Veronika C. Stark

Background/Objectives: Cardiovascular manifestations in pediatric Marfan syndrome (MFS) exhibit substantial heterogeneity. Early identification of patients at elevated risk of requiring cardiac surgery is essential to optimizing outcomes. This study aimed to determine phenotypic features associated with cardiovascular surgery in genetically confirmed pediatric MFS. Methods: Among the 1006 children evaluated, 214 with genetically verified MFS were included in the analysis. We categorized patients by the presence or absence of cardiac surgery during childhood. Systemic and cardiovascular features were assessed. We applied binary logistic regression to identify independent associated manifestations with surgical intervention. Results: 20/214 patients (9.3%, 11.5 ± 5.5 years) underwent cardiac surgery (50% aortic root replacement, 20% mitral valve surgery, 30% combined interventions). Extracardiac features—Marfan-type facial features, pectus carinatum, pes planus, hindfoot deformity, and myopia of ≥3 diopters—were significantly associated with an increased probability of surgery (OR 3.0–4.6). Tricuspid valve prolapse and pulmonary artery dilatation were more prevalent in surgical patients. Surgical patients exhibited higher systemic manifestation scores (9.2 vs. 5.2; p ≤ 0.05) per revised Ghent criteria (RGC). Conclusions: A higher systemic score (RGC) correlates with increased risk for surgery. Marfan-type facial features, pectus carinatum, pes planus, hindfoot deformity, and myopia ≥ 3 diopters were strongly associated with the need for early cardiac surgery. Comprehensive phenotypic assessment, including systemic manifestation scoring, enables risk stratification and supports timely surgical planning in pediatric MFS.

Background/Objectives: Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease that presents particular therapeutic challenges in children. It is characterized by pulmonary vasoconstriction and vascular remodeling, leading to right ventricular strain and eventually right heart failure. Although advances in pharmacotherapy have improved outcomes, treatment options remain limited. This review aims to evaluate the potential role of sotatercept, a novel fusion protein recently approved for adult PAH, and to assess the translatability of adult data to the pediatric population. Methods: A narrative synthesis of preclinical studies and randomized controlled trials was conducted to summarize the current evidence on sotatercept. In addition, pathophysiological, developmental, and therapeutic differences between adult and pediatric PAH were critically examined to assess relevance and applicability to younger patients. Results: Clinical trials in adults (PULSAR, STELLAR, ZENITH, HYPERION) confirm sotatercept’s efficacy on background therapy, with significant reductions in pulmonary vascular resistance, improvements in 6 min walk distance, enhanced right ventricular function, and risk reductions in clinical worsening events. However, extrapolation to pediatric PAH faces challenges including etiological differences (e.g., PAH-CHD predominance, PPHN in infants), age-inappropriate endpoints (e.g., 6MWD infeasible in young children), variable growth-related pharmacokinetics, and compensatory RV physiology delaying overt failure. Safety concerns are manageable in adults but raise pediatric-specific alarms: activin inhibition’s theoretical tumorigenic potential (dual tumor suppressor/promoter role), pubertal/fertility disruption (FSH suppression, gonadal maturation delay), and skeletal growth interference—unproven clinically yet demanding long-term monitoring. The ongoing MOONBEAM trial will provide initial pharmacokinetic/safety data in children. Conclusions: Sotatercept represents a promising, first-in-class therapeutic option for PAH with the potential to transform disease management. Nevertheless, dedicated pediatric studies are crucial to confirm safety, efficacy, and appropriate dosing and to define its role in the long-term treatment of children with PAH.

BACKGROUND: Heterozygous pathogenic variants in the central region (exon 23–34) of FBN2 cause a hereditary connective tissue disorder named congenital contractural arachnodactyly, which presents with obligatory skeletal features but rarely with vascular manifestations. Scarce data exist on the association between FBN2 variants and aortic disease. This study aimed to investigate whether the location of FBN2 variants correlates with distinct clinical features, including aortic disease. METHODS: In this case-controlled cohort study, we ascertained clinical features, sequenced 62 (candidate) disease genes, and classified variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines in 392 patients with suspected connective tissue or thoracic aortic diseases. We summarized our results and published data and compared clinical manifestations between patients with variants outside and within the central region of FBN2 . RESULTS: Heterozygous FBN2 variants outside the central region were identified in 10 patients from 5 families. Two variants were of uncertain significance, 1 was likely pathogenic, and 2 were pathogenic. A total of 60% of these patients had thoracic aortic disease, but only 20% were diagnosed with congenital contractural arachnodactyly according to an established clinical scoring system. Combined data from the literature and this study revealed that patients with FBN2 variants outside the central region presented with aortic dilatation (55.0% versus 9.9%; P P =0.011) compared with those with central region variants. CONCLUSIONS: Our results suggest that heterozygous FBN2 variants outside the central region predispose individuals to thoracic aortic disease and are less associated with the typical clinical presentation of congenital contractural arachnodactyly than pathogenic variants in the FBN2 central region.

Introduction: Transforming growth factor β (TGFβ) metabolism plays an important role in the pathogenesis of Marfan syndrome (MFS). Accordingly, drug therapy uses TGFβ receptor blockade to slow down the cardiovascular manifestations, above all aortic root dilatation. Angiotensin II type 1 receptor blockers (ARBs) have been shown to reduce TGFβ levels in adults. Data on childhood are lacking and are now being investigated in the TiGer For Kids study presented here.Methods: We examined 125 children without chronic disease and 31 pediatric Marfan patients with a proven FBN1 variant with regard to TGFβ levels. In addition, we measured TGFβ levels during the initiation of ARB therapy in pediatric Marfan patients.Results: In children without chronic disease, TGFβ levels were found to decrease from childhood to adolescence (p < 0.0125). We could not measure a relevantly increased TGFβ level in pediatric Marfan patients. However, we showed a significant suppression of the TGFβ level after treatment with ARBs (p < 0.0125) and a renewed increase shortly before the next dose.Discussion: The TGFβ level in childhood changes in an age-dependent manner and decreases with age. The TGFβ level drops significantly after taking ARBs. Based on our experience and data, a TGFβ receptor blockade in childhood seems reasonable. So far, TGFβ level cannot be used as an MFS screening biomarker.

Aim In Marfan syndrome, various cardiovascular pathologies, such as aortic dilatation and mitral valve pathologies, already occur in childhood and determine course of the disease. This study aimed to establish additional cardiovascular risk markers for severe Marfan phenotypes. We investigated tricuspid valve prolapse (TVP) and its predictive value for outcome of paediatric Marfan disease. Methods In this retrospective, observational cohort study we identified 130 paediatric Marfan patients (10.7±4.8 years) with FBN1 variants. We divided patients into two groups based on TVP presence and performed a cross-sectional analysis to investigate the association of TVP with other cardiovascular, ocular and systemic pathologies, at first and last visit. A longitudinal analysis was performed with follow-up data. Results At baseline, patients with TVP had higher incidence of aortic root dilatation (p=0.013), mitral valve prolapse (p=0.0001), and systemic manifestations (p=0.025) than patients without TVP. At follow-up, previous presence of TVP predicted higher probability of aortic root dilatation (p=0.002), mitral valve prolapse (p=0.0001), and systemic manifestations (p=0.002). Conclusion This shows that TVP is linked to both cardiac and extracardiac Marfan manifestations and TVP is an important marker for a disease severity in these children. Therefore, TVP should be assessed routinely using echocardiography in paediatric Marfan patients.

Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype–phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child.

Background: Care for patients with Marfan syndrome (MFS) has improved substantially in recent decades. Increasing clinical knowledge and genetic analysis allow early diagnosis of the disease in childhood. Because of the earlier initiation to preventive and medical treatment, patients’ life expectancy has risen. To ensure optimal care, pediatric patients require a safe follow-up regime, multidisciplinary care, and a safe transition to adult care. Methods: We collected a sample of 149 pediatric Marfan patients, of whom 34 patients had already been transferred to adult care or who were currently transitioning. First, we evaluated clinical aspects of patients that manifest in childhood and are present in the transition process. Second, we analyzed the transition process itself. Results: We found age-dependent manifestation of organ pathologies. Dilatation of the sinus of Valsalva showed a particularly high prevalence during the transition process and 62% of patients required medical treatment. Mean onset of aortic root dilatation was 9.9±5.8 years. Concerning systemic manifestation in MFS skin striae, wrist and thumb sign, and reduced elbow extension occurred significantly more often in patients who were transitioning than in younger children with MFS. All other clinical Marfan features showed an increased prevalence in patients who were transitioning compared with younger patients. In our cohort, transition was successful in 20 patients (58.9%), 12 patients (35.3%) are still in the transition process and 2 patients (5.9%) were lost to follow up. Conclusions: Marfan patients in the transition process are already under a chronic disease condition with a high onset of especially cardiovascular pathologies. Although early medical treatment in childhood is effective, the pathologies of the connective tissue require lifelong attention and influence life in many ways. The big challenge during transition is the double change of responsibility from the parents and pediatric doctor to the patient and adult doctor. Consequently, patients in transition process require special attention and close contact with the doctor and the family. A reevaluation by the supervising pediatric Marfan specialist of the successful transition to adult care is indispensable before the pediatric care of Marfan patients is completed.

Aortic root dilatation and its complications are known to be the most important and life limiting features in patients with Marfan syndrome (MFS). Since monitoring of patients, preventive medical and surgical treatments are available nowadays, other MFS pathologies are becoming more relevant for the outcome of the disease. Main pulmonary artery (MPA) dilatation is a cardiac finding, which has not been fully investigated in children. Due to the similarities in tissue composition of the aortic and pulmonary root, MPA dilatation may cause complications and require treatment. In addition, it may be a predictor for severe connective tissue involvement. We retrospectively examined 135 pediatric patients with MFS. 8.1% showed MPA dilatation. MPA dilatation was associated with earlier occurrence of aortic dilatation, mitral valve prolapse, and systemic manifestations of MFS compared with patients without MPA dilatation (p < 0.05). The presence of MPA dilatation was also associated with a higher incidence of ectopia lentis (p < 0.05). Medical treatment was started earlier in MPA dilatation patients than in those without (p < 0.05). We conclude that MPA dilatation is a sign of more severe vascular and connective tissue involvement. Regular examination of the pulmonary artery is essential in MFS to avoid complications. As medical treatment of life threatening MFS events has improved, other features of MFS need to be investigated to improve quality of life.

Alveolar capillary dysplasia (ACD) is a rare neonatal lung disease characterized anatomically by a defective and hypoplastic development of pulmonary alveoli leading to persistent pulmonary hypertension (PPHN) and finally lethal respiratory failure. It is often associated with congenital left heart obstruction. Given the fatal prognosis an early diagnosis is important. However, due to the fast onset of PPHN in neonates and lack of pathognomonic signs for its cause, safe and fast detection of ACD is challenging. Therefore, following the exclusion of cardiac and common pulmonary causes, lung biopsy becomes essential for diagnosis. We hereby report a case of ACD with atrial septal defect type one and hypoplastic aortic arch with an ante-mortem diagnosis and discuss the current state of medicine in relation to ACD.

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