: 596-605, 1963. [PubMed: 14103260]
Schaedel, C., Marthinsen, L., Kristoffersson, A.-C., Kornfalt, R., Nilsson, K. O., Orlenius, B., Holmberg, L. Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the alpha-subunit of the epithelial sodium channel. J. Pediat. 135: 739-745, 1999. [PubMed: 10586178] [Full Text: https://doi.org/10.1016/s0022-3476(99)70094-6]
Scheinman, S. J., Guay-Woodford, L. M., Thakker, R. V., Warnock, D. G. Genetic disorders of renal electrolyte transport. New Eng. J. Med. 340: 1177-1187, 1999. [PubMed: 10202170] [Full Text: https://doi.org/10.1056/NEJM199904153401507]
Shackleton, C. H. L., Snodgrass, G. J. A. I., Horth, C. H. Urinary steroid excretion by an infant with an unusual salt-losing syndrome. (Abstract) Acta Endocr. 177 (suppl.): 306, 1973.
Speiser, P. W., Stoner, E., New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Chrousos, G. P.; Loriaux, D. L.; Lipsett, M. B.: Steroid Hormone Resistance: Mechanisms and Clinical Aspects. New York: Plenum Press (pub.) 1986. Pp. 173-195.
Strautnieks, S. S., Thompson, R. J., Hanukoglu, A., Dillon, M. J., Hanukoglu, I., Kuhnle, U., Seckl, J., Gardiner, R. M., Chung, E. Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. Hum. Molec. Genet. 5: 293-299, 1996. [PubMed: 8824886] [Full Text: https://doi.org/10.1093/hmg/5.2.293]