Alternative titles; symbols
ORPHA: 171871, 756; DO: 0060855;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q31.23 | Pseudohypoaldosteronism type I, autosomal dominant | 177735 | Autosomal dominant | 3 | NR3C2 | 600983 |
A number sign (#) is used with this entry because autosomal dominant pseudohypoaldosteronism type I (PHA1A) is caused by heterozygous mutation in the mineralocorticoid receptor gene (MCR, NR3C2; 600983) on chromosome 4q31.
Autosomal dominant pseudohypoaldosteronism type I (PHA1A) is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998).
Autosomal recessive pseudohypoaldosteronism type I (see PHA1B1, 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Cheek and Perry (1958) first described pseudohypoaldosteronism in infancy due to a renal tubular defect. The patient had renal salt wasting associated with normal renal and adrenal function. The condition was corrected by sodium chloride supplementation, but was refractory to exogenous mineralocorticoid without added salt. The authors suggested a defect in renal tubular response to mineralocorticoids. There was no family history of a similar disorder. Armanini et al. (1985) studied the original patient of Cheek and Perry (1958), then 28 years old, and found absent or greatly reduced high-affinity receptor binding sites for aldosterone on monocytes, suggesting that the basic defect resides in the aldosterone receptor. Other reports of the same condition soon followed the report of Cheek and Perry (1958) (Donnell et al., 1959 and Raine and Roy, 1962); the parents of all of these children were clinically unaffected.
Hanukoglu (1991) reported a family with autosomal dominant inheritance of PHA (Hanukoglu et al., 1978). The proband presented with renal salt wasting in infancy, associated with vomiting, failure to thrive, and short stature. Laboratory studies showed hyponatremia and hyperkalemia, with a dramatic response to a high salt diet. Sodium supplementation was discontinued at the age of 2 years. There were 7 additional family members from 3 generations who had variable expression of PHA, ranging from asymptomatic to moderate. In affected members, pseudohypoaldosteronism persisted over 13 years; however, the plasma renin (179820) activity (PRA) decreased gradually to near-normal values. Persistent pseudohypoaldosteronism in the face of a decrease in PRA was interpreted by Hanukoglu (1991) as reflecting the development of tertiary pseudohypoaldosteronism due to autonomously functioning zona glomerulosa of the adrenal.
Riepe et al. (2006) reported 7 patients presenting with isolated renal salt loss from 6 families in Italy and Germany. All manifested in early infancy with poor weight gain, failure to thrive, dehydration, or vomiting. The diagnosis of PHA1 was established by the confirmation of hyponatremia, hyperkalemia, elevated plasma renin activity or direct renin concentrations, and high plasma aldosterone levels. All patients were treated with oral sodium supplementation.
The transmission pattern of PHA1 in the family reported by Hanukoglu (1991) was consistent with autosomal dominant inheritance with variable expression.
In 4 familial cases of autosomal dominant type I pseudohypoaldosteronism and in 1 sporadic patient, Geller et al. (1998) identified 4 different heterozygous mutations in the mineralocorticoid receptor gene (600983.0001-600983.0004).
In affected members of a Japanese family with PHA1A, Tajima et al. (2000) found a heterozygous mutation in the MCR gene (L924P; 600983.0007).
Viemann et al. (2001) reported the results of a genetic study in a sporadic case and in 5 patients from 2 families with autosomal dominant PHA1. In the sporadic case they identified a frameshift mutation (2871insC; 600983.0006) in exon 9 of the MCR gene. This mutation alters the last 27 amino acids of the hormone-binding domain.
Sartorato et al. (2003) analyzed the NR3C2 gene in 14 families with autosomal dominant or sporadic PHA1. They detected 6 heterozygous mutations that affected protein structure and function differently (see, e.g., 600983.0008-600983.0013). The authors concluded that NR3C2 mutations are a common feature of autosomal dominant PHA1, being found in 70% of their familial cases.
Riepe et al. (2006) detected 6 heterozygous NR3C2 mutations in 7 PHA1 patients from 6 unrelated families: 2 previously described frameshift mutations (1131dupT, 600983.0008 and 2871dupC, 600983.0006), 2 novel nonsense mutations (600983.0017-600983.0018), and 2 novel missense mutations (600983.0019-600983.0020).
Pujo et al. (2007) identified 22 abnormalities of the NR3C2 gene in 33 patients with type I pseudohypoaldosteronism. Altogether, 68% of the mutations were dominantly transmitted, while 18% were de novo mutations.
Viemann et al. (2001) did not find mutations in the MCR gene in 2 kindreds with autosomal dominant PHA1, suggesting genetic heterogeneity.
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]
Cheek, D. B., Perry, J. W. A salt-wasting syndrome in infancy. Arch. Dis. Child. 33: 252-256, 1958. [PubMed: 13545877] [Full Text: https://doi.org/10.1136/adc.33.169.252]
Donnell, G. N., Litman, N., Roldan, M. Pseudohypo-adrenocorticism: renal sodium loss, hyponatremia and hyperkalemia due to a renal tubular insensitivity to mineralocorticoids. Am. J. Dis. Child. 97: 813-828, 1959.
Geller, D. S., Rodriguez-Soriano, J., Boado, A. V., Schifter, S., Bayer, M., Chang, S. S., Lifton, R. P. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nature Genet. 19: 279-281, 1998. [PubMed: 9662404] [Full Text: https://doi.org/10.1038/966]
Hanukoglu, A., Fried, D., Gotlieb, A. Inheritance of pseudohypoaldosteronism. (Letter) Lancet 311: 1359 only, 1978. Note: Originally Volume I. [PubMed: 78119] [Full Text: https://doi.org/10.1016/s0140-6736(78)92428-5]
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]
Pujo, L., Fagart, J., Gary, F., Papadimitriou, D. T., Claes, A., Jeunemaitre, X., Zennaro, M.-C. Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. Hum. Mutat. 28: 33-40, 2007. [PubMed: 16972228] [Full Text: https://doi.org/10.1002/humu.20371]
Raine, D. N., Roy, J. A salt-losing syndrome in infancy: pseudo-hypoadrenocorticalism. Arch. Dis. Child. 37: 548-556, 1962. [PubMed: 13990509] [Full Text: https://doi.org/10.1136/adc.37.195.548]
Riepe, F. G., Finkeldei, J., de Sanctis, L., Einaudi, S., Testa, A., Karges, B., Peter, M., Viemann, M., Grotzinger, J., Sippell, W. G., Fejes-Toth, G., Krone, N. Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type I. J. Clin. Endocr. Metab. 91: 4552-4561, 2006. [PubMed: 16954160] [Full Text: https://doi.org/10.1210/jc.2006-1161]
Sartorato, P., Lapeyraque, A.-L., Armanini, D., Kuhnle, U., Khaldi, Y., Salomon, R., Abadie, V., Di Battista, E., Naselli, A., Racine, A., Bosio, M., Caprio, M., and 10 others. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type 1 pseudohypoaldosteronism. J. Clin. Endocr. Metab. 88: 2508-2517, 2003. [PubMed: 12788847] [Full Text: https://doi.org/10.1210/jc.2002-021932]
Tajima, T., Kitagawa, H., Yokoya, S., Tachibana, K., Adachi, M., Nakae, J., Suwa, S, Katoh, S., Fujieda, K. A novel missense mutation of mineralocorticoid receptor gene in one Japanese family with a renal form of pseudohypoaldosteronism type 1. J. Clin. Endocr. Metab. 85: 4690-4694, 2000. [PubMed: 11134129] [Full Text: https://doi.org/10.1210/jcem.85.12.7078]
Viemann, M., Peter, M., Lopez-Siguero, J. P., Simic-Schleicher, G., Sippell, W. G. Evidence for genetic heterogeneity of pseudohypoaldosteronism type 1: identification of a novel mutation in the human mineralocorticoid receptor in one sporadic case and no mutations in two autosomal dominant kindreds. J. Clin. Endocr. Metab. 86: 2056-2059, 2001. [PubMed: 11344206] [Full Text: https://doi.org/10.1210/jcem.86.5.7449]