Discussion

Williams–Beuren syndrome (WBS) is a rare congenital multisystem disorder affecting the vascular system, connective tissue, and central nervous system. Williams et al. [3] first reported it in 1961. They studied a group of patients with supravalvular aortic stenosis (SVAS), ``elfin'' faces, growth delay, mild intellectual disability, and a personality that was very friendly and outgoing [2]. A year later, Beuren) [4] broadened the clinical spectrum by describing 11 additional patients with the same unique combination of cardiovascular anomalies, facial dysmorphism, and neurodevelopmental characteristics, thereby defining what is now referred to as Williams–Beuren syndrome [9]. This syndrome affects about 1 in 7500-20,000 live births and mostly occurs sporadically [10]. It is panethnic, although the frequency of specific clinical manifestations may differ among populations. For example, cardiovascular abnormalities are less common in the Greek population [11]. At the same time, peripheral pulmonary artery stenosis is reported to be more common than supravalvular aortic stenosis in the Hong Kong Chinese population [12]. Elastin constitutes approximately fifty percent of the aorta's dry weight and is found all over the arterial tree. The arterial wall can store energy during systole and release it during diastole due to its unique biomechanical properties. This enables the cardiovascular system to function efficiently [13]. In Williams–Beuren syndrome, hemizygosity of the elastin gene (ELN) can result in an important reduction in both the quantity and quality of elastin in the arterial media. This deficiency results in increased arterial stiffness and loss of elastic recoil, significantly altering arterial mechanics [9,14]. Consequently, affected children develop a distinctive generalized arteriopathy, characterized by hypertrophy of the arterial media, abnormal accumulation of smooth muscle cells, and progressive luminal narrowing [15]. Histopathological studies reveal intima–media thickening, irregular elastic fibers, collagen deposition, and smooth muscle hypertrophy, which contribute to both stenotic lesions and arterial rigidity [16]. The production of elastic fibers begins in the late stages of pregnancy and nearly ceases after puberty. Consequently, the problems with elastogenesis in childhood can have a lasting impact on structure [17]. The cardiovascular system is disproportionately impacted in Williams–Beuren syndrome (WBS) due to the importance of elastin for the normal development of large elastic arteries and cardiac valves. Therefore, the most common cardiovascular manifestation of the syndrome is supravalvular aortic stenosis (SVAS) [9]. Williams–Beuren syndrome (WBS) is caused by a contiguous gene deletion on chromosome 7q11.23, typically spanning 1.55- 1.84 Mb and affecting approximately 26-28 genes [18]. The elastin gene (ELN) is the most important in this interval. Its haploinsufficiency is an essential component of the arteriopathy that is characteristic of WBS. It affects medium- and large-sized arteries and leads to progressive narrowing of the artery wall [18]. Standard karyotyping cannot detect the microdeletion. Instead, it must be found using fluorescence in situ hybridization (FISH). The deletion generally occurs de novo; most cases are sporadic and don't have a family history [5,19,20]. Antenatal 7diagnosis of Williams–Beuren syndrome (WBS) is possible based on the identification of characteristic cardiovascular lesions in utero. Both sexes are equally affected. If a parent is affected, there is a 50% risk of recurrence; only a few familial cases have been reported [16]. There is no newborn screening for WBS; therefore, clinical diagnosis typically relies on identifying suggestive signs and symptoms in infancy or childhood [21]. Typical facial characteristics include a small nose with a hypoplastic nasal bridge, macrostomia, large and thick lips, prominent cheeks, a small chin, periorbital fullness, a stellate iris pattern, hypertelorism, a saddle nose, and dental anomalies [2,18,20]. Patients are characterized as exceptionally communicative, sociable, and friendly, exhibiting an excessively extroverted personality [2]. Developmental delay is almost omnipresent, reported in up to 90% of individuals, and about 75% of older children and adults have intellectual disability (IQ < 70), with the remainder frequently having borderline IQ or specific neuropsychological deficits [21]. The cognitive profile is characterized by a disparity between relatively intact language abilities and deficient visuospatial skills, as well as hypersociability, anxiety disorders, hyperacusis, and notable sensitivity to auditory stimuli, frequently associated with a pronounced affinity for music [5,21]. Many patients show signs of poor weight gain, difficulties with food intake, excessive crying, sleep disorders, constipation, and rectal prolapse from infancy. Inguinal hernias occur in about one-third of the time [21]. Linear growth is usually lower than that of siblings and peers. Infants with WBS are often thin or underweight, but many adults with WBS become overweight [18]. Structural cardiovascular abnormalities are the main cause of morbidity and mortality in Williams–Beuren syndrome (WBS) [9,13,15,20,21,[23], [24], [25]]. Patients with WBS often have hypertension, which is one of the most common cardiovascular diseases. affecting approximately 32% of children and up to 50% of adults [8,26,21]. Blood pressure frequently starts at an elevated level during childhood and tends to rise as individuals age. It can occur more often in males [26,21]. Many factors contribute to the development of hypertension in WBS, including arterial stenoses (renal artery stenosis, coarctation of the aorta, middle aortic syndrome), arterial stiffness, and increased sympathetic activity, as indicated by elevated heart rates in both normotensive and hypertensive patients [8,21]. Renal artery stenosis plays a substantial role in hypertension, with reports finding its presence in 7%-58% of patients with WBS in various studies [8,26]. Studies have found that 60%-80% of patients have congenital heart disease, with prevalence rising to 80%-93% in the first year of life [6,13,15,20,22,25]. The most common lesions are Supravalvular aortic stenosis (SVAS), which occurs in 37%-75% of patients [13,14,20,22]. Peripheral or branch pulmonary artery stenosis (PPS/PAS) occurs in about 37%-75% of cases, especially in infants, and tends to improve spontaneously over time [13,20,22]. Other cardiac issues include coarctation of the aorta (CoA), tubular hypoplasia of the aorta, a bicuspid aortic valve (BAV), mitral valve prolapse (MVP), mitral regurgitation, ventricular or atrial septal defects, atrioventricular septal defects, and arrhythmias [13,20,22]. Arteriopathy is frequently generalized and progressive, characterized by stenoses of the aorta and the renal, coronary, mesenteric, and cerebral arteries, resulting in left ventricular outflow tract obstruction, reduced pulmonary blood flow, systemic hypertension, and compromised organ perfusion. There have been reports of cerebrovascular stroke, myocardial infarction, and sudden death linked to coronary ostial stenosis or biventricular outflow tract obstruction [9,15,25]. Endocrine disorders are common and include hypercalcemia, glucose metabolism disturbances, and (subclinical) hypothyroidism (5%-10%) [18,21]. Idiopathic infantile hypercalcemia affects approximately 5%-10% of children, typically between 6 and 30 months of age, and may manifest as irritability, poor oral intake, vomiting, constipation, and muscle cramps [21]. Hypercalcemia is usually temporary and improves during childhood [21]. Patients with WBS have higher median calcium levels than those without, and increased intestinal calcium absorption has been reported. However, the full explanation of this condition remains unknown [21]. Idiopathic hypercalcemia may lead to dehydration, hypercalciuria, and nephrocalcinosis [21]. Certain studies indicate a correlation between infantile hypercalcemia and subsequent hypertension, although a definitive causal relationship has not been explicitly established [8,21,26]. Renal and urinary tract anomalies occur in 17%-17.7% of patients with WBS, a prevalence significantly higher than that observed in the general population [2]. These include cystic kidneys, hydronephrosis, renal agenesis or hypoplasia, ectopic kidneys, vesicoureteral reflux, diverticula, nephrocalcinosis, and ischemic disorders [2]. In 1 study, 1% of patients had renal artery stenosis (RAS); in another, 6.2% [5]. In other groups, when systematic angiography is done, the rate of arterial stenosis (including renal) ranges from 44% to 61% [8,26]. Other manifestations include gastrointestinal dysmotility (gastroesophageal reflux, constipation, and diverticular disease) [18,25]. Musculoskeletal anomalies such as joint stiffness and scoliosis have also been observed [18]. Neurological signs such as abnormal tone, hyperreflexia, and cerebellar findings have also been observed [18]. Ophthalmologic issues include hyperopia, nasolacrimal duct obstruction, and strabismus; an ophthalmologic evaluation is recommended at the time of diagnosis [25]. Audiologic problems: mild-to-moderate sensorineural hearing loss in 60% of children and up to 90% of adults; recurrent otitis media and marked sound sensitivity are common [25].

Many different types of imaging are used to diagnose and describe vascular lesions in WBS:•Echocardiography is the best technique to identify SVAS, PAS, intracardiac defects, LV hypertrophy, and outflow tract gradients [2,13,20].•Doppler sonography (renal Doppler ultrasound) is a common first test for RAS. It is noninvasive and not too expensive, but it depends on the operator. The failure rate can be as high as 30%, while sensitivity ranges from 60% to 98% and specificity from 62% to 98% [26].•CT angiography (CTA) provides obvious images of the aorta (including coarctation and collateral circulation), pulmonary arteries, and renal arteries. However, it needs iodinated contrast and ionizing radiation [2,20,23,24,26].•MR angiography (MRA) is extremely sensitive (64%-93%) and specific (72%-97%) for lesions in the kidneys and aorta. It doesn't use ionizing radiation, but it might overestimate or underestimate some lesions. Performing MR angiography (MRA) on young children is also challenging [20,23,26]. Trautman et al. reported a sensitivity of 88% for CTA and 80% for MRA in older children with renal artery stenosis [27].

Cardiovascular CT angiography and multidetector CT provide excellent visualization of complex aortic anatomy, coronary abnormalities, distal pulmonary arteries, and abdominal aortic involvement. They are also crucial for planning surgery and other interventions [26]. Conventional angiography remains the reference standard for detailed anatomical and hemodynamic assessment, including measurement of pressure gradients across stenotic lesions. However, it is invasive and has more risks [9]. There are no dependable noninvasive screening approaches for RAS, nor are there imaging modalities that can exclude children from undergoing angiography [28]. Furthermore, angiography remains the preferred method for diagnosing RAS [29]. Hypertension is common in Williams–Beuren syndrome (WBS), necessitating systematic blood pressure (BP) monitoring at diagnosis, every 3 months during the initial year, and annually thereafter, utilizing an appropriate cuff and measuring BP in both upper and at least 1 lower limb to rule out coarctation or diffuse aortic hypoplasia [9,25]. Anxiety, the white coat effect, and changes in blood flow patterns (like the Coanda effect in SVAS) can all affect blood pressure readings in the office. To obtain the most accurate readings, BP should be taken when the child is calm, preferably at the end of the visit. When available, ambulatory BP monitoring can help confirm sustained hypertension and distinguish it from white-coat hypertension [9,21]. In a hypertensive WBS patient, the initial evaluation must include fundamental biochemistry, renal function assessment, fasting glucose evaluation, urinalysis and urine culture, renal ultrasound with Doppler ultrasound, and echocardiography to identify left ventricular hypertrophy and aortic abnormalities [9]. Because renal ultrasound can be normal even with renovascular disease, CT or MR angiography is necessary when there is clinical suspicion of renal artery stenosis or aortic involvement (eg, abdominal bruit, refractory or severe hypertension) [9,26].

Managing cardiovascular disease in Williams–Beuren syndrome (WBS) involves surgical or endovascular correction of obstructive lesions, meticulous management of hypertension, and multidisciplinary follow-up. Generally, about 20% of patients with WBS will need at least 1 surgical or transcatheter procedure for cardiac issues. This figure rises to nearly 30% among those who present in the first year of life [20]. Renovascular hypertension resulting from renal artery stenosis (RAS) can require surgical revascularization. Splenorenal bypass is a standard procedure that produces favorable results in children with refractory hypertension and unilateral renal impairment [25]. Case reports indicate the advantages of percutaneous intervention in pediatric patients with RAS. After balloon angioplasty, reported rates of restenosis range from 20% to 25% [30]. To date, no particular kind of antihypertensive drug is better in WBS, and there are no data-driven suggestions for first-line therapy [15]. Some authors prefer angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) because these patients are known to have an activated renin–angiotensin–aldosterone system and sympathetic overactivity [8]. However, these agents are relatively contraindicated in the presence of, or suspicion of, RAS due to the risk of acute deterioration in renal function [13,15,21]. In this case, dihydropyridine calcium channel blockers are often considered the best first-line treatment because they are effective and safe in the presence of RAS [8,15]. Conventional approaches to hypertension, such as sodium restriction or diuretic agents, are ineffective in lowering hypertension because they increase renin release [27]. Another beneficial option is β-blockers, which may also lower the risk of ventricular arrhythmias and sudden death in patients with QTc prolongation or a higher adrenergic response [13,15]. In hypertensive children with suspected RAS, salt intake should be minimal, and the use of diuretics should be avoided [27]. In practice, the selection of antihypertensive medication must be personalized, considering the pattern of vascular involvement, the likelihood of renal artery stenosis (RAS), concomitant cardiac lesions, the QTc interval, and potential contraindications, to ensure effective blood pressure control without compromising perfusion through established vascular stenoses [15]. RAAS-blocking agents should only be introduced after significant RAS has been excluded or is under careful observation. When very high blood pressure is associated with end-organ damage (such as left ventricular hypertrophy, renal dysfunction, or neurological symptoms) and can't be fully explained by a fixed anatomical obstruction, antihypertensive therapy must be initiated and carefully adjusted with close clinical and biological monitoring [21]. Beyond cardiovascular management, care of patients with WBS includes occupational, physical, speech, and language therapy as needed, systematic monitoring of growth and development, and assessment for attention-deficit/hyperactivity disorder with appropriate intervention when indicated. Annual hearing and vision evaluations, yearly 4-extremity blood pressure and urinalysis, periodic urine calcium/creatinine ratio (every 2 years), serum calcium (annually if elevated or symptomatic, otherwise every 2-3 years), and thyroid function tests (approximately every 4 years) are recommended, together with continuous dietary monitoring and avoidance of multivitamin or vitamin D supplementation in patients with hypercalcemia [15,20]. Surgical revascularization should be considered for all pediatric patients with renal artery stenosis (RAS), since these interventions might eliminate the necessity for lifetime pharmaceutical treatment while maintaining renal function. Poor blood pressure management, resistance to medical therapy, or a decline in renal function following adequate pharmacological intervention may be considered less significant reasons for revascularization surgery [27]. Percutaneous transluminal angioplasty. Compared with surgical revascularization, PTA is associated with a lower risk of complications, a shorter hospital stay, and lower costs. Children with hypertension and over 75% stenosis in a renal artery may be eligible for PTA, especially in the presence of collateral arteries and in the absence of other causes of hypertension as determined by screening procedures and clinical evaluations [27].

Cardiovascular manifestations are present at birth in nearly half of patients with Williams–Beuren syndrome (WBS), with symptoms evident in approximately 47% of cases [20]. Surgical intervention for cardiovascular lesions is often recommended when diagnosed in infancy [20]. Coarctation of the aorta, renal artery stenosis, and hypertension are generally progressive conditions. In contrast, supravalvular aortic stenosis (SVAS) may remain stable in certain patients; however, it can also progress. This variability requires consideration of surgical intervention at lower pressure gradients than in valvular aortic stenosis [2,20]. Longitudinal observations indicate that branch pulmonary artery stenosis frequently ameliorates over time, whereas supravalvular aortic stenosis typically advances and, if untreated, may result in heart failure and mortality [2]. Cardiovascular complications are the predominant cause of mortality in Williams–Beuren syndrome (WBS), with cardiovascular mortality rates estimated to be 25-100 times higher than those in the age-matched general population [14,31,32]. The risk of sudden cardiac death is also 25-100 times higher, with an estimated rate of about 1 in 1,000 patient-years [14,31,32]. Coronary artery stenosis and severe biventricular outflow tract obstruction have been reported as mechanisms leading to myocardial ischemia and malignant arrhythmias, with myocardial infarction documented in several patients [27]. Multiple fatal incidents occur in the periprocedural situation, especially during sedation or anesthesia (frequently for cardiac catheterization), where decreased cardiac output due to coronary disorders and fixed outflow obstruction can severely impair myocardial perfusion [33]. Patients with Williams–Beuren syndrome (WBS) should have lifelong structured cardiovascular surveillance due to the prevalence and potential progression of arterial stenoses. It is recommended to have a clinical and cardiovascular exam every 3 months during the first year of life, once a year from ages 1 to 5, and every 2 to 3 years thereafter. If there is serious vascular disease, the exams should be done more often [15]. At every visit, blood pressure should be measured in all 4 limbs, and a 12-lead ECG (with QTc analysis) should be performed. At 1 year, a 24-hour ambulatory ECG should be performed, then once a year until age 5, and every 2 years thereafter [15]. Echocardiography is necessary at diagnosis, at least once a year until age 5, and thereafter based on the type and severity of cardiovascular disorders. In cases of severe supravalvular aortic stenosis (SVAS), a CT or MRI of the aorta is recommended, potentially extending to the head and neck vessels; renal ultrasound is required in patients with hypertension or when abdominal bruits are present, and carotid ultrasound is necessary in the presence of carotid bruits [15].