Introduction

Hypertension among children and adolescents is still underdiagnosed or missed in the clinical setting [1•]. This is especially true of high-risk children under 3 years of age and includes those children who have a genetic syndrome with a known increased risk for systemic hypertension. The reported prevalence of hypertension in childhood is 2–4% but is significantly higher in the 3 genetic syndromes that are discussed in this manuscript. There is a robust body of evidence that now clearly shows that elevated blood pressure in children and adolescence manifests with end-organ changes and that untreated hypertension in adolescents and young adults increases risk for early onset of cardiovascular disease in adulthood [2, 3•]. Children with elevated BP trajectories, even as early as 7 years of age, are more likely to have hypertension as adults when compared with children who have normal BP during childhood [4, 5].

Turner syndrome (TS), neurofibromatosis type 1 (NF1), and William Syndrome (WS) are 3 genetic conditions that are all associated with an increased risk of hypertension. The hypertension in most instances is secondary and occurs for a variety of reasons. In this review, we focus on the manifestations and causes of hypertension in children and adolescents with these three genetic conditions, namely Turner syndrome (TS), neurofibromatosis type 1 (NF1), and Williams Syndrome (WS) (Table 1).

Table 1 Secondary causes of hypertension in TS, NF1, and WS
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Discussion

Turner Syndrome

Turners syndrome (TS) occurs in about 50 in 100,000 (1/2000) newborn girls and arises from a complete or partial loss of the second X chromosome (45XO). TS is the only known monosomy that is compatible with life [6] and is associated with short stature, primary ovarian failure, congenital cardiac defects, and a 3-fold increase in age-related mortality [7]. TS may be complicated by a number of cardiovascular risk factors including diabetes, hypertension, and, particularly, problematic, aortic root dilatation and dissection [8, 9]. The frequency of HTN among girls with TS is as high as 20–40% [10] in childhood and increases to 60% in young women [11]. The causes and contributing factors to hypertension in TS are multifactorial.

Causes of Hypertension in TS

One study noted that at least 33% of girls with TS have congenital anomalies of the kidneys and urinary tract (CAKUT) and that 50% develop complications related to CAKUT including urinary tract infections, proteinuria, and hypertension [12]. However, renal function in TS is usually normal [13••].

Renal Parenchymal

Renal scarring is secondary to renal parenchymal infection (pyelonephritis), which may manifest with proteinuria and with renin-driven hypertension [14].

Anatomical

The most commonly noted anatomical renal findings in TS are horseshoe kidneys (20%), crossed-fused ectopia, pelvic ectopia, renal cystic dysplasia, hydronephrosis, and renal agenesis. Reflux, duplicated collecting systems and ureteric stricture also occur [13••, 15]. The genetic factors that increase risk of CAKUT in TS girls are as of yet unknown and are not associated with either Collectrin or HNF-1β gene mutations [16].

Renal Vascular

Multiple renal arteries may vascularize each kidney in Turner syndrome, particularly when the renal arteries are associated with renal ectopia. The renal arteries may uncommonly be stenosed, resulting in renin-mediated renovascular hypertension.

Coarctation of the Aorta

Coarctation of the aorta occurs in about 6 to 11% of TS girls. Of girls diagnosed with coarctation of the aorta at least 12.6% have karyotype-confirmed TS. Such a high frequency, combined with the known clinical benefits of an early diagnosis of TS, supports genetic screening for TS syndrome in female infants and children presenting with coarctation of the aorta [17, 18]. Even after coarctation repair hypertension may persist, often as “masked” hypertension, in up to 40% of children [19, 20]. Of note, mid-aortic syndrome does not seem to be specifically associated with TS.

Factors That May Contribute to Development of Hypertension in TS

Aortic Wall Distensability

Intrinsic abnormalities in the structure of the aorta may contribute to elevation of the BP in TS patients [9, 21, 22]. Aortic wall function in the descending aorta is impaired in TS with lower distensibility among those with coarctation of the aorta, and all TS patients have a higher Aix, and elevated central diastolic blood pressure when compared with sex- and age-matched controls [21, 23].

Sympathovagal Tone

TS women have significantly higher diastolic BP in the supine position compared to controls, and the adaptive rise in BP, when changing from a sitting to a standing position is reduced [24].

Obesity

Increased obesity risk in TS further highlights the importance of understanding the cardiometabolic risk (CMR) in TS. BMI, however, may not accurately depict body fatness and cardiometabolic risk in the setting of short stature and altered body proportions. Greater subcutaneous fat has been observed in TS compared to BMI-matched controls; given that visceral rather than somatic adiposity is related to CMR, the difference suggests BMI may not accurately capture CMR in TS. In fact, in one study in contrast to controls, no correlations were found between BMI and insulin sensitivity or lipids in TS [12]. These results highlight the importance of evaluating BMI as a screening tool to identify excess adiposity and cardiometabolic risk in TS.

Estrogen

Girls and women with TS have decreased estradiol levels. The average estradiol level among girls with TS (6.4 +/− 4.9 pmol/l estradiol equivalents) is much lower than in the normal prepubertal girls (12.7 +/− 10.8 pmol/l estradiol equivalents). Of note, carotid intimal medial thickness (CIMT) has a linear association with systolic BP that is inversely proportional to estragon levels [25, 26]. Estragon replacement use may help not only with cardiometabolic risk reduction but also with BP control in TS [27]. However, although a study utilizing 24-h ABPM was able to show a reduction in heart rate with the use of estriodiol therapy, the study was unable to show an effect on systolic and diastolic BP, which increased significantly in late adolescence into early adulthood [28].

Management of HTN in TS

Hypertension, which is still underdiagnosed, is of particular concern in TS given the increased risk of aortic root dissection and aneurysm [29]. A Swedish study in TS girls and young adults showed that the risk of aortic dissection was more than 12 times greater than in an age and sex matched control population [30]. The extent to which control of the BP helps reduce the risk of aortic dissection/aneurysm is not yet fully elucidated [31••]. Left ventricular hypertrophy (LVH) is a common cardiac occurrence in TS. Of note LVH is seen in TS with in-office BP in the normal range, making it crucial to consider masked hypertension or a loss of diurnal variation as identified by the absence of nocturnal dipping. In-office BP measurements may miss hypertension in as many as 4 out of every 5 girls with TS, underscoring the importance of ABPM monitoring in this group of patients [21, 32]. Indeed, ABPM has been identified as the best tool to identify masked hypertension and to predict hypertension induced left ventricular hypertrophy in TS [29].

Non-pharmacological medical management of hypertension should be aimed at weight control and regulation of sodium intake. Pharmacological management is similar to those children and young women without TS [10]. In the absence of identification of a secondary cause for the hypertension, one should consider using long-acting angiotensin receptor blockers (ATIIR inhibitors) and possibly β-blockers. The rationale for this choice of antihypertensive agents is inferred in that they are effective in slowing the rate of aortic dilatation in other genetic aortopathies such as Marfan and Ehlers-Danlos Syndromes [33, 34].

Neurofibromatosis 1

NF1 occurs in about 1/2500 to 1/3000 live births and about half of affected persons have a novel mutation. NF1 has an AD inheritance and the gene is situated on chromosome 17q11.2. Mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway. The major known function of the NF1 gene product neurofibromin is to downregulate RAS, thus acting as a tumor suppressor, explaining the occurrence of tissue overgrowth and tumor formation in NF1. Vasculopathies are the least emphasized but most important manifestation of NF1, both as a cause of morbidity and mortality in children and young adults. Neurofibromin is expressed in the vascular endothelium and in vascular smooth muscle. The loss of neurofibromin in these tissues is thought to underlie the NF1 vasculopathy [35]. Cardiovascular manifestations of NF1 that may result in systemic hypertension include renal artery stenosis, mid-aortic syndrome, and neuroendocrine tumors, namely pheochromocytoma, paraganglioma, and neuroblastoma [36]. Cerebrovascular disease is also part of the spectrum of the NF1 vasculopathy. Moya moya syndrome, cerebral aneurysm, internal carotid, and cerebral artery stenosis/occlusion have all been reported in NF1 and may occur in conjunction with the peripheral vasculopathy [37]. Of note, up to 20% of patients with NF1 may develop hypertension [38••].

Causes of Hypertension in NF1

Renal Parenchymal

Renal parenchymal changes in NF1 are unusual. Occasionally parenchymal changes present as areas of segmental hypoplasia (Ask-Upmark Kidney (AUK)) or more often are secondary to obstruction because of neurofibromas in the bladder with subsequent reflux and urogenital tract infection. AUK is characterized by a scarred segment of the kidney with primitive tubular and glomerular structures [39]. This condition is suspected when segmental hypoplasia is noted in the absence of recurrent urinary tract infections and vesicoureteral reflux or renal parenchymal ischemia. Plasma and renal vein renin levels may be increased, and contrast-enhanced angiography (CTA) and dimercaptosuccinic acid scintigraphy (DSMA) show areas of hypoperfusion and reduced kidney size.

Obstructive Uropathy

Neurofibromas while frequent in NF1 are an infrequent cause of bladder outlet obstruction that may lead to obstruction, hypertension, and infrequently chronic kidney damage [40, 41]. The hypertension may occur as described above or may be secondary to the obstruction itself with salt and water retention.

Renal Vascular

Renal artery stenosis (RAS) occurs in over 7% of children and adolescents with NF1 and may be bilateral [36]. The imaging appearance of RAS in NFI can mimic that of FMD; however, the stenosis is more often at the renal aortic take-off than in the middle sections of the renal arteries, whereas in FMD, RAS occurs more often in the mid and distal portions of the main renal artery [42]. RAS may also occur secondary to external compression from, for example, a plexiform neurofibroma.

Mid-aortic Syndrome

Mid-aortic syndrome (MAS) is characterized by narrowing of the abdominal aorta, often with involvement of the renal and splanchnic arterial branches. Although uncommon, accounting for 0.5 to 2% of all cases of aortic narrowing [43], MAS is an important cause of renovascular hypertension in children and adolescents with NF1. Hypertension is severe and extensive disease requires treatment with several anti-hypertensive medications and/or surgical repair (Fig. 1). A multidisciplinary approach with long-term monitoring is important for conservation of end-organ function and quality of life [44••].

Fig. 1
figure 1

This 3D reconstruction of a CTA abdomen from a 6-year-old female with NFI shows middle-abdominal aortic stenosis, celiac axis stenosis, superior mesenteric artery stenosis, and bilateral renal artery stenosis (white arrows). An arc of Riolan arising from the inferior mesenteric artery is shown (yellow arrow), indicating collateral revascularization to the foregut

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Pheochromocytoma/Paraganglioma

Pheochromocytoma/paraganglioma is detected in about 0.7% of persons with NF1. Routine screening for pheochromocytoma in NFI is not recommended as it is not cost-effective. Work-up for pheochromocytoma should be done in those with unexplained paroxysmal palpitations, headache, dizziness, and sweating [45]. Work-up should include a 24-h urine collection for catecholamine and serum metanephrine measurements with MIBG imaging as indicated.

Factors That May Contribute to Development of Hypertension in NF1

The pathophysiology behind the vasculopathy in NF1 can be broadly categorized into large vessel and small vessel involvement [46]. The histopathologic picture as outlined below is variable.

Large Vessels

Neurofibromatosis or ganglioneuromatous tissue around large vessels such as the aorta, carotid, and proximal renal arteries can cause intimal proliferation, thinning of media, and fragmentation of elastic tissue leading to stenosis and aneurysms. Medium-sized elastic and muscular arteries show predominance of intimal vascular smooth muscle cell proliferation with variable degrees of fibrosis and neo-angiogenesis [47]. In the renal arteries, the pathology is indistinguishable from that of FMD. Carotid artery intima-media thickness (cIMT) is increased in NF1 compared with normal controls [48••].

Small Vessels

Small vessels show mainly intimal proliferation [48••]. Endothelial function is significantly damped in NF1 subjects with reduced small vessel dilatation after ischemia and exercise when compared with controls [48••].

Management of HTN in NF1

The management of HTN in NF1 depends on the underlying cause. RAS may be treated conservatively with anti-hypertensive medications; ACEi and ARBs can be used after the stenosis has been shown to be unilateral [49]. Endovascular management is the preferred approach for management of most NF1-associated RAS. The lesions are amenable to renal angioplasty and respond well to cutting balloon therapy [50, 51]. Hypertension usually persists after renal angioplasty; however, the increased blood pressure is easier to control [52, 53]. Surgery is required for refractory and long-segment stenosis [54•].

Williams-Beuren Syndrome

Williams-Beuren Syndrome (WBS) is characterized by a variable microdeletion of chromosome 7q11.23 that usually occurs de novo. The WBS critical microdeletion region is associated with loss of 26–28 genes, but even in atypical patients with smaller deletions, the deletion always includes the gene that encodes for elastin (ELN). The resulting hemizygosity of ELN is responsible for the vascular abnormalities. Cardiovascular abnormalities occur in over 80% of WBS patients; most have a generalized arteriopathy [55]. Supravalvular aortic stenosis (SVAS) occurs in about two-thirds of patients. Systemic arterial abnormalities include focal or diffuse narrowing that may involve the thoracic or abdominal aorta, coronary, renal, and other visceral arteries [56]. In-office diagnosis of systemic hypertension is made in about 30% of WBS children and adolescents and is most often asymptomatic [57]. As discussed below though, the actual prevalence of systemic hypertension is at least 50%. Cardiovascular complications are the major cause of death in patients with WBS. Other major clinical features of WBS include distinctive facial features that changes with age, decreased linear growth, usually thin as children and overweight as adults, hypercalcemia, abnormal glucose metabolism, subclinical hypothyroidism, dental anomalies (small, abnormally shaped teeth, absent teeth, malocclusion), gastrointestinal dysmotility (reflux, constipation), diverticular disease, musculoskeletal anomalies (joint stiffness, scoliosis), sensorineural hearing loss, genitourinary anomalies (urinary frequency, bladder diverticuli), neurological problems (abnormal tone, hyperreflexia, and cerebellar findings), mild to moderate cognitive delay, average full-scale IQ is 55–60, range from 40 to 90, with relative strengths in selected language domains and a prominent weakness in the visuospatial domain, characteristic personality, and anxiety-driven emotional traits.

Causes of Hypertension in WS

Most WBS persons have hypertension related to the diffuse underlying vasculopathy that is influenced by additional syndrome-related factors [58]. Only a minority have renal artery stenosis, diffuse narrowing of the aorta, aortic coarctation, or a combination of abnormalities as causative factors for hypertension. Renal artery stenosis is usually found at the take-off from the aorta and may be unilateral or bilateral [59]. Three studies using 24-h ambulatory monitoring found hypertension in 40–70% of patients, most without overt aortic or renovascular narrowing [60,61,62]. Of interest, the risk of hypertension is decreased in WBS patients whose deletion includes the NCF1 gene [63].

Factors That May Contribute to Development of Hypertension in WBS

Elastin

Human and mouse studies have established that defects in the elastin gene, leading to elastin haploinsufficiency, underlies the arteriopathy seen in WBS. Abnormal elastin production results in vascular stiffness [64] with occlusive vascular abnormalities including supra-valvular aortic stenosis and stenosis of other large muscular arteries including the renal arteries [65]. Vascular wall elastin helps direct smooth muscle phenotype and function [66]. Prior studies have reported that elastin haploinsufficiency results in subendothelial migration and vascular smooth muscle cell hyperplasia causing intrusion on the vascular lumen and arterial stenoses. However, more recent work suggests that the stenoses seen in WBS arise from deficient circumferential arterial growth and is the primary determinant of aortic luminal narrowing in the setting of elastin haploinsufficiency [67].

Hypercalcemia

Hypercalcemia occurs in approximately 15% of children with the WBS [68]. It may occur at any age and monitoring of calcium homeostasis is recommended [69]. A single study found a higher incidence of hypertension in WBS diagnosed with infantile hypercalcemia.

However, no direct links between hypertension and hypercalcemia in WBS have been firmly established [60]. Hypercalcemia may be accompanied by hypercalciuria, although isolated hypercalciuria can occur predisposing to development of nephrocalcinosis and kidney injury [59, 70]. The hypercalcemia is responsive to treatment with glucocorticoids and bisphosphonates [68].

Anxiety

WBS patients conceal their anticipatory anxiety, phobias, and perseverative tendencies with a generally social and friendly demeanor. In-office blood pressure is often initially elevated and should be repeated using manual means at the end of the visit.

Impaired Glucose Metabolism

Adolescents and adults with WBS have increased fat mass, decreased lean mass, impaired glucose homeostasis, and reduced bone-mineral-density [71].

Hypothyroidism

Subclinical hypothyroidism occurs in 15 to 30% of WBS patients who may have mild thyroid hypoplasia on ultrasonography [72, 73]. Overt hypothyroidism is infrequent and anti-thyroid antibodies are not reported in WBS.

Management of HTN in WS

Medical control of hypertension in WBS is very important. Dietary management for weight control and limitation of sodium intake should be instituted as indicated. A secondary cause for the hypertension should be evaluated using tomographic imaging (computed tomography or MRI) to assess the aorta and renal arteries, as Doppler ultrasound provides suboptimal assessment [74•]. Digital subtraction angiography, however, remains as the gold standard for vascular assessment, particularly of the renal vessels. Medical management may require use of more than one antihypertensive agent. ACEi or ARBs can be used after bilateral RAS in ruled out. Importantly, in a study done in a heterozygous (ELNþ/_) murine model, the renal interlobar artery basal tone and myogenic response were increased, renal blood flow was lower, and there was damage to the glomerular filtration barrier at the level of the podocyte foot processes, a finding that was independent of BP. The increased vascular tone and exaggerated myogenic response was normalized after administration of candesartan, a long-acting AT1 blocker (ARB). These findings suggest that ARBs could be an attractive antihypertensive therapy for patients with WBS [75]. Calcium channel blockers (Dihydropyridine) can be used as first-line of therapy, and β-blockers can also be used and may give additional benefit with respect to prevention of arrhythmia and sudden death [76].

In order to [64], in a randomized controlled trial conducted over a 12–18-month period, minoxidil was shown to improve elastogenesis as evidenced by an increase in functional intima media thickness in children with WBS [77•]. Additional pharmacological treatments such as mammalian target of rapamycin inhibitors are being explored for treatment of the vasculopathy [78, 79••].

Conclusion

Hypertension is frequently found in children and adolescents with TS, NF1, and WS.

These children form part of the subset of genetic causes of hypertension where blood pressure should be measured at routine office visits including in those children under 3 years of age. Hypertension is most often secondary and the underlying cause should be sought and managed as clinically indicated. It is of vital importance that concomitant with diagnosis of these conditions, careful attention is paid to the cardiovascular system with vigilant screening and monitoring of the blood pressure for hypertension. Accurate early diagnosis and management of hypertension will prevent target organ damage and ensure a healthier transition to adulthood for persons afflicted with these conditions.