American Academy of Pediatrics

TABLE 15

Endocrine Causes of HTN

Name of Disorder	Genetic Mutation	Mode of Inheritance	Clinical Feature(s)	Biochemical Mechanism and Notes	Ref No(s).
Catecholamine excess
PCC, paraganglioma	VHL (49%)	De novo, AD	HTN	Diagnostic test: fractionated plasma^a and/or urine metanephrines and normetanephrines	248–254
	SDHB (15%)		Palpitations, headache, sweating
	SDHD (10%)		Abdominal mass
	RET		Incidental radiographic finding
			Family screening
Mineralocorticoid excess
Specific etiologies addressed below		Screening test: ARR: PAC, PRA preferably obtained between 8:00 and 10:00 am			255,256
Consider if:
Early onset HTN
Potassium level abnormalities
Family history of primary aldosteronism
Resistant HTN
Congenital adrenal hyperplasia
11β–hydroxylase deficiency	CYP11B1 (loss of function)	AR	HTN	Elevated levels of DOC, 11-deoxycortisol, androstenedione, testosterone, and DHEAS	257–259
			Hypokalemia	Higher prevalence in Moroccan Jews
			Acne, hirsutism, and virilization in girls
			Pseudoprecocious puberty in boys
			11% of congenital adrenal hyperplasia
17-α hydroxylase deficiency	CYP17 (loss of function)	AR	HTN and hypokalemia	Elevated DOC and corticosterone	260–262
			Low aldosterone and renin	Decreased androstenedione, testosterone and DHEAS
			Undervirilized boys, sexual infantilism in girls	Prominent in Dutch Mennonites
			<1% of congenital adrenal hyperplasia
Familial hyperaldosteronism
Type 1	Hybrid CYP11B1 and CYP11B2 (11β-hydroxylase–aldosterone synthase, gain of function)	AD	Young subjects with PA	Excessive, ACTH-regulated aldosterone production	263,264
			Family history of young strokes	Prescription with low-dose dexamethasone
				May add low-dose spironolactone, calcium channel blocker, or potassium supplementation
Type 2	Unknown, possibly 7p22	AD (prevalence varies from 1.2% to 6%)	PA in the patient with an affected first-degree relative	Excessive autonomous aldosterone production	265–267
			Unresponsive to dexamethasone
			May have adrenal adenoma or bilateral adrenal hyperplasia
Type 3	KCNJ5 G-protein potassium channel (loss of function)	AD	Early onset severe HTN in the first family described	Mutation leads to loss of potassium+ sensitivity causing sodium+ influx that activates Ca⁺⁺ channels, leading to aldosterone synthesis	268–270
Type 3	KCNJ5 G-protein potassium channel (loss of function)	AD	Milder phenotypes also seen		268–270
Type 4	CACNA1D coding for calcium channel (gain of function)	AD	PA and HTN age <10 y	Increased Ca⁺⁺ channel sensitivity causing increased aldosterone synthesis	271,272
Type 4	CACNA1D coding for calcium channel (gain of function)	AD	Variable developmental abnormalities		271,272
Other genetic causes
Carney complex	PRKAR1A	AD	Skin pigmentation	Rare familial cause	273,274
Carney complex	PRKAR1A	AD	Pituitary and other tumors	Rare familial cause	273,274
McCune Albright syndrome	GNAS, α-subunit	Somatic	Cutaneous pigmentation	Tumors in the breast, thyroid, pituitary gland, or testicles may be present	275,276
McCune Albright syndrome	GNAS, α-subunit	Somatic	Fibrous dysplasia		275,276
Primary glucocorticoid resistance (Chrousos syndrome)	NR3C1 (loss of function glucocorticoid receptor)	AD	HTN	Loss of function of glucocorticoid receptor	277–279
			Ambiguous genitalia
			Precocious puberty
			Androgen excess, menstrual abnormalities or infertility in women
Apparent mineralocorticoid excess	HSD11B2 (loss of function)	AR	HTN	Reduced or absent activity of 11 β-HSD2: cortisol gains access to MR	280,281
			Hypokalemia	Mimicked by licorice toxicity
			Low birth weight
			Failure to thrive
			Polyuria, polydipsia
Liddle syndrome	SCNN1B β-subunit–SCNN1G γ-subunit (activating mutation)		Severe HTN	Constitutive activation of the epithelial sodium channel causing salt retention and volume expansion	282,283
			Hypokalemia
			Metabolic alkalosis
			Muscle weakness
Geller syndrome	MCR (mineralocorticoid-d receptor, activating mutation)	AD	Onset of HTN <20 y	Constitutive activation of MR	284
Geller syndrome	MCR (mineralocorticoid-d receptor, activating mutation)	AD	Exacerbated by pregnancy	Also activated by progesterone	284
Pseudohypo-aldosteronism type 2 (Gordon syndrome)	WNK1,4; KLHL3; CUL3; SPAK (activating mutation)	AD	Short stature	Increased activity of sodium chloride cotransporter causing salt retention and volume expansion	285–287
			Hyperkalemic and hyperchloremic metabolic acidosis
			Borderline HTN
Glucocorticoid excess
Cushing syndrome, adrenocortical carcinoma, iatrogenic excess	To be discovered	—	HTN	Likely attributable to increased DOC, sensitivity to vasoconstriction, cardiac output, activation of RAS	288–290
	To be discovered	—	Other signs of Cushing syndrome		288–290
Other endocrine abnormalities
Hyperthyroidism	To be discovered	—	Tachycardia	Mechanism increased cardiac output, stroke volume, and decreased peripheral resistance	291,292
			HTN	Initial prescription with β blockers
			Tremors
			Other signs of hyperthyroidism
Hyperparathyroidism	—	—	Hypercalcemia	Mechanism unknown, may not remit after treatment of hyperparathyroidism	293,294
Hyperparathyroidism	—	—	Other signs of hyperparathyroidism		293,294

Name of Disorder	Genetic Mutation	Mode of Inheritance	Clinical Feature(s)	Biochemical Mechanism and Notes	Ref No(s).
Catecholamine excess
PCC, paraganglioma	VHL (49%)	De novo, AD	HTN	Diagnostic test: fractionated plasma^a and/or urine metanephrines and normetanephrines	248–254
	SDHB (15%)		Palpitations, headache, sweating
	SDHD (10%)		Abdominal mass
	RET		Incidental radiographic finding
			Family screening
Mineralocorticoid excess
Specific etiologies addressed below		Screening test: ARR: PAC, PRA preferably obtained between 8:00 and 10:00 am			255,256
Consider if:
Early onset HTN
Potassium level abnormalities
Family history of primary aldosteronism
Resistant HTN
Congenital adrenal hyperplasia
11β–hydroxylase deficiency	CYP11B1 (loss of function)	AR	HTN	Elevated levels of DOC, 11-deoxycortisol, androstenedione, testosterone, and DHEAS	257–259
			Hypokalemia	Higher prevalence in Moroccan Jews
			Acne, hirsutism, and virilization in girls
			Pseudoprecocious puberty in boys
			11% of congenital adrenal hyperplasia
17-α hydroxylase deficiency	CYP17 (loss of function)	AR	HTN and hypokalemia	Elevated DOC and corticosterone	260–262
			Low aldosterone and renin	Decreased androstenedione, testosterone and DHEAS
			Undervirilized boys, sexual infantilism in girls	Prominent in Dutch Mennonites
			<1% of congenital adrenal hyperplasia
Familial hyperaldosteronism
Type 1	Hybrid CYP11B1 and CYP11B2 (11β-hydroxylase–aldosterone synthase, gain of function)	AD	Young subjects with PA	Excessive, ACTH-regulated aldosterone production	263,264
			Family history of young strokes	Prescription with low-dose dexamethasone
				May add low-dose spironolactone, calcium channel blocker, or potassium supplementation
Type 2	Unknown, possibly 7p22	AD (prevalence varies from 1.2% to 6%)	PA in the patient with an affected first-degree relative	Excessive autonomous aldosterone production	265–267
			Unresponsive to dexamethasone
			May have adrenal adenoma or bilateral adrenal hyperplasia
Type 3	KCNJ5 G-protein potassium channel (loss of function)	AD	Early onset severe HTN in the first family described	Mutation leads to loss of potassium+ sensitivity causing sodium+ influx that activates Ca⁺⁺ channels, leading to aldosterone synthesis	268–270
Type 3	KCNJ5 G-protein potassium channel (loss of function)	AD	Milder phenotypes also seen		268–270
Type 4	CACNA1D coding for calcium channel (gain of function)	AD	PA and HTN age <10 y	Increased Ca⁺⁺ channel sensitivity causing increased aldosterone synthesis	271,272
Type 4	CACNA1D coding for calcium channel (gain of function)	AD	Variable developmental abnormalities		271,272
Other genetic causes
Carney complex	PRKAR1A	AD	Skin pigmentation	Rare familial cause	273,274
Carney complex	PRKAR1A	AD	Pituitary and other tumors	Rare familial cause	273,274
McCune Albright syndrome	GNAS, α-subunit	Somatic	Cutaneous pigmentation	Tumors in the breast, thyroid, pituitary gland, or testicles may be present	275,276
McCune Albright syndrome	GNAS, α-subunit	Somatic	Fibrous dysplasia		275,276
Primary glucocorticoid resistance (Chrousos syndrome)	NR3C1 (loss of function glucocorticoid receptor)	AD	HTN	Loss of function of glucocorticoid receptor	277–279
			Ambiguous genitalia
			Precocious puberty
			Androgen excess, menstrual abnormalities or infertility in women
Apparent mineralocorticoid excess	HSD11B2 (loss of function)	AR	HTN	Reduced or absent activity of 11 β-HSD2: cortisol gains access to MR	280,281
			Hypokalemia	Mimicked by licorice toxicity
			Low birth weight
			Failure to thrive
			Polyuria, polydipsia
Liddle syndrome	SCNN1B β-subunit–SCNN1G γ-subunit (activating mutation)		Severe HTN	Constitutive activation of the epithelial sodium channel causing salt retention and volume expansion	282,283
			Hypokalemia
			Metabolic alkalosis
			Muscle weakness
Geller syndrome	MCR (mineralocorticoid-d receptor, activating mutation)	AD	Onset of HTN <20 y	Constitutive activation of MR	284
Geller syndrome	MCR (mineralocorticoid-d receptor, activating mutation)	AD	Exacerbated by pregnancy	Also activated by progesterone	284
Pseudohypo-aldosteronism type 2 (Gordon syndrome)	WNK1,4; KLHL3; CUL3; SPAK (activating mutation)	AD	Short stature	Increased activity of sodium chloride cotransporter causing salt retention and volume expansion	285–287
			Hyperkalemic and hyperchloremic metabolic acidosis
			Borderline HTN
Glucocorticoid excess
Cushing syndrome, adrenocortical carcinoma, iatrogenic excess	To be discovered	—	HTN	Likely attributable to increased DOC, sensitivity to vasoconstriction, cardiac output, activation of RAS	288–290
	To be discovered	—	Other signs of Cushing syndrome		288–290
Other endocrine abnormalities
Hyperthyroidism	To be discovered	—	Tachycardia	Mechanism increased cardiac output, stroke volume, and decreased peripheral resistance	291,292
			HTN	Initial prescription with β blockers
			Tremors
			Other signs of hyperthyroidism
Hyperparathyroidism	—	—	Hypercalcemia	Mechanism unknown, may not remit after treatment of hyperparathyroidism	293,294
Hyperparathyroidism	—	—	Other signs of hyperparathyroidism		293,294

ACTH, adrenocorticotropic hormone; AD, autosomal dominant; AR, autosomal recessive; DHEAS, dehydroepiandrosterone sulfate; DOC, deoxycortisol; MR, magnetic resonance; PA, primary hyperaldosteronism; PAC, plasma aldosterone concentration; RAS, renin angiotensin system; —, not applicable.

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