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Hereditary Causes of Hypertension
Questions
1
How common are hereditary forms of hypertension?
Evidence from family studies, including monozygotic and dizygotic twins, reveal that up to 50% of hypertension is heritable. However, the collective effect of all the known monogenic causes of hypertension and blood pressure (BP) loci identified through genome-wide association and exome sequencing studies explain only ∼2% of BP heritability. Monogenic causes of hypertension are rare, with fewer than 100 families identified per cause. For example, the occurrence of Liddle syndrome in the general population is too infrequent to calculate an accurate prevalence. In select populations (e.g., among teenagers and young adults with difficult-to-control hypertension in which primary aldosteronism and renovascular disease have been excluded) the prevalence of Liddle syndrome by genetic testing was 1.5%.
2
When should genetic testing be pursued?
Guideline recommendations for the evaluation of hypertension and resistant hypertension do not include genetic testing. A hypertension specialist may undertake specific genetic testing in patients with difficult-to-control hypertension presenting early in life and in those who have had negative screening studies for primary aldosteronism, fibromuscular dysplasia, aortic coarctation, cortisol excess, and pheochromocytoma. Clinical presentation of monogenetic causes of hypertension typically includes a low plasma renin activity, a family history of resistant hypertension or a family member with a stroke before age 50 years old, and abnormal serum electrolyte values ( Table 15.1 ).
Table 15.1
Monogenic Causes of Hypertension
| SYNDROME | GENE INVOLVED | INHERITANCE | MECHANISM RESULTING IN HYPERTENSION | CLINICAL PRESENTATION | TYPICAL LABORATORY FINDINGS | TREATMENT |
|---|---|---|---|---|---|---|
| Familial hyperkalemic hypertension c | CUL3 b KLHL3 b WNK1 a WNK4 b |
AD and AR | Increased activity of sodium-chloride cotransporter in distal convoluted tubule | Salt-sensitive hypertension that is resistant to antihypertensive medications other than thiazide diuretics | ↓ Aldo ↓ Renin ↑ Potassium ↓ Bicarbonate | Long-acting thiazide diuretic |
| Glucocorticoid remedial aldosteronism d | CYP11B1 chimeric fusion with CYP11B2 | AD | Adrenocorticotropic hormone (ACTH) results in release of aldosterone from adrenal cortex | Resistant hypertension in childhood with a family history of early-onset stroke; not identified in Black populations | ↑↑ Aldo ↓ Renin ↓/N Potassium ↑/N Bicarbonate | Glucocorticoids amiloride |
| Familial hyperaldosteronism type II | CLCN2 a | AD | Increased aldosterone secretion from adrenal gland | Early-onset primary aldosteronism or bilateral adrenal hyperplasia | ↑↑ Aldo ↓ Renin ↓/N Potassium ↑/N Bicarbonate | MR antagonist, amiloride |
| Familial hyperaldosteronism type III | KCNJ5 a | AD | Increased aldosterone secretion from adrenal gland | Early-onset primary aldosteronism with massive bilateral adrenal hyperplasia and poor response to MR antagonists | ↑↑ Aldo ↓ Renin ↓ Potassium ↑ Bicarbonate | MR antagonist, adrenalectomy (often bilateral) |
| Familial hyperaldosteronism type IV | CACNA1H a | AD | Increased aldosterone secretion from adrenal gland | Early-onset primary aldosteronism | ↑↑ Aldo ↓ Renin ↓/N Potassium ↑/N Bicarbonate | MR antagonist, amiloride |
| Sporadic aldosterone-producing adenoma | ATP1A1 ATP2B3 CACNA1D CACNA1H KCNJ5 |
Somatic | Aldosterone-producing adenoma | Resistant hypertension in adulthood | ↑ Aldo ↓ Renin ↓ Potassium ↑ Bicarbonate | MR antagonist, adrenalectomy (unilateral) |
| Liddle syndrome | SCNN1B a SCNN1G a |
AD | Increased activity of epithelial sodium channel (ENaC) in collecting tubule/duct | Blood pressure (BP) unresponsive to antihypertensive medications except for ENaC-blocking agents | ↓ Aldo ↓ Renin ↓/N Potassium ↑/N Bicarbonate | Amiloride |
| Apparent mineralocorticoid excess | HSD11B2 b | AR | Cortisol binds MR due to lack of enzyme activity to degrade cortisol intracellularly | Severe phenotype presents during infancy with low birth weight and failure to thrive with severe hypertension | ↓ Aldo ↓ Renin ↓ Potassium ↑ Bicarbonate | MR antagonist, kidney transplant curative |
| Hypertension with brachydactyly type E | PDE3A a | AD | Salt-resistant form of hypertension without clear mechanism | Neurovascular contact at the rostral ventrolateral medulla, brachydactyly, family history of death from stroke before age 50 years | N Aldo N Renin | Not yet defined |
| Activating MR mutation | NR3C2 a | AD | Progesterone activates MR receptor | Severe HTN during pregnancy; BP rises with spironolactone | ↓ Aldo ↓ Renin ↓ Potassium N Bicarbonate | Amiloride, delivery of fetus |
| Congenital adrenal hyperplasia | CYP11B1 b CYP17A1 b |
AR | Overproduction of 21-hydroxylated steroids that activate the MR | Virilization in girls and precocious puberty in boys (CYP11B1); primary amenorrhea and delayed sexual development in girls and ambiguous genitalia in boys (CYP17A1) | ↓ Aldo ↓ Renin ↓/N Potassium | MR antagonist |
Aldo, Aldosterone; AD, autosomal dominant; AR, autosomal recessive; HTN, hypertension; MR, mineralocorticoid receptor; N, normal.
c Also known as pseudohypoaldosteronism type II and Gordon syndrome.
3
Which hereditary causes of hypertension present in pediatric populations?
Although severe phenotypes manifest during infancy, the majority of monogenic causes of hypertension do not become clinically identifiable until late childhood or early adulthood. One exception to delayed presentation is congenital adrenal hyperplasia . The two subtypes of congenital adrenal hyperplasia that result in hypertension present during infancy. Defects in 11β-hydroxylase (loss of function mutations of CYP11B1 ) result in an increased sex hormone with androgenic action causing virilization in girls and precocious puberty in boys. Defects in 17α-hydroxylase result in primary amenorrhea and delayed sexual development in girls and ambiguous genitalia in boys.
Recessive missense mutations in HSD11B2 , which encodes the 11β-hydroxysteroid dehydrogenase type 2 enzyme, cause the syndrome of apparent mineralocorticoid excess (AME). Without HSD11B2 enzyme activity, intracellular cortisol binds and activates the mineralocorticoid receptor (MR). Individuals with the inherited form of AME syndrome present with severe and early-onset hypertension during infancy and childhood. AME syndrome can also be acquired later in life by consuming natural licorice (or licorice-flavored chewing tobacco) that inhibits the activity of HSD11B2 , resulting in resistant hypertension with low levels of aldosterone and suppressed renin activity.
Chimeric fusion of the 11β-hydroxylase gene (CYP11B1) with the coding sequences of aldosterone synthase (CYP11B2) results in the release of aldosterone by adrenocorticotropic hormone, which is named glucocorticoid-remedial aldosteronism . Glucocorticoid-remedial aldosteronism (also known as familial hyperaldosteronism type 1) presents as resistant hypertension in childhood and is associated with stroke before age 45 years old.
An activating mutation in the MR presents as severe hypertension in childhood with 100% of cases having hypertension before age 20. In vitro study of MR with the activating mutation showed normal activation from binding with aldosterone but basal activity in the absence of hormonal binding. In addition, mutated MR was activated by progesterone at high levels and by the MR antagonist spironolactone. Females with an activating MR mutation experience severe hypertension during pregnancy, when progesterone levels reach 100 times normal.
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