Alternative titles; symbols
SNOMEDCT: 703234002; ORPHA: 251274; DO: 446;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q24.3 | Hyperaldosteronism, familial, type III | 613677 | Autosomal dominant | 3 | KCNJ5 | 600734 |
A number sign (#) is used with this entry because of evidence that familial hyperaldosteronism type III (HALD3) is caused by heterozygous mutation in the KCNJ5 gene (600734) on chromosome 11q24.
For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900).
Hyperaldosteronism type III (HALD3) is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or HALD1; 103900), patients with HALD3 present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in HALD3 are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (Geller et al., 2008).
Geller et al. (2008) reported a novel familial form of aldosteronism in a father and 2 daughters. All were diagnosed with severe secondary hypertension (HTN) refractory to medical treatment by age 7 years. Geller et al. (2008) performed a variety of clinical, biochemical, and genetic studies to attempt to clarify the underlying molecular defect. Biochemical studies revealed hyporeninemia, hyperaldosteronism, and very high levels of 18-oxocortisol and 18-hydroxycortisol, steroids that reflect oxidation by both steroid 17-alpha hydroxylase and aldosterone synthase. These enzymes are normally compartmentalized in the adrenal fasciculata and glomerulosa, respectively. Administration of dexamethasone failed to suppress either aldosterone or cortisol secretion; these findings distinguished this clinical syndrome from glucocorticoid-remediable aldosteronism (GRA; 103900), another autosomal dominant form of HTN, and suggested a global defect in the regulation of adrenal steroid production. Because of unrelenting HTN, all 3 subjects underwent bilateral adrenalectomy, which in each case corrected the HTN. Adrenal glands showed dramatic enlargement, with paired adrenal weights as high as 82 grams. Histology revealed massive hyperplasia and cellular hypertrophy of a single cortical compartment that had features of adrenal fasciculata or a transitional zone, with an atrophic glomerulosa.
Mulatero et al. (2012) described an Italian mother and daughter with primary hyperaldosteronism in whom the presence of the chimeric gene responsible for GRA had been excluded. The mother, who had a history of polyuria in the first decade of life, was initially reported to be hypertensive at age 18 years. Primary aldosteronism was diagnosed at 27 years of age, when she presented with hypertension, hypokalemia, decreased plasma renin activity, and elevated aldosterone levels that did not normalize after dexamethasone administration. On electrocardiogram, QTc was slightly prolonged at 456 ms, even after normalization of potassium levels. The daughter had polyuria and polydipsia at 2 years of age, and evaluation revealed hypertension, hypokalemia, and severe hyperaldosteronism with hypotonic urine and hypercalciuria. CT scans of the adrenal glands were normal in both patients, and symptoms in both were controlled with medication.
Scholl et al. (2012) studied 4 unrelated kindreds with very early-onset primary aldosteronism, with all but 1 of the 10 affected members diagnosed before 6 years of age. In 2 of the families, blood pressure was difficult to control, and aldosteronism progressed with age. The 38-year-old proband of the first family presented at 22 months of age with muscle weakness, severe hypokalemia, and hypertension that persisted despite treatment with spironolactone. She underwent removal of a hyperplastic left adrenal gland at 32 months of age, but her symptoms persisted, and the right adrenal gland was removed at 4.3 years of age; both adrenal glands were markedly enlarged and showed hyperplasia of the zona glomerulosa and fasciculata. The bilateral adrenalectomy normalized blood pressure and K+ levels. The proband had 2 affected daughters, both of whom were diagnosed before 2 years of age and had hypertension refractory to spironolactone treatment; both had normalization of blood pressure, potassium, and aldosterone levels after bilateral adrenalectomy. The affected individual in the second family presented at 4 years of age with hypertension, hypokalemia, metabolic alkalosis, and an elevated serum aldosterone level with suppressed plasma renin activity. Ultrasound of the abdomen was normal. She had difficult-to-control hypertension, and was lost to follow-up. In the third and fourth families, spironolactone normalized blood pressure, and there was no progression of disease with age. The proband of the third family was a 38-year-old woman, previously described by Greco et al. (1982), who presented at 26 months of age with hypertension and hyperaldosteronism. Treatment with spironolactone normalized her blood pressure, and she did not have progression of hypertension or growth of the adrenal glands with age; CT scan at age 37 years revealed no adrenal abnormality. She had 2 affected children, both diagnosed before 2 years of age and successfully treated with spironolactone. Her affected father, who was reported by Bartter and Biglieri (1958), had early hypertension and aldosteronism and underwent near-total bilateral adrenalectomy at 14 years of age, before the availability of mineralocorticoid receptor antagonists. The glands were described as histologically normal, and he was normotensive and normokalemic thereafter. The fourth family consisted of a father and son who both presented in the first few years of life with hypertension and elevated aldosterone. The father underwent bilateral adrenalectomy at 6 years of age; the son was successfully treated with spironolactone.
Charmandari et al. (2012) reported a mother and daughter with severe primary aldosteronism and bilateral massive adrenal hyperplasia resulting in early-onset hypertension refractory to medical treatment. The mother, who was diagnosed at 7 years of age, underwent bilateral adrenalectomy at age 13 due to persistent hypertension, with complete normalization of blood pressure and serum potassium levels postoperatively. The daughter, who presented at 2 years of age with severe hypertension, hypokalemia, hyperaldosteronism, and suppressed plasma renin activity, had normal growth and development, with no hirsutism or virilization at puberty. Hypertension persisted at age 15 despite treatment with multiple medications, including spironolactone. MRI of the adrenal glands confirmed massive bilateral adrenal hyperplasia, and she underwent near-total bilateral adrenalectomy. Over subsequent years, further hyperplasia of the remaining right adrenal gland was documented, and she had recurrence of the symptoms and signs of primary hyperaldosteronism; removal of the remaining gland was planned.
The transmission pattern of HALD3 in the family reported by Geller et al. (2008) and Choi et al. (2011) was consistent with autosomal dominant inheritance.
In the family with hyperaldosteronism reported by Geller et al. (2008), Choi et al. (2011) identified a missense mutation in the potassium channel gene KCNJ5 at codon 158 (T158A; 600734.0002). This mutation produced increased sodium conductance and caused severe hypertension. Choi et al. (2011) also identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5, G151R (600734.0004), and L168R, that were present in 8 of 22 human aldosterone-producing adrenal adenomas studied. These 2 mutations produced increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation.
Mulatero et al. (2012) analyzed the candidate gene KCNJ5 in 21 European families with primary hyperaldosteronism in which the presence of the chimeric gene responsible for type I familial hyperaldosteronism had been excluded. In an affected Italian mother and daughter, they identified heterozygosity for a missense mutation (G151E; 600734.0005) that was not found in 7 unaffected family members. In addition, they identified 3 somatic KCNJ5 mutations, T158A, G151R, and L168R, in aldosterone-producing adenomas (APAs) from 3 unrelated affected individuals.
After exclusion of chimeric fusion of CYP11B1/CYP11B2 or mutation in the AT1R gene (106165) in a mother and daughter with severe aldosteronism requiring total adrenalectomy, Charmandari et al. (2012) sequenced the candidate genes KCNK3 (603220), KCNK5 (603493), KCNK9 (605874), and KCNJ5, and identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; 600734.0006).
Murthy et al. (2014) analyzed the KCNJ5 gene in 251 patients with apparent sporadic florid primary aldosteronism, and identified 3 heterozygous missense mutations, G247R (rs200170681; 600734.0003), E246K (600734.0007), and R52H (rs144062083). In addition, 12 (5%) of the 251 patients carried the rare SNP E282Q (rs7102584), present at a population frequency of 2% in the 1000 Genomes cohort. Although remote from the KCNJ5 selectivity filter, 3 of the 4 variants (E246K, R52H, and E282Q) were shown to alter inward rectification, conduction of Na+ currents, and angiotensin II (106150)-induced aldosterone release in the H295R cell line, a well-established model for the human zona glomerulosa cell. Results of electrophysiologic analysis of the G247R channel, however, were indistinguishable from those of the wildtype channel.
Kokunai et al. (2014) identified the T158A mutation in the KCNJ5 gene in a patient with prolonged QU on ECG who developed a hypokalemic paralytic attack and primary aldosteronism 2 years later. The patient was 1 of 21 patients with a phenotype resembling Andersen-Tawil syndrome (LQT7; 170390) who did not carry a mutation in the KCNJ2 gene (600681). The findings expanded the phenotype associated with this mutation.
Reviews
Mulatero et al. (2013) reviewed the role of KCNJ5 in adrenal pathophysiology and provided an overview of the clinical and biochemical phenotypes resulting from KCNJ5 mutations in patients with sporadic and familial primary aldosteronism. The authors stated that the prevalence of FH III appeared to be 7% of patients with familial aldosteronism and 0.3% of all cases of primary hyperaldosteronism. In addition, they noted that the total prevalence of reported KCNJ5 mutations in aldosterone-producing adrenal adenomas (APAs) was 40%.
Exclusion Studies
In a family with hyperaldosteronism, Geller et al. (2008) excluded mutation at the aldosterone synthase locus (CYP11B2; 124080), further distinguishing the disorder from glucocorticoid-remediable aldosteronism. They also failed to identify disease-causing mutations in DAX1 (300473), AD4BP (NR5A1; 184757), NUR77 (NR4A1; 139139), and NURR1 (NR4A2; 601828) by direct sequencing of coding exons.
In affected individuals with early-onset primary aldosteronism from 4 unrelated families that were known to be negative for chimeric fusion of the CYP11B1 (610613) and CYP11B2 (124080) genes, Scholl et al. (2012) identified heterozygosity for 2 different missense mutations at the same codon in the KCNJ5 gene: G151R (600734.0004) in 2 families with severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control, and G151E (600734.0005) in 2 families that had more easily controlled hypertension and no evidence of adrenal hyperplasia. Histopathology of adrenalectomized patients with the G151R mutation showed adrenal enlargement and hyperplasia of the adrenal cortex in all but the youngest patient, who underwent surgery at 18 months of age. Adrenal histology from 1 patient carrying the G151E mutation, who underwent adrenalectomy before availability of spironolactone for the treatment of hypertension, was reported as normal. Electrophysiologic analysis demonstrated that although both mutations alter the K+ selectivity of the channel, the G151E mutation causes much greater Na+ conductance than G151R, resulting in rapid Na(+)-dependent cell lethality. Scholl et al. (2012) proposed that the increased lethality associated with the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus paradoxically resulting in a milder phenotype in those patients.
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Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D. A., Hatch, M. M., Hurt, D. E., Lin, L., Xekouki, P., Stratakis, C. A., Chrousos, G. P. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J. Clin. Endocr. Metab. 97: E1532-E1539, 2012. [PubMed: 22628607] [Full Text: https://doi.org/10.1210/jc.2012-1334]
Choi, M., Scholl, U. I., Yue, P., Bjorklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C. J., Lolis, E., Wisgerhof, M. V., Geller, D. S., Mane, S., Hellman, P., Westin, G., Akerstrom, G., Wang, W., Carling, T., Lifton, R. P. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331: 768-772, 2011. [PubMed: 21311022] [Full Text: https://doi.org/10.1126/science.1198785]
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Greco, R. G., Carroll, J. E., Morris, D. J., Grekin, R. J., Melby, J. C. Familial hyperaldosteronism, not suppressed by dexamethasone. J. Clin. Endocr. Metab. 55: 1013-1016, 1982. [PubMed: 7119083] [Full Text: https://doi.org/10.1210/jcem-55-5-1013]
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Murthy, M., Xu, S., Massimo, G., Wolley, M., Gordon, R. D., Stowasser, M., O'Shaughnessy, K. M. Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. Hypertension 63: 783-789, 2014. [PubMed: 24420545] [Full Text: https://doi.org/10.1161/HYPERTENSIONAHA.113.02234]
Scholl, U. I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M. J., Couch, R., Hammer, L. K., Harley, F. L., Farhi, A., Wang, W.-H., Lifton, R. P. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc. Nat. Acad. Sci. 109: 2533-2538, 2012. [PubMed: 22308486] [Full Text: https://doi.org/10.1073/pnas.1121407109]