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The purpose of this study is to evaluate the diagnostic and therapeutic yield of a specialized clinic for children with suspicion of a hereditary thoracic aortic disease (HTAD), including Marfan Syndrome (MFS), and to investigate the diagnostic value of presenting symptoms and findings during evaluation. This retrospective observational study included all patients younger than 18 years old at initial referral between 1998 and 2018. Clinical data, medical treatment, surgical interventions, and clinical events during surveillance were collected until December 2023. A case-control comparison between patients with and without an eventual diagnosis of HTAD was performed using logistic regression analysis to investigate the diagnostic value of collected variables. A total of 355 children were referred and evaluated at the clinic, resulting in 89 new diagnoses, with a diagnostic yield of 21% HTAD, including 59 cases of MFS. Younger age at referral, ectopia lentis, aortic dilatation, and facial features were among the strongest predictors of MFS and other HTAD, while pectus excavatum and arm span-height ratio had no predictive value at childhood age. Of patients with MFS, 65% received antihypertensive medication, and 8% of patients with HTAD underwent prophylactic aortic surgery, in some cases even during childhood. Conclusion: Evaluation of children for HTAD in our specialized Marfan clinic resulted in a high diagnostic yield and subsequent therapeutic implications. Indeed, early recognition of symptoms and signs and referral to such a specialized clinic may lead to early diagnosis, surveillance, and timely treatment, thereby possibly limiting acute aortic events and even mortality. [ABSTRACT FROM AUTHOR]

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS‐related height increase across populations. Height and weight data of individuals with MFS aged 0–21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype–phenotype relationships, FBN1 variant type was included as an independent variable in height‐for‐age and BMI‐for‐age models. MFS‐related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height‐for‐age, BMI‐for‐age, and weight‐for‐height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1‐HI variants were associated with taller height in both sexes, and decreased BMI in females (p‐values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS. [ABSTRACT FROM AUTHOR]

Disease‐causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross‐sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease‐causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high‐arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy‐related complications. Nevertheless, homozygosity may be driving a more severe phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients. [ABSTRACT FROM AUTHOR]