Diagnosis and management of systemic hypertension due to renovascular and aortic stenosis in patients with Williams-Beuren syndrome

Rev Assoc Med Bras ramb Revista da Associação Médica Brasileira Rev. Assoc. Med. Bras. 0104-4230 1806-9282 Associação Médica Brasileira RESUMO OBJETIVO Descrever a incidência, o diagnóstico e o tratamento da hipertensão arterial sistêmica relacionada com estenose da artéria renal em pacientes com síndrome de Williams-Beuren. MÉTODOS Sessenta e cinco pacientes com síndrome de Williams-Beuren foram avaliados quanto à presença de hipertensão. Os pacientes foram submetidos à ultrassonografia com Doppler das artérias renais e ecocardiograma Doppler. Aqueles com suspeita de hipertensão renovascular foram submetidos à tomografia computadorizada ou angiografia por ressonância magnética da aorta e vasos renais ou angiografia convencional. RESULTADOS A hipertensão arterial sistêmica foi diagnosticada em 21/65 pacientes com síndrome de Williams-Beuren (32%, 13 do sexo masculino), com idade média de 13,9 anos (5 meses-20 anos). Em 8/21 pacientes foi detectada a hipertensão renovascular. Angioplastia não teve sucesso em cinco pacientes com estenose da artéria renal, necessitando de tratamento adicional. O ecocardiograma Doppler mostrou anormalidades cardíacas em 16/21 (76%) pacientes hipertensos. CONCLUSÃO As anormalidades cardíacas e hipertensão arterial em pacientes com síndrome de Williams-Beuren são muito frequentes, sendo necessários uma avaliação minuciosa e seguimento para diminuir o risco cardiovascular e a morbimortalidade desses pacientes INTRODUCTION Williams-Beuren syndrome (WBS) is a genetic disorder characterized by facial dysmorphisms, congenital heart defects, growth retardation, infantile hypercalcemia, renal and vascular abnormalities, and intellectual disability1. Clinical diagnosis is usually performed during childhood when the typical facial changes and cognitive profile become more apparent1 (Figure 1). Genetic confirmation can be carried out using FISH2 (fluorescence in situ hybridization) or MLPA3 (multiplex ligation-dependent probe amplification), or microarray tests for identification of the causal microdeletion at 7q11.23. Urinary tract system abnormalities in WBS have been described in approximately 18% of patients4,5,6 and include renal ectopia, hydronephrosis, renal agenesis or hypoplasia, vesicoureteral reflux, and voiding dysfunction. Nephrocalcinosis, proteinuria, and chronic renal failure have also been reported in some cases series4,5,6 FIGURE 1 : Female patient, at age 9y4m, with facial characteristics of WBS: periorbital fullness, short nose, malar hypoplasia, long philtrum, and thick lips. Cardiovascular abnormalities are also quite common in patients with WBS and have been observed in more than 80% of cases7,8. Supravalvular aortic stenosis (SVAS) is the most frequent abnormality, with an estimated incidence of 64%(9,10). Systemic arterial abnormalities include localized or diffuse narrowing of the thoracic or abdominal aorta, coronary, renal and other visceral arteries11,12. According to Lacolley et al.13 vascular injury in patients with WBS may be associated with reduced elastin synthesis and increased proliferation of vascular smooth muscle cells. Arterial hypertension arterial (SAH) is also observed with high prevalence in WBS14. In a minority of patients, renal artery stenosis, diffuse narrowing of the aorta, aortic coarctation or a combination of these abnormalities have been implicated4,5. Renal artery stenosis is usually found at the origin of the renal arteries7 (Figure 2). Nonetheless, there are few reports about the origin and management of SAH in WBS, and the diagnosis is often not made. FIGURE 2 : Digital subtraction angiography demonstrates discreet stenosis of the abdominal aorta anda severe stenosis of the left and right renal arteries. Also note several collateral arteries from the aorta on the left side This study aimed to describe the incidence of hypertension among 65 patients with WBS, as well as the diagnosis and management of hypertension due to renovascular or aortic stenosis. METHODS Sixty-five patients who were being treated from 1993 to 2010 at the Pediatric Nephrology and Genetics Units at the Institute of Children, Hospital das Clínicas of the Faculty of Medicine of the University of São Paulo were included in this study. All patients were diagnosed with WBS based on clinical findings and had the presence of the 7q11.23 microdeletion confirmed by the FISH (2) or MLPA test (with a specific kit for WBS) (3). Patients with blood pressure (BP) values at or above the 95th percentile for age, gender, and height confirmed on 3 different occasions15 were included in the study and followed prospectively. Clinical and laboratory parameters such as the age of onset of hypertension, associated symptoms, baseline BP, fundus examination, microalbuminuria/creatinine16 and calcium/creatinine ratio17 in spot urine samples, estimated creatinine clearance18, and serum ionized calcium were evaluated. All enrolled patients were initially investigated by Doppler echocardiography(DE) and renal ultrasound (RU) with color-flow Doppler sonography of the renal arteries (DS). Those with findings of renal artery stenosis19 or hypertension stage II15 with a normal DS underwent computed tomographic angiography (CTA)(20) and/or gadolinium-enhanced magnetic resonance angiography (MRA) of the aorta and renal vessels21. Patients with unclear diagnosis by CTA and/or MRA or who required vascular therapeutic intervention (angioplasty) underwent conventional angiography (CA). RESULTS Of the 65 patients with WBS included in this study, 21 (32%; mean age of 13.9 years, range: 5 months to 20 years, 13 males) had hypertension and were submitted to further imaging studies. In this group, the mean age at WBS diagnosis was 5.2 years (ranging from 8 months to 12 years). All patients were asymptomatic, and hypertension was detected by active investigation during routine medical visits. The evaluation of the renal arteries by DS was normal in 12/21 patients. Of these, five patients did not undergo a CTA or MRA scan because of a low clinical suspicion of hypertension due to renovascular or aortic stenosis. In these five patients, BP was adequately controlled with one or two medications, and none had secondary involvement of target organs during follow-up. Of the 12 patients with normal DS results, seven had persistent severe hypertension and were therefore submitted to further testing. Two of them had findings consistent with SAH associated with vascular stenosis, as detected by CTA and conventional arteriography (one had abdominal aorta narrowing, and the other had right renal artery stenosis), indicating that DS resulted in false negative results for these patients. The remaining five patients had normal CTA results. Nine patients with DS suggesting renal artery stenosis were also submitted to CTA or MRA, and only six patients had vascular lesions confirmed by one of these methods. In three patients, the DS yielded false positive results. Of the 21 hypertensive patients, 16 underwent DS followed by complementary renal and aortic vascular investigation with CTA or MRA. The DS showed discordant results when compared with CTA or MRA in five of those patients (31%). Hypertension associated with renal or aortic lesions was confirmed in 8/21 patients (Table 1), corresponding to 12% of the cases of WBS and 38% of patients with arterial hypertension. Renal artery stenosis was detected in six patients (28.6%), aortic coarctation in one patient, and diffuse narrowing of the aorta in another one. One patient with renal artery stenosis also had aortic stenosis. TABLE 1 : RENAL AND AORTIC VASCULAR LESIONS IN 8/21 PATIENTS WITH WILLIAMS-BEUREN SYNDROME AND SYSTEMIC ARTERIAL HYPERTENSION. Patients Type of lesion Renal artery stenosis 6 unilateral 2 / bilateral 4* Aorta coarctation 1 thoracic Diffuse aorta narrowing 1 descendent and abdominal *One patient also had aortic stenosis. Percutaneous transluminal balloon angioplasty was performed in five patients with renal artery stenosis, and it was unilateral in two and bilateral in three patients. In one patient with bilateral stenosis, a stent was placed in the renal arteries. All four patients who underwent angioplasty had treatment failure, and two of them required surgical intervention for stenosis correction. An aortorenal graft was performed in one patient. For another patient who had stenosis of both renal arteries and of the aorta, an iliac renal graft, as well as a graft of the descending aorta to the infrarenal abdominal aorta, were inserted. Two patients who did not undergo surgical intervention continued with conservative treatment with antihypertensive medications (amlodipine, carvedilol, hydralazine, and diuretic). Two patients with lesions of the aorta underwent surgical correction. All patients underwent DE at the initial examination, and the alterations found are described in Table 2. SVAS was the most prevalent malformation (46%). Two patients underwent surgical correction of SVAS and had mitral valve regurgitation, eccentric left ventricular hypertrophy, and left ventricular systolic dysfunction. Three patients with mitral valve prolapse also had eccentric left ventricular hypertrophy and left ventricular systolic dysfunction. TABLE 2 : ECHOCARDIOGRAPHIC FEATURES IN THE 21 WBS PATIENTS WITH SYSTEMIC ARTERIAL HYPERTENSION. Echocardiographic features n (%) Supravalvular aortic stenosis 10 (47.6%) Mitral valve prolapse 6 (28.6%) Normal 5 (24%) Hypercalciuria was found in four patients, and hypercalcemia was diagnosed in one patient. Estimated creatinine clearance and albuminuria at the beginning of the study are shown in Table 3. One patient had hypertension after clinically presenting hemolytic uremic syndrome. Unilateral pyelocalyceal dilatation was observed in 2/21 patients submitted to renal sonography. TABLE 3 : LABORATORY FEATURES (MEAN; RANGE) IN 21 PATIENTS WITH WBS AND ARTERIAL HYPERTENSION. Laboratory features Mean; range n Serum ionized calcium Hypercalcemiaa 1.23 (1.1-1.4) mmol/L 1 Urinary calcium Hypercalciuriab 0.15 (0-0.94) mg/mg creatinine 4 eGFRc CKD class II 118.23 (68-183) ml/min/1.73m2 3 Albuminuria Microalbuminuria d 13.31 (3.55-36.79) mg/g creatinine 1 a serum ionized calcium >1.4mmol/L ; b calcium /creatinine ratio of random spot urine > 0.21 mg/mg 17; c glomerular filtration rate estimated by serum creatinine18 , d albumin/creatinine ratio of random urine >30 mg/g creatinine16; CKD: chronic kidney disease22 In this series, three patients died during follow-up due to heart failure: one patient with surgically corrected SVAS, one with both bilateral renal artery and aortic stenosis who had been submitted to angioplasty and iliac-renal and aortic grafts, and one with SVAS who died following heart transplantation. DISCUSSION WBS is a congenital multisystem disease affecting the cardiovascular system, nervous system, and connective tissues that often involves hypertension, although the etiology of this symptom is not fully understood. Possible explanations include disorganization of the elastic layer and hypertrophy of smooth muscle cells and collagen fibers. As a result, diffuse or localized progressive narrowing of the arterial wall leads to increased arterial stiffness and sympathetic activity23. The prevalence of hypertension in WBS is widely variable4,5,6,8,14 (5 to 70% in series including all ages and 5 to 46% in children). It can appear as early as infancy, but the average age of diagnosis varies from 6.5 to 38 years. In the present study, the incidence of hypertension was 32%, with a mean age of diagnosis of 13.9 years (range: 5 months to 20 years). As observed by other authors8, we confirmed that patients with WBS are initially asymptomatic for hypertension, which highlights the need for health professionals to actively measure BP in these children in all routine visits. In the present study, which included only children and adolescents, systemic arterial hypertension associated with vascular stenosis was observed in 8/21 hypertensive patients (38%), which included renal artery stenosis (28.6%) and aortic lesions. In the literature; the frequency of arterial stenosis is variable across case series (e.g., 2 to 70%)5,8,12,14,22. Renal DS is usually indicated as an initial diagnostic method for screening of arterial stenosis. It is a non-invasive, relatively inexpensive test that is available in most centers but may have a high rate of technical failure (approximately 30%)24 because it is an operator-dependent method that also requires patients’ cooperation. In our study, we found a similar failure rate for DS (31%). The main difficulties are the detection of intra-renal and bilateral stenosis, the presence of obesity and the inadequate preparation of the patient. In WBS, psychomotor and behavioral disorders (agitation and anxiety) may represent additional complications1. The sensitivity and specificity of DS in the detection of vascular stenosis have been shown to be between 60 and 98% and between 62 and 98%, respectively24;25. It should be emphasized that the current sample was too small, since we conducted further imaging tests only on severely hypertensive patients, hindering this type of analysis. Computed tomographic angiography or MRA is commonly used in patients with WBS, but these techniques are not always available and require sedation or general anesthesia in children. MRA has high sensitivity (64-93%) and specificity (72-97%)25,26 but may overestimate renal arterial lesions or underdiagnose intra-renal lesions. On the other hand, CTA requires the use of iodinated contrast and ionizing radiation. Most of our patients underwent CTA because of the limited availability of the MRA equipment at our unit. However, we were unable to establish the accuracy of these methods in our study, because only some of the patients who received MRA or CTA also underwent CA, which is considered the gold standard in the diagnosis of arterial stenosis21. Angioplasty was performed in five patients with stenosis of the renal artery but was unsuccessful, as observed by other authors26,27. Patients with aortic coarctation or stenosis were treated with surgical correction, with graft insertion in severe cases. Other causes of hypertension such as hypercalcemia, renal scarring secondary to recurrent urinary infections, obesity, and essential hypertension may also be involved in hypertension in WBS. Hypercalcemia is frequently described in WBS 29 and occurred transiently in one patient in this study. It may manifest early or later in life, and patients should, therefore, be periodically monitored for possible calcium disturbances1,6,9. Broder et al.30 found a higher incidence of hypertension in patients with infantile hypercalcemia, but to date, no direct links between hypertension and hypercalcemia have been established. Congenital cardiovascular abnormalities are prevalent in patients with WBS and can occur in about 75% of cases7,8. SVAS is the most prevalent disease, and is also present in up to 75% of cases9,14,30. Mitral valve prolapse, bicuspid aortic valve, and coronary abnormalities have also been described10,11,12. SVAS may be severe in up to 30% of patients30, and surgical correction is necessary in such cases27. Consistent with earlier reports10,12,23, the most common cardiovascular abnormality observed in our study was SVAS, and it was severe in two patients who required surgical intervention. 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