Multidisciplinary approach to screening and management of children with Fabry disease: practice at a Tertiary Children’s Hospital in China

Background Fabry disease (FD) remains poorly recognized, especially in children in China. Considering the diversity and nonspecific clinical manifestations accompanying with life-threatening aspect of this disease, methods to improve effective screening and management of the suspects are needed. This study aims to explore how it can be done effectively from a multidisciplinary perspective for children with FD at a tertiary children’s hospital in China. Methods A multidisciplinary team (MDT) of pediatric FD experts was launched at Children’s Hospital of Fudan University. Children with high-risk characteristics were referred by the MDT screening team using the dried blood spot (DBS) triple-test (α-galactosidase A, globotriaosylsphingosine, GLA gene). For newborns who were undergoing genetic testing in the hospital, the GLA gene was listed as a routine analysis gene. Evaluation, family screening, and genetic counselling were implemented after screening by the MDT management team. Results Before the establishment of the MDT, no case was diagnosed with FD in the hospital. However, twelve months following the MDT program's implementation, thirty-five children with high-risk profiles were referred for screening by DBS triple-test, with a yield of diagnosis of 14.3% (5/35). These 5 diagnosed children were referred due to a high-risk profile of pain accompanied by dermatological angiokeratoma and hypohidrosis (n = 2), pain accompanied by abnormal liver function (n = 1), pain only (n = 1), and unexplained renal tubular dysfunction (n = 1). Two neonates were detected early with GLA mutations in the hospital, with a yield of detection of 0.14% (2/1420). Furthermore, another 3 children diagnosed with FD were referred from other hospitals. Family screening of these 10 diagnosed children indicated that 9 boys inherited it from their mothers and 1 girl inherited it from her father. Four of them started to receive enzyme replacement therapy. Conclusion Screening and management of children with FD is effective based on a defined screening protocol and a multidisciplinary approach. We should pay more attention to the high-risk profiles of pain, angiokeratoma, decreased sweating, and unexplained chronic kidney disease in children.

Family genetic screening in rare hereditary diseases

Family genetic testing of probands with newly diagnosed rare hereditary diseases including Fabry disease improves early diagnosis and allows to initiate specific treatment, if available, at earlier stage in affected family members. Diagnosis of Fabry disease, an X-linked lysosomal storage disorder affecting kidneys, heart, brain and other organs, is usually late due to low awareness of physicians about rare diseases. Moreover, early symptoms can be non-specific (e.g. gastrointestinal disorders and autonomic neuropathy) or misleading (e.g. recurrent unexplained fever) whereas characteristic skin rash and keratopathy (cornea verticillata) are frequently overlooked. Undiagnosed patients with Fabry disease can be detected by screening in at-risk populations, such as patients with end-stage renal disease undergoing dialysis or renal transplantation, patients with unexplained left ventricular hypertrophy, and young adults with a history of stroke or transient ischemic attack who have a higher prevalence of the disease compared to general population. High-risk screening paves the way to family screening to identify affected relatives, including children, who can benefit from earlier treatment and genetic counselling. The major barriers to family screening include costs of testing, cultural and societal issues, stigma associated with a diagnosis of genetic disease, low contacts in the family, weak infrastructure, national regulations.

Yield from family screening in a national adolescent cardiac screening program

Introduction Cascade family screening in patients with confirmed or suspected inherited cardiac disorders is now well established. This may refute or confirm a familial clinical diagnosis and is particularly relevant in young adolescent individuals as it may be too early to manifest a distinct phenotype. Objectives A large cohort of 2708 adolescents aged 14–16 years gave consent to participate in a national cardiac screening program (BEAT-IT). Individuals with suspected inherited cardiac disorders were extensively evaluated. Their relatives were also invited to undergo screening. This study reports the yield of this family cardiac screening program. Methodology Family members of probands with suspected or confirmed inherited cardiac conditions were offered cardiac screening. A standard clinical screening protocol for all first-degree family members included a resting 12-lead ECG and echocardiogram. Those with a channelopathy suspicion also underwent postural ECGs and exercise testing. Screening second-degree relatives was also performed in a cascade fashion when clinically indicated. Relatives with a normal baseline screen were offered surveillance if younger than 25 years or a proband clinical diagnosis. Those with an abnormal ECG and/or echocardiogram were referred for further evaluation. Results 17 probands (63% females) were suspected of harbouring inherited heart disease. Another 2 were diagnosed with a clinical phenotype. The mean age was 15.3±0.58 years. All were Caucasian. 77 family members underwent cardiac screening, with a mean age of 42.5±16.43 at first evaluation. The majority were female (n=44, 57.1%). 12 (15.6%) had an abnormal ECG. 6 (7.8%) had an abnormal echocardiogram, with 2 (2.6%) consistent with cardiomyopathy. 8 (10.4%) were diagnosed with an inherited cardiac condition (n=2 HCM, n=1 DCM, n=5 LQTS). Another 7 (9.1%) are under surveillance because of a pathological ECG in the absence of a clinical phenotype. The highest clinical yield was in the Long QT group (n=5, 55.6%). Family members (n=25) referred because of proband lateral TWI were the second most likely to require clinical follow-up because of a pathological ECG or a clinical diagnosis (n=7, 28.0%). Relatives referred because of isolated anterior TWI on the proband's ECG had the lowest diagnostic yield (n=17, 0%). After excluding families of probands with isolated anterior TWI (n=18), the overall clinical yield increased to 13.6%. Another 11.9% are under surveillance because of a pathological ECG. Conclusion The yield of family screening as part of a national cardiac screening program was 10.4%. This increases to 13.6% when excluding probands with anterior TWI, with 11.9% under surveillance because of a pathological ECG. To our knowledge, this is the first such study of its kind. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Beating Hearts MaltaResearch, Innovation and Development Trust (University of Malta)

Family screening in patients with isolated bicuspid aortic valve

Aim To determine the prevalence of undiagnosed bicuspid aortic valve (BAV) and isolated aortic dilatation in first-degree relatives (FDRs) of patients with isolated BAV and to explore the recurrence risk of BAV in different subgroups of probands with BAV. Recent American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines recommend family screening in patients with associated aortopathy only. Methods During follow-up visits, patients with isolated BAV received a printed invitation for their FDRs advising cardiac screening. Results From 2012–2019, 257 FDRs of 118 adult BAV patients were screened, among whom 63 (53%) index patients had undergone aortic valve surgery (AVS), including concomitant aortic replacement in 25 (21%). Of the non-operated index patients, 31 (26%) had aortic dilatation (> 40 mm). Mean age of the FDRs was 48 years (range 4–83) and 42% were male. The FDR group comprised 20 parents, 103 siblings and 134 offspring. Among these FDRs, 12 (4.7%) had a previously undiagnosed BAV and 23 (8.9%) had an isolated aortic dilatation. FDRs of the probands with previous AVS (n = 147) had a risk ratio for BAV of 2.25 (95% confidence interval (CI) 0.62–8.10). FDRs of the probands with BAV and repaired or unrepaired aortic dilatation (n = 127) had a risk ratio for BAV of 0.51 (95% CI 0.16–1.66). Conclusion Screening FDRs of patients with isolated BAV resulted in a reasonable yield of 14% new cases of BAV or isolated aortic dilatation. A trend towards an increased risk of BAV in FDRs was observed in the probands with previous AVS, whereas this risk seemed to be diminished in the probands with associated aortic dilatation. This latter finding does not support the restrictive ACC/AHA recommendation.

Familial Evaluation in Idiopathic Ventricular Fibrillation

Background: Familial cascade screening is well established in patients with heritable cardiac disease and in cases of sudden arrhythmic death syndrome. The clinical benefit of family screening in idiopathic ventricular fibrillation (IVF) is unknown. Methods: Patients with IVF were identified from national and institutional registries. All underwent systematic and comprehensive clinical evaluation to exclude identifiable causes of cardiac arrest with a minimum requirement of ECG, cardiac (echocardiogram or magnetic resonance imaging) and coronary imaging, exercise ECG, and sodium channel blocker provocation. Additional investigations including genetic testing were performed at the physician’s discretion. First-degree relatives who were assessed with at least a 12-lead ECG were included in the final cohort. Results of additional investigations, performed at the physician’s discretion, were also recorded. Results were coded as normal, abnormal, or minor findings. Results: We identified 201 first-degree relatives of 96 IVF patients. In addition to a 12-lead ECG, echocardiography was performed in 159 (79%) and ≥1 additional investigation in 162 (80%) relatives. An inherited arrhythmia syndrome was diagnosed in 5 (3%) individuals from 4 (4%) families. Two relatives hosted the DPP6 risk haplotype identified in a single proband, one of whom received a primary prevention implantable cardioverter defibrillator. In 3 separate families, an asymptomatic parent of the IVF proband developed a type 1 Brugada ECG pattern during sodium channel blocker provocation. All were managed with lifestyle measures only. The early repolarization (ER) ECG pattern was present in 16% probands and was more common in relatives in those families than those where the proband did not have early repolarization (25% versus 8%, P =0.04). Conclusions: The yield of family screening in relatives of IVF probands is low when the proband is comprehensively investigated. The significance of J wave syndromes in relatives and the role for systematic sodium channel blocker provocation are, however, uncertain and require further research.