Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany - a mixed-methods study.

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.

Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype.

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).

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.

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.

Ocular manifestation in Marfan syndrome: corneal biomechanical properties relate to increased systemic score points.

PURPOSE: To evaluate corneal deformation to an air puff as a new noninvasive tool to document disease status in Marfan syndrome (MFS) METHODS: Prospective observational cohort study. We included patients diagnosed with MFS who had their routine cardiovascular follow-up and applied the revised Ghent nosology to define two subgroups according to a high (≥ 7) and a low (< 7 points) systemic score. Dynamic Scheimpflug-based biomechanical analyses (CorvisST® [CST; Oculus GmbH]) were performed. The main outcome measure was the displacement of the corneal apex as given by the parameters highest concavity (HC; in ms), peak distance (PD; in mm), and highest concavity deformation amplitude (DA; mm). RESULTS: Forty-three eyes of 43 individuals (19 female, 24 male; mean age 42.0 ± 12.0 years, range 18-67 years) diagnosed with MFS were included. Applying the Ghent criteria, 21 patients had an advanced systemic score of ≥ 7, and 22 had score points < 7. There were no differences in age or sex between both groups. In contrast, HC was faster (P = 0.004), and PD (P < 0.001) was longer in those individuals with systemic score ≥ 7; maximum DA did not result in a statistically significant difference between the groups (P = 0.250). CONCLUSIONS: In vivo noninvasive biomechanical analyses with CST offer a new, non-invasive method to identify pathologic corneal deformation responses in adults with MFS. In the future, corneal deformation to an air puff could thus assist early identification of patients with high Ghent score as an adjunct to existing diagnostic tests.

Diagnostic accuracy study of routine echocardiography for bicuspid aortic valve: a retrospective study and meta-analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is the standard procedure to distinguish tricuspid aortic valve (TAV) from bicuspid aortic valve (BAV). Published studies assessed the accuracy of TTE for BAV under ideal conditions. Conversely, we aimed at assessing accuracy of TTE for BAV under routine conditions. METHODS: This retrospective, cross-sectional study of 216 adults included 132 men aged 62±14 years. Of these, 108 had BAV and 108 were age-matched individuals with TAV. All diagnoses were confirmed at surgery. We assessed TTE in two patient groups. First, in the (I) group of all 216 individuals, where we assessed accuracy for BAV according to the original diagnoses as documented by the primary investigators during original TTE examination. Second, we assessed accuracy for BAV according to expert re-evaluation in (II) all 158 TTE with availability of original recordings. Third, we performed a meta-analysis of published results on the accuracy of TTE for BAV according to PRISMA standards. RESULTS: Sensitivity, specificity and accuracy of (I) primary investigators was 46.3%, 97.2, and 71.8% as compared to (II) expert re-evaluation with 59.7%, 93%, and 77.8%, respectively. Sensitivity was significantly higher at re-evaluation (P<0.001). TTE at a non-tertiary care center (P=0.012), presence of aortic aneurysm (P=0.001) and presence of severe aortic valve calcification (P=0.003) predicted an inaccurate diagnosis of BAV. Conversely, meta-analysis of published TTE studies identified a pooled sensitivity of 87.7% and a pooled specificity of 88.3% for BAV. CONCLUSIONS: The current study shows that TTE yields almost ideal diagnostic accuracy when ideal investigators examine ideal patients. However, the study also shows that TTE yields suboptimal diagnostic accuracy under routine conditions. TTE in non-tertiary care settings, concomitant aortic aneurysm, and presence of severe aortic valve calcification predict an inaccurate diagnosis of BAV.

Warfarin anticoagulation in acute type A aortic dissection survivors (WATAS).

BACKGROUND: Early survivors of acute type A aortic dissection (AAAD) remain at risk for late death and late aortic events. However, the frequency and long-term effects of warfarin anticoagulation on long-term outcome in post-surgical AAAD survivors have not been elucidated. METHODS: Two tertiary care centers performed a retrospective observational cohort study of warfarin anticoagulation in AAAD in 243 persons with early survival of surgical repair (WATAS). Serial postoperative tomographic imaging was available in 106 persons. RESULTS: A total of 88 postoperative AAAD survivors (36%) were on long-term warfarin anticoagulation. The indication for anticoagulation was a mechanical aortic prosthesis in 46 (52%), atrial fibrillation in 33 (38%), stroke in 7 (8%), and pulmonary embolism in 1 (1%). The indication for anticoagulation remained unclear in 1 person (1%). Survival and aortic event free survival were 98.3±0.01 and 98.7±0.01 at 1 year, and 76.4±0.03 and 91.8±0.02 at 5 years, respectively, with no differences irrespective of warfarin anticoagulation. Multivariate Cox regression analysis established higher age (P<0.001), and operation extending into the descending aorta (P=0.030) as independent predictors of late death. Follow-up without tomographic imaging independently predicted increased long-term mortality (P<0.001) and lower rates of documented aortic events (P=0.003). Kaplan-Meyer analysis showed a relationship of aortic diameter growth ≥0.5 cm per year with late death (P=0.041) and with late aortic events (P<0.001). However, rapid aortic growth did not relate to warfarin anticoagulation. CONCLUSIONS: Warfarin anticoagulation is frequent in postsurgical AAAD and it is administered for vital indications. Warfarin anticoagulation does not relate to late mortality or to late aortic events. Rapid aortic growth predicts late mortality and late aortic events, but warfarin anticoagulation is not associated with aortic growth. Follow-up tomographic imaging is mandatory for long-term survival after surgical repair of AAAD.

The role of the multidisciplinary health care team in the management of patients with Marfan syndrome.

Marfan syndrome (MFS) is a rare, severe, chronic, life-threatening disease with multiorgan involvement that requires optimal multidisciplinary care to normalize both prognosis and quality of life. In this article, each key team member of all the medical disciplines of a multidisciplinary health care team at the Hamburg Marfan center gives a personal account of his or her contribution in the management of patients with MFS. The authors show how, with the support of health care managers, key team members organize themselves in an organizational structure to create a common meaning, to maximize therapeutic success for patients with MFS. First, we show how the initiative and collaboration of patient representatives, scientists, and physicians resulted in the foundation of Marfan centers, initially in the US and later in Germany, and how and why such centers evolved over time. Then, we elucidate the three main structural elements; a team of coordinators, core disciplines, and auxiliary disciplines of health care. Moreover, we explain how a multidisciplinary health care team integrates into many other health care structures of a university medical center, including external quality assurance; quality management system; clinical risk management; center for rare diseases; aorta center; health care teams for pregnancy, for neonates, and for rehabilitation; and in structures for patient centeredness. We provide accounts of medical goals and standards for each core discipline, including pediatricians, pediatric cardiologists, cardiologists, human geneticists, heart surgeons, vascular surgeons, vascular interventionists, orthopedic surgeons, ophthalmologists, and nurses; and of auxiliary disciplines including forensic pathologists, radiologists, rhythmologists, pulmonologists, sleep specialists, orthodontists, dentists, neurologists, obstetric surgeons, psychiatrist/psychologist, and rehabilitation specialists. We conclude that a multidisciplinary health care team is a means to maximize therapeutic success.

Economic and care considerations of Marfan syndrome.

INTRODUCTION: Marfan syndrome is a rare multisystem disease of the connective tissue, which affects multiple organ systems. advances in healthcare have doubled the life-expectancy of patients over the past three decades. to date, there is no comprehensive review that consolidates economic considerations and care for marfan patients. Areas covered: Present research suggests that there may be a link between treatment pattern, disease progression and economic costs of Marfan syndrome. It indicates that an early detection of the disease and preventive interventions achieve a dual aim. From a patient perspective, it may reduce the amount of emergency surgery or intervention, and inpatient stays. In addition, it slows disease progression, lowers lifestyle restrictions, reduces psychological stress, and improves health-related quality of life. Expert commentary: Early detection and preventive measures are likely to achieve a dual aim by simultaneously containing costs and reducing the number and length of inpatient stays.

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse.

BACKGROUND: Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. METHODS: This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 ± 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 ± 15 years with mean follow-up of 66 ± 49 months. RESULTS: At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .017) as independent predictors of mitral valve surgery. CONCLUSIONS: The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome.

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.

The main pulmonary artery in adults: a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome.

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.