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What is the difference between mendelian (or monogenic) forms of hypertension and essential hypertension?
Essential hypertension has a multifactorial etiology, including demographic and environmental (dietary) factors, and genetic predisposition, which results from multiple gene–gene and gene–environment interactions. Large genome-wide association studies among various populations mapped many gene loci for essential hypertension; however these loci have been predicted to have a very small effect on individual blood pressure variation, often estimated to be less than 2%. In contrast, Mendelian (or monogenic) forms of hypertension have a large effect on blood pressure level, with identifiable and often effectively treatable causes. The most common mechanism involves activation of the mineralocorticoid pathway, leading to increased kidney sodium reabsorption and volume expansion. Up to 20% of cases with resistant hypertension have either aldosterone-producing adrenal adenomas (APA) or bilateral adrenal hyperplasia. Based on recent DNA sequencing studies from adrenal adenoma tissues, ∼50% of APA cases are caused by somatic mutations in genes controlling adrenal zona glomerulosa cell proliferation and aldosterone production. APA is the most common form of secondary hypertension, estimated to affect up to ∼10% of patients with hypertension. Nevertheless, most monogenic forms of hypertension are exceedingly rare and estimated to be less than 2% of newly diagnosed hypertension. They result from mutations in a single gene and are mostly inherited in a Mendelian pattern. Since the early 1990s, more than 20 genes have been implicated in the etiology of Mendelian hypertension.
Similarly, many Mendelian genes have been identified that lower blood pressure, with renal salt wasting being the main mechanism.
Monogenic Syndromes of Hypertension
SYNDROME | MAIN FEATURES | TREATMENT | LOCUS | INHERITANCE | DISEASE GENE |
---|---|---|---|---|---|
Liddle syndrome | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressed | ENaC inhibitors | 16p12 | AD | ENaC (Epithelial Na+ channel) |
Glucocorticoid-remediable aldosteronism (GRA) | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin suppressed• Aldosterone normal or elevated• “Unusual” urine steroid metabolites | Corticosteroid therapy | 8q24 | AD | CYP11B1/CYP11B2 (chimeric gene) |
Apparent mineralocorticoid excess (AME) | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressed• Nephrocalcinosis can be seen• Elevated urinary cortisol-to-cortisone ratio | Spironolactone and ENaC inhibitors | 16q22 | AR | 11 β -HSD 2 |
Mineralocorticoid receptor (MR) activating mutation | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressed• Exacerbated in pregnancy• Spironolactone acts as agonist | ENaC inhibitors | 4q31 | AD | NR3C2 |
Aldosterone-producing adrenal adenomas (APA) | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin suppressed• Aldosterone elevated• Imaging can show adrenal adenoma | Spironolactone or eplerenone adenomectomy | 11q24 3p21 1p13 Xq28 | De novo/AD de novo De novo De novo | KCNJ5 CACNA1D ATP1A1ATP2B3 |
Congenital adrenal hyperplasia (CAH) | • Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressed• ACTH elevated• Mineralocorticoids (e.g., DOC) elevated• Glucocorticoid deficiency and abnormal sex hormones | Corticosteroid therapy | 10q248q24 | AR AR | 17 α-hydroxylase 11 β-hydroxylase |
Pseudohypoaldosteronism type 2 (PHA 2) | • Salt-sensitive• Hyperkalemia and metabolic acidosis• Renin suppressed• Aldosterone normal• Hypercalciuria can be seen | Thiazide diuretics | 12p13 17q215q312q36 | AD AD AR/ de novo | WNK1 WNK4 Kelch-like3 Cullin3 |
Pheochromocytoma | • Labile hypertension• Orthostatic hypotension• Renin and aldosterone elevated• Hypokalemia can be seen• Elevated metanephrines | AlphablockerSurgery | 10q11 17q11 3p25 1p36 1q23 11q23 12q13 etc. | AD/ de novo de novo | Ret NF1 VHL SDHB SDHC SDHD KMT2D etc. |
Hypertension-brachydactyly syndrome | • Not salt-sensitive• Renin and aldosterone suppressed• Baroreceptor dysfunction• Orthostatic hypertension• Short stature• Brachydactyly type E | Multidrug therapy | 12p12 | AD | PDE3A |
Hypertension, hypomagnesemia, and hypercholesterolemia; mitochondrial | • Hypomagnesemia• Hyperlipidemia• Incomplete penetrance | Multidrug therapy | mDNA | Maternal | tRNAIle |
AD, Autosomal-dominant; AR, autosomal-recessive; ATP1A1, Na+/K+ ATPase α-1 subunit; ATP2B3, ATPase, Ca++ transporting, plasma membrane3; 11 β HSD, 11β-hydroxysteroid dehydrogynase 2; CACNA1D, calcium channel, voltage-dependent, L type, α-1D subunit; DOC, Deoxycorticosterone; KCNJ5, K+ inwardly-rectifying channel, subfamily J, member 5; KMT2D, Histone-lysine N-methyltransferase 2D; mDNA, mitochondrial DNA; NF1, neurofibromatosis 1; PDE3A, phosphodiesterase 3A; Ret, rearranged during transfection; SDHB/C/D, succinate dehydrogenase subunit B, C or D; PDE3A, phosphodiesterase 3A; tRNAIle, tRNA Isoleucin; Ret, rearranged during transfection; VHL, von Hippel-Lindau; WNK1, With-No-Lysine(K) 1.
Monogenic Syndromes of Renal Salt-Wasting Lowering Blood Pressure
SYNDROME | INHERITANCE | MAIN FEATURES | TREATMENT | LOCUS | DISEASE GENE |
---|---|---|---|---|---|
Bartter syndrome (TAL) Type 1 Type 2 Type 3 Type 4 Type 4b Type 5 | AR AR AR AR AR AD | • Hypokalemia and metabolic alkalosis• Renin and Aldosterone elevated• Nephrocalcinosis (types 1 and 2)• Neonatal manifestation (types 1, 2, 4, and 4b)• Deafness (types 4 and 4b)• Hypercalciuria• Renal failure (rare) | • Increase salt intake• Potassium supplementation• NSAIDs• K+-sparing diuretic | 15q21 11q24 1p36 1p32 1p36 3q13 | SLC12A1 (NKCC2) KCNJ1 (ROMK) CLCNKB BSND (Barttin) CLCNKB/CLCNKA CASR |
Gitelman syndrome (DCT) | AR | • Hypokalemia and metabolic alkalosis• Renin and Aldosterone elevated• Hypomagnesemia• Hypocalciuria• Increased bone density• Chondrocalcinosis (rare) | • Increase salt intake• Potassium supplementation• Magnesium supplementation• K+-sparing diuretic• NSAIDs | 16q13 | SLC12A3 (NCCT) |
EAST syndrome (DCT, CNT, and CD) | AR | • Hypokalemia and metabolic alkalosis• Renin and Aldosterone elevated• Hypomagnesemia• Hypocalciuria• Seizures• Hearing loss | • Increase salt intake• Potassium supplementation• Magnesium supplementation• K-sparing diuretics | 1q23 | KCNJ10 |
Pseudohypo-aldosteronism Type 1 (PHA I) (CD) | AD AR AR AR | • Hyperkalemia and metabolic acidosis• Renin elevated• Failure to thrive• Resistance to steroid treatment | • Saline infusion• Bicarbonate supplementation• Dialysis | 4q31 12p13 16p13 16p13 | NR3C2 SCNN1A SCNN1B SCNN1G |
ACE, angiotensin-converting-enzyme; AD, Autosomal-dominant; AGT, angiotensinogen; AGT1R, angiotensin 2 type 1 receptor; AR, autosomal-recessive; BSND, Barttin; CD, collecting duct; CLCNKB, chloride channel, voltage-sensitive Kb; CNT , connecting tubule; DCT, distal convoluted tubule; EAST, Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy; KCNJ1, potassium inwardly-rectifying channel, subfamily J, member 1; Kir 4.1, inward rectifier-type K + -channel, member 4.1; NR3C2, nuclear receptor subfamily 3, group C, member 2; NSAIDs, nonsteroidal antiinflammatory drugs; REN, renin; SCNN1A, 1B or 1C, sodium channel, non-voltage-gated 1, α-subunit, β-subunit or γ-subunit (genes encoding for ENaC subunits); SLC12A1, solute carrier family 12, member 1; TAL, thick ascending limb.