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Background Rare diseases are often complex, chronic and many of them life-shortening. In Germany, healthcare for rare diseases is organized in expert centers for rare diseases. Most patients additionally have regional general practicioners and specialists for basic medical care. Thus, collaboration and information exchange between sectors is highly relevant. Our study focuses on the patient and caregiver perspective on intersectoral and interdisciplinary care between local healthcare professionals (HCPs) and centers for rare diseases in Germany. The aims were (1) to investigate patients’ and caregivers’ general experience of healthcare, (2) to analyse patients’ and caregivers’ perception of collaboration and cooperation between local healthcare professionals and expert centers for rare diseases and (3) to investigate patients’ and caregivers’ satisfaction with healthcare in the expert centers for rare diseases. Results In total 299 individuals of whom 176 were patients and 123 were caregivers to pediatric patients participated in a survey using a questionnaire comprising several instruments and constructs. Fifty participants were additionally interviewed using a semistructured guideline. Most patients reported to receive written information about their care, have a contact person for medical issues and experienced interdisciplinary exchange within the centers for rare diseases. Patients and caregivers in our sample were mainly satisfied with the healthcare in the centers for rare diseases. The qualitative interviews showed a rather mixed picture including experiences of uncoordinated care, low engagement and communication difficulties between professionals of different sectors. Patients reported several factors that influenced the organization and quality of healthcare e.g. engagement and health literacy in patients or engagement of HCPs. Conclusions Our findings indicate the high relevance of transferring affected patients to specialized care as fast as possible to provide best medical treatment and increase patient satisfaction. Intersectoral collaboration should exceed written information exchange and should unburden patients of being and feeling responsible for communication between sectors and specialists. Results indicate a lack of inclusion of psychosocial aspects in routine care, which suggests opportunities for necessary improvements.

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1 . We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1 . Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype–phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1 -negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).

SARS-CoV-2 is still a major burden for global health despite effective vaccines. With the reduction of social distancing measures, infection rates are increasing in children, while data on the pediatric immune response to SARS-CoV-2 infection is still lacking. Although the typical disease course in children has been mild, emerging variants may present new challenges in this age group. Peripheral blood mononuclear cells (PBMC) from 51 convalescent children, 24 seronegative siblings from early 2020, and 51 unexposed controls were stimulated with SARS-CoV-2-derived peptide MegaPools from the ancestral and beta variants. Flow cytometric determination of activation-induced markers and secreted cytokines were used to quantify the CD4+ T cell response. The average time after infection was over 80 days. CD4+ T cell responses were detected in 61% of convalescent children and were markedly reduced in preschool children. Cross-reactive T cells for the SARS-CoV-2 beta variant were identified in 45% of cases after infection with an ancestral SARS-CoV-2 variant. The CD4+ T cell response was accompanied most predominantly by IFN-γ and Granzyme B secretion. An antiviral CD4+ T cell response was present in children after ancestral SARS-CoV-2 infection, which was reduced in the youngest age group. We detected significant cross-reactivity of CD4+ T cell responses to the more recently evolved immune-escaping beta variant. Our findings have epidemiologic relevance for children regarding novel viral variants of concern and vaccination efforts.

Background: Severe neonatal Ebstein’s anomaly (EA) is associated with a high risk of mortality. A new therapeutic approach aims to combine the advantages of Starnes’ procedure in stabilizing critically ill neonates with the long-term superiority of biventricular physiology after cone reconstruction. Case report: The echocardiography of a male preterm (36 weeks’ gestation; birth weight 2400 g) demonstrated EA Carpentier type C, membranous pulmonary atresia, and hypoplastic pulmonary arteries (PAs). After undergoing the Starnes procedure postnatally, multiple dilatations of the AP shunt and the Starnes fenestration followed. Cone reconstruction was performed at 15 months of age. Surgical revision addressed tricuspid and pulmonary valve insufficiency and PA bifurcation stenosis. Subsequently, PA branch stenosis with severe impairment of right ventricular function and dilatation required stent implantation. At the last follow-up, at 3 years of age, the patient was asymptomatic with sufficient exercise tolerance. Discussion: The American Association for Thoracic Surgery recently recommended evaluating all Starnes patients for potential conversion to cone. Consequently, the Starnes procedure should be modified to facilitate subsequent biventricular correction. Both the optimal timing of conversion and the appropriate assessment to reliably evaluate feasibility and the prospects for success require further investigation. Conclusions: Conversion from Starnes to cone is technically feasible, even in cases of severe EA, prematurity, low birth weight, and additional cardiac comorbidities, and provides promising initial results. Further research is needed to define candidacy and the optimal timing of conversion, and to assess long-term outcomes. The high therapeutic effort and complexity make this treatment approach suitable only for quaternary centers.

Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Coinjection of human CDKL1wild-type RNA, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularly with ciliary transport molecules. Expression of CDKL1 variants in heterologous cells interfered with cilia formation and length, CDKL1 localization, and p38 MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

Purpose Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. Methods We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. Results We identified 1 pathogenic variant (PV; in FBN1 or SMAD3 ) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1 , FBN1 , FBN2 , LOX , MYH11 , SMAD3 , TGFBR1 , or TGFBR2 ) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. Conclusion Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

Objectives Cardiovascular pathology, including aortic root dilation at the level of sinus of Valsalva (SV), is one of the major causes of morbidity in paediatric patients with Marfan syndrome (MFS). β-Blocker (BB) is well established to slow aortic dilation in MFS. Less is known about the effectiveness of angiotensin II receptor blocker (ARB) on aortic dilation in paediatric patients with MFS. Methods 215 patients with MFS (9.01±5.7 years) were subject to a standardised diagnostic programme. Aortic root dilation was evaluated and followed up by echocardiography. In 48 cases, BB and ARB effects on aortic root dilation were evaluated. Effect of treatment was measured by comparison of z scores of SV before and after treatment initiation. Results Treatment by ARB and BB leads to significant reduction of SV dilation (p<0.05). The deviation of SV enlargement from normal as expressed by the rate of change in z scores was significantly reduced by a mean difference of −0.56±0.71 z scores (p<0.001) under ARB therapy and by a mean difference of −0.35±0.68 z scores (p<0.05) under BB therapy. The prophylactic effect of ARB and BB on aortic root dilation is similar in both groups (p>0.05). Conclusions Both concepts lead to a significant reduction of SV dilation. The effect of ARB and BB is similar. This is the first study concerning the comparison of ARB and BB in previously untreated paediatric patients with MFS. The results of the study show that both treatment strategies are beneficial in paediatric and adolescent 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.

Due to age dependent organ manifestation, diagnosis of Marfan syndrome (MFS) is a challenge, especially in childhood. It is important to identify children at risk of MFS as soon as possible to direct those to appropriate treatment but also to avoid stigmatization due to false diagnosis. We published the Kid-Short Marfan Score (Kid-SMS) in 2012 to stratify the pre-test probability of MFS in childhood. Hence we now evaluate the predictive performance of Kid-SMS in a new cohort of children. We prospectively investigated 106 patients who were suspected of having MFS. At baseline, children were examined according to Kid-SMS. At baseline and follow-up visit, diagnosis of MFS was established or rejected using standard current diagnostic criteria according to the revised Ghent Criteria (Ghent-2). At baseline 43 patients were identified with a risk of MFS according to Kid-SMS whereas 21 patients had Ghent-2 diagnosis of MFS. Sensitivity was 100%, specificity 77%, negative predictive value 100% and Likelihood ratio of Kid-SMS 4.3. During follow-up period, three other patients with a stratified risk for MFS were diagnosed according to Ghent-2. We confirm very good predictive performance of Kid-SMS with excellent sensitivity and negative predictive value but restricted specificity. Kid-SMS avoids stigmatization due to diagnosis of MFS and thus restriction to quality of life. Especially outpatient pediatricians and pediatric cardiologists can use it for primary assessment.

Background Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). Methods We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. Results MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86–1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P  < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P  < .001), and no patient required surgery. Mean MPA-r were increased in MFS ( P  < .001), but ratios >1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P  = .161). MPA-r related to aortic root diameters ( P  = .042), reduced left ventricular ejection fraction ( P  = .006), and increased pulmonary artery systolic pressures ( P  = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. Conclusions We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP.