Unveiling Mysteries in Congenital Diseases: A Case Report of Williams-Beuren Syndrome

Abstract

Williams-Beuren syndrome (WBS) is an autosomal dominant genetic disorder closely associated with cardiovascular malformations, distinctive facial features, impaired cognitive ability, abnormal growth and development, endocrine dysfunction, and other related systems. In patients with WBS, the presence of cardiovascular malformations often necessitates genetic testing. This testing not only confirms the diagnosis but also facilitates the identification of associated syndromic features. Early and accurate diagnosis through genetic testing is instrumental for guiding further investigations, and initiating targeted therapies and support services. Such proactive management can substantially improve prognosis and quality of life for patients with WBS. Although surgery remains the most effective approach for repairing cardiovascular malformations, its implementation entails notable surgical risks. Clinicians should prioritize the identification and diagnosis of WBS, and strive to develop an effective management model involving collaboration among hospitals, families, and society. Here, we presented a case report of a patient with WBS and congenital heart disease, to contribute to a deeper understanding of this condition.

Main article text

Abbreviations: CNV-seq, copy number variation sequencing; CTA, computed tomography angiography; ELN, elastin gene; Mb, megabase; PDA, patent ductus arteriosus; SVAS, supravalvular aortic stenosis; WBS, Williams-Beuren syndrome.

Background

Williams-Beuren syndrome (WBS) (OMIM 194050) was first described by J. C. P. Williams in 1961. Subsequently, A.J. Beuren reported additional cases, thereby leading to the name WBS [1]. The syndrome is characterized by a spectrum of features including cardiovascular anomalies, distinct facial features, developmental delays, endocrine dysfunction, and hypercalcemia. A notable aspect of WBS is its frequent association with congenital heart diseases, notably supravalvular aortic stenosis (SVAS) (OMIM 185500), supravalvular pulmonary stenosis (OMIM 185590), and arterial hypertension (OMIM 145500), which are among the most prevalent cardiac conditions observed in patients with WBS [2, 3].

Cardiovascular complications are the primary cause of mortality in patients with WBS. Comparative studies have revealed that the cardiovascular mortality rate in individuals with WBS was 25 to 100 times greater than that in the age-matched normal population [4]. Surgical correction of cardiac vascular malformations is necessary in approximately 30% of children with SVAS, and the mortality rate associated with surgical intervention is approximately 6% [5, 6]. This stark contrast highlights the substantial health burden posed by cardiovascular issues in WBS.

Despite the increasing number of reported cases of WBS in recent years, this disease remains rare. Here, we present a case report of WBS with patent ductus arteriosus (PDA) (OMIM 617039) that was missed 13 years prior, to raise awareness among clinicians about the importance of routine screening and timely identification of such conditions in children with congenital heart disease.

Case Presentation

A 13-year-old girl who had been experiencing recurring dizziness and headache for more than 3 months, with worsening symptoms for the prior 2 weeks, was admitted to the Second Xiangya Hospital. She had undergone arterial catheterization for PDA at the age of 1 year and had no history of seizures.

At admission, the patient presented with elevated blood pressure in both upper limbs (R: 160/83 mmHg L:154/93 mmHg) and a distinctive facial phenotype. She displayed a friendly personality and enthusiastically engaged in communication with physicians, often imitating the tone used by adults and eagerly discussing various topics. Nevertheless, her calculation skills were found to be poor, and her learning ability was below average for her age group. An audible grade 3/6 systolic whistle-like murmur was noted in the aortic valve area, and no pathological murmurs were detected in other regions.

Digital X-ray imaging revealed dense shadows in the projection area of the aortic node (Figure 1). Subsequently, computed tomography angiography (CTA) of the entire aorta revealed slight localized narrowing in the segment of the aortic arch (Figure 2). Notably the stenosis was identified as noneccentric, thus ruling out its association with the closure of a PDA.

Figure 1

Panel A shows an anteroposterior X-ray chest radiograph, and panel B shows a lateral X-ray chest radiograph, for our patient. Both lungs exhibited a clear texture with no apparent primary lesions. The heart shadow appeared small, and both diaphragms were within the normal range. In the aortic arch projection area, indicated by the red arrows in panels A and B, a dense shadow is evident.

Figure 2

Panels A to D present three-dimensional volume rendering images of the patient’s aortic CTA. The corresponding segment of the aortic arch, indicated by the arrow, was slightly narrowed locally, and had a diameter of 5 mm at the narrowest point. The remaining aorta and the large branches ran normally. Panels E to G present the maximum intensity projection images of the aortic CTA, with the arrow indicating the enhanced shadow corresponding to the closure device for the patient’s PDA. Panel H presents the multi-planar reconstruction image of the aortic CTA, revealing no apparent calcification, or localized tumor-like dilation or dissection, in the patient’s aortic vascular wall at the location indicated by the arrow.

Whole-exome sequencing was conducted at the Medical Genetics Department. This process involved targeting the coding regions of relevant genes by using a second-generation sequencing platform involving targeted region capture and amplification. The nomenclature of the identified variants followed the guidelines recommended by the Human Genome Variation Society (2016 update) [7]. The analysis and interpretation of the patient’s genetic data were based on the gene names recorded in the HUGO Gene Nomenclature Committee database. In addition, copy number variation sequencing (CNV-seq) was used to detect copy number variations in the patient’s genome. This comprehensive approach led to the identification of a 1.46 megabase (Mb) deletion in the 7q11.23 region of seq[hg19] (chr7: 72718227–74131386). Notably, this deletion is a novel discovery that had not been documented in human genomic polymorphism databases (Figure 3). This variation in copy number plays a crucial role in diagnosis of WBS. The diagnosis was confirmed through multidisciplinary consultation at the hospital, thus leading to a recommendation of surgical intervention. However, considering the patient’s age and surgical risk, we recommended stent implantation between the ages of 20 and 30 years to delay surgery. After this procedure, the patient’s parents were given an option to leave the hospital and undergo regular outpatient observation to ensure timely monitoring of the condition.

Figure 3

The patient’s copy number variation-associated profile. The results indicated a deletion of approximately 1.46 Mb in the seq[hg19] 7q11.23 (chr7: 72718227–74131386) region. The red line demarcates the extent of the deleted region. According to the ClinGen database, the deleted region encompasses ELN and is associated with symptoms related to haploinsufficiency. Additionally, the 7q11.23 recurrent segment associated with the WBS was included, thus collectively contributing to a ClinGen Haploinsufficiency score of 3.

Discussion

In this study, we explored the genetic basis of WBS, which results from a developmental abnormality due to a deletion in the 7q11.23 region. This deletion spans approximately 1.55 Mb and results in the loss of 26–28 genes. Among these genes, the elastin gene (ELN) (OMIM 130160), encoding the elastin protein, plays a major role: ELN absence or dysfunction is a key factor contributing to the cardiovascular and connective tissue anomalies observed in WBS [2]. WBS is a relatively rare genetic disorder that affects multiple systems and manifests as cardiovascular abnormalities, endocrine imbalances, intellectual disability, emotional disorders, and distinctive facial features.

Cardiovascular abnormalities are the primary reason why patients with WBS seek medical attention. The predominant cardiovascular abnormality in WBS is SVAS located at the sinotubular junction above the aortic valve. This condition results from thickening of the vascular media due to overgrowth of vascular smooth muscle, thereby leading to stenosis between the aortic walls [2, 8]. In approximately 70% of cases, concurrent stenosis of the aortic valve can occur in various areas, including the aortic arch, descending aorta, pulmonary artery, coronary artery, renal artery, mesenteric artery, and intracranial artery [1]. The reported occurrence rate of SVAS in patients with WBS ranges from 45% to 75%. Two common types of SVAS in patients with WBS include discrete hourglass stenosis at the tracheal junction and diffuse long segment stenosis of the ascending aorta [9–12]. Although reports on coronary artery disease are limited, severe coronary artery disease significantly contributes to mortality in patients with WBS.

At the genetic level, deletion of ELN plays a critical role in the development of cardiovascular malformations in WBS. This aspect is particularly evident in familial SVAS, in which ELN mutations are frequently observed, thus underscoring their pathogenic significance in SVAS [13]. ELN encodes elastin, which has notable elasticity and ability to undergo reversible deformation. This characteristic is crucial for the function of the aorta: during systole, elastin enables arterial dilation and energy accumulation, which are subsequently used to transport blood to peripheral organs during diastole, thus ensuring consistent blood circulation throughout the body [3]. In patients with WBS, the loss of ELN leads to an elastin deficiency culminating in the various cardiovascular abnormalities characteristic of the syndrome.

Although SVAS is a prevalent cardiovascular abnormality in WBS, many patients initially seek medical attention for other congenital heart diseases, such as pulmonary artery stenosis and mitral valve prolapse. PDA is a rare complication in patients with WBS, and reports of this complication are limited [14]. Particularly in cases in which cardiovascular abnormalities are solely characterized by PDA, the lack of sensitivity in WBS diagnosis can often lead to a missed diagnosis. In patients receiving occluder treatment, differentiating between blood vessel narrowing caused by the occluder and vascular stenosis due to WBS is crucial. Noneccentric stenosis may provide some diagnostic clues for WBS, and enhanced genetic testing can further aid in diagnosis.

Cardiovascular complications are the leading cause of death in patients with WBS. A study has revealed that patients with WBS have a cardiovascular-associated mortality rate 25 to 100 times greater than that of the age-matched normal population [4]. Unfortunately, no current drugs significantly improve the long-term prognosis of patients with WBS, and surgical interventions are the most effective option for improving cardiovascular abnormalities in patients. Genetic testing and diagnosis results may prompt further investigation to identify features associated with the syndrome, thus forming the foundation for early targeted treatment and supportive services, with the potential to improve patient prognosis. Currently, surgery remains the sole approach for improving the long-term prognosis of patients with cardiovascular malformations and WBS. Patients with common cardiovascular abnormalities typically undergo surgical repair. For SVAS, patch aortoplasty is a commonly used operative procedure, with early mortality rates ranging from 1−9% (median or mean age at operation, 6−16 years) and a 20-year survival rate of 77−97% after SVAS repair [15, 16]. In patients with severe left main coronary obstruction, interventions such as patch enlargement of the coronary ostia, excision of a fused aortic leaflet, and bypass grafting can be used [17].

In addition to cardiovascular abnormalities, patients with WBS commonly present with other systemic features recognizable to clinicians, including distinctive facial characteristics and growth retardation. Young children with WBS are often described as cute or pixielike, with a flat nasal bridge, short upturned nose, periorbital puffiness, a long philtrum, and a delicate chin.

Their distinctive facial phenotype is complemented by their cheerful and sociable personalities. Patients tend to mimic adult tones and engage with clinicians in a cheerful manner, seemingly unaffected by social isolation due to WBS. However, patients with WBS are in fact deficient in mathematical calculation, spatial thinking and other logical aspects, thus impeding their ability to master the skills expected of children. Children with WBS often face difficulties in completing their studies as scheduled. Additionally, their overly friendly demeanor poses challenges in discerning whether others are friendly, thus often resulting in incidents of bullying. Clinicians should be aware of the reported anxiety, fear, paranoia, and other mental conditions prevalent in most patients with WBS [18].

Conclusion

In conclusion, WBS is a relatively rare genetic disease resulting from gene deletion, and increasing numbers of cases have been reported in recent years. However, owing to the lack of systemic training in genetics, clinicians might not promptly and accurately recognize this hereditary disease. Nevertheless, patients with WBS typically exhibit specific clinical features, particularly those associated with congenital cardiovascular deformities, intellectual disability, growth retardation, or endocrine abnormalities. Therefore, patients should be advised to undergo prompt genetic testing. Early surgical intervention plays a critical role in the long-term prognoses of patients with WBS, and physicians should provide guidance to families and increase awareness of WBS in society. Our findings underscored the need for the establishment of dedicated hospital-based units for patients with WBS and their families, focused on effective disease management.

Data Availability Statement

No new data were generated or analyzed in support of this research.

Ethics Statement

This case study was conducted in accordance with ethical principles and adhered to the guidelines of the Declaration of Helsinki. Re-evaluation by the Ethics Review Committee concluded that formal ethics approval was not required for this type of case report. Nonetheless, we maintained strict adherence to patient confidentiality and privacy protocols. Informed written consent was obtained from the parents, who also served as the legal guardians, of the minor patients included in this study. All patient data were anonymized to ensure the protection of personal information.

Author Contributions

Professors Qiming Liu and Yichao Xiao performed the diagnosis and analysis of this case. Cancan Wang collected the relevant information for this patient, and Zixi Zhang wrote the manuscript, which was subsequently revised by Yichao Xiao and Qiuzhen Lin. All authors contributed to the discussion and approved the final manuscript.

Conflict of Interest

Qingming Liu is the editorial board member of Cardiovascular Innovations and Applications. Qingming Liu was not involved in the peer review or decision-making process of the manuscript. The other authors have no conflict of interest to declare.

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