Difference between mendelian forms of hypertension and essential hypertension

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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

SYNDROMEMAIN FEATURESTREATMENTLOCUSINHERITANCEDISEASE GENE
Liddle syndrome• Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressedENaC inhibitors16p12ADENaC (Epithelial Na+ channel)
Glucocorticoid-remediable aldosteronism (GRA)• Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin suppressed• Aldosterone normal or elevated• “Unusual” urine steroid metabolitesCorticosteroid therapy8q24ADCYP11B1/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 ratioSpironolactone and ENaC inhibitors16q22AR11 β -HSD 2
Mineralocorticoid receptor (MR) activating mutation• Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin and aldosterone suppressed• Exacerbated in pregnancy• Spironolactone acts as agonistENaC inhibitors4q31ADNR3C2
Aldosterone-producing adrenal adenomas (APA)• Salt-sensitive• Hypokalemia and metabolic alkalosis• Renin suppressed• Aldosterone elevated• Imaging can show adrenal adenomaSpironolactone or eplerenone adenomectomy11q24 3p21 1p13 Xq28De 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 hormonesCorticosteroid therapy10q248q24AR
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 seenThiazide diuretics12p13 17q215q312q36AD
AD
AR/
de novo
WNK1
WNK4
Kelch-like3 Cullin3
Pheochromocytoma• Labile hypertension• Orthostatic hypotension• Renin and aldosterone elevated• Hypokalemia can be seen• Elevated metanephrinesAlphablockerSurgery10q11
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 EMultidrug therapy12p12ADPDE3A
Hypertension, hypomagnesemia, and hypercholesterolemia; mitochondrial• Hypomagnesemia• Hyperlipidemia• Incomplete penetranceMultidrug therapymDNAMaternaltRNAIle

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

SYNDROMEINHERITANCEMAIN FEATURESTREATMENTLOCUSDISEASE 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 diuretic15q21
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• NSAIDs16q13SLC12A3 (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 diuretics1q23KCNJ10
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• Dialysis4q31
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.

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