Table 2.
Overview of the causes of monogenic hypertension and their OMIM genotype and phenotype numbers.
| Condition | Mode of inheritance | OMIM phenotype number(s) | OMIM genotype numbers(s) | Cytogenetic loci | Pathophysiology | Management |
|---|---|---|---|---|---|---|
| Liddle syndrome | Autosomal dominant | 177200 | 600760 (SCNN1B) 600761 (SCNN1G) | 16p12.2 | Hyperactive ENaC reabsorbs sodium at elevated levels, resulting in volume expansion and hypertension | Patients present with early onset HTN with hypokalemia non-responsive to conventional therapy. Genetic testing confirms the diagnosis. Use ENaC inhibitory agents: amiloride, triamterene. |
| Congenital adrenal hyperplasia | Autosomal recessive | 202010 (type IV) | 610613 (CYP11B1) | 8q24.3 | Defects in steroid synthesis cause buildup of intermediate metabolites with MR activity | Patients present with HTN at very young ages along with atypical sexual development . Glucocorticoid supplementation to suppress ACTH expression treats HTN; potentially add MR antagonists for better control. Therapy should also be individualized to address aspects of sexual dysfunction. |
| Autosomal recessive | 202110 (type V) | 609300 (CYP17A1) | 10q24.32 | |||
| Syndrome of apparent mineralocorticoid excess | Autosomal recessive | 218030 | 614232 (HSD11B2) | 16q22.1 | HSD11B2 deficiency allows excess cortisol stimulation at the MR | Therapy uses MR antagonists to alleviate overactivity and may call for ACTH suppression with excess cortisol |
| Geller syndrome | Autosomal dominant | 605115 | 600983 (NR3C2) | 4q31.23 | Genetic mutations in the MR alter its structure and binding affinities, allowing atypical stimulation by other steroids, especially progesterone | Presents by early adult life; most critical in pregnant women. Management would be with delivery of the child and subsequent monitoring. Spironolactone is to be avoided. |
| Gordon syndrome (pseudohypoaldosteronism type II) | Autosomal dominant | 145260 (type IIA) | Unspecified | 1q31-1q42 | Mutations in regulatory proteins for the NCC channel allow for unchecked activity, causing subsequent electrolyte and fluid overabsorption | Thiazide diuretic therapy directly treats NCC hyperactivity. |
| Autosomal dominant | 614491 (type IIB) | 601844 (WNK4) | 17q21.2 | |||
| Autosomal dominant | 614492 (type IIC) | 605232 (WNK1) | 12p13.33 | |||
| Autosomal recessive or dominant | 614495 (type IID) | 605775 (KLHL3) | 5q31.2 | |||
| Autosomal dominant | 614496 (type IIE) | 603136 (CUL3) | 2q36.2 | |||
| Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism) | Autosomal dominant | 103900 | 610613 (CYP11B1) | 8q24.3 | Unequal crossing over between the CYP11B1 and CYP11B2 genes generates a chimeric product that is ACTH-sensitive and produces aldosterone | Treatment with glucocorticoids to reduce ACTH secretion, supplemented with MR antagonists if necessary. Patients should be screened regularly for HTN-induced cerebrovascular sequelae |
| Familial hyperaldosteronism type II | Autosomal dominant | 605635 | 600570 (CLCN2) | 3q27.1 | Hyperplasia or benign neoplasia within the adrenal cortex results in excess aldosterone production | Medical management with MR antagonists with potential surgical resection |
| Familial hyperaldosteronism type III | Autosomal dominant | 613677 | 600735 (KCNJ5) | 11q24.3 | Gain-of-function mutations in potassium channels allow adrenal cortical cells to depolarize and subsequently activate aldosterone synthase | Medical management with MR antagonists with potential surgical resection |
| Familial hyperaldosteronism type IV | Autosomal dominant | 617027 | 607904 (CACNA1H) | 16p13.3 | Gain-of-function mutations in calcium channels delay inactivation of cells, allowing enhancing aldosterone synthase activity | Medical management with MR antagonists with potential surgical resection |
| Familial pheochromocytoma | Autosomal dominant | 171300 | 605995 (KIF1B) | 1p36.22 | Neoplasia of the adrenal medulla generates heightened levels of norepinephrine and epinephrine | Medical management with catecholamine antagonists and other antihypertensives prior to surgical resection. Continuous monitoring and genetic testing may prove helpful with syndromic causes |
| 185470 (SDHB) | 1p36.13 | |||||
| 613403 (TMEM127) | 2q11.2 | |||||
| 608537 (VHL) | 3p25.3 | |||||
| 600837 (GDNF) | 5p13.2 | |||||
| 164761 (RET) | 10q11.21 | |||||
| 602690 (SDHD) | 11q23.1 | |||||
| 154950 (MAX) | 14q23.3 | |||||
| Hypertension and Brachydactyly Syndrome | Autosomal dominant | 112410 | 123805 (PDE3A) | 12p12.2 | Gain-of-function mutations generate increased cAMP levels causing enhanced vascular smooth muscle proliferation, accompanied by brachydactyly due to dysfunctional chondrogenesis | High concentration milrinone therapy with possible benefits from phosphodiesterase inhibitors to increase cGMP levels |
Gene names are in parentheses next to the genotype number, where applicable. HTN, hypertension; ENaC, epithelial sodium channel; ACTH, adrenocorticotropic hormone; MR, mineralocorticoid receptor; NCC, sodium chloride cotransporter.