Clinical features and management of arterial hypertension in children with Williams–Beuren syndrome

Karim Bouchireb 2 Olivia Boyer 1 2 Damien Bonnet 0 Francis Brunelle 6 Stephane Decramer 5 Gilbert Landthaler 4 Aurelia Liutkus 3 Patrick Niaudet 1 2 Remi Salomon 1 2 0 Department of Pediatric Cardiology 1 Universite Paris Descartes , Faculte de me decine , France 2 Department of Pediatric Nephrology, Centre de Re fe rence des Maladies Re nales He re ditaires de l'Enfant et de l'Adulte, Hopital Necker-Enfants Malades , Paris 3 Department of Pediatric Nephrology, Hopital Femmes Me`re Enfants , Lyon , France 4 Department of Pediatric Nephrology, Hopital Charles Nicolle , Rouen 5 Department of Pediatric Nephrology, Hopital D'Enfants , Toulouse 6 Department of Pediatric Radiology, Hopital Necker-Enfants Malades , Paris Background. Hypertension is a common finding in children with Williams-Beuren syndrome (WBS). Methods. The aim of this retrospective study was to review the clinical presentation of systemic hypertension in WBS children, its origin and management. We included 41 children with confirmed WBS who were referred to the paediatric nephrology or cardiology unit for hypertension. Results. The mean age at diagnosis of hypertension was 4.7 years. Out of 41, 24 patients had systolic blood pressure (BP) between +10 and +30 mmHg above the 95th percentile (1.645 SD), and 20/41 patients had diastolic BP between the 95th percentile (1.645 SD) and >10 mmHg. Thirty-nine patients were asymptomatic. Arteriography, performed in 17/41 patients, revealed a renal artery stenosis (RAS) in 10 patients (58%). Echocardiography was performed in all patients and showed isthmic coarctation in four patients (9%). Calcium channel blockers were used in half of the patients (22/41) and seemed to control hypertension in most cases. Interventional treatment of RAS was performed in five patients (three angioplasty and two surgical bypass). It controlled hypertension in one patient but remained ineffective in the four others. Conclusions. Medical treatment essentially calcium blockers improved hypertension in most cases. Interventional treatment of RAS has not been encouraging. C The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: Introduction WilliamsBeuren syndrome (WBS) (OMIM # 194050) is caused by a heterozygous microdeletion of the chromosome region 7q11.23, including among others the elastin gene. The main clinical features include a distinctive facial appearance with elfin facies, mental and statural deficiencies, cardiovascular abnormalities (commonly supravalvular aortic stenosis) and occasionally infantile hypercalcaemia [1]. WBS children are also at risk for systemic hypertension, with a frequency ranging from 5 to 70% in the literature (Table 1). A clear aetiology is found in only a minority of patients including renal artery stenosis (RAS) and/or diffuse aortic narrowing and/or aortic coarctation. The vascular lesions in WBS seem to be linked to reduced elastin synthesis and increased proliferation of vascular smooth muscle cells [2], but the exact pathways connecting the elastin deficiency to increased vascular cell proliferation are still unknown. Pathological vascular lesions in WBS include increased intimamedia thickness with thick irregular elastic fibres, swirling collagen and hypertrophied smooth muscle cells. However, the compliance of the large elastic arteries is not modified in these patients [8]. There are few data on the clinical characteristics and management of hypertension in these children. We report on a multicentric retrospective study including 41 WBS patients with systemic hypertension. Our aim was to study the clinical presentation and the aetiologic investigations of hypertension on the one hand and to evaluate the medical or endovascular management on the other hand. Patients and methods Clinical and biological data A total of 19 paediatric nephrology units in France, Belgium and Canada were invited to participate in this retrospective study. A questionnaire for all children aged 20 years or less with a diagnosis of WBS associated with hypertension was filled. Thirteen centres (11 in France, 1 in Belgium and 1 in Canada) provided clinical information concerning 41 WBS patients referred for systemic hypertension between 1990 and 2008. Hypertension was defined for patients aged 17 years as average systolic BP (SBP) and/or diastolic BP (DBP) 95th percentile for gender, age and height on 3 occasions, based upon the 2004 National High Blood Pressure Education Program Working Group (NHBPEP) [3]. For patients aged >17 years at diagnosis, hypertension was defined as SBP 140 mmHg and/or DBP 90 mmHg [4]. BP was rarely reported of both arms which Prevalence of hypertension 7/42 (17%) 19/32 (59%) 7/10 (70%) 2/40 (5%) 19/45 (42.2%) 8/20 (40%) 6/13 (46%) 9/21 (42%) 17/25 (68%) 23/42 (55%) 12/20 (60%) 3/20 (15%) 26/57 (45%) 7/22 (31%) Age of patients (years) Morris et al. [1] Ingelfinger et al. [11] Lopez Rangel et al. [16] Pober et al. [10] Wessel et al. [9] Broder et al. [17] Aggoun et al. [8] Rose et al. [12] Eronen et al. [13] Cherniske et al. [18] Sugayama et al. [19] Del Campo et al. [20] Ferrero et al. [14] would have eliminated the Coanda effect related to supravalvular aortic stenosis that may cause elevated BP only in the right arm [15]. The patients medical history was reviewed with emphasis on the occurrence of hypertension, including age, circumstances of diagnosis, BP measurements and symptoms related to hypertension. Left ventricular hypertrophy on initial echocardiography was noted. Other main features of WBS such as congenital heart defects and mental retardation were also noted. For each patient, serum creatinine values and total calcaemia from the diagnosis of WBS until the last follow-up were recorded. Hypercalcaemia was defined as a serum calcium >2.75 mmol/l. Renal function assessed by estimated glomerular filtration rate (eGFR) according to the Schwartz formula was recorded, and renal insufficiency was defined as eGFR < 75 ml/ min/1.73 m2. Radiological findings Data from kidney ultrasonography (US) performed when hypertension was diagnosed were recorded. Doppler US of renal artery, CT angiography and conventional renal arteriography were recorded when performed. Treatment outcomes The results of the medical treatment or revascularization procedures were classified as follows: (1) resolved hypertension, when SBP and DBP became <95th percentile (for gender, height and weight) without any medication, but after a treatment with one or more antihypertensive agents and/or after revascularization procedure; (2) controlled hypertension, when SBP and DBP become <95th percentile with an ongoing antihypertensive treatment, whether they underwent a revascularization procedure or not (surgical reconstruction or angioplasty) and (3) unchanged hypertension, when hypertension persisted on antihypertensive agents or after a renal artery or aortic intervention. The results of (...truncated)