Introduction
According to the Polish Society of Hypertension guidelines, arterial hypertension can be defined as average systolic blood pressure (SBP) of ≥ 140 mm Hg and/or diastolic blood pressure (DBP) of ≥ 90 mm Hg at least on two different visits [1]. Despite most arterial hypertension cases (about 90%) having multifactorial etiology, including sedentary lifestyle, obesity, and high sodium intake, the presence of a secondary form of hypertension should be remembered due to its association with a higher risk of cardiovascular and neurological complications. A rare subtype of secondary hypertension is monogenic hypertension (MH). This hereditary condition can occur due to germinal or somatic mutations, with the dominant and recessive type of inheritance involved in renal or adrenal blood pressure regulation [2, 3]. MH is characterized by early-onset, severe, refractory hypertension, the coexistence of acid-base and ion disturbances (most common are alkalosis and hypokalemia), positive family history, and low renin level [4, 5]. Most MH cases develop due to increased (mineralocorticoid-dependent or mineralocorticoid-independent) sodium reuptake [6]. However, in Bilginturan syndrome, hypertension is associated with an increased smooth muscle tone [6]. The study aimed to form an update about monogenic hypertension.
Classification of monogenic hypertension
Despite the rare occurrence of MH, it significantly impacts blood pressure (BP), leading to an increase in its value on average 20–50 mm Hg [2, 7]. The clinical presentation of MH can be different than described above; BP level can be normal or mildly elevated without electrolyte disturbances [4]. Moreover, mild symptoms cannot exclude the presence of MH because the overall phenotype is also influenced by genetic and non-genetic factors [4]. Table 1 shows the genetic syndromes associated with MH.
|
Name |
Underlying gene and type of inheritance |
Serum potassium, pH and HCO3- |
Diagnostic indicators |
|
Familial hyperaldosteronism type I (FH I) |
CYP11B1/CYP11B2 hybrid gene AD |
K or = pH HCO3– |
High ARR high urinary 18-OHF elevated 18-hydroxycortisol/tetrahydroaldosterone ratio presence of CYP11B1/CYP11B2 hybrid gene intracranial accidents before < 40 years old |
|
Familial hyperaldosteronism type II (FH II) |
CLCN2 AD |
K pH HCO3– |
High or normal ARR, low aldosterone 2 or more family members with PA |
|
Familial hyperaldosteronism type III (FH III) |
KCNJ5 AD |
K pH HCO3 |
High urinary 18-OHF (10–100 times higher than in FH I) Paradoxal reaction on dexamethasone — increase in blood pressure Bilateral adrenal hyperplasia lack of suppression in DST |
|
Familial hyperaldosteronism type IV (FH IV) |
CACNA1H AD |
K pH HCO3– |
High ARR Genetic testing |
|
Primary aldosteronism with seizures and neurological abnormalities (PASNA) |
CACAN1D AD Due to very severe phenotype occurs only de novo |
K pH HCO3 |
High ARR Coexistence of neurologic abnormalities seizures and cerebral palsy with early-onset hypertension Genetic testing |
|
Glucocorticoid resistance |
NR3C1 AR/AD |
K or = pH or = HCO3– or = |
Elevated level of urinary free cortisol Cortisol > 50 nmol/L after overnight DST |
|
Liddle syndrome |
SCNN1A, SCNN1B, SCNN1G AD |
K or = pH HCO3– |
Low urinary aldosterone or its metabolites |
|
Gordon syndrome pseudohypoaldosteronism type II (PHA II) |
CUL3 KLHL3, WNK1, WNK4 AD/AR |
K or = pH HCO3– |
In WNK mutation presence of hypercalciuria |
|
Apparent mineralocorticoid excess (AME) |
HSD11B2 AR |
K or = pH HCO3– |
Urinary cortisol metabolites , Urinary cortisone metabolites Urinary THF + 5aTHF:THE > 1 or free cortisol:cortisone > 0.5 |
|
Congenital adrenal hyperplasia type IV (CAH IV) |
CYP11B1 AR |
K or = pH or = HCO3– |
High level of 11-deoxycortisol and deoxycorticosterone |
|
Congenital adrenal hyperplasia type V (CAH V) |
CYP17A1 AR |
K or = pH or = HCO3– |
High progesterone relative to 17a-progesterone |
|
Geller syndrome Activating mineralocorticoid receptor mutation |
NR3C2 AD |
K or = pH HCO3– |
Exacerbation of hypertension after spironolactone and in pregnancy |
|
Hypertension with brachydactyly Bilginturan syndrome |
PDE3A AD |
K or = pH HCO3– |
Brachydactyly type E Genetic testing |
Most often, the occurrence of monogenic hypertension is associated with a single-gene mutation leading to excessive production of aldosterone, impairment of sodium homeostasis, and adrenal steroid metabolism [8]. As a result, in these disorders, hypertension develops due to plasma volume expansion being the dominant and most often the only symptom of the disease [5, 8]. However, in some conditions, monogenic hypertension coexists with skin lesions, tumors, and neurological disorders and does not dominate the clinical picture in patients. Genetic disorders associated with the development of hypertension are presented in Table 2.
|
Genetic syndrome |
Type of mutation |
Characteristic feature |
|
Neurofibromatosis type 1 |
NF1 (AD) |
Cafe-au-lait spots, neurofibromas, optic nerve glioma, inguinal or axillary freckling, Lisch nodules |
|
Von Hippel Lindau Syndrome |
VHL (AD) |
retinal angioma, spinal or cerebellar hemangioblastoma, adrenal or extra-adrenal pheochromocytoma |
|
Sclerosis nodularis |
TSC1, TSC2 (AD) |
Facial angiofibroma, hypomelanotic macules, shagreen patches |
|
Paraganglioma |
SDHA, SDHAF2, SDHB, SDHC, SDHD |
Tumors or extra-adrenal paraganglia, pheochromocytoma |
|
Multiple endocrine neoplasia type 2A (MEN 2A) |
RET (AD) |
Pheochromocytoma, medullary thyroid carcinoma |
Familial hyperaldosteronism
Among all cases of secondary hypertension, the most common form is primary hyperaldosteronism (PA) [9]. Most cases are sporadic; however, 6% are genetically determined and related to the development of monogenic hypertension [10]. There are 4 forms of familial hyperaldosteronism, which differ in the clinical course and the method of treatment.
Familial hyperaldosteronism I (FH I)
Familial hyperaldosteronism I (FH I) or glucocorticoid remediable aldosteronism (GRA) is the first identified disorder associated with developing MH [11]. Its prevalence ranges from less than 1 to 3.1% in pediatric cohorts, and according to some authors [12], it is considered the most common form of monogenic hypertension [13].
This condition is a result of the unequal crossover of genes coding 11b-hydroxylase (CYP11b-1) and aldosterone synthase (CYP11b-2), which leads to the formation of a protein with the possibility of inducing the ectopic production of aldosterone independent of renin. The mutation is inherited as an autosomal dominant trait, resulting in the dependency of aldosterone synthesis on adrenocorticotropic hormone (ACTH) instead of angiotensin II [14, 15].
FH I is characterized by moderate to severe hypertension, developing usually under 20 years of age [10, 13]. Moreover, low plasma renin, metabolic alkalosis, and mild hypokalemia despite high aldosterone levels are present [2, 16]. Clinical presentation can vary within the same family, normal potassium level is present in about 50% furthermore, some patients do not develop hypertension [8, 17, 18].
In FH I, cerebrovascular accidents are frequent; their incidence is approximately 48 % [19]. Patients are at high risk of hemorrhagic stroke in connection with the rupture of intracranial aneurysms [2, 7]. Therefore, in FH I, brain MRI should be performed in adolescence and repeated every 5 years [8].
The gold standard of FH I is genetic analysis for the chimeric gene, which significantly shortens the diagnostic process. Before genetic testing, urinary steroid hormone analysis and dexamethasone suppression tests are recommended [7, 20].
The first-line treatment of FH I is low-dose glucocorticoids to suppress ACTH [2, 7]. If the therapeutic goal is not achieved, mineralocorticoid receptor antagonists (spironolactone or eplerenone), ENaC antagonists (amiloride, triamterene), or thiazide diuretics can be added [2, 7, 19]. ENaC antagonists might be preferred in children to avoid side effects of glucocorticoids [9].
Interestingly, there have been reports of blood pressure normalization in pregnancy in patients with FH I without the need for treatment [21]. This is attributed to the influence of progesterone, the levels of which are significantly elevated during pregnancy [21].
Familial hyperaldosteronism II (FH II)
Familial hyperaldosteronism II is the most common form of all familial subtypes of hyperaldosteronism; its prevalence ranges from 1.2 to 6% of PA [19, 22]. Its pathogenesis is unclear; however, the most common present mutation responsible for its development is CLCN2 (gene localized on 7p22 (band 11q13), which is inherited autosomally dominantly [19, 23]. The CLCN2 gene encodes a voltage-gated chloride channel 2 (ClC-2) essential for resting membranę potential and regulating cell volume [24]. In the adrenal cortex, particularly within the zona glomerulosa (the outermost layer responsible for aldosterone production), ClC-2’s role is pivotal in modulating the membranę potential [25]. This regulation is crucial for activating voltage-gated calcium channels (VGCCs), which influence the intracellular calcium levels critical for aldosterone synthesis [25]. The dysregulated chloride conductance due to the CLCN2 mutation causes cell membrane hyperpolarization. This hyperpolarization paradoxically leads to the enhanced activation of T-type calcium channels rather than the expected inhibition [26]. The increased calcium influx elevates intracellular calcium concentrations, a critical second messenger for activating the calcium/calmodulin-dependent protein kinase (CaMK) pathway. This activation, in turn, stimulates the expression and activity of aldosterone synthase (CYP11B2), the key enzyme responsible for converting corticosterone to aldosterone in the final step of its biosynthesis [26]. The hyperactivation of aldosterone synthase due to increased intracellular calcium levels forms the crux of FH II pathophysiology. Elevated aldosterone levels lead to the classic symptoms of PA: resistant hypertension, hypokalemia, and metabolic alkalosis [27]. The clinical course of FH II is similar to sporadic nonfamilial PA [9]. The symptoms most often start to appear in adulthood. However, the age of diagnosis ranges from 14 to 72 years [9, 19]. Diagnosis is made based on the presence of at least two members of the family primary aldosteronism and excluding the hybrid CYP11B1/2 gene [9]. This subtype of FH is resistant to glucocorticoids due to independence from ACTH; however, treatment similar to the one used in idiopathic PA (mineralocorticoid receptor antagonists, calcium channel) is effective [15, 18]. Histological examination reveals hyperplasia or adenomas [23].
Familial hyperaldosteronism III (FH III)
Familial hyperaldosteronism III (FH III) is a rare disorder; it constitutes 0.3% of all PA cases and 8% among all FH [28]. It is developing due to the presence of various mutations in the KCNJ5 gene. It leads to increased calcium ion availability in the glomerulus cells, and this initiates aldosterone synthesis [23]. There is a strong correlation between genotype and phenotype [2, 28]. FH III can be characterized by early-onset, severe hypertension, hypokalemia, metabolic acidosis, significant elevation of aldosterone, polyuria, polydipsia, nycturia, and headache [12, 19]. For FH III, massive bilateral adrenal gland enlargement about 3–6 times is characteristic [9]. Moreover, high production of 18-hydroxycorticoid and 18-oxocorticoid is observed; its level exceeds the norm 100 to 10000 times [9, 19]. In the dexamethasone suppression test, the aldosterone level increases to twice the baseline, and there are no changes in cortisol level [19].
Diagnosis of FH III is made based on biochemical abnormalities, magnetic resonance imaging (MRI), or computed tomography (CT)-imaging — massive bilateral adrenal hypertrophy is a hallmark and genetic testing [9]. Hypertension in FH III does not respond to glucocorticoid; on the contrary, a paradoxical increase in its value is observed [9, 12]. Furthermore, unlike in other forms of familial aldosteronism, hypertension usually does not respond to aldosterone antagonists [19, 29]. Most FH III cases are resistant to pharmacological treatment and require bilateral adrenalectomy; however, mild phenotypes of hypertension can be cured with mineralocorticoid antagonists [2, 9, 28, 29].
Familial hyperaldosteronism IV (FH IV)
Familial hyperaldosteronism IV is a rare disorder associated with the presence of an autosomal dominant mutation in the CACNA1H gene [28]. The first germline defects were described in 2015 in five unrelated people with early-onset PA (age 10). They shared the same novel heterozygous variant (p.M1549V) [30]. Due to incomplete penetrance, the clinical manifestation of this disorder can significantly differ [18]. The patients can present refractory hypertension, hypokalemia, metabolic alkalosis, or normal blood pressure and potassium levels [18, 28].
The development of hypertension is associated with the mutation of the CACNA1H gene, which encodes the a1H subunit of the T-type calcium channel Cav3.2 expressed in various tissues, including the adrenal glands [26]. T-type calcium channels are low-voltage-activated channels that play a crucial role in controlling calcium influx in response to small depolarizations of the cell membrane [26]. In the adrenal zona glomerulosa, where aldosterone is produced, these channels are involved in regulating intracellular calcium levels, a critical factor in aldosterone biosynthesis [31]. The overproduction of aldosterone due to the hyperactive Cav3.2 channels results in persistent activation of the mineralocorticoid receptors in the kidneys. This activation increases sodium reabsorption and potassium excretion in the renal tubules, causing volume expansion, elevated blood pressure, and hypokalemia [26]. The hypertension observed in FH IV is often severe and may develop at a young age due to the early onset of aldosterone overproduction driven by the CACNA1H mutation.
In FH IV, there are no abnormalities (mass or hyperplasia) in imaging examinations [13, 28]. Moreover, patients do not present seizures and neuromuscular lesions [28]. Calcium channel blockers and mineralocorticoid antagonists can be used in treatment [28].
While the CACNA1H mutation is a primary driver of FH IV, environmental factors may interact with this genetic predisposition to influence the severity and progression of the disease. High dietary sodium intake is one of the most significant environmental factors known to exacerbate hypertension in individuals with primary aldosteronism, including those with FH IV [32]. Excessive sodium intake can further stimulate aldosterone secretion and amplify its effects on blood pressure, potentially accelerating the development of hypertension. Other environmental factors, such as stress and exposure to chronic low-level toxins (e.g., smoking or pollutants), may also modulate the expression of the CACNA1H gene or the activity of the Cav3.2 channels, potentially influencing the severity of aldosterone production and the clinical manifestation of FH IV [27].
Primary aldosteronism with seizures and neurological abnormalities (PASNA)
PASNA is a disorder with unknown prevalence associated with the presence of primary hyperaldosteronism and neurological symptoms [12, 13]. This syndrome is caused by a mutation in the L-type calcium channel CaV1.3 (CACNA1D gene) [33], which leads to the activation of calcium signaling and, in this way, increases aldosterone production [12, 13]. The mutation is also responsible for causing adrenal aldosterone-producing adenomas and micronodules [33]. PASNA manifests as early-onset severe hypertension, hypokalemia, seizures and cerebral palsy, cardiac defects, and congenital hyperinsulinemic hypoglycemia [2, 12].
Treatment with a calcium channel blocker (amlodipine) allows obtaining successful control of blood pressure [12]. In the mice model, a good response for isradipine was observed — considering intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance. This study may carry implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome [33].
Primary glucocorticoid resistance (PGR)
Primary glucocorticoid resistance (PGR), also known as Chrousos syndrome, is a rare condition caused by a mutation of the NR3C1 gene [2, 34]. In PGR, there is an impairment in glucocorticoid negative feedback loops, leading to hyperactivation of the hypothalamus–pituitary–adrenal (HPA) axis. Due to increased plasma adrenocorticotropic hormone level (ACTH) adrenal hyperplasia and elevated levels of adrenal androgens, steroid precursors with mineralocorticoid activity are observed [34].
More than 30 different types of NR3C1 mutations have been identified so far. Therefore, there is a wide variation in symptoms among patients [35]. Patients with PGR can be asymptomatic with alterations in laboratory results or can present adrenal hyperplasia (81%), hirsutism (77%), hypertension (48%), hypokalemia, metabolic alkalosis, rarer acne, menstrual irregularities and oligospermia [2, 34]. Furthermore, in some patients, due to increased levels of corticotropin-releasing hormone (CRH), anxiety and depression can be present [34]. Importantly, in primary glucocorticoid resistance, there is hypercortisolemia without symptoms of Cushing’s syndrome [35].
Suppression of morning ACTH can be achieved by administering low doses of dexamethasone at midnight, which leads to a reduction of mineralocorticoids and androgen levels [36]. Treatment of PGR is based on titration of a dose of dexamethasone depending on clinical symptoms [36].
Liddle syndrome (LS)
Liddle syndrome (LS) is a rare hereditary disorder associated with the development of early-onset salt-sensitive hypertension due to the presence of mutation-type gain-of-function in the SCNN1A, SCNN1B, and SCNN1G genes encoding epithelial sodium channel (ENaC) subunits- respectively a, b and g [4, 16, 19]. This condition is present worldwide without gender and race preferences and usually starts between 10 and 30 years old [19]. Its prevalence is still underestimated. However, some authors indicate it as probably the most common form of MH [4, 17, 37]. Among young hypertensive in China, its occurrence ranged from 0.91 to 1.52% [4, 37], and in the global population, it is estimated to be less than 1/106 [19].
The most characteristic features of LH are hypokalemia up to 2.4–3.5 mmol/L, metabolic alkalosis, suppressed plasma renin activity, low plasma aldosterone, mild to severe hypertension with early-developed complications, and positive family history of sudden death [2, 17, 19, 37]. Due to the presence of many mutations leading to the development of LS — about thirty-one have been identified so far; there is a wide variation in symptoms between patients. Sometimes, patients with LS are normotensive or have normal potassium levels; therefore, they are diagnosed in adulthood [2, 37].
The development of hypertension during LS is associated with activating mutations of the gene encoding ENaC in the distal tubule, which leads to excessive sodium and water reabsorption. This mechanism is consistent with Guyton’s theory [2]. No effective LS gene therapy has been developed so far [19].
Treatment of LS is based on a salt-restricted diet and therapy with ENaC blockers (amiloride and triamterene) [2, 19]. Most often, inhibition of sodium reabsorption leads to normokalemia; however, despite that fact, some patients require potassium supplementation [7].
Suspicion of LS is based on clinical manifestation and detailed family interviews [19]. Consideration of this diagnosis should be taken into account in the case of patients with hyporenin and hypoaldosteronism [19]. The clinical diagnosis of LS can be made after normalization of blood pressure and potassium levels after the 4-week treatment of triamterene (100 mg/d) or amiloride (10 mg/d) [20]. However, the gold standard for diagnosis of LS is genetic testing [19]. It is also useful in identifying relatives carrying the same mutation and can lead to proper therapy. The review of Lu et al. demonstrated that 12% of patients within the study group of 108 have a family history of stroke and are often associated with complications such as left ventricular hypertrophy or stroke [38]. Significant improvements in blood pressure and serum potassium concentration were observed in all patients in that study (one patient died of an unknown cause) after starting ENaC inhibitor therapy. Thanks to that, there was no reported case of cardiovascular disease-associated events [38]. Early diagnosis and proper treatment can prevent complications and improve a patient’s life quality; however, generally, this disorder does not have the possibility of self-healing [19].
Pseudohypoaldosteronism type 2 (Gordon syndrome)
Gordon syndrome, also known as pseudohypoaldosteronism type 2 (PHA II), is a condition caused by a mutation in four genes, WNK1, WNK4, CUL3, and KLHL3, responsible for regulating sodium and potassium balance in the kidney [2]. The WNK1 and WNK4 genes encode kinases that regulate the sodium-chloride cotransporter (NCC) in the distal convoluted tubule, while CUL3 and KLHL3 are involved in the ubiquitination and degradation of WNK kinases [2].
Genetic testing is crucial in diagnosing PHA II, particularly in confirming the diagnosis in atypical clinical cases. However, there are significant challenges and limitations associated with genetic testing for this condition. Due to genetic heterogeneity, genetic tests must cover multiple genes to identify the causative mutation, increasing the testing cost. Additionally, not all mutations in these genes are well characterized, leading to potential challenges in interpreting the clinical significance of variants of unknown significance (VUS) that may be identified during testing [2].
Patients with PHA II can present with a wide range of clinical features, some of which may be atypical or overlap with other conditions. Due to increased sodium reabsorption, early-onset hypertension usually is present. Which usually appears in the second decade of life [5]. The most severe cases of Gordon syndrome are characterized by short stature and intellectual disability [2]. Moreover, in this condition, early-onset hyperkalemia up to 9 mmol/L without renal dysfunction, metabolic acidosis, sometimes hypercalciuria, and hypocalcemia can be present [2, 6, 16, 20]. Most often, aldosterone and renin levels are low; however, aldosterone can be normal or even elevated in some patients because hyperkalemia can stimulate its release [16, 20]. A Spanish family of 6 people diagnosed with mild adulthood hypertension and a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly) were described [39].
Unfortunately, some patients may present with normokalemia or mild hypertension, making the diagnosis less straightforward [40]. In such cases, the clinical suspicion of PHA II may be low, leading to delays in ordering genetic testing or misinterpretation of genetic test results if the clinical picture does not align with the typical phenotype [41]. Atypical presentations can also complicate the identification of pathogenic mutations. For example, mutations in the WNK1 gene can lead to varying degrees of disease severity, and some patients may harbor mutations that do not fully explain the clinical symptoms. In such cases, the absence of a clear genotype-phenotype correlation can be a significant limitation in using genetic testing as a definitive diagnostic tool [41]. Another challenge in genetic testing for PHA II is the incomplete penetrance and variable expressivity of the condition. Not all individuals with a pathogenic mutation will develop the full clinical syndrome, and those who do may exhibit different severities of symptoms [42]. This variability can make it difficult to predict the clinical course of the disease based on genetic testing alone, particularly in family members who may carry the same mutation but show no or only mild symptoms [43]. The presence of incomplete penetrance also raises ethical concerns regarding genetic counseling and testing in asymptomatic individuals, especially in the context of familial screening. There may be uncertainties about whether a positive genetic test result will necessarily lead to disease, complicating the decision-making process for patients and clinicians [40]. While next-generation sequencing (NGS) has greatly improved the ability to detect genetic mutations associated with PHA II, there are still limitations. For instance, NGS may not reliably detect large deletions, duplications, or complex rearrangements in the WNK1, WNK4, CUL3, and KLHL3 genes, potentially leading to false-negative results [44].
Furthermore, interpreting genetic variants, particularly rare or novel mutations, remains challenging due to limited data on the pathogenicity of many variants identified in these genes [45]. In addition, genetic testing technologies may not capture epigenetic changes regulatory mutations outside of the coding regions of the relevant genes, which could contribute to the PHA II phenotype in some cases. This limitation highlights the need for ongoing research and development in genetic testing methodologies to improve the detection and interpretation of pathogenic variants.
In general, the presence of CUL3 mutation with the autosomal recessive type of inheritance is associated with the highest severity and infant onset of symptoms, whereas in the case of WNK1 (autosomal dominant) mutation, patients usually present mild symptoms [2].
Treatment of Gordon syndrome is based on pharmacological therapy [19]. As a first-line treatment, thiazides are recommended due to their inhibitory impact on NCC [2, 5]. Implementation of proper medication redirects electrolyte balance and normalizes BP levels [2, 5, 20]. In patients with mild phenotypes, a low-salt diet alone may be an effective treatment [2].
Apparent mineralocorticoid excess (AME)
Apparent mineralocorticoid excess is a rare inherited disorder caused by autosomal recessive mutation of the gene encoding 11b-hydroxysteroid dehydrogenase type 2 (11bHSD2)- an enzyme physiologically responsible for the conversion of cortisol to cortisone [19, 46].
The development of symptoms in AME is strictly associated with a deficiency of 11bHSD2, which leads to excessive cortisol levels and induces activating of mineralocorticoid receptor (MR) activation [46]. The symptoms are heterogeneous, and their intensity depends strictly on the type of mutation. In AME type I patients develop severe hypertension in early childhood with essential hypokalemia, whereas AME type II begins in adulthood and is usually associated with isolated milder hypertension [2]. Most often, the first manifestation of this condition is hypoaldosteronism [19]. In AME I, due to the inactivation of 11bHSD2, patients develop salt-sensitive hypertension often accompanied by growth failure, delayed bone age and puberty, polyuria, polydipsia, left ventricle hypertrophy, and renal calcinosis [2, 19]. Moreover, in severe cases, AME I death due to arrhythmia or intracranial hemorrhage can take place [19].
In AME II, 11bHSD2 activity is low, and its clinical presentation is sometimes similar to PA with predominant elevated BP and low renin [19]. In 50–75% of patients with AME, nephrocalcinosis due to hypercalciuria is observed, and rarer patients develop kidney cysts due to chronic hypokalemia [2]. The urinary 24-hour free cortisol-to-cortisone ratio is the sensitive test in diagnosing AME [19]. A normal ratio is 1:1, whereas, in the case of AME, its value ranges from 6.7 to 33 [2, 7]. Moreover, in diagnostics of AME urinary level of metabolites, such as tetrahydrocortisol (THF), 5-alfa tetrahydrocortisol (5aTHF), and tetrahydrocortisone (THE), is used [THF5aTHF]/THE > 1.0) [2]. A certain diagnosis can be made based on genetic tests, especially in patients with a mild phenotype [20]. Treatment of AME comprises a low-salt diet and the implementation of spironolactone as a first line [7]. In case of ineffectiveness of therapy ENaC blockers, dexamethasone (reduce urinary and plasma cortisol due to suppression of ACTH and due to that normalizes blood pressure), nifedipine can be used [2, 4, 19]. Patients with hypercalciuria or nephrocalcinosis should be introduced to thiazide diuretics [4].
Congenital adrenal hyperplasia (CAH)
Congenital adrenal hyperplasia type IV and V are a group of syndromes associated with the development of early-onset hypertension and hypokalemia [19]. In these disorders, the presence of hypertension is a result of the overproduction of intermediate products with affinity to MR activation [15].
CAH type IV is caused by 11b -hydroxylase deficiency (11b-OHD), accounting for 0.2–8% of all CAH cases [2]. It is associated with hyperandrogenemia, which leads to rapid somatic growth, skeletal maturation, virilization in girls, and premature puberty in boys [2, 20]. Moreover, two-thirds of patients with CAH type IV develop hypertension in the first decade of life; however, the onset of AH in the newborn period has been described [5].
In CAH type IV, an elevated serum 11-deoxycortisol, 11-deoxycorticosterone, and adrenal androgens are observed [46]. Moreover, low renin plasma activity and low aldosterone, high ACTH, hypernatremia, and hypokalemia are usually present [5, 19]. However, the gold diagnostics standard is genetic testing [19].
The first-line treatment of CAH type IV is based on hydrocortisone (10–15 mg/m2/day), which reduces the production of hypertension-inducing metabolites and normalizes androgen secretion and cortisol insufficiency. If blood pressure is not controlled with this treatment, the implementation of spironolactone is the most recommended [2, 5, 7].
The CAH type V is associated with 17a-hydroxylase deficiency (17a-OHD), which leads to impairment of cortisol and sex hormone production [5]. It can be characterized by hypokalemia, hypertension, delayed puberty, and primary amenorrhea in girls and the presence of ambiguous genitalia or impaired masculinization in boys. AH appears due to an excessive level of mineralocorticoids, corticosterone, and deoxycorticosterone, most often in late childhood to adolescence [2, 7]. Most patients are diagnosed during adolescence; however, 4% of CAH type V cases start in infancy [2]. In treating AH, medications similar to those used in type IV are used [20].
Another form of CAH is P450 oxidoreductase deficiency (PORD), caused by biallelic mutations in the POR gene, which is essential for the proper functioning of more than 50 enzymes in the cytochrome P450 family, such as 17a-hydroxylase, 21-hydroxylase and P450 aromatase [47]. Thus, POR mutations lead to a malfunction of different enzymes, leading to complex disorders of steroid hormone production [47]. The phenotype depends on the exact enzyme of which function is affected by the POR mutation and the level of this disturbance [47]. Most often, the patients do not have mineralocorticoid deficiency, and because of that, abnormal CYP17A1 activity may cause hypertension in adult age (47). In patients of European origin, A287P is the most common POR mutation that impairs 17a-hydroxylase activity and can lead to hypertension. Genetic testing is usually required to confirm the diagnosis [47].
Activating mineralocorticoid receptor mutation (Geller syndrome)
Geller syndrome is a rare autosomal dominant disorder. Since its description by Geller et al. in 2000, less than 10 cases of Geller syndrome have been reported [48], developing due to MR-activated mutation leading to increased affinity of steroid hormones such as progesterone for MR [19]. The mutation is localized on chromosome 4q31, caused by substituting leucine for serine at amino acid 810 [48]. As a result, elevated renal sodium reabsorption and potassium secretion are present. This condition can be characterized by early-onset severe hypertension, mild hypokalemia, reduced plasma renin activity, and low aldosterone level [2, 7].
A characteristic feature of Geller syndrome is the exacerbation of arterial hypertension (AH) during pregnancy because of the progesterone effect, and it usually resolves post-partum [48]; however, the occurrence of this condition is not limited to women [19]. Pregnancy in the course of Geller syndrome is at high risk, and, therefore, it should be closely monitored [4, 7, 17]. Hindosh et al. presented the case of a 22-year-old female diagnosed with preeclampsia who presented with hypokalemia, resistant to treatment till the end of the third trimester. There was no history of hypertension or hypokalemia before her pregnancy. Preeclampsia worsened during hospitalization. Induction of labor was indispensable and eventually ended with cesarean section. After delivery, blood pressure normalized, and hypokalemia withdrew, even though potassium supplements had been discontinued [48].
The diagnosis is based on clinical manifestation, results of biochemical tests, and definitively on genetic testing [4]. In treatment, thiazide diuretics, ENaC antagonists, and a low-sodium diet should be implemented [2, 7, 17]. Aldosterone antagonists should be strictly avoided because they exacerbate the symptoms [2, 4].
Hypertension and brachydactyly syndrome (Bilginturan syndrome)
A Bilginturan syndrome is caused by a gain of function mutation in the cGMP-inhibited cAMP phosphodiesterase 3A gene (PDE3A), which leads to the acceleration of smooth vascular muscle proliferation and causes AH [5]. The presence of hypertension in this condition is also associated with disturbing baroreceptor reflexes or neurogenic mechanisms [49]. It should be underlined that it is a sodium-independent monogenic form of hypertension. Hypertension often starts in childhood and is strongly age-dependent [5, 11, 50]. It is usually severe and, in untreated patients, is complicated by a stroke and death before 50 years of age [50]. However, patients may present with varying severity of symptoms, such as mild hypertension occurring later, which makes diagnosis harder [50]. Besides hypertension in Bilginturan syndrome, shortening of phalanges, metacarpals (brachydactyly type E), and stature are present [5, 49]. Moreover, in this condition, abnormal cerebellar vessels can be observed [49]. In the treatment of AH in Bilginturan syndrome, beta-blockers with good response, converting enzyme inhibitors, angiotensin receptor blockers, vasodilators like calcium-channel blockers, and dihydralazine can be used; however, there are no established guidelines [49].
Diagnostic algorithm for monogenic hypertension
The authors have prepared an algorithm (Fig. 1) to help in the proper diagnosis of various forms of MH.
Conclusion
Proper diagnosis of MH is essential because therapeutic differences allow blood pressure control to be obtained. Moreover, due to the early onset of AH in the course of MH, complications such as myocardial infarction, stroke, kidney failure, and hypertensive retinopathy appear earlier and more often than in other patients. Therefore, patients from high-risk groups should be efficiently identified, and they should have promptly implemented personalized treatment. Most often, treatment of hypertension in these syndromes is based on diuretics because the development of AH is associated with increased sodium reabsorption. It should be remembered to avoid aldosterone antagonists in the treatment of hypertension in the course of Geller syndrome. Moreover, patients with this condition require increased supervision of BP during pregnancy.
Author contributions
Contribution to the study concept and design, drafting of the manuscript, critical revision of the manuscript: A.O.C., D.S. and J.B.; literature review: A.O.C., D.S. and J.B.; and supervision: A.O.C. All authors have read and agreed with the published version of the manuscript.
Acknowledgments
There is nothing to declare.
Funding
There is nothing to declare.
Conflict of interest
The authors have no conflict of interest related to this publication.