Monogenic Hypertension in Neonates and Children

Low-renin Mendelian hypertensions: channel, mineralocorticoid and steroidogenesis disorders

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

The only GeneReviews chapter devoted to one of these entities is "Pseudohypoaldosteronism Type II" (NBK65707, created on 10 November 2011 and updated on 16 February 2017) [18]. The relevant European Reference Networks are Endo-ERN, for familial hyperaldosteronism, apparent mineralocorticoid excess and the forms of congenital adrenal hyperplasia, and ERKNet, for tubulopathies and hypertension of renal cause [7, 27, 28].

The blood pressure thresholds used throughout this article are those of the American Academy of Pediatrics: between 1 and less than 13 years, normal blood pressure below the 90th percentile for age, sex and height, elevated blood pressure from the 90th to less than the 95th percentile or 120/80 mmHg (whichever is lower), stage 1 hypertension from the 95th percentile to less than the 95th percentile plus 12 mmHg or 130/80 to 139/89 mmHg, and stage 2 hypertension from the 95th percentile plus 12 mmHg or 140/90 mmHg; from 13 years adult values apply [29]. In the neonate there is no validated definition: close monitoring is recommended with consistent readings above the 95th percentile for postmenstrual age, and evaluation and treatment should be considered above the 99th percentile [30].

1. Introduction

Monogenic hypertension refers to a group of hereditary disorders in which a single genetic alteration disturbs the renal or adrenal regulation of blood pressure and produces, through convergent mechanisms, expansion of the extracellular volume. Raina and colleagues organised these mechanisms into three groups: excessive sodium reabsorption through hyperactive channels, overstimulation of the mineralocorticoid receptor due to altered steroidogenesis, and excessive mineralocorticoid production; the last two can be read as indirect routes to the first, since all end in increased tubular salt reabsorption [17]. The common laboratory denominator is suppressed renin, and practical subclassification rests on the aldosterone level, which separates the low-aldosterone forms (Liddle syndrome, congenital adrenal hyperplasia due to 11β- or 17α-hydroxylase deficiency, apparent mineralocorticoid excess and Geller syndrome), the form with aldosterone normal or only slightly raised for the serum potassium (Gordon syndrome) and the high-aldosterone forms (familial hyperaldosteronism types I to IV and primary aldosteronism with seizures and neurological abnormalities) [7, 17]. The same classification appears, in summary form, in the Portuguese-language clinical genetics literature, which estimates the heritability of systolic and diastolic blood pressure in family studies at 30 to 50% and places monogenic forms as a small proportion of cases of hypertension [31].

The history of these entities begins in 1963, when Liddle, Bledsoe and Coppage described in a 16-year-old girl a familial disorder that mimicked primary aldosteronism but with negligible aldosterone secretion: the patient had a blood pressure of 180/110 mmHg, serum potassium of 2.8 mmol/L and metabolic alkalosis, did not respond to spironolactone and did respond to triamterene, which increased urinary sodium excretion and reduced potassium excretion; the combination of triamterene 100 mg every eight hours with a low-sodium diet normalised diastolic pressure and serum potassium [1, 32, 33]. Three generations were affected, and Botero-Velez and colleagues demonstrated in 1994, on studying the index patient at 49 years and 43 relatives, autosomal dominant inheritance with male-to-male transmission and wide variability in severity, age at onset, serum potassium and aldosterone excretion [1, 33]. The index patient developed chronic renal failure due to hypertensive nephrosclerosis and received a kidney transplant in 1989, after which blood pressure and potassium normalised and the renin and aldosterone responses to salt restriction returned to normal, which localised the defect to the kidney [1].

In 1966 Sutherland, Ruse and Laidlaw described a father and son with hypertension, low plasma renin activity and increased aldosterone secretion who responded to dexamethasone, the picture that came to be called glucocorticoid-remediable aldosteronism [34, 35]. In 1974 Werder and colleagues published the case of a three-year-old girl with low birth weight, short stature, polydipsia, polyuria and hypertension, with hypernatraemia, hypokalaemia, metabolic alkalosis, suppressed renin and aldosterone and low urinary tetrahydrocortisone with normal plasma cortisol; New and colleagues characterised the biochemical profile of similar patients in 1977 and, in 1979, Ulick and colleagues proposed the term apparent mineralocorticoid excess for a disorder of peripheral cortisol metabolism with hypertension, hypokalaemia, low renin and response to spironolactone without demonstrable mineralocorticoid overproduction [6, 36]. Follow-up of Werder's patient, published by Atanasov and colleagues in 2007, shows what is at stake: she re-presented at 40 years with subarachnoid haemorrhage and end-stage kidney disease due to untreated hypertension [36]. In 1986 Gordon systematised the syndrome of hypertension and hyperkalaemia with normal glomerular filtration, corrected by thiazides, that bears his name, although scattered cases had been described since 1970 [18, 37, 38].

Molecular identification was concentrated in the 1990s and 2000s and is owed largely to Richard Lifton's group. In 1992 Lifton and colleagues showed that glucocorticoid-remediable aldosteronism results from a chimeric gene in which the 5' regulatory sequences of CYP11B1 are fused to the coding region of CYP11B2, with complete linkage to chromosome 8q (maximum lod 5.23) [35, 39]. In 1994 Shimkets and colleagues identified in the original Liddle kindred a premature stop codon in the β subunit of the epithelial sodium channel, and in 1995 Hansson and colleagues demonstrated genetic heterogeneity by finding a truncation of the γ subunit in a Japanese family [40, 41]. Also in 1995 Mune and colleagues identified HSD11B2 variants in nine patients from eight families with apparent mineralocorticoid excess, and Wilson and colleagues described the variant NM_000196.4:c.1009C>T p.(Arg337Cys) in the homozygous state in three siblings of consanguineous Iranian parents [42, 43]. In 1996 Chang and colleagues showed that loss of function of the same epithelial sodium channel subunits causes the opposite picture, pseudohypoaldosteronism type I with salt wasting and hyperkalaemic acidosis [44]. In 2000 Geller and colleagues, screening the mineralocorticoid receptor in 75 patients with severe early-onset hypertension, found an activating variant that makes progesterone and spironolactone agonists of the receptor [16]. In 2001 Wilson and colleagues implicated the kinases WNK1 and WNK4 in pseudohypoaldosteronism type II, and in 2012 Boyden and colleagues and Louis-Dit-Picard and colleagues added KLHL3 and CUL3, which explain most families [45–47]. The last decade has widened the group of familial hyperaldosteronisms: KCNJ5 in 2011, CACNA1D in 2013, CACNA1H in 2015 and CLCN2 in 2018 [13, 15, 48–50]. In 2015 Maass and colleagues identified gain-of-function variants of PDE3A in the hypertension with brachydactyly described by Bilginturan in 1973 [26].

Nomenclature requires care on three points. The term "pseudohypoaldosteronism" arose to describe persistent hyperkalaemia with normal or raised aldosterone and strictly applies to type I, in which there is mineralocorticoid resistance with volume depletion; in type II it is a misnomer, because patients are hypertensive, and part of the literature therefore prefers familial hyperkalaemic hypertension [18]. Liddle syndrome has also been called pseudohyperaldosteronism, because it mimics hyperaldosteronism with hypertension, hypokalaemia and alkalosis although aldosterone is suppressed [17]. And historical epithelial sodium channel variants were numbered according to the homologous rat sequence: the variant of the original Liddle kindred, published as p.Arg564Ter, corresponds to NM_000336.3:c.1696C>T p.(Arg566Ter) in current human numbering, and the γ subunit truncation published as p.Trp574Ter corresponds to NM_001039.4:c.1719G>A p.(Trp573Ter) [1, 51, 52].

This article covers the class of monogenic hypertensions with neonatal and paediatric expression uniformly, from mechanism to follow-up, and includes within its scope the approach to hypertension in the neonate, because it is in that setting that suspicion arises. Some entities are described here only as far as needed for differential diagnosis and therapeutic decision-making: congenital adrenal hyperplasia due to 11β-hydroxylase deficiency and 17α-hydroxylase deficiency, hypertension with brachydactyly, Bartter and Gitelman syndromes, which are the normotensive or hypotensive mirror image of these disorders, and hereditary phaeochromocytoma and paraganglioma, which constitute the group of monogenic hypertension due to adrenergic excess [17].

2. Molecular Genetics and Pathophysiology

2.1 The distal nephron as the final common pathway

The distal convoluted tubule and the connecting tubule determine the final, regulated fraction of sodium chloride reabsorption and, with it, extracellular volume and blood pressure. In the apical membrane of the distal convoluted tubule acts the thiazide-sensitive sodium-chloride cotransporter, encoded by SLC12A3, and downstream, in the connecting tubule and collecting duct, acts the epithelial sodium channel, formed by the α, β and γ subunits encoded by SCNN1A, SCNN1B and SCNN1G [1, 18]. Sodium reabsorption through the epithelial channel creates a lumen-negative potential difference that favours potassium secretion through the ROMK channel and hydrogen secretion by the ATPase of α-intercalated cells; the basolateral sodium-potassium pump exchanges three sodium ions for two potassium ions [1, 17]. It is this chain that explains why excess apical sodium activity produces hypertension, hypokalaemia and metabolic alkalosis at the same time, and why excess activity of the upstream cotransporter produces the opposite picture of hyperkalaemia and acidosis: by retaining sodium in the distal convoluted tubule, too little sodium reaches the epithelial channel to sustain potassium and hydrogen secretion [17, 18].

Aldosterone is the physiological regulator of this pathway and acts through the mineralocorticoid receptor encoded by NR3C2. The receptor is not selective: in vitro it has equivalent affinity for aldosterone and cortisol, and it is 11β-hydroxysteroid dehydrogenase type 2, encoded by HSD11B2, that converts cortisol to inactive cortisone in target tissues and thus ensures functional selectivity for aldosterone [6]. As cortisol circulates at concentrations far higher than those of aldosterone, the integrity of this enzyme is a condition of normal regulation [17].

2.2 Gain of function of the epithelial sodium channel: Liddle syndrome

The three subunits of the epithelial sodium channel have two transmembrane domains, a large extracellular loop and short intracellular N and C termini, with 30 to 40% identity between them. At the carboxyl terminus of all of them there is a conserved proline-rich motif, PPxY, called the PY motif, which is the binding site of the ubiquitin ligase Nedd4, responsible for internalisation and proteasomal degradation of the channel [1, 17]. The great majority of causal variants of Liddle syndrome are missense, nonsense or frameshift variants that eliminate or disrupt this motif: without it, the channel is not removed from the apical membrane and accumulates, increasing the amiloride-sensitive sodium current, as demonstrated in Xenopus laevis oocytes [1]. Tetti and colleagues counted 31 causal variants in 72 families from four continents, with ten missense variants in thirty families, eight nonsense in twenty-one and twelve frameshift in twenty, twenty-four of them in the β subunit and six in the γ subunit [1]. Additional mechanisms have been documented: increased open probability, an increased fraction of proteolytically cleaved channel and reduced feedback inhibition by intracellular sodium. The γ variant NM_001039.4:c.1589A>G p.(Asn530Ser), located in the second transmembrane segment and not affecting the PY motif, doubles the current without increasing surface expression, and the α variant NM_001038.6:c.1435T>C p.(Cys479Arg), which destroys a disulphide bridge in the extracellular domain, increases the intrinsic activity of the channel, a mechanism distinct from truncations [1, 4]. In mice homozygous for the variant corresponding to human NM_000336.3:c.1696C>T p.(Arg566Ter), the transition zone between the late distal convoluted tubule and the connecting tubule is the main site of hyperactivity, which is largely aldosterone-independent [1].

2.3 Loss of function of 11β-hydroxysteroid dehydrogenase type 2

HSD11B2 is located at 16q22.1, spans about 6.2 kb and five exons, and encodes a nicotinamide adenine dinucleotide-dependent dehydrogenase of 405 amino acids, organised into a cofactor-binding domain and a substrate-binding domain [6]. When enzymatic activity is lost, cortisol is not converted to cortisone in target tissues, occupies the mineralocorticoid receptor and increases transcription of the epithelial sodium channel and the sodium-potassium pump, with sodium retention, potassium loss and secondary suppression of renin and aldosterone; in urine, the cortisol metabolites tetrahydrocortisol and allo-tetrahydrocortisol increase and the cortisone metabolite tetrahydrocortisone decreases [6]. Fifty-one deleterious variants have been described, most in exons 3 to 5, with missense variants predominating and nonsense, frameshift and splicing variants in smaller numbers; the substitution IVS3+14C>T (historical intronic notation, with no confirmed conversion to NM_000196.4) alters pre-messenger RNA processing and causes loss of exon 4, which encodes the catalytic domain, producing inactive protein, whereas IVS3+1G>A (historical notation) allows some normal processing and causes moderate deficiency; the apparently silent variant published as c.771C>G p.(Val254=) creates an aberrant donor site that truncates the protein in exon 5 [6]; in NM_000196.4, c.771C>G corresponds to p.(Val257=) in VariantValidator, so the codon position and the nucleotide position of the published designation do not match and the variant retains its original designation [52]. The molecular mechanisms fall into four categories: loss of protein stability, with reduction of the half-life from 21 hours in the wild-type enzyme to 3 hours in NM_000196.4:c.1012T>C p.(Tyr338His) and 4 hours in p.(Arg337Cys), and importance of the arginine and tyrosine cluster at residues 335 to 339; reduced affinity for the substrate, as in the variants p.Ala221Gly, p.Tyr226Asn and p.Leu363Pro (published protein designations), which replace hydrophobic side chains with hydrophilic ones near the cortisol-binding site; reduced affinity for the cofactor, as in p.Leu114_Glu115del and p.Thr267Ala (published designations) and in NM_000196.4:c.667G>A p.(Asp223Asn); and disruption of the dimer interface, involving residues Arg186, Ala237, Asp244 and Leu251 [6, 53]. The severity of the phenotype follows the residual activity of the enzyme [54]. The enzyme is also expressed in the placenta, where it acts as a barrier to maternal glucocorticoids; its absence exposes the fetus to maternal cortisol and contributes to the intrauterine growth restriction that characterises the classic form [6]. In the adult brain, the nucleus of the solitary tract is the only site where the mineralocorticoid receptor and the enzyme are co-expressed, and mice with brain-specific inactivation of Hsd11b2 develop hypertension by tripling their salt intake, an effect inhibited by spironolactone, which suggests that salt appetite contributes to the phenotype [6].

2.4 Constitutive activation and resistance of the mineralocorticoid receptor

The NR3C2 variant p.Ser810Leu produces constitutive receptor activity and alters ligand specificity: steroids lacking a 21-hydroxyl group, normally antagonists, become potent agonists, including progesterone and spironolactone itself, and cortisone and 11-dehydrocorticosterone also activate the receptor [16, 55]. As progesterone rises about a hundredfold in pregnancy, reaching concentrations of 500 nmol/L, the phenotype worsens markedly during gestation [16, 56]. In ClinVar, NM_000901.5:c.2429C>T p.(Ser810Leu) is classified as of uncertain significance, despite the published functional and segregation evidence, so interpretation of the result should rest on the clinical picture and functional data and not only on the database classification [16, 51]. Loss of function of the same gene causes autosomal dominant renal pseudohypoaldosteronism type I, with neonatal salt wasting that improves with age — the physiological opposite, at the same locus [55].

In generalised glucocorticoid resistance, inactivating NR3C1 variants prevent negative feedback by cortisol; compensatory hypersecretion of adrenocorticotropic hormone increases cortisol but also deoxycorticosterone, corticosterone and adrenal androgens, resulting in hypertension and hypokalaemic alkalosis without the stigmata of Cushing syndrome [24, 55]. Fifteen missense, three nonsense, three frameshift, one splice-site and two alternative-splicing variants have been described in association with this phenotype [24].

2.5 The WNK-SPAK-cotransporter pathway in pseudohypoaldosteronism type II

WNK kinases owe their name to the substitution of lysine by cysteine at a conserved residue of the catalytic domain ("with no lysine"), and they regulate coordinated sodium, potassium and chloride transport in several epithelia [18]. The long isoform of WNK1 activates the kinase SPAK, which phosphorylates and activates the sodium-chloride cotransporter; the kidney-specific short isoform binds to the long isoform and inhibits it. WNK4 mainly stimulates the cotransporter in vivo and can inhibit ROMK, increase paracellular chloride permeability through phosphorylation of claudins and regulate the epithelial sodium channel and the TRPV4 and TRPV5 channels [18]. KLHL3 and CUL3 form the cullin-RING E3 ubiquitin ligase complex that degrades WNK kinases: KLHL3 has a BTB domain that binds CUL3 and a six-bladed Kelch propeller that binds substrates, and its binding to WNK4 causes ubiquitination and degradation [18]. Any alteration that increases the cellular content of active WNK, or prevents its degradation, increases cotransporter activity and reproduces the phenotype. This is what is observed gene by gene: CUL3 variants lie in intron 8, exon 9 or intron 9 and alter processing of exon 9, resulting in an in-frame deletion of 57 amino acids; dominant KLHL3 variants are missense variants clustered in the segments linking the β strands of the Kelch propeller and abolish substrate binding, whereas recessive variants are distributed across the whole gene and include frameshifts and premature stop codons; WNK4 variants are all missense and lie in exons 7 and 17, clustered in a conserved acidic segment immediately distal to the kinase domain that is critical for binding to KLHL3; WNK4 variants define subtype IIB (OMIM 614491) and WNK1 variants subtype IIC (OMIM 614492), whereas KLHL3 variants define subtype IID (OMIM 614495) and CUL3 variants subtype IIE (OMIM 614496) [57–59]; the two known WNK1 variants are intronic deletions of 41 kb and 21 kb in intron 1, which do not alter the coding sequence but increase transcription and expression of the long isoform in the distal convoluted tubule [18]. Decisive proof of the mechanism came from animal models: mice transgenic for Wnk4 with the Gln562Glu variant, orthologous to human NM_032387.5:c.1693C>G p.(Gln565Glu), have hyperkalaemia, higher blood pressure, hypercalciuria, hyperplasia of the distal convoluted tubule and increased cotransporter expression, and all these changes disappear when they are crossed with mice lacking the cotransporter [18].

2.6 Adrenal steroidogenesis and zona glomerulosa channels

In familial hyperaldosteronism type I, unequal crossing-over between CYP11B1 and CYP11B2, with a breakpoint in the first two to four introns, generates a hybrid gene that carries the CYP11B1 promoter and the CYP11B2 coding sequence: aldosterone synthase activity becomes expressed in the zona fasciculata and regulated by adrenocorticotropic hormone instead of angiotensin II, and intracellular co-expression of the two enzymatic activities produces aldosterone and 18-oxocortisol [7, 39]. It is an anti-Lepore-type rearrangement, analogous to that of the anti-Lepore haemoglobins, and its stoichiometry matters: hybrid constructs with up to three CYP11B1 exons produce aldosterone at nearly normal levels, whereas those containing five or more exons produce no detectable aldosterone [35].

In types II to IV and in primary aldosteronism with seizures and neurological abnormalities, the common point is depolarisation of the zona glomerulosa cell and calcium entry, which is the main signal for aldosterone synthesis. Gain-of-function variants of CLCN2 increase the conductance of the ClC-2 chloride channel and chloride efflux; those of KCNJ5 make the Kir3.4 potassium channel permeable to sodium; those of CACNA1H impair inactivation of the CaV3.2 calcium channel and shift its activation to more negative potentials; and those of CACNA1D directly increase calcium influx through CaV1.3 [7, 13, 15, 48, 49]. Variant correlation is clinically useful in type III (NM_000890.5): c.472A>G p.(Thr158Ala), c.451G>C or c.451G>A p.(Gly151Arg), c.470T>G p.(Ile157Ser) and p.Glu145Gln (published designation) are associated with severe, refractory early-onset hypertension with greatly enlarged adrenals, whereas c.452G>A p.(Gly151Glu) causes cell lethality in vitro and a mild phenotype without hyperplasia, treatable with a mineralocorticoid receptor antagonist; the variant c.455A>G p.(Tyr152Cys), classified in ClinVar as of uncertain significance, was described as having a milder, later phenotype in the body of the Endo-ERN guideline and included among the severe variants in the recommendation on surgery in the same document, an internal discrepancy worth knowing when interpreting the literature [7, 51]. In type IV (NM_021098.3), c.4645A>G p.(Met1549Val) and c.4647G>T p.(Met1549Ile) are associated with early onset, and p.Ser196Leu (published designation), c.6248C>T p.(Pro2083Leu) and c.5852T>A p.(Val1951Glu) have been identified in adults, with doubtful pathogenicity for the last, found in the germline of a patient with an aldosterone-producing adenoma cured by adrenalectomy; in ClinVar, p.(Pro2083Leu) is classified as benign or likely benign and p.(Val1951Glu) as likely benign, which reinforces the reservation about the causal role of these adult variants; penetrance is incomplete, with normotensive carriers who have low renin and normal aldosterone [7, 60, 61].

Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency and due to 17α-hydroxylase deficiency belong to this group for a simple pharmacological reason: both blocks divert steroidogenesis to the 17-deoxy pathway and cause accumulation of 11-deoxycorticosterone, a potent mineralocorticoid, resulting in hyporeninaemic hypertension and hypokalaemia; the difference between the two lies in the fate of the sex steroids, preserved in the former, with virilisation, and abolished in the latter, with sexual infantilism [17, 21, 55].

2.7 Reference variants

2.8 Allelic disorders and mechanism inversion

Several of these genes cause disorders of opposite physiological direction, and it is the direction of the functional effect, not the gene, that determines phenotype and treatment. Biallelic loss of function of the epithelial sodium channel subunits causes systemic pseudohypoaldosteronism type I, with neonatal salt wasting, hyponatraemia, hyperkalaemia and acidosis with very high aldosterone and renin, a picture that requires sodium chloride and potassium removal and does not respond to mineralocorticoid replacement [44, 55, 64]. Loss of function of NR3C2 gives renal pseudohypoaldosteronism type I, dominant and with a favourable prognosis, with spontaneous improvement with age [55, 65]. Biallelic loss of function of CLCN2 causes leukoencephalopathy with ataxia, and the historical association of the same gene with idiopathic generalised epilepsy was classified as refuted by ClinGen on 15 March 2022 [55]. Loss of function of CACNA1D causes sinoatrial node dysfunction with deafness, autosomal recessive [55]. Loss of function of KCNJ5, which encodes the Kir3.4 subunit of the acetylcholine-activated potassium current, appears in long QT syndrome classifications as type 13 (LQT13), with less than 1% of genotyped cases, but ClinGen classified the relationship between KCNJ5 and long QT syndrome as disputed on 15 December 2020, so a KCNJ5 variant found in an arrhythmia study should not be interpreted as a diagnosis of long QT nor confused with familial hyperaldosteronism type III, which results from gain of function [55, 66]. Loss of function of specific WNK1 exons causes hereditary sensory and autonomic neuropathy type 2A, autosomal recessive, and missense variants of the same gene have been described in two individuals with salt-wasting hypokalaemic tubulopathy [18]. CUL3 haploinsufficiency causes a neurodevelopmental disorder with or without autism or seizures, described in a cohort of 37 individuals, a phenotype that does not overlap with the renal one [55]. The epithelial sodium channel subunits also have a weak association, at the limited level in GenCC, with a cystic fibrosis-like airway disease with bronchiectasis [55]. Finally, KCNJ5, CACNA1D and CACNA1H have recurrent somatic variants in adult aldosterone-producing adenomas; a somatic finding in an adrenal nodule confers no hereditary risk and does not implicate relatives [15, 48, 55].

3. Clinical Spectrum and Manifestations by System

3.1 Hypertension in the neonate as the setting

Neonatal hypertension occurs in 1 to 2% of neonates admitted to neonatal intensive care, with historical estimates between 0.2 and 3%; in the multicentre AWAKEN study, on the epidemiology of acute kidney injury in the neonate, 1.8% of the cohort had hypertension and a further 3.7% had undiagnosed hypertension [30]. In the preterm infant, the cause is mainly iatrogenic or linked to complications of prematurity; in the term neonate an underlying disease is more likely [30]. The published aetiological distribution attributes 13 to 38% of cases to renal parenchymal disease, 15 to 20% to renovascular causes, 30 to 60% to pulmonary causes, 8 to 15% to neurological causes, 8 to 9% to drugs, 4 to 6% to endocrine causes and 0 to 4% to cardiac causes, and a 2017 study classified about half of cases as unexplained hypertension [30]. Thrombi associated with umbilical artery catheters occur in about 25% of neonates with such a catheter, and hypertension can arise without a thrombus visible on imaging; renal vein thrombosis, the most frequent non-catheter-associated thrombosis in infancy, has a reported symptomatic incidence of 2.2 per 100,000 live births and leaves persistent hypertension in one in five cases [30]. Bronchopulmonary dysplasia is associated with hypertension in 43% of infants, compared with 4.5% of those without chronic lung disease, with presentation at around 40 weeks' postmenstrual age and resolution over about 25 weeks, through a mechanism of sodium retention with mineralocorticoid receptor activation and low renin [30]. Endocrine causes are therefore a minority within a minority, which is why recognition of a distinctive biochemical pattern carries so much weight.

The natural history of these acquired causes is favourable: most prematurity-related neonatal hypertension resolves in the first or second year of life. In an Australian neonatal intensive care cohort, 41% of hypertensive neonates went home on antihypertensives and only 15% were still taking them at 3 to 6 months; in an earlier American study, 56% were normotensive at one month, 67% at six months and 81% at one year [30]. Persistence of hypertension, or its reappearance, is precisely what should direct attention to a monogenic cause.

3.2 Liddle syndrome

The typical presentation is early, resistant, salt-sensitive hypertension, with a family history of young-onset hypertension and sudden death, accompanied by hypokalaemia, metabolic alkalosis, suppressed plasma renin activity and low serum aldosterone [1]. Age at onset is usually between late childhood and adolescence, with a mean age of about 15 years in the largest series of patients with γ subunit variants, in which most had potassium below 3.0 mmol/L [3, 17]. A systematic review of published cases quantifies the variability: hypertension in 92.4%, hypokalaemia defined as potassium below 3.5 mmol/L in 71.8% and hypoaldosteronaemia defined as aldosterone below 5 ng/dL in 58.2% [1]. There are normotensive carriers and patients diagnosed at an advanced age, and variability exists between families with different variants and within the same family, probably owing to sodium intake and polymorphisms in sodium transport genes [1].

Symptoms derive from hypokalaemia and hypertension. Hypokalaemia produces muscle weakness, polyuria, because low potassium concentrations in tubular fluid prevent adequate function of the sodium-potassium-chloride cotransporter of the thick ascending limb and of the sodium-potassium pump of the collecting duct and downregulate aquaporin-2 channels, and polydipsia secondary to polyuria [1]. Hypertension produces headache, dizziness, retinopathy, chronic kidney disease, left ventricular hypertrophy and sudden death, attributed to malignant arrhythmias triggered by severe hypokalaemia [1]. The untreated natural history is documented in the original kindred: the index patient progressed to end-stage renal failure due to nephrosclerosis and underwent transplantation; in the family described by Tamura and colleagues, one of the brothers was on haemodialysis at 37 years due to nephrosclerosis and the mother died at 72 years after prolonged haemodialysis; in the African American family of Hansson and colleagues, the mother, diagnosed at 15 years, had a stroke at 21 years with residual hemiparesis [33]. The presentation can be atypical: there are cases of isolated hypokalaemia without hypertension, and hypokalaemia is not a universal finding in affected families [33, 55].

3.3 Apparent mineralocorticoid excess

The classic form begins between infancy and youth and manifests as low birth weight, refractory hypertension, growth failure, polyuria, polydipsia and failure to thrive, with marked hypokalaemia, metabolic alkalosis, suppressed plasma renin activity, low aldosterone and increased cortisol-to-cortisone ratios in urine or serum; nephrocalcinosis and renal cysts are frequent, probably owing to prolonged hypokalaemia [6]. Serum cortisol is normal and there are no stigmata of Cushing syndrome or Addison disease, which is explained by the prolonged half-life of cortisol with reduced production under normal regulation of the hypothalamic-pituitary-adrenal axis [6]. The non-classic form, also called AME type 2, arises in adolescence or adulthood, with normal or slightly raised blood pressure, about 141.0/88.5 mmHg on average, normal potassium, low renin, normal aldosterone and only a slight increase in urinary ratios; it often goes undetected until adulthood [6]. A cross-sectional study identified partial enzyme deficiency in 7.1% of a primary care cohort in Chile, a result that, given its magnitude, mainly measures functional variation rather than classic Mendelian disease [6]. Heterozygotes with a single pathogenic variant can have phenotypes ranging from normal to moderate, through haploinsufficiency or a partial dominant-negative effect [6].

The series of three Chinese children documents the paediatric phenotype with figures: all were born small for gestational age, with weights of 1550 g, 2100 g and 2500 g, and all had severe hypokalaemia, metabolic alkalosis, hypertension, nephrocalcinosis and hypercalciuria with normal glomerular filtration, while maintaining normal intellectual and motor development; height deviations at presentation were −4.38, −3.05 and −3.87 standard deviations [54]. The first patient, diagnosed at 12 years after hypokalaemia and raised blood pressure had been noted at 6 months, had a minimum potassium of 1.23 mmol/L, blood pressure of 155/110 mmHg, left ventricular hypertrophy with an ejection fraction of 50 to 60%, focal cerebral atrophy and cystic changes of the left parietal lobe on magnetic resonance imaging, and an estimated glomerular filtration rate that fell from 87.9 to 76.2 mL/min/1.73 m² during follow-up [54]. Renal and cardiovascular risk is the dominant prognostic feature and is quantified in section 11.

3.4 Familial hyperaldosteronism types I to IV and PASNA

Patients with familial hyperaldosteronism present with variable degrees of hypertension, hypokalaemia, metabolic alkalosis, suppressed renin and increased aldosterone production, typically with onset early in life [7]. In type I, the clinical phenotype varies widely in age at onset, severity and penetrance: some carriers have severe early hypertension with marked increases in aldosterone and 18-oxocortisol and others are normotensive and normokalaemic; a history of early cardiovascular and cerebrovascular events is common but not universal, with an increased prevalence of intracranial aneurysms and haemorrhagic stroke; there is no correlation between the recombination point of the two genes and severity, but maternal inheritance was associated with higher pressures and, in another study, hypertension was more severe in males and proportional to the production of aldosterone and 18-oxocortisol [7, 35]. Raina and colleagues describe most patients as having severe hypertension in childhood or even infancy, and cite an incidence of intracerebral haemorrhage of 11 to 18% with a mortality of 61%, at a mean age of 31.7 years with a standard deviation of 11.3 years [17]. Hypokalaemia is usually mild and few patients develop metabolic alkalosis [17].

In type II, the usual presentation is classic bilateral hyperaldosteronism before 20 years, with incomplete penetrance and variable expressivity. In the family followed by Scholl and colleagues there were seven affected members, six with hypertension between 16 and 24 years, with a positive fludrocortisone suppression test and non-lateralised production; one carrier was normotensive but had a raised aldosterone/renin ratio and another was normotensive with a normal ratio [67]. Among nine patients from seven additional families, age at onset ranged from childhood to young adulthood, and one patient presented in infancy with resolution of hypertension at 2 years [67]. Fernandes-Rosa and colleagues described a 9-year-old girl with hypertension, hypokalaemia, raised aldosterone and suppressed renin, without adrenal abnormalities on imaging [50, 67]. In the family with a CLCN2 variant, fewer than 30% of proven carriers had hypokalaemia, although almost all had a raised aldosterone/renin ratio [7].

Type III is the most florid form and is diagnosed mainly in the paediatric age group. The first family described was a father and two daughters, all with severe secondary hypertension refractory to medical treatment by 7 years of age, with hyporeninaemia, hyperaldosteronism and very high levels of 18-oxocortisol and 18-hydroxycortisol; dexamethasone suppressed neither aldosterone nor cortisol, and all three underwent bilateral adrenalectomy, which corrected the hypertension in all; the removed glands weighed up to 82 g per pair and showed massive hyperplasia and cellular hypertrophy of a cortical compartment with features of the fasciculata or of a transitional zone, with an atrophic glomerulosa [68]. There are also diabetes insipidus-like symptoms due to the associated polyuria [55]. Monticone and colleagues counted, up to 2017, only eleven families with six different variants [11].

In type IV, the five unrelated patients of the original description all presented with hypertension by 10 years of age, with raised aldosterone despite low renin and no visible adrenal mass or hyperplasia at presentation, and without seizures or neurological disease; two had an affected parent, in one case the variant was de novo, and in another the carrier father was normotensive with low renin and normal aldosterone [13, 61]. Targeted screening for the same variant in 1632 additional patients, including 324 with primary aldosteronism diagnosed after 10 years, 96 with hypertension and bilateral adrenal hyperplasia and 1212 referred for suspected genetic hypertension without aldosteronism, found no further carriers, which confines the variant to the very early-onset phenotype [61].

Primary aldosteronism with seizures and neurological abnormalities is the entity with the earliest expression in the whole group. Of the two patients in the original description, the first, of European ancestry, had hypertension diagnosed at birth, with biventricular hypertrophy, ventricular septal defect, pulmonary hypertension and second-degree atrioventricular block, high aldosterone with low renin and a raised ratio, uncontrolled hypertension with hypokalaemia, generalised tonic-clonic seizures from 7 months, cortical blindness, spasticity and cerebral palsy, spontaneous passage of a renal calculus at 2 years and, at 3 years, absence of walking and speech; the second, African American, had cerebral palsy with spastic quadriplegia, mild athetosis, severe intellectual disability and complex partial and generalised seizures, and at 5 years had marked persistent hypertension, polydipsia, hypokalaemia and metabolic alkalosis, with high aldosterone, suppressed renin, normal adrenal computed tomography and mild left ventricular hypertrophy [15, 69]. Neither had a family history of early hypertension or epilepsy, consistent with de novo variants. Hyperinsulinism with hypoglycaemia and cardiac defects occur in some cases, not all carriers develop primary aldosteronism and there are cases in which autism is the dominant feature [7].

3.5 Pseudohypoaldosteronism type II

More than 180 individuals and families have been published. The presentation is heterogeneous, and the most constant finding, in children and young adults, is hyperkalaemia, with serum potassium of about 5.0 to 6.0 mmol/L in mild forms and above 8.0 mmol/L in severe forms, against a reference range of about 3.5 to 5.1 mmol/L [18]. As in essential hypertension, blood pressure is usually normal in younger patients and hypertension develops later, so the absence of hypertension does not exclude the diagnosis [18]. Hyperchloraemia, metabolic acidosis, suppressed plasma renin and variable but relatively low aldosterone for the degree of hyperkalaemia are associated, given that raised potassium is a potent stimulus for aldosterone secretion; hypercalciuria is well documented, with normal serum calcium and parathyroid hormone, and exposes patients to lithiasis and osteoporosis [17, 18]. In a subgroup, short stature, myalgia, periodic paralysis and dental anomalies are described, possibly in patients with more severe hyperkalaemia and acidosis, although published exceptions exist [18]. Spitzer-Weinstein syndrome, described in children with metabolic acidosis and hyperkalaemia, is considered an early presentation of the same disease [17].

The correlation with gene is consistent and of practical value. Carriers of a heterozygous CUL3 variant have more severe hyperkalaemia and metabolic acidosis, earlier hypertension and a greater likelihood of growth impairment; manifestations are generally milder in carriers of WNK1 or WNK4 variants; and patients with biallelic KLHL3 variants may be more severe than heterozygotes [18, 70]. The severity ranking established by Boyden and colleagues is WNK1 less severe than WNK4 and than dominant or recessive KLHL3, and all less severe than dominant CUL3 [46, 70]. Without treatment, patients with raised blood pressure are exposed to the usual complications of hypertension, including heart disease, renal impairment and stroke [18].

3.6 Geller syndrome and glucocorticoid resistance

In the original Geller syndrome family, the index case was a 15-year-old boy with severe hypertension, suppressed plasma renin activity and low aldosterone with no other cause; of 23 relatives assessed, 11 had severe hypertension diagnosed before 20 years and 12 had normal pressures, with exact cosegregation of the variant with the phenotype; carriers had markedly higher pressures despite medication, suppressed aldosterone and a non-significant trend towards lower potassium, with no effect of sex or age on expression; three deceased relatives with early hypertension died of heart failure before 50 years [16, 56]. Two female carriers had five pregnancies, all complicated by marked worsening of hypertension [16]. Normal potassium, in hypertension with suppressed renin and aldosterone, is the feature that distinguishes this picture from the other low-aldosterone forms [17].

In generalised glucocorticoid resistance, expression ranges from an asymptomatic biochemical finding to mineralocorticoid excess with hypertension and hypokalaemic alkalosis and to androgen excess, with ambiguous genitalia at birth in 46,XX individuals, hirsutism, acne, male-pattern alopecia, precocious puberty, menstrual irregularities and subfertility; chronic fatigue, anxiety and depression are attributed to hypercortisolism and increased corticotropin-releasing hormone [24, 55]. In the original family, a presumably homozygous man had mineralocorticoid excess with hypertension, hypokalaemia and alkalosis, and a brother with severe hypertension died of stroke at 54 years; heterozygotes had slightly raised mean plasma cortisol and increased urinary free cortisol [24]. Onset ranges from birth to adulthood and many cases go unrecognised for years, so the entity should be considered in hyperandrogenism or in hypertension of undetermined cause [55].

4. Clinical Recognition and Warning Signs

The first condition for recognising these disorders is to measure blood pressure with the correct technique, because measurement error is the most frequent cause of misleading values in paediatrics. The American Academy of Pediatrics recommends measuring blood pressure annually from 3 years of age, and at every visit, including below 3 years, in children with obesity, on drugs that raise blood pressure, with renal disease, with obstruction or coarctation of the aortic arch, with diabetes or with any condition that required admission to neonatal intensive care, a history of prematurity, intrauterine growth restriction, very low birth weight or umbilical artery catheterisation [29, 30]. The diagnosis of hypertension requires readings confirmed by auscultation at or above the 95th percentile at three separate visits; oscillometric devices are for screening and, if a value is raised, the result should be confirmed by auscultation, with the first reading discarded and the subsequent ones averaged [29]. Adherence to these recommendations is poor: in an analysis of one health system, only 38% of preterm, very low birth weight or neonatal intensive care graduate children had their blood pressure measured in the first three years of life, and 45% of those measured had a raised systolic value requiring reassessment [30].

In the neonate, intra-arterial measurement by radial or umbilical catheter is the reference standard in critically ill patients; oscillometric devices are more accurate for mean pressure, tend to overestimate systolic pressure and lose accuracy with a mean pressure below 30 mmHg [30]. The cuff should have a bladder that encircles at least 75% of the arm circumference, with a width-to-circumference ratio of about 0.5; up to 6 months of age, leg measurements are equivalent to arm measurements, but the International Neonatal Consortium recommends reserving them for the first days of life or for situations in which the arm cannot be used [30]. The suggested protocol uses an oscillometric device on the right arm, 15 minutes after cuff placement and at least an hour and a half after feeding, with the infant at rest, with three readings at two-minute intervals; this standardised technique gives lower and less variable values than routine measurement [30].

When to suspect a monogenic cause. The consensus recommendation of the American Academy of Pediatrics is explicit: monogenic hypertension should be suspected in patients with a family history of early-onset hypertension, hypokalaemia, suppressed plasma renin or a raised aldosterone/renin ratio [29]. The European guideline on familial hyperaldosteronism recommends investigating primary aldosteronism in any patient with hypertension of onset before 40 years, and recommends genetic testing in all patients with hyperaldosteronism with hypertension diagnosed before 20 years, noting that the younger the patient, the greater the likelihood of a genetic cause [7]. The Endocrine Society guideline adds genetic screening of all first-degree relatives of patients with familial hyperaldosteronism and of all patients with primary aldosteronism of onset before 20 years [71].

The signs that should raise suspicion, in order of practical usefulness, are as follows. Hypertension in a neonate or infant that persists beyond the first year of life, or that reappears after having resolved, especially in a term neonate without an umbilical catheter, without chronic lung disease and with a normal renal Doppler ultrasound [30]. Spontaneous hypokalaemia, not explained by diuretics, vomiting, nasogastric drainage or diarrhoea, associated with hypertension: it points to the forms with gain of epithelial sodium channel activity or excess mineralocorticoid activity [1, 6]. Hyperkalaemia with normal glomerular filtration and hyperchloraemic metabolic acidosis, with or without hypertension, which points to Gordon syndrome and its paediatric form historically called Spitzer-Weinstein syndrome [17, 18]. Low birth weight with postnatal growth failure, polyuria, polydipsia and nephrocalcinosis, which is the signature of apparent mineralocorticoid excess and, in the Chinese paediatric series, was present in all patients [6, 54]. Atypical genitalia in a 46,XX neonate, or peripheral precocious puberty with accelerated bone maturation, with hypertension and hypokalaemia instead of salt wasting, which points to 11β-hydroxylase deficiency rather than 21-hydroxylase deficiency [21, 55]. Delayed puberty with hypertension and hypokalaemia in adolescence, which points to 17α-hydroxylase deficiency [55]. Hypertension with seizures, spasticity and global developmental delay from the neonatal period, which points to primary aldosteronism with neurological abnormalities [15]. Marked worsening of hypertension in pregnancy in a woman with hypertension of onset before 20 years and normal potassium, which points to Geller syndrome [16]. Severe hypertension with type E brachydactyly and slightly reduced stature, which points to PDE3A and is investigated with a hand radiograph and blood pressure measurement [26, 72]. Biochemical hypercortisolism without Cushingoid stigmata, with hypertension and hyperandrogenism, which points to generalised glucocorticoid resistance [55]. Finally, response to treatment is a sign: lack of response to spironolactone in a hypertensive, hypokalaemic patient with suppressed renin and aldosterone is an additional clinical criterion for suspecting Liddle syndrome, and an immediate response to amiloride or triamterene confirms the pathophysiological orientation [1, 73].

The emergency signs are those of severe hypertension at any age: encephalopathy with seizures or altered consciousness, heart failure, pulmonary oedema, hypertensive retinopathy, acute kidney injury and, in profound hypokalaemia, paralysis and arrhythmias. In the neonate with hypertension and signs of organ damage, the paediatric guideline and the neonatal literature converge on the need for intravenous treatment with gradual reduction of blood pressure, described in section 7 [29, 30]. In Liddle syndrome, sudden death from arrhythmia secondary to severe hypokalaemia has been described, and a family history of sudden death at a young age is part of the picture [1].

Newborn screening. None of these entities is the object of population newborn screening. Congenital adrenal hyperplasia is screened in many programmes by 17-hydroxyprogesterone, but this marker detects 21-hydroxylase deficiency and not 11β- or 17α-hydroxylase deficiency, which can go entirely unnoticed on screening; assessment of a neonate with atypical genitalia or salt wasting should therefore include measurement of the precursors specific to each block and not rely on a normal screening result [55, 74]. The targeted screening that does exist is familial: in first-degree relatives of a patient with a known variant, blood pressure and serum potassium are measured and targeted genetic testing is offered, regardless of phenotype [7, 18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Baseline assessment of neonatal and paediatric hypertension

Assessment begins with the history, which includes maternal and infant medication, and a physical examination aimed at detecting dysmorphic features suggestive of a genetic syndrome, abdominal distension or masses, signs of heart failure and, when indicated, an ophthalmological examination to assess retinopathy [30]. First-line laboratory and imaging investigation in the neonate comprises a full blood count, electrolytes with sodium, potassium, chloride and bicarbonate, urea and creatinine, urinalysis, renal Doppler ultrasound and echocardiography; detailed investigation, when the first-line work-up is normal or there is a specific suspicion, adds plasma renin activity, aldosterone, cortisol, thyroid function, cranial ultrasound, serum calcium, renal scintigraphy and angiography, in a list reproduced from the review by Dionne and Flynn on the management of severe hypertension in the neonate [75], bearing in mind that computed tomography, magnetic resonance or digital subtraction angiography is technically difficult and less accurate in small infants, who may need to be treated medically until they reach a size that makes it feasible [30]. Renal Doppler ultrasound is not the reference examination for renal vascular anomalies, and in many centres the Doppler study has to be requested separately from the ultrasound [30].

In the paediatric age group, the American Academy of Pediatrics dispenses with an extensive evaluation for secondary causes in children aged 6 years or older who have a family history of hypertension, overweight or obesity and no finding in the history or examination suggestive of a secondary cause; below that age, or with suggestive findings, assessment is targeted [29]. The electrocardiogram should not be used to assess left ventricular hypertrophy; echocardiography is recommended when pharmacological treatment is being considered, and hypertrophy is defined as left ventricular mass greater than 51 g/m^2.7 above 8 years of age, or greater than 115 g per body surface area in boys and 95 g in girls [29].

5.2 The discriminating step: renin, aldosterone and potassium

What separates this group of disorders from other causes of hypertension is the combination of suppressed renin with a defined pattern of aldosterone and potassium. Measured together, and before starting drugs that alter the renin-angiotensin-aldosterone axis, these three parameters guide almost the whole differential diagnosis [17, 30].

The aldosterone/renin ratio is the preferred screening test for primary aldosteronism, more sensitive than potassium or aldosterone alone and more specific than renin alone, but it must be interpreted with specific paediatric thresholds, because the ratio is lower in the normotensive paediatric population than in adults [7]. The thresholds suggested by the Endo-ERN guideline are, for adults, 20 with aldosterone in ng/dL and plasma renin activity in ng/mL/h, 550 with aldosterone in pmol/L and the same renin, 2 with aldosterone in ng/dL and direct renin in mU/L and 36 with aldosterone in pmol/L and direct renin; for children, 10, 225, 1 and 18, respectively [7]. The Endocrine Society guideline, aimed at adults and applicable from 16 years, confirms that in the paediatric age group screening should be considered positive at a lower threshold than in adults [71]. With the paediatric threshold of 10, the eight affected members under 20 years of a large family with familial hyperaldosteronism type I were correctly identified, and in a cohort of 130 hypertensive children the ratio was above 10 in 5 (3.9%), with aldosterone above 17.7 ng/dL in 9 (6.9%) and renin activity of 0.5 ng/mL/h or less in 4 (3.1%); of the eight children with the hybrid gene identified in that cohort and among their relatives, all had a ratio above 10 but only one had hypokalaemia [7]. Hypokalaemia therefore does not serve as an entry criterion: in the family with familial hyperaldosteronism type II, fewer than 30% of carriers had it [7].

Two interpretive pitfalls deserve note. Isolated low renin does not mean primary aldosteronism: there are patients with low renin due to high salt intake and patients with Liddle syndrome, in whom aldosterone is also suppressed, so the Endocrine Society guideline requires a non-suppressed aldosterone together with low renin to consider the patient at risk of primary aldosteronism [71]. And a raised ratio can be a false positive when renin is very low with equally low aldosterone, or when aldosterone is very high with normal renin, so the two values should always be read separately [7].

5.3 Biochemical confirmation tests by entity

In apparent mineralocorticoid excess, the characteristic biochemical test is the 24-hour urinary steroid profile: the ratio between cortisol metabolites and the cortisone metabolite, (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone, and the ratio between free cortisol and cortisone, both raised in the classic form and only slightly raised in the non-classic form [6, 17]. This profile does not distinguish the hereditary disease from acquired inhibition of the same enzyme, so a history of ingestion of liquorice, carbenoxolone or azole antifungals must be excluded, and definitive confirmation is molecular [6]. Traditional laboratory assessment, without the cortisol/cortisone ratio, does not allow Liddle syndrome, Bartter syndrome or primary glucocorticoid resistance to be excluded [6].

In 11β-hydroxylase deficiency, the biochemistry is elevation of 11-deoxycortisol and 11-deoxycorticosterone with raised adrenal androgens, in a setting of hyporeninaemic hypokalaemic hypertension, followed by sequencing of CYP11B1 by a method capable of resolving the paralogue CYP11B2; screening by 17-hydroxyprogesterone points towards 21-hydroxylase deficiency and does not exclude this block [55, 74]. In 17α-hydroxylase deficiency, steroid analysis after adrenocorticotropic hormone stimulation shows atypically raised pregnenolone and progesterone relative to their 17-hydroxylated derivatives [17].

In familial hyperaldosteronism type I, elevation of 18-hydroxycortisol and 18-oxocortisol is characteristic and also occurs, to a lesser degree, in type III, but the assay is unavailable in most countries, so diagnosis rests on genetics [7]. The clinical diagnosis can be obtained by the dexamethasone suppression test, 0.5 mg every 6 hours for 4 days, considered positive when values fall below 4 to 5 ng/dL, but the test is not 100% accurate and a positive result requires genetic confirmation; the preferred alternative is long-PCR amplification of the hybrid gene [7]. In the other types, the dexamethasone test is negative: in type III dexamethasone suppresses neither aldosterone nor cortisol, which distinguishes it from type I [68].

Confirmatory tests for primary aldosteronism (fludrocortisone suppression, oral or intravenous saline loading and the captopril test) are suggested only above 16 years and when the clinical or biochemical diagnosis remains unclear; they are omitted when there is spontaneous hypokalaemia, suppressed renin, a raised ratio and aldosterone above 20 ng/dL (555 pmol/L), and are unnecessary in members of families with a known germline variant [7, 71]. The meta-analysis of thresholds conducted for the Endo-ERN guideline estimated, for intravenous saline loading, an optimal threshold of 7.07 ng/dL with sensitivity of 0.86 (95% confidence interval 0.73 to 0.93) and specificity of 0.89 (0.78 to 0.94), and for the captopril test 10.67 ng/dL with sensitivity of 0.91 (0.82 to 0.96) and specificity of 0.81 (0.66 to 0.90), with very low to low certainty of evidence and no usable studies for fludrocortisone suppression and oral loading [7]. In resistant hypertension or hypertension with hypokalaemia and overt biochemical evidence of renin-independent aldosterone production, defined as renin activity below 0.2 ng/mL/h or direct renin below 2 mU/L with aldosterone above 15 ng/dL by liquid chromatography-tandem mass spectrometry or above 20 ng/dL by immunoassay, the suppression test is not recommended because of the risk of false negatives [71].

In pseudohypoaldosteronism type II, there are no formal published diagnostic criteria. The findings that support suspicion are hypertension, generally from adolescence but also described in children, hyperkalaemia in the absence of impaired glomerular filtration, serum bicarbonate of 14 to 24 mmol/L against a reference range of about 22 to 29, chloride of 105 to 117 mmol/L against a range of about 99 to 108, suppressed plasma renin, variable but relatively suppressed aldosterone for the serum potassium, normal calcium and parathyroid hormone with hypercalciuria in some patients, and a first-degree relative with similar findings, the absence of whom does not exclude the diagnosis [18].

5.4 Molecular diagnosis

The Endo-ERN guideline recommends, in patients with confirmed primary aldosteronism and hypertension diagnosed before 20 years, sequencing of the genes responsible for familial hyperaldosteronism and for primary aldosteronism with neurological abnormalities, preferably by a next-generation sequencing panel, adding long-range PCR for the type I hybrid gene, because the phenotypes overlap and do not allow the type to be determined reliably [7]. The practical limitation is availability and reimbursement of the test; when it is not available locally, international centres that perform it routinely can be used [7].

In pseudohypoaldosteronism type II, the gene-by-gene approach follows relative frequency and variant type: it is reasonable to sequence CUL3 and KLHL3 first; if, in a suspected recessive inheritance, only one KLHL3 variant is identified, targeted deletion/duplication analysis of that gene should be requested; WNK4 sequencing follows; if nothing is found, testing for WNK1 deletions and duplications, which are large intronic deletions not detectable by conventional sequencing; and finally WNK1 sequencing. Alternatively, a panel including the four genes is used [18]. The proportions published in 86 families are 25/86 for CUL3, 41/86 for KLHL3, with 29 families with a heterozygous variant and 12 with biallelic variants, 8/86 for WNK1 and 8/86 for WNK4; in at least ten families no variant was identified in any of the four genes, and there is an additional locus mapped to 1q31-q42 whose gene remains unknown [18, 38]. In a study that documented the denominator, 4 of 52 patients had no variant in the four genes [18].

In Liddle syndrome, diagnosis rests on sequencing of SCNN1A, SCNN1B and SCNN1G, indicated in the presence of early-onset hypertension, hypokalaemia, and low renin and aldosterone, with or without a positive family history, and genetic screening should be extended to first-degree relatives because of dominant inheritance with a 50% risk of transmission and phenotypic variability [1]. In apparent mineralocorticoid excess, sequencing of HSD11B2 is indispensable, and exome sequencing is particularly useful in patients with atypical or overlapping presentations or when the biochemical profile is unavailable [6].

5.5 Limits of the tests

No negative result excludes these disorders. In sequencing, the large intronic WNK1 deletions are not detected by exon sequencing methods, which is why deletion/duplication analysis of that gene is a separate step of the algorithm [18]. In CUL3, all known variants affect processing of exon 9 and lie in introns or in splicing enhancer elements, which requires the analysis to cover intronic boundaries and not only the coding sequence [70]. In KLHL3, the detection rate of deletion/duplication analysis has not been determined [18]. In forms in which the phenotype is due to a rearrangement, such as the hybrid gene of familial hyperaldosteronism type I, conventional sequencing does not detect it and targeted long-PCR amplification is required [7]. In CYP11B1, the high homology with CYP11B2 demands methods that resolve the paralogue [55].

The proportion of variants detectable by a method is not the clinical sensitivity of the test, and interpretation of the variants found is the step most prone to error. The neonatal case of Liddle syndrome described in section 10 illustrates this well: the patient had four heterozygous variants in two different channel subunits, two of them described in the literature as polymorphisms associated with hypertension and increased channel activity, and the authors attributed the severe phenotype to the combined effect, explicitly allowing that one of the variants might have a pathological effect not yet documented [73]. In the Chinese paediatric series of apparent mineralocorticoid excess, one of the causal variants, NM_000196.4:c.650T>C p.(Val217Ala) in the homozygous state, is classified as of uncertain significance by the American College of Medical Genetics and Genomics criteria despite deleterious predictions and the full phenotype [54]. And the NR3C2 variant p.(Ser810Leu), with functional and cosegregation evidence published since 2000, remains classified in ClinVar as of uncertain significance [16, 51]. A database classification is a datum to be weighed, not a conclusion, and numbering conversions between historical and current nomenclatures should be confirmed in VariantValidator or ClinVar and never calculated manually [51, 52].

The laboratory report should name the gene, the reference transcript with its version, HGVS nomenclature at DNA and protein level, zygosity, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, and the interpretation in the light of the phenotype. For variants of uncertain significance, family segregation studies, with measurement of blood pressure, potassium, renin and aldosterone in parents and siblings, are often what allows reclassification [7, 18].

5.6 Imaging and lateralisation studies

The Endo-ERN guideline suggests adrenal imaging by computed tomography or magnetic resonance imaging in all patients with proven familial hyperaldosteronism, to exclude aldosterone-producing carcinoma and to inform any surgical decisions; in young patients, and particularly in females, magnetic resonance is preferred to reduce radiation exposure [7]. Adrenal venous sampling is, in principle, futile in these disorders, because all genetic forms affect both glands, and it is not suggested below 16 years for lack of experience and literature; it makes sense only when there are two patients with primary aldosteronism in the same family without an identified variant, a situation in which the cause may be different and one of the relatives may have unilateral disease [7]. The Endocrine Society guideline says the same from the adult side: in types I to IV, because they are bilateral disease, venous sampling is not necessary and adrenalectomy is generally not indicated [71]. Imaging is useful in type III with massive bilateral hyperplasia, in which bilateral adrenalectomy is considered [7].

5.7 Practical algorithm

Faced with a child or neonate with confirmed hypertension, the pathway is as follows. First, confirm the measurement with appropriate technique and cuff and classify the value by percentiles for age, sex and height, or by postmenstrual-age percentiles in the neonate [29, 30]. Second, exclude the frequent causes with the baseline work-up: electrolytes, renal function, urinalysis, renal Doppler ultrasound and echocardiography, and review exposure to umbilical catheters, corticosteroids, non-steroidal anti-inflammatory drugs and other drugs [30]. Third, if hypertension persists without a cause, measure potassium, bicarbonate, chloride, plasma renin activity or direct renin and aldosterone, preferably before starting drugs that interfere with the axis, and place the patient in the table of biochemical patterns [17]. Fourth, add the biochemical test targeted to the pattern identified: urinary steroid profile when apparent mineralocorticoid excess is suspected, steroid precursors when an adrenal enzymatic block is suspected, hybrid steroids or a dexamethasone test when familial hyperaldosteronism type I is suspected [6, 7]. Fifth, request genetic testing targeted to the pattern, or a panel covering the whole group when the pattern is ambiguous, with long-PCR for the hybrid gene whenever aldosterone is raised [7]. Sixth, once the diagnosis is established, assess target-organ damage with echocardiography, creatinine with estimated glomerular filtration rate, urinary albumin/creatinine ratio and fundoscopy, and extend assessment to first-degree relatives [7, 29].

5.8 Prenatal and preimplantation diagnosis

Once the familial variant or variants have been identified, prenatal diagnosis in an at-risk pregnancy and preimplantation genetic testing are technically possible in all these entities, as is explicitly recorded for pseudohypoaldosteronism type II [18]. The decision depends on the expected severity and on the fact that all these disorders are treatable, a central element of the counselling discussed in section 8.

6. Differential Diagnosis

The first axis of the differential is potassium. In the hypertensive child with spontaneous hypokalaemia, the entities to consider are Liddle syndrome, apparent mineralocorticoid excess, the two steroidogenesis blocks that produce deoxycorticosterone, glucocorticoid resistance and familial hyperaldosteronism; the distinction is made by aldosterone, suppressed in the first four and raised in the last [17]. In the hypertensive child with hyperkalaemia, the hypothesis is pseudohypoaldosteronism type II, and suppressed renin separates it from other causes of hyperkalaemia: chronic kidney disease, especially diabetic, which is the most common cause; hypoaldosteronism and acquired type 4 renal tubular acidosis, particularly with marked volume depletion; drug effects, such as potassium-sparing diuretics, non-steroidal anti-inflammatory drugs, angiotensin inhibitors, trimethoprim and ciclosporin; and primary adrenal insufficiency or deficiency of a steroidogenesis enzyme — in all of these renin is increased, whereas in pseudohypoaldosteronism type II it is suppressed [18].

The second axis is the direction of the defect in the same gene. The epithelial sodium channel subunits produce hypertension with hypokalaemia when they gain function and neonatal salt wasting with hyperkalaemia and acidosis when they lose it; the mineralocorticoid receptor produces hypertension exacerbated by pregnancy when it gains function and renal salt wasting that improves with age when it loses it [16, 44, 55]. Faced with a genetic result, the clinical question is not only which gene, but what the direction of the functional effect is, because treatment and the prognosis communicated to the family depend on it.

The third axis is the distinction between hereditary disease and phenocopy. In apparent mineralocorticoid excess, excessive ingestion of liquorice or carbenoxolone and azole antifungals inhibit the same enzyme and reproduce all the biochemistry, including the raised urinary ratio, but resolve on withdrawal of the agent, so a detailed drug and dietary history is part of the diagnosis [6, 17]. In primary aldosteronism, somatic KCNJ5 and CACNA1D variants in adrenal adenomas and micronodules are tumour-restricted events, with no hereditary risk and no implication for relatives, and their frequency varies widely with ancestry, between 53 and 96.7% of adenomas in East Asian cohorts, 33.9 to 46.5% in European cohorts and about 34.2% in African patients [55]. In the paediatric patient, however, an aldosterone-producing adenoma is rare and the likelihood of a germline cause is high [7].

The fourth axis is the neonatal context. In a neonate with hypertension, renovascular, parenchymal and pulmonary causes explain the great majority of cases, and assessment should begin with them; the presence of hypernatraemia with hypokalaemic metabolic alkalosis in a neonate should, however, immediately raise the hypothesis of a tubulopathy, and when there is associated hypertension the differential includes congenital adrenal hyperplasia, primary aldosteronism, apparent mineralocorticoid excess, glucocorticoid-remediable aldosteronism, renal artery stenosis and a deoxycorticosterone-producing tumour [30, 73]. The genetic syndromes with renovascular hypertension — neurofibromatosis type 1, Williams syndrome and Marfan syndrome — and structural kidney diseases, such as autosomal recessive polycystic kidney disease and congenital anomalies of the kidney and urinary tract, complete the syndromic differential of the hypertensive infant [30].

7. Treatments and Risk Management Strategies

7.1 General principle: treatment follows the mechanism

In these disorders, the correct antihypertensive is the one that blocks the altered molecular step, and the wrong antihypertensive may have no effect or may worsen the picture. Liddle syndrome responds to epithelial sodium channel blockers and not to spironolactone, because the channel is constitutively activated independently of the mineralocorticoid receptor [1]. Apparent mineralocorticoid excess responds to mineralocorticoid receptor blockade, because cortisol occupies the receptor [6]. Pseudohypoaldosteronism type II responds to thiazides, which inhibit the hyperactive cotransporter [18]. Familial hyperaldosteronism type I responds to glucocorticoid, which suppresses the adrenocorticotropic hormone that drives the hybrid gene, and types II to IV respond to mineralocorticoid receptor antagonists, because aldosterone production does not depend on adrenocorticotropic hormone [7]. In Geller syndrome, spironolactone is an agonist of the mutant receptor and is contraindicated [16, 17]. And in congenital adrenal hyperplasias with hypertension, glucocorticoid at a suppressive dose removes the stimulus that produces deoxycorticosterone [55]. In all of them, sodium restriction enhances the pharmacological effect, because all are, in essence, forms of salt-sensitive hypertension [1, 7].

The second general rule is that normalisation of blood pressure is not the only goal. The Endo-ERN guideline recommends seeking simultaneous normalisation of blood pressure, the aldosterone/renin ratio and potassium, because autonomous aldosterone secretion in the presence of sodium increases cardiovascular risk independently of blood pressure, with myocardial inflammation and fibrosis, vascular remodelling and tubulointerstitial fibrosis; the same authors point out that studies on the optimal blood pressure target in these disorders are lacking [7]. In the paediatric age group, the American Academy of Pediatrics target is reduction of systolic and diastolic pressure below the 90th percentile and below 130/80 mmHg in adolescents aged 13 years or older [29].

7.2 Treatment by entity

Liddle syndrome. The specific treatment is the potassium-sparing diuretics that block the epithelial sodium channel, amiloride and triamterene, whose efficacy increases with salt restriction to about 2 g of sodium chloride per day, through competition between drug and sodium in the channel pore; they normalise blood pressure, serum potassium, renin activity and aldosterone [1]. Monitoring of electrolytes during treatment is recommended, although hyperkalaemia is rare with normal renal function and non-excessive potassium intake [1]. The historical dose in Liddle's index case was triamterene 100 mg every eight hours with a low-sodium diet, which normalised diastolic pressure and raised potassium to 5 mmol/L; in the Italian case of a 13-year-old boy, amiloride 5 mg per day controlled blood pressure, from 184/109 to 120/65 mmHg, and normalised potassium, from 3.2 to 4.8 mmol/L [1]. In the largest published series of patients with a γ subunit variant, the twelve patients were treated with triamterene, with good blood pressure control and normalisation of potassium, and two had a reversible rise in creatinine that resolved on withdrawal [3]. Spironolactone improves neither hypertension nor hypokalaemia, and its ineffectiveness is an additional clinical criterion for suspicion [1, 79].

Apparent mineralocorticoid excess. A salt-restricted diet is necessary in both the classic and non-classic forms. Targeted treatment is a mineralocorticoid receptor antagonist, spironolactone or eplerenone, usually in combination with a potassium-sparing diuretic, with amiloride blocking the epithelial sodium channel, and with other antihypertensives as needed; potassium supplementation is usual [6]. The doses described in the reference review are 2 to 10 mg/kg/day of mineralocorticoid receptor antagonist in the classic form and 12.5 to 25 mg per day in the non-classic form [6]. The Chinese paediatric series documents practice and also its limits: two children were controlled with spironolactone 5.5 mg/kg/day, with normal potassium and pressures of 108/70 and 95 to 100/60 to 65 mmHg, whereas in the most severe patient spironolactone, increased up to 6.8 mg/kg/day, neither stabilised potassium nor controlled blood pressure, which remained at 135 to 140/80 to 90 mmHg, and replacement with eplerenone, gradually increased up to 5 mg/kg/day, improved control to about 120/80 mmHg [54]. Glucocorticoids have been used in adults with the classic form to suppress adrenocorticotropic hormone-dependent corticosteroid production, and metyrapone was effective in a group of three children studied in 1986, which indicates that the steroid occupying the receptor is 11β-hydroxylated; administration of cortisol or adrenocorticotropic hormone worsens hypertension [6, 36]. Kidney transplantation has been described as curative in patients with end-stage kidney disease, with disappearance of manifestations and withdrawal of spironolactone, because the kidney is the main site of enzyme activity [6, 54].

Familial hyperaldosteronism type I. First-line treatment in adults is a low-dose glucocorticoid that partially suppresses pituitary adrenocorticotropic hormone secretion, preferably a synthetic glucocorticoid with a longer action than hydrocortisone, dexamethasone or prednisone, with most publications using dexamethasone between 0.125 and 2.0 mg per day; a mineralocorticoid receptor antagonist is the alternative in those who do not tolerate glucocorticoid and is the first choice in children under 16 years, in whom eplerenone may be preferable because it avoids the antiandrogenic effects of spironolactone [7]. In children in whom the aldosterone/renin ratio or potassium does not normalise with the antagonist, very low doses of dexamethasone are added: in patients with genetically proven type I, 0.125 to 0.25 mg of dexamethasone per day or 2.5 to 5 mg of prednisolone per day maintained normal blood pressure for 0.5 to 3.8 years of follow-up without the need for another antihypertensive, with a normal and stable or falling left ventricular mass index [7]. Overtreatment must be avoided, because iatrogenic Cushing syndrome and impaired linear growth in children have resulted from it; the minimum dose that normalises blood pressure and potassium is used, and renin and aldosterone help assess adequacy [7]. An important point of interpretation: in eight patients kept normotensive by glucocorticoid for 1.3 to 4.5 years, urinary 18-oxocortisol remained above normal, so blood pressure control was achieved with only partial suppression of adrenocorticotropic hormone-regulated aldosterone production, and the authors warn against the risk of Cushingoid effects in pursuing normalisation of hybrid steroids [35].

Familial hyperaldosteronism types II to IV and primary aldosteronism with neurological abnormalities. A mineralocorticoid receptor antagonist is first line; in primary aldosteronism with seizures and neurological abnormalities, calcium channel blockers are added, mechanistically attractive because the CaV1.3 channel is sensitive to dihydropyridines — nifedipine gave adequate blood pressure control and improved muscle tone in a child with a de novo CACNA1D variant, an observation in a single case and not established therapy —, as well as antiseizure medications and developmental support [7, 55]. Amiloride is second line in types II, III and IV when the aldosterone/renin ratio or potassium does not normalise with the antagonist or when the antagonist is not tolerated, and there is a case of type III due to p.Gly151Glu treated successfully with canrenone and amiloride, with rapid normalisation of electrolytes and complete normalisation of blood pressure; if blood pressure remains uncontrolled, calcium channel blockers are considered [7]. In type III, most published cases were resistant to aggressive therapy, including mineralocorticoid receptor blockade and amiloride, and required bilateral adrenalectomy to control blood pressure, with massive bilateral cortical hyperplasia in the removed glands; patients with p.Gly151Glu, by contrast, are medically treatable [7, 68].

Pseudohypoaldosteronism type II. The electrolyte abnormalities and blood pressure are frequently corrected with a thiazide, and the metabolic abnormalities and hypertension generally improve within the first week; the dose is titrated until blood pressure normalises, may have to be increased over time and may require additional antihypertensives [18]. OMIM summarises the evidence of Boyden and colleagues with a sentence that needs no comment: thiazides correct the abnormalities in virtually all patients [70]. There are no recommendations on the age at which treatment should begin, but affected children who have hypertension are generally treated [18]. There is no dose published specifically for this disease; the hydrochlorothiazide dose used in hypertensive neonates and infants is 1 to 3 mg/kg/day, in one or two doses, with monitoring for hyponatraemia, hypokalaemia and alkalosis, and this is the reference available for the paediatric age group, extrapolated from a general antihypertensive indication and not from the disease [30]. In untreated patients, avoiding excess salt and potassium in the diet is recommended, because both worsen hypertension and hyperkalaemia [18].

Geller syndrome. The goal is blood pressure control with drugs that do not activate the mutant receptor, and spironolactone is contraindicated because it behaves as an agonist; in pregnancy with severe worsening, the main treatment described is delivery, and management outside pregnancy, in women and men, is not well defined [16, 17]. Progesterone and steroids lacking a 21-hydroxyl group should be avoided for the same mechanistic reason [16].

Generalised glucocorticoid resistance. Only symptomatic patients are treated, with the aim of suppressing excess adrenocorticotropic hormone and reducing adrenal steroids with mineralocorticoid or androgenic activity; a mineralocorticoid-sparing synthetic glucocorticoid is used, typically oral dexamethasone 1 to 3 mg once daily at night, with the dose strictly titrated to the clinical and biochemical response to avoid iatrogenic Cushing syndrome and the development of an adrenocorticotropic hormone-secreting adenoma; hypertension and hypokalaemia are treated in parallel [24, 55]. Mifepristone is not a treatment for this disease: it is a glucocorticoid receptor antagonist and receptor blockade would worsen the resistance; its endocrine approval (Korlym, NDA 202107) is for control of hyperglycaemia secondary to hypercortisolism in endogenous Cushing syndrome [55].

Congenital adrenal hyperplasias with hypertension. In 11β-hydroxylase deficiency, treatment is glucocorticoid at a dose sufficient to suppress adrenocorticotropic hormone, with hydrocortisone in children, titrated between cortisol replacement and suppression of androgen excess without causing glucocorticoid excess, which is the central difficulty; spironolactone, amiloride and calcium channel blockers may be needed for hypertension, and mineralocorticoid replacement is not necessary, because this form causes mineralocorticoid excess rather than loss [17, 55]. In 17α-hydroxylase deficiency, induction and maintenance of puberty with sex steroids is added; in the largest paediatric cohort, of 97 Turkish patients, all received glucocorticoid, 66 received sex steroids and 57 of 63 treated (90%) required antihypertensives, in addition to correction of hypokalaemia [55]. A frequent confusion should be noted: osilodrostat (Isturisa®) is an 11β-hydroxylase inhibitor and not a treatment for deficiency of that enzyme; its indication is endogenous hypercortisolism of Cushing syndrome in adults [55].

7.3 Dosage, formulations and safety

Supportive antihypertensive medication in the neonate deserves a note of its own, because none of these drugs is approved for neonatal use by any regulatory agency [30]. In mild to moderate or chronic cases without contraindication to the enteral route, calcium channel blockers are the first oral line, with isradipine preferred in the acute setting for its rapid onset of action and amlodipine in the chronic setting; the other oral options are hydralazine 0.25 to 1 mg/kg/dose, three to four times daily, up to 5 mg/kg/day, thiazide diuretics or spironolactone 1 to 3 mg/kg/day, and the beta-blockers propranolol 0.5 to 5 mg/kg/day or labetalol 1 to 10 mg/kg/day, avoided in chronic lung disease [30]. Loop diuretics can be used but carry a greater risk of electrolyte disturbances, worsening of acute kidney injury and hypercalciuria [30]. In severe acute hypertension, intermittent intravenous labetalol or hydralazine is used and, in hypertensive emergency with organ damage, a continuous infusion of nicardipine 0.5 to 4 µg/kg/min via a central line or of sodium nitroprusside, started at 0.25 µg/kg/min up to 8 µg/kg/min, with monitoring for thiocyanate toxicity, preferably with an arterial line or, in its absence, with oscillometric measurement every 5 to 15 minutes [30]. Reduction should be gradual, with one third of the way to the normal value in the first 6 hours, another third in the following 24 to 36 hours and the remainder in 48 to 72 hours, with a final target below the 95th percentile for postmenstrual age; in children and adolescents with severe acute hypertension and life-threatening symptoms, the equivalent recommendation of the American Academy of Pediatrics is to reduce blood pressure by no more than 25% of the planned reduction in the first 8 hours [29, 30].

7.4 Drugs and circumstances to avoid

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are generally avoided in the neonate, because of the risk of adverse effects and the importance of the renin-angiotensin-aldosterone axis in renal development: in one study, more than 20% of neonates given an angiotensin-converting enzyme inhibitor had adverse effects, the most frequent being hyperkalaemia, acute kidney injury, hypotension and death; normal glomerular maturation continues until 36 weeks of gestation, so use is avoided until 40 to 42 weeks of postnatal age when possible [30]. Maternal exposure to blockers of the same axis during pregnancy is associated with oligohydramnios, intrauterine growth restriction, limb and bone defects, neonatal acute renal failure, anuria, hypotension, respiratory distress, cerebral complications and death, and significant interruption of the axis during fetal development causes renal tubular dysgenesis, calvarial defects, oligohydramnios and Potter sequence [30].

Spironolactone is useless in Liddle syndrome and worsens Geller syndrome [1, 16]. Glucocorticoid is not a treatment for familial hyperaldosteronism type III nor for types II and IV, and waiting for a glucocorticoid response in these forms delays definitive treatment [7, 55]. In apparent mineralocorticoid excess, administration of cortisol or adrenocorticotropic hormone worsens hypertension, and liquorice, carbenoxolone and azole antifungals inhibit the residual enzyme and should be avoided [6, 36]. In untreated pseudohypoaldosteronism type II, excess salt and potassium in the diet are avoided [18]. In patients with hyperkalaemia, drugs that worsen it — potassium-sparing agents, non-steroidal anti-inflammatory drugs, angiotensin axis inhibitors, trimethoprim and ciclosporin — should be reviewed [18]. In the neonate, perinatal dexamethasone and prenatal tocolytic non-steroidal anti-inflammatory drugs are associated with a greater likelihood of neonatal hypertension [30].

7.5 Pregnancy, lactation and the perioperative period

In the pregnancy of a woman with pseudohypoaldosteronism type II, electrolytes and blood pressure should be monitored regularly and antihypertensive medication adjusted; some antihypertensives, including thiazides, have been associated with adverse fetal outcomes, especially in the first trimester, so the ideal time to discuss the risk is before conception, and referral to an obstetric service experienced in high-risk pregnancy is recommended [18].

In familial hyperaldosteronism, the Endo-ERN guideline recommends normalising blood pressure before conception and strictly monitoring potassium and blood pressure during pregnancy. Women treated with dexamethasone for type I should stop it, because it crosses the placenta, and monitor blood pressure and potassium in the first trimester; if blood pressure becomes uncontrolled, the options of choice are those for pregnancies without primary aldosteronism, methyldopa, long-acting nifedipine and labetalol, and if blood pressure rises in the second or third trimester, low to very low-dose dexamethasone may be used with the aim of normalising blood pressure, aldosterone, renin and potassium. Mineralocorticoid receptor antagonists and potentially teratogenic antihypertensives should be stopped 4 to 6 weeks before conception; in a patient with severe hypertension and hypokalaemia who wishes to become pregnant, switching from spironolactone to eplerenone at the minimum effective dose may be considered, as it has not been associated with adverse outcomes. When primary aldosteronism is diagnosed during pregnancy, standard therapy is started and confirmatory testing and subtyping are deferred until after delivery; with poor blood pressure control or refractory hypokalaemia, eplerenone or amiloride may be considered, avoiding spironolactone, especially in the first trimester, because of its antiandrogenic effects. Women with type I do not appear to have a greatly increased risk of pre-eclampsia, but those with chronic hypertension may worsen during gestation [7]. In Liddle syndrome, amiloride has been described as safe and effective in pregnancy, with adequate blood pressure values and normal serum potassium [1]. In Geller syndrome, pregnancy is the period of maximum risk, because of the hundredfold increase in progesterone, which activates the mutant receptor [16].

In the perioperative period, two points are specific to this group. Profound hypokalaemia should be corrected before any anaesthesia, because of the risk of arrhythmia, and potassium and acid-base balance should be monitored postoperatively, because nil-by-mouth status and fluids alter the sodium intake on which the effect of epithelial sodium channel blockers and thiazides depends [1, 18]. In patients with congenital adrenal hyperplasia undergoing surgery, the glucocorticoid stress-dose rules specific to that disease apply. In bilateral adrenalectomy for familial hyperaldosteronism type III, the consequence is lifelong dependence on glucocorticoid and mineralocorticoid replacement, a central element of the decision [68].

In transition to adult care, the general paediatric recommendation is that adolescents with elevated blood pressure or hypertension, treated or not, transfer to an adult care provider by 22 years of age, with transfer of clinical information [29]. In these disorders, transition should ensure that the molecular diagnosis and the therapeutic rationale are explicitly communicated, because the likelihood of an adult patient with "essential" hypertension being treated with a drug inappropriate to the mechanism is real.

7.6 Regulatory status

None of these disorders has a drug approved for the specific indication, with the partial exception of congenital adrenal hyperplasia, and none of the drugs used has an approved paediatric indication for them. This is not a limitation of clinical knowledge but a fact to communicate to families and record in the medical record: all the treatment described above is supported by guidelines and observational series, not by randomised trials in these populations.

7.7 Evidence of efficacy: what exists and what is missing

The reading of these data has three limits. First, there is no randomised trial in any of the disorders in this article, and the Endo-ERN guideline explicitly classifies the quality of therapeutic evidence as very low, because of the small number of patients, non-standardised follow-up and the absence of formal comparisons between drugs or doses; recommendations were nonetheless issued because therapeutic decisions have to be made [7]. Second, the studies do not allow conclusions as to the optimal treatment, the optimal dose in type I or the optimal timing of adrenalectomy in type III, and effects on long-term cardiovascular outcomes are not defined [7]. Third, the figures from the baxdrostat trial belong to a population of adults with uncontrolled hypertension and not to these disorders: the apparent relative reduction cannot be transposed to a paediatric patient with familial hyperaldosteronism, and the label states that safety and efficacy below 18 years have not been established [81].

The justification for treating, despite this evidence base, comes from the documented risk of untreated disease. In the comparison between patients with primary aldosteronism and patients with primary hypertension, a meta-analysis of 31 studies, with 3838 and 9284 patients respectively, showed increased odds of stroke, with an odds ratio of 2.58 (95% confidence interval 1.93 to 3.45), coronary heart disease, 1.77 (1.10 to 2.83), atrial fibrillation, 3.52 (2.06 to 5.99), and heart failure, 2.05 (1.11 to 3.78), at a median of 8.8 years after the diagnosis of hypertension, and another meta-analysis of 46 studies, with 6056 and 9733 patients, showed increased odds of albuminuria, 2.09 (1.40 to 3.12), and proteinuria, 2.68 (1.89 to 3.79) [71]. These data are from adults, but they describe the natural fate of an aldosterone excess that, in the familial forms, begins in childhood.

7.8 Developments in the last twelve months

The regulatory development of the period is the approval, in the United States, of the first aldosterone synthase inhibitor with its own label: baxdrostat, marketed as Baxfendy®, with a label effective 7 August 2026, indicated in combination with other antihypertensives for hypertension in uncontrolled adults, as 1 and 2 mg tablets [81]. The pivotal BaxHTN trial is completed, with an actual primary completion date of 21 May 2025 and 796 participants in the registry [83]. The level of evidence is therefore that of a marketing authorisation supported by a published phase 3 trial, but in an indication that is none of the disorders in this article.

In parallel, lorundrostat, another aldosterone synthase inhibitor, had phase 2 results published in 2026 in the Explore-CKD trial, in participants with uncontrolled hypertension and chronic kidney disease; the level of evidence is that of a published phase 2 trial, without marketing authorisation and without data in monogenic forms [84]. Throughout 2026 several network meta-analyses comparing aldosterone synthase inhibitors in resistant hypertension were published, all in adult populations with uncontrolled hypertension and none with data in the Mendelian disorders [84]. The 2024 Endo-ERN guideline already anticipated this class and esaxerenone, a non-steroidal mineralocorticoid receptor antagonist, as future options in primary aldosteronism, while recording that finerenone, apararenone and ocedurenone have not been tested in this disease [7]. The Endocrine Society guideline includes finerenone in its comparative table with the observation that data in patients with primary aldosteronism are very limited and with a dose of 10 to 20 mg per day marked as unknown for this indication [71]. The search performed identified no trials, gene therapy programmes or regulatory submissions specifically directed at Liddle syndrome, apparent mineralocorticoid excess, pseudohypoaldosteronism type II, Geller syndrome or familial hyperaldosteronism; the GeneReviews chapter on pseudohypoaldosteronism type II also identifies no investigational therapies for the disease [18]. A negative search does not prove non-existence, and what is documented is that, as of 31 October 2026, no therapeutic development directed at these entities was found.

7.9 Discrepancies between sources

The two main guidelines diverge on one point with direct clinical consequence. The 2025 Endocrine Society guideline suggests, for primary aldosteronism in general, the use of mineralocorticoid receptor antagonists rather than epithelial sodium channel inhibitors, with a conditional recommendation and very low-quality evidence [71]. The 2024 Endo-ERN guideline, directed at the familial forms, places amiloride as second line when the aldosterone/renin ratio or potassium does not normalise with the antagonist, and notes that amiloride does not bring the beneficial effects of spironolactone on endothelial function [7]. The two are compatible in practice, and the resulting order is mineralocorticoid receptor antagonist first, amiloride as adjunct or alternative, and calcium channel blocker when the first ones fail or are not tolerated. In the paediatric age group, however, the hierarchy is reversed in type I, in which the Endo-ERN guideline places the mineralocorticoid receptor antagonist first in children and glucocorticoid only as an adjunct, unlike in adults [7].

A second discrepancy is internal to the Endo-ERN guideline and concerns the severity attributed to the KCNJ5 variant p.Tyr152Cys, described in the text as associated with a milder and later phenotype and included, in the recommendation on surgery, among the variants with a severe phenotype [7]. The surgical decision in a patient with this variant should therefore rest on the observed phenotype and not on the classification of the variant.

A third difference is one of scope. The Endocrine Society guideline declares itself applicable to patients older than 16 years and refers to lower aldosterone/renin ratio thresholds in the paediatric age group, without quantifying them; it is the Endo-ERN guideline that provides the concrete paediatric thresholds [7, 71]. For the neonate, neither is applicable, and the available reference is the neonatal hypertension literature, which explicitly acknowledges that the correct definition of neonatal hypertension is not known and that current norms come from single-centre studies with small numbers [30].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks by inheritance pattern

Most of the entities in this article are autosomal dominant, and most probands have an affected parent, so the risk for each child of a patient is 50% [7, 18]. The systematic exception is the disorders due to biallelic loss of function: apparent mineralocorticoid excess and the congenital adrenal hyperplasias are autosomal recessive, with a 25% risk for each sibling of a patient, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier; the parents are obligate carriers [6, 74].

Pseudohypoaldosteronism type II requires a more careful formulation, because it has two inheritance patterns within the same group of genes, and both are established: it is in most cases autosomal dominant, but the form associated with KLHL3, designated type IID, can also be autosomal recessive [18]. ClinGen classifies the relationship between KLHL3 and this disease as definitive, with a semidominant mode of inheritance, and OMIM lists the phenotype as dominant and recessive; in the 86 genotyped families, KLHL3 explained 41, of which 29 had a heterozygous variant and 12 biallelic variants [18, 55]. Counselling therefore depends on the specific molecular result: with a heterozygous variant, the risk for children is 50%; with biallelic variants, the parents are carriers, the risk for siblings is 25% and the patient's children will be obligate carriers; carriers of a recessive KLHL3 variant are typically asymptomatic and do not appear to be at risk of developing the disease, although there is no prolonged clinical analysis of this group [18].

De novo variants are frequent in specific genes and change the calculation. In pseudohypoaldosteronism type II, 15 of 182 published cases were de novo, 14 of them due to a heterozygous CUL3 variant and one due to a KLHL3 variant; in the series of Boyden and colleagues, 8 of the 17 CUL3 variants identified were de novo [18, 70]. Primary aldosteronism with seizures and neurological abnormalities is almost always caused by de novo CACNA1D variants, and the severe neurological abnormalities prevent transmission in most cases, although father-to-two-sons transmission has been described in a family with a mild presentation without aldosteronism [7, 15]. In familial hyperaldosteronism type IV, the p.Met1549Val variant arose de novo in one of the five original probands [61]. In hypertension with brachydactyly, the PDE3A variant was de novo in a South African family [85]. When the proband's variant is not detectable in the leucocyte DNA of either parent, the possible explanations are de novo occurrence or germline mosaicism in a parent; no cases of germline mosaicism have been described in pseudohypoaldosteronism type II, but the possibility remains, and the risk for siblings is slightly higher than that of the general population, although below 1% [18].

Incomplete penetrance is the second reason not to reassure a family on the basis of the parents' phenotype. In familial hyperaldosteronism type I, there are carriers of the variant who are normotensive and normokalaemic, while other members of the same family have severe, early hypertension [7]. In type II, there are normotensive carriers with a raised aldosterone/renin ratio and normotensive carriers with a normal ratio [67]. In type IV, a carrier father was normotensive with low renin and normal aldosterone, and in one family the carrier mother was unaffected [61]. In Liddle syndrome, the systematic review found hypertension in 92.4% of published patients, which implies normotensive carriers, and there are cases diagnosed at an advanced age [1]. In pseudohypoaldosteronism type II, when the parents are clinically unaffected the risk for siblings appears low, but remains increased by the possibility of reduced penetrance in a parent, and an apparently negative family history can be considered negative only after appropriate evaluations have been performed [18].

8.2 Cascade testing and evaluation of at-risk relatives

Evaluation of at-risk relatives is, in this group of disorders, an intervention with immediate therapeutic consequence, which is why the guidelines are firm. In pseudohypoaldosteronism type II, it is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives in order to identify as early as possible those who would benefit from prompt treatment, by measurement of serum potassium and blood pressure and by targeted genetic testing when the familial variant is known [18]. In familial hyperaldosteronism, the Endo-ERN guideline suggests clinical and biochemical evaluation of all first-degree relatives and, when possible, direct sequencing of the mutated gene in all of them, regardless of phenotype, because hypertension is common and increases with age and its diagnosis is not enough to establish the disease; the rationale is that aldosterone excess damages the heart and kidney partly independently of blood pressure, and cardiac damage has been observed in patients with normal blood pressure [7]. The same guideline honestly records that there is no evidence confirming the benefit of early treatment, and accepts that testing may be dispensed with in normotensive individuals over 60 years, although evidence is lacking [7]. The Endocrine Society guideline recommends genetic screening of all first-degree relatives of patients with familial hyperaldosteronism and of all patients with primary aldosteronism of onset before 20 years [71]. In Liddle syndrome, genetic screening should be performed in first-degree relatives of a carrier, because of dominant inheritance with a 50% risk of transmission and the phenotypic variability described in some families [1]. In apparent mineralocorticoid excess, the increase in the number of asymptomatic cases detected in families with a positive history makes genetic counselling necessary to clarify family involvement [6].

Carrier detection in the recessive forms requires prior identification of the familial variants [18]. In consanguineous families, which are the rule in apparent mineralocorticoid excess, information about risk should be given to the couple and, when applicable, to the extended family, because the variants occur preferentially in consanguineous or endogamous groups and in populations with a founder effect [6].

8.3 Prenatal diagnosis, preimplantation testing and counselling of minors

Once the familial variants have been identified, prenatal diagnosis in an at-risk pregnancy and preimplantation genetic testing are possible, as is explicitly recorded for pseudohypoaldosteronism type II [18]. The ideal time to determine genetic risk, clarify carrier status and discuss the availability of these options is before pregnancy, and it is appropriate to offer genetic counselling, including discussion of the risks to offspring and of reproductive options, to young adults who are affected, carriers or at risk of being carriers [18]. There may be differences in perspective among professionals and within families regarding the use of prenatal diagnosis, and discussion of these issues is useful, the decision being a personal one [18]. DNA banking from affected patients deserves consideration, because testing methodology and understanding of genes and variants will improve in the future [18].

Counselling of minors has a clear orientation here that distinguishes it from untreatable disorders: as all these entities are treatable and treatment prevents target-organ damage, testing of at-risk children is indicated for medical and not merely informational reasons, and should not be deferred until adulthood. In families with an apparent de novo variant, when neither parent has the variant or clinical evidence of the disease, the variant is probably de novo, but non-medical explanations should also be considered, such as alternative paternity or maternity, including situations of assisted reproduction, and undisclosed adoption [18].

8.4 Specific counselling in pregnancy

Two entities require targeted preconception counselling. In Geller syndrome, pregnancy is the period of maximum risk, because of the approximately hundredfold increase in progesterone, which activates the mutant receptor; the two female carriers in the original family had five pregnancies, all complicated by marked worsening of hypertension, and spironolactone is contraindicated [16]. In familial hyperaldosteronism, normalisation of blood pressure before conception is recommended, with withdrawal of dexamethasone in women with type I, because it crosses the placenta, and withdrawal of mineralocorticoid receptor antagonists 4 to 6 weeks before conception, with replacement by first-line drugs for pregnancy [7]. The choice of drugs and management details are given in section 7.

In families with congenital adrenal hyperplasia, counselling includes the risk of atypical genitalia in a 46,XX fetus and the controversy over prenatal dexamethasone.

8.5 Information to convey to the family

Three messages summarise counselling in this group. The first is that the molecular diagnosis changes treatment: the same picture of hypertension with hypokalaemia treated with the wrong drug may not improve, and identifying the gene allows choice of the drug that blocks the altered step [1, 7]. The second is that early identification prevents organ damage: the contrast between the five Israeli patients with apparent mineralocorticoid excess diagnosed in early childhood, who maintained normal renal function after 11 years, and the two diagnosed later, who progressed to end-stage kidney disease, is the clearest argument available [82]. The third is that a negative genetic result in a relative tested for the known familial variant excludes the disease, but a negative result in the proband does not exclude it, because in at least ten families with pseudohypoaldosteronism type II no variant was identified in any of the four known genes and there is an additional locus whose gene is unknown [18].

9. Special Considerations: Population Diversity and Epidemiology

9.1 The denominator of the problem

Hypertension affects about 34% of adults aged 20 years or older in the United States, and 4.11% of individuals aged 12 to 19 years in that country have hypertension measured at a single session; in the clinical setting, with repeated measurements, the prevalence of confirmed hypertension in children and adolescents is about 3.5%, with consistently higher values in boys, 15 to 19%, than in girls, 7 to 12%, for elevated blood pressure [17, 29]. It is against this denominator that the rarity of monogenic forms is measured, and the clinical rule that follows from it is that the younger the hypertensive patient, the greater the likelihood of a secondary cause and, among secondary causes, of a genetic cause [7, 17].

The prevalence of primary aldosteronism in the adult hypertensive population is at least 5 to 13%, and familial forms account for 1 to 5% of cases of primary aldosteronism, an estimate that the Endo-ERN guideline considers probably overestimated, because it includes families with two cases without genetic confirmation, placing the true prevalence of familial hyperaldosteronism below 1% of cases of primary aldosteronism; conversely, some cases are missed because of incomplete penetrance or because they are de novo [7]. In the paediatric age group, the guideline assumes that the prevalence of primary aldosteronism in the hypertensive population is not negligible, and in a cohort of 130 hypertensive children 3.9% had an aldosterone/renin ratio above 10 and 3.1% had the type I hybrid gene, with four additional affected children identified among 21 first-degree relatives [7].

9.2 Prevalences by entity and what each figure measures

The available estimates are of three types, and confusing them is the main source of error. There are prevalence classes estimated by Orphanet, there are counts of published cases or families, and there are prevalences measured in cohorts of hypertensive patients, which are not population prevalences.

Two figures deserve an explicit caveat. The first is the 1.52% and 0.91% of Liddle syndrome in Chinese hypertensive patients: this is a prevalence in a selected population of hypertensive patients after exclusion of the most common secondary causes, and not a population prevalence; its usefulness is to indicate that the disease is underdiagnosed and not to quantify the number of patients in a population [1]. Raina and colleagues also cite estimates of 1.5% with genetic testing in a Chinese population and 6% among hypertensive patients in a study of American veterans in Louisiana, but do so by attribution to studies they do not transcribe, so the second figure in particular should be treated as reported and not as verified [17]. The second is the 7.1% partial 11β-hydroxysteroid dehydrogenase type 2 deficiency in a primary care cohort in Chile: given its magnitude, it measures functional variation of the enzyme in a general population and not the classic Mendelian disease, whose worldwide count is fewer than one hundred families [6]. A third figure to interpret with care is the proportion of cases of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: 5 to 8% of all cases, with a much higher proportion, of about 15%, in Muslim and Jewish populations of the Middle East, according to sources cited indirectly by Raina and colleagues [17, 21].

9.3 Founder populations and consanguineous groups

Apparent mineralocorticoid excess is the clearest example of a disease concentrated by consanguinity and founder effect. In the compilation of more than one hundred genetically confirmed patients assembled by Lu and colleagues, the largest group is from Oman, with several families and several recurrent variants, including p.Arg74Glyfs*43, p.Thr267Ala, p.Leu114_Glu115del and p.Val321_Val322insAlaProVal (published designations) and, in NM_000196.4, c.662C>T p.(Ala221Val) and c.622C>T p.(Arg208Cys); these are followed by Iranian, Indian, Saudi, Qatari, Kuwaiti, Italian, French, Japanese, Chinese and Native North American patients, including from the Chippewa nation, North American Mennonites with the variant c.680C>T p.(Pro227Leu), African Americans and Chileans [6]. The disease has been observed in many ethnic groups, including Caucasians, African Americans, Asians and Amerindians [17]. In Portugal, a consanguineous family with two patients homozygous for NM_000196.4:c.983C>T p.(Ala328Val) has been described; in Brazil, two patients from distinct, likewise consanguineous families have been described, one with c.556C>T p.(Arg186Cys) and the other with p.(Ala328Val) [6]. The consanguineous Sardinian family described by Li and colleagues, with the variant c.835C>T p.(Arg279Cys) in the homozygous state, is notable for another reason: the affected members were over 30 years of age, with mineralocorticoid hypertension and altered cortisol metabolism, whereas heterozygotes were phenotypically normal with subtle defects of cortisol metabolism, which illustrates the existence of late-expressing forms [36]. The Mennonite family with p.(Pro227Leu) had a mild form with low-renin hypertension without the typical features, with cortisol-to-cortisone conversion of 58%, compared with 0 to 6% in typical forms and 90 to 95% in normal individuals, which led the authors to suggest that patients with low-renin essential hypertension, about 40% of the total, undergo genetic analysis of HSD11B2 [36].

In 11β-hydroxylase deficiency, the variant NM_000497.4:c.1343G>A p.(Arg448His) in the homozygous state is the cause in Jews of Moroccan origin, and the classic series of Rosler and colleagues assembled 26 patients from 18 Jewish families from Morocco, Tunisia, Turkey and Iran, with consanguinity in seven; the disease is substantially more frequent in Middle Eastern and North African groups, so the European estimate should not be applied to those populations [21, 55]. In 17α-hydroxylase deficiency, two variants account for 82% of Brazilian alleles, a deletion of exons 1 to 6 accounted for 42 of 97 Turkish cases and the variant NM_000102.4:c.985_987delinsAA p.(Tyr329LysfsTer90) (published as c.985_987delTACinsAA) accounted for 28 of 52 alleles in a Chinese cohort [55]. In Liddle syndrome, genome analysis of three apparently unrelated Italian families carrying the β variant published as p.Pro617Leu, which in ClinVar corresponds to NM_000336.3:c.1850C>T p.(Pro617Leu), revealed a common ancestor, and the estimate of the number of generations between patients led the authors to suggest that the real prevalence is much higher than estimated; the polymorphic βENaC variant NM_000336.3:c.1781C>T p.(Thr594Met), benign or likely benign in ClinVar, is highly prevalent in populations of Black African origin, with a frequency that increases with the severity of hypertension and a significant association with low renin activity [1, 51].

In familial hyperaldosteronism type III, the somatic KCNJ5 frequencies in adult aldosterone-producing adenomas vary markedly with ancestry, between 53 and 96.7% in East Asian cohorts, 33.9 to 46.5% in European cohorts and about 34.2% in African patients; these figures concern somatic events in tumours and not germline disease, but they are relevant for interpreting the genetic literature on this gene [55].

9.4 Stated gaps

There are no population prevalence data for any of these disorders in Portugal or Brazil, and the sources consulted do not contain them; the only national data identified are the individual published cases, one Portuguese family and two Brazilian patients with apparent mineralocorticoid excess, and the Brazilian allele frequencies in 17α-hydroxylase deficiency [6, 55]. The absence of these data in the sources consulted does not demonstrate that none have been published. For pseudohypoaldosteronism type II, the prevalence is declared unknown by GeneReviews itself, and a count of 180 individuals and families cannot be converted into a prevalence [18]. For familial hyperaldosteronism types I and II, Orphanet assigns no prevalence class [8, 9]. For Geller syndrome, there is no estimate of any kind, and the published basis is the original family with 11 affected members and later isolated cases [16].

9.5 Special populations

In the preterm neonate, hypertension is mainly a consequence of prematurity and its complications, not of genetic causes, and resolves in most cases in the first or second year of life; the practical consequence is that persistence of hypertension in this population should prompt reconsideration of the diagnosis and not merely an increase in dose [30]. The same population carries, however, an independent long-term risk: adults born preterm have higher office and ambulatory blood pressures and a risk of hypertension 1.2 to 2.5 times that of those born at term, and children born small for gestational age are more likely to have hypertension in childhood, with 18% having hypertension on ambulatory monitoring between 6 and 10 years of age, compared with no child in the group born with appropriate weight [30]. This risk adds to that of the monogenic disease and justifies lifelong blood pressure surveillance in patients who are both preterm and carriers of a variant.

In children with chronic kidney disease, about 50% are hypertensive, and hypertension should be assessed at every contact, with a target 24-hour mean arterial pressure below the 50th percentile on ambulatory monitoring and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker when proteinuria is present [29]. This guidance is relevant for patients with apparent mineralocorticoid excess and nephrocalcinosis, who constitute the subgroup with the highest renal risk among the entities covered [6].

9.6 Reference networks and resources

The European Reference Network for rare endocrine conditions, Endo-ERN, is the relevant structure for familial hyperaldosteronism, apparent mineralocorticoid excess and the congenital adrenal hyperplasias, and is the author of the only guideline devoted to familial hyperaldosteronism, developed with European Union funding [7, 27]. The European Reference Network for rare kidney diseases, ERKNet, is the relevant structure for tubulopathies, including Liddle syndrome and the pseudohypoaldosteronisms, and for hypertension of renal cause [28]. The GeneReviews chapter on pseudohypoaldosteronism type II lists, as support organisations, the Genetic Disorders of Mucociliary Clearance Consortium and Metabolic Support UK, a listing that reflects the difficulty of finding associations devoted to diseases with so few identified patients [18]. The Orphanet entries for each entity refer to the national associations registered on the portal, and are the practical starting point for referring a family [2, 5]. The Endo-ERN guideline recommends that these patients be preferably followed by a multidisciplinary expert team, and points out that some recommendations may not be feasible in certain countries and should be interpreted in the context of available resources — an observation that, in the Portuguese case, applies directly to the unavailability of triamterene and single-agent amiloride [7, 80].

10. Illustrative Clinical Case

10.1 Liddle syndrome with neonatal presentation

The case described by Steyn and colleagues, from an academic hospital in Pretoria, South Africa, is the most complete report of neonatal presentation of a monogenic hypertension in this group [73]. The patient, a boy of Ethiopian ancestry born in November 2012, with no known parental consanguinity, was admitted on the fifth day of life with severe hypernatraemic dehydration and acute renal failure. On examination he was severely wasted and dehydrated, with absent femoral pulses; abdominal ultrasound showed a thrombus in the aorta, which the authors attributed to hyperviscosity associated with severe dehydration and which resolved with heparin, and the neonate was sent home in December 2012 after the renal failure had resolved with rehydration. One week after discharge, at the follow-up visit, he was hypertensive.

During subsequent admissions, over years of follow-up, no coagulation abnormalities or new thrombus were found, renal ultrasound showed no anomalies and echocardiography detected no cardiac abnormalities. Laboratory results up to 8 years of age showed potassium between 2.0 and 3.0 mmol/L, against a local reference range of 3.7 to 5.9 mmol/L, sodium between 159 and 171 mmol/L, against a range of 136 to 145, and metabolic alkalosis with bicarbonate between 29 and 34 mmol/L, against a range of 23 to 29; spot urinary potassium was raised, between 12 and 22 mmol/L, against a reference value below 10, despite low serum potassium. The time sequence of the values is instructive: at birth he had sodium 171 mmol/L, potassium 5.5 mmol/L, chloride 129 mmol/L, bicarbonate 8 mmol/L, urea 58.1 mmol/L and creatinine 530 µmol/L, a picture dominated by dehydration and renal failure; at 10 months potassium was 1.7 mmol/L, at 2 years 1.3 mmol/L, at 4 years 6.1 mmol/L with bicarbonate of 14 mmol/L, in an episode reflecting variability in adherence and therapy, and at 8 years 1.8 mmol/L. Serum aldosterone was below 27.0 pmol/L, against a supine range of 49 to 643 pmol/L, and plasma renin concentration was 0.5 mIU/L, against a range of 6.5 to 36.2 mIU/L: both suppressed, the pattern that defines the group of low-aldosterone disorders [73].

The diagnostic pathway took time. In 2019, targeted testing for the variant NM_000336.3:c.1688G>A p.(Arg563Gln) and for exon 13 variants of the β subunit of the epithelial sodium channel, the most common causes of Liddle syndrome in South Africa, was negative. In 2020, with external funding, all exons and exon-intron boundaries of the three subunit genes were amplified and sequenced, and two pairs of heterozygous variants were identified: in SCNN1A (NM_001038.6), c.1000G>A p.(Ala334Thr) in exon 5 and c.1987A>G p.(Thr663Ala) in exon 13; in SCNN1B (NM_000336.3), c.7G>A p.(Val3Met) in exon 2 and c.1325G>T p.(Gly442Val) in exon 9; no variants were detected in the coding region of SCNN1G. The Sanger electropherograms, with the genomic coordinates of each variant in GRCh38.p14, are in Figure 1 of the article [73]. The variants p.(Gly442Val) and p.(Ala334Thr) had previously been described as polymorphisms associated with hypertension and increased channel activity, with a 1.6-fold increase in activity in functional studies for the latter, and the authors attribute the severe phenotype to the combined effect of variants in different subunits, allowing that one of them might have a pathological effect not yet documented [73]. In ClinVar, p.(Ala334Thr), p.(Thr663Ala) and p.(Gly442Val) are classified as benign or likely benign and p.(Val3Met) as of uncertain significance [51].

The course is the most useful part of the report. The patient was initially treated with multiple antihypertensives and potassium supplements, with poor adherence to therapy and follow-up and several readmissions; effective blood pressure control was achieved only with the introduction of amiloride at the end of 2018, years after presentation, and it was this response that raised the suspicion of an epithelial sodium channel abnormality and prompted genetic testing [73]. The management described does not represent recommended practice: the correct sequence today is to measure renin and aldosterone early in an infant with hypertension and hypokalaemic metabolic alkalosis and, faced with the pattern of double suppression, to start an epithelial sodium channel blocker and request genetic testing in parallel, rather than trying successive antihypertensives for years [1, 7]. The authors themselves draw their conclusion from this delay: any infant with hypertension and metabolic alkalosis, with or without hypokalaemia, should raise the suspicion of Liddle syndrome, even without a family history of hypertension, and delay in treatment is associated with growth failure and hypertensive morbidity and mortality due to cardiovascular disease, cerebrovascular disease, nephrosclerosis and progressive renal failure [73].

The differential the authors work through is also the practical differential of any neonate with this picture: in a neonate with hypernatraemia and hypokalaemic metabolic alkalosis, diuretics, persistent vomiting, losses through free nasogastric drainage or a tubulopathy such as Gitelman or Bartter syndrome are considered; if there is associated hypertension, congenital adrenal hyperplasia, primary hyperaldosteronism, apparent mineralocorticoid excess, glucocorticoid-remediable aldosteronism, renal artery stenosis and a deoxycorticosterone-producing tumour are added [73].

10.2 Counterpoint: late and early diagnosis in apparent mineralocorticoid excess

The series of three Chinese children published by Ding and colleagues offers the quantitative counterpoint [54]. The first patient, a girl born at term weighing 1550 g, had hypokalaemia and raised blood pressure noted at 6 months of age, but was diagnosed only at 12 years; at presentation she had a height of 124.1 cm, corresponding to −4.38 standard deviations, blood pressure of 155/110 mmHg, potassium of 3.14 mmol/L with a historical minimum of 1.23 mmol/L, renin of 3.23 pg/mL/h, aldosterone of 7.05 ng/dL, a urinary calcium/creatinine ratio of 0.44 and nephrocalcinosis, as well as left ventricular hypertrophy with an ejection fraction between 50 and 60%, dilatation of the aortic sinuses and minimal aortic regurgitation, and focal cerebral atrophy with cystic changes in the left parietal lobe on magnetic resonance imaging. With spironolactone increased up to 6.8 mg/kg/day and metoprolol, potassium did not stabilise and systolic pressure remained between 135 and 140 mmHg; replacement with eplerenone, gradually increased up to 5 mg/kg/day, improved control to about 120/80 mmHg. The estimated glomerular filtration rate fell from 87.9 to 76.2 mL/min/1.73 m² during follow-up, up to 14 years and 10 months of age. The variant was NM_000196.4:c.650T>C p.(Val217Ala) in the homozygous state, classified as of uncertain significance by the American College of Medical Genetics and Genomics criteria despite deleterious predictions and the full phenotype [54].

The other two children, diagnosed at 8.9 and 3.3 years, with initial pressures of 142/91 and 121/83 mmHg, were both controlled with spironolactone 5.5 mg/kg/day, with normal potassium and pressures of 108/70 and 95 to 100/60 to 65 mmHg, without left ventricular hypertrophy or hypertensive retinopathy, and with an estimated glomerular filtration rate of 102.6 and 137.6 mL/min/1.73 m² at the last assessment [54]. The second of these patients had initially been labelled as Bartter syndrome at 22 months, because of polydipsia and polyuria, a misattribution that the presence of hypertension should have excluded.

The contrast between the three patients in the same series, and between the five Israeli patients diagnosed in early childhood, who maintained normal renal function after 11 years of follow-up, and the two diagnosed late, already with chronic kidney disease, who progressed to end-stage kidney disease requiring dialysis and transplantation, is the best demonstration that the prognosis of these disorders depends on the time to diagnosis [54, 82].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis by entity

The prognosis of these disorders is determined by three variables: the time between the onset of hypertension and effective treatment, the degree of organ damage already present at diagnosis and, in the forms with aldosterone excess, the effect of the mineralocorticoid on the heart and kidney independently of blood pressure [7, 82].

In apparent mineralocorticoid excess, the figures are the most complete. In the series of 36 patients with the classic form assembled by Yau and colleagues, cardiovascular mortality was 19%, nephrocalcinosis persisted in 89% and 15% had renal failure [6]. In the Israeli cohort of seven patients from two families, followed for 11 years, the five diagnosed in early childhood maintained a normal estimated glomerular filtration rate at the last assessment, whereas the two who presented in late childhood with already established chronic kidney disease progressed to end-stage kidney disease requiring dialysis and transplantation; one patient in the cohort survived a cardiac arrest related to a potassium disturbance during treatment [82]. In an Iranian family of three siblings followed for 20 years by Razzaghy-Azar and colleagues, the eldest brother, with the longest diagnostic delay, developed left ventricular dysfunction and renal failure requiring transplantation, whereas the other two had no target-organ damage [6]. The complications described are early stroke, hypertensive myocardial hypertrophy, hypertensive retinopathy and deterioration of renal function, and Werder's original patient, untreated, re-presented at 40 years with subarachnoid haemorrhage and end-stage kidney disease [6, 36]. The long-term prognosis of the non-classic form remains unknown [6].

In Liddle syndrome, the untreated natural history includes hypertensive nephrosclerosis with progression to end-stage kidney disease, documented in Liddle's index patient, transplanted in 1989, and in a Japanese brother on haemodialysis at 37 years, stroke at a young age, as in the 21-year-old mother of Hansson's African American family, and sudden death, attributed to arrhythmias triggered by severe hypokalaemia [1, 33]. Treatment with epithelial sodium channel blockers normalises blood pressure, potassium, renin and aldosterone, and kidney transplantation corrects the disorder, which confirms that the defect is renal [1].

In familial hyperaldosteronism type I, a history of early cardiovascular and cerebrovascular events is common but not universal, with an increased prevalence of intracranial aneurysms and haemorrhagic stroke; Raina and colleagues cite an incidence of intracerebral haemorrhage of 11 to 18%, with an associated mortality of 61% at a mean age of 31.7 years with a standard deviation of 11.3 years, and recommend, by attribution to sources they do not transcribe, cerebrovascular screening every 5 years after puberty with computed tomography or magnetic resonance angiography [7, 17]. In patients treated with low-dose dexamethasone, the left ventricular mass index remained normal and stable or fell during 0.5 to 3.8 years of follow-up [7].

In type III, most published patients required bilateral adrenalectomy to control blood pressure, an intervention that corrected hypertension in the three patients of the original family but implies lifelong dependence on hormone replacement; patients with the p.Gly151Glu variant have medically treatable early-onset aldosteronism [7, 68]. In type IV, incomplete penetrance means that some carriers never develop hypertension, and the prognosis of those who do is that of treated primary aldosteronism [61]. In primary aldosteronism with seizures and neurological abnormalities, the prognosis is dominated by the neurological disease, with global developmental delay and absence of walking and speech at 3 years in one of the original patients, and not by hypertension, which is the treatable component [15].

In pseudohypoaldosteronism type II, hyperkalaemia and acidosis generally correct within the first week of thiazide treatment, and the prognosis thereafter is that of blood pressure control; untreated patients with raised blood pressure are at risk of heart disease, renal impairment and stroke, and hypercalciuria exposes them to lithiasis and osteoporosis [17, 18]. Carriers of CUL3 variants have the most severe phenotype in the group, with more marked hyperkalaemia and acidosis, earlier hypertension and a greater likelihood of growth impairment, so identifying the gene has direct prognostic value [46, 70].

In Geller syndrome, three deceased relatives with early-onset hypertension died of heart failure before 50 years, and pregnancy is the period of maximum risk [16]. In hypertension with brachydactyly, death from stroke before 50 years is the outcome of untreated disease, but the kidney is spared and, unexpectedly for decades of severe hypertension, hypertensive cardiac damage does not develop, which makes this entity a useful pathophysiological counterpoint [26, 77].

The baseline risk against which any of these prognoses is measured is that of aldosterone excess in general: compared with patients with primary hypertension, patients with primary aldosteronism have increased odds of stroke, coronary heart disease, atrial fibrillation, heart failure, albuminuria and proteinuria, with the odds ratios presented in section 7 [71].

11.2 Surveillance table

The intervals in this table are the same as those used in section 7 for drug titration: 2 to 3 months for biochemical reassessment after each adjustment of the mineralocorticoid receptor antagonist, 8 to 12 weeks between dose adjustments, 3 to 6 months for overall clinical and biochemical assessment and 4 to 6 weeks in children on antihypertensives until blood pressure is controlled [7, 29, 71].

11.3 What surveillance does not resolve

Two limitations should be recorded. The first is that there is no formal evidence that early detection of cardiac damage improves prognosis in these disorders, nor that early treatment of asymptomatic carriers brings demonstrated benefit; the recommendation to monitor rests on the observation that left ventricular hypertrophy is the main predictor of adverse events in hypertensive patients and that its regression predicts a better prognosis, and on the observation of cardiac damage in normotensive patients with familial hyperaldosteronism [7]. The second is that there are no studies on the optimal blood pressure target in familial hyperaldosteronism, no data defining the optimal timing of adrenalectomy in type III, and no systematic assessment of the effects of prolonged treatment on quality of life and cardiovascular events [7]. The surveillance described is therefore prudent and supported by the mechanism and by analogy with hypertension in general, and not by trials in these populations.

12. Summary and Final Considerations

The monogenic hypertensions of neonates and children form a small group of disorders with a common laboratory pattern, suppressed renin, and a pathophysiological architecture that converges on the distal nephron: either the epithelial sodium channel is constitutively activated, as in Liddle syndrome, or the mineralocorticoid receptor is inappropriately occupied, as in apparent mineralocorticoid excess, glucocorticoid resistance and the congenital adrenal hyperplasias that accumulate deoxycorticosterone, or it is constitutively active, as in Geller syndrome, or aldosterone is produced in excess by a chimeric gene or by gain-of-function ion channels in the zona glomerulosa, as in familial hyperaldosteronism types I to IV, or the upstream sodium-chloride cotransporter is hyperactive because of failure of its degradation, as in pseudohypoaldosteronism type II.

The clinical consequence of this design is that the specific diagnosis changes treatment. Three simple and inexpensive tests — serum potassium with acid-base balance, plasma renin activity or direct renin, and aldosterone — distinguish most of these entities from one another and from the renal, renovascular and pulmonary causes that explain almost all neonatal hypertension. The combination of hypertension with hypokalaemia and suppressed aldosterone points to the channel or the receptor; with raised aldosterone, to the zona glomerulosa; with hyperkalaemia and hyperchloraemic acidosis, to the WNK pathway. From there, targeted genetic testing or a panel covering the whole group, with specific amplification of the hybrid gene whenever aldosterone is raised, establishes the definitive diagnosis. The European guideline devoted to familial hyperaldosteronism recommends genetic testing in all patients with primary aldosteronism whose hypertension was diagnosed before 20 years, and the American guideline extends genetic screening to all first-degree relatives of patients with familial forms.

Treatment is mechanistically determined and, in most cases, effective with old and accessible drugs: epithelial sodium channel blockers in Liddle syndrome, mineralocorticoid receptor antagonists in apparent mineralocorticoid excess and familial hyperaldosteronism types II to IV, low-dose glucocorticoid in type I, with the receptor antagonist preceding glucocorticoid in children, a thiazide in pseudohypoaldosteronism type II and suppressive glucocorticoid in the congenital adrenal hyperplasias. Sodium restriction enhances all of them. The wrong drug has its own consequences: spironolactone is useless in Liddle syndrome and worsens Geller syndrome, and glucocorticoid does not resolve the familial hyperaldosteronisms that do not depend on adrenocorticotropic hormone. None of these drugs has an approved indication for these disorders in the paediatric age group, and in Portugal triamterene is not available and amiloride exists only in fixed combination with a thiazide, an access limitation that constrains titration and should be anticipated.

The evidence base is weak and should be presented as such: there are no randomised trials in any of these disorders, the largest series have about ten patients and the European guideline explicitly classifies the quality of therapeutic evidence as very low. The therapeutic development of the last year, the approval of the first aldosterone synthase inhibitor in the United States, concerns adults with uncontrolled hypertension and has neither an indication nor data in the monogenic forms or in the paediatric age group. What supports the decision to treat is the documented risk of untreated disease, and that is well established: cardiovascular mortality of 19% and renal failure in 15% in a series of 36 patients with apparent mineralocorticoid excess, progression to end-stage kidney disease in patients diagnosed late compared with preserved renal function after 11 years in those diagnosed in early childhood, stroke in adolescents and young adults with uncontrolled Liddle syndrome, and intracerebral haemorrhage with high mortality in familial hyperaldosteronism type I.

From this follows the main practical message. In a neonate or child with hypertension that persists without an identified renal, renovascular, pulmonary or iatrogenic cause, with unexplained hypokalaemia or hyperkalaemia, or with a family history of young-onset hypertension, sudden death or early stroke, measurement of potassium, renin and aldosterone before starting drugs that interfere with the axis, followed by targeted genetic testing, is a short pathway that transforms a hypertension regarded as essential and poorly controlled into a disease with specific treatment. The neonatal case described in this article, in which blood pressure control was achieved only six years after presentation, with the introduction of the mechanistically correct drug, measures exactly what is lost when that pathway is not followed.

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