This naming convention has also been adopted by The Ehlers Danlos Society (EDS, 2017), who previously used Villefranche nosology to classify EDS types. Unfortunately, no cure for EDS currently exists, and treatments may include physical therapy, braces, counseling, and pain medication.
Vascular EDS (vEDS) is characterized by “arterial aneurysm, dissection and rupture, bowel rupture, and rupture of the gravid uterus” and affects 1 in 50,000 to 200,000 individuals. These arterial aneurysms may be life threatening. As noted in the table above, this disorder is due to mutations in the COL3A1 or COL1A1 genes, with a sequence analysis of COL3A1 thought to identify approximately 98% of vEDS cases. A diagnosis depends on clinical features, including family history. Aneurysms occur in other types of EDS, including classical EDS (cEDS), due to vascular fragility. Johansen, et al. (2020) published a recent cross-sectional study with data collected from 18 patients with genetically verified vEDS and 34 patients with genetically verified LDS. The median age at diagnosis was 34 years. “Most respondents (87%) had cardiovascular surveillance visits, 58% yearly or more often, and still 29% had no antihypertensive medications.”
Loeys-Dietz syndrome
Loeys-Dietz syndrome (LDS) was first described in 2005 and is now considered an autosomal dominant connective tissue disorder characterized by “aortic aneurysms and generalized arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate.” LDS was initially characterized by mutations in the transforming growth factor β receptor I (TGFBR1) and transforming growth factor β receptor II (TGFBR2) genes; however, additional genes have been identified, including the mothers against decapentaplegic homolog 3 (SMAD3) gene, the transforming growth factor β 2 ligand (TGFB2) gene, and the transforming growth factor β 3 ligand (TGFB3) gene. If a mutation is identified in all three genes, transforming growth factor-β (TGF-β) signaling is affected and patients typically exhibit similar craniofacial, cutaneous, cardiovascular, and skeletal features. Vascular involvement in LDS has recently been studied by Jud and Hafner (2019) who published a case study which followed a woman with a history of ectasias of the aortic arch, abdominal aorta, carotid bulbs, and common femoral arteries, as well as an asymptomatic aneurysm in superior mesenteric artery. In comparing surgical outcomes between those with LDS versus MFS, it was found that LDS patients had a greater likelihood of reoperation for aortic arch aneurysms than MFS patients, and that those with mutations in TGFBR1 had higher rates of reoperation than those with TGFBR2 mutations.
Epidermolysis bullosa
Epidermolysis bullosa (EB) is a group of hereditary diseases characterized by mucosa and skin fragility due to mutations that affect skin structural proteins, causing the skin to easily blister. Four major types of EB have been identified and include EB simplex, junctional EB, dystrophic EB, and Kindler syndrome. Unfortunately, there is currently no effective therapeutic option for this disorder, and treatment largely focuses on wound management. All the major EB types may result from mutations in the keratin 5 (KRT5) or keratin 14 (KRT14) gene. These two genes work together to encourage strength in the epidermis. Mutations prevent the keratin from assembling in necessary networks, leading to fragility. Further, a rare type of EB, known as Ogna, has been associated with mutations in the PLEC gene, leading to issues in the attachment of the epidermis to other layers of the skin. Ryan, et al. (2016) note that ventricular dysfunction and aortic dilation have been identified in patients with recessive dystrophic EB.
Clinical Utility and Validity
More than 90% of patients with the typical Marfan phenotype have mutations involving the gene encoding the connective tissue protein fibrillin-1 (FBN1). Out of a sample of 93 patients with MFS, 85 (91%) were found to have a FBN1 mutation. The eight remaining patients did not display any drastically different clinical features or family history, and the authors suggest that FBN1 mutations that go undetected are due to technical limitations. Most patients have a family history of MFS, but up to 25% have a mutation de novo. Mutations are in one of five categories: nonsense, frameshift (deletion, insertion), splicing errors, a missense mutation that substitutes or creates cysteine residues, or a missense mutation affecting a conserved EGF sequence. Although the phenotypic variability is wide, mutations involving exon skipping tend to result in more severe disease. Genetic findings have importance in the diagnosis, risk stratification, and clinical management of patients, as well as identifying potentially affected relatives.
Becerra-Munoz et al. (2018) conducted a prospective cohort study to summarize variants in FBN1 and establish a genotype-phenotype correlation. Genotype-phenotype correlations have identified that patients with MFS and truncating variants in FBN1 presented a higher proportion of aortic events compared to a more benign course in patients with missense mutations. A total of 84 patients fulfilled the Ghent diagnostic criteria, and of these 84, 44 had missense mutations and 35 had truncating mutations. However, of the 44 with missense mutations, only six had suffered an aortic event (such as aortic aneurysm) whereas 20 of the 35 with a truncating mutation had suffered an aortic event. Up to 10% of patients with the Marfan phenotype have no identifiable mutation in the FBN1 gene. Rather, mutations are identified in TGF-beta receptor 1 (TGFBR1) and TGFBR2 genes. It has been proposed that patients with the Marfan phenotype and TGFBR1 or TGFBR2 mutations be classified as having LDS to properly address the potential for more aggressive vascular disease than seen in MFS.
The diagnosis of MFS is now established by an FBN1 pathogenic variant known to be associated with Marfan syndrome AND one of the following: aortic root enlargement (Z-score ≥2.0), ectopia lentis, demonstration of aortic root enlargement (Z-score ≥2.0) and ectopia lentis OR a defined combination of features throughout the body yielding a systemic score ≥7. These features are summarized in the 2010 Ghent nosology, which is slightly altered for patients under 20 years old. Due to the identification of FBN1 as the genetic basis for MFS and its subsequent effects, the understanding of MFS as a structural disorder has become one of a developmental abnormality with broad effects on the morphogenesis and function of multiple organ systems. Importantly, this also introduced new biological targets for treatment strategies in MFS.
Current clinical studies have elucidated a medical regimen for patients with MFS to help control the progression of cardiovascular manifestations and resulting mortality. The standard of care for medical management includes the use of β-blockers with supplementation or replacement by angiotensin receptor blockers (ARBs). However, the best course of treatment is a subject of ongoing research. However, a Cochrane review concluded, “Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan Syndrome, we could draw no definitive conclusions for clinical practice.” The authors concluded that further, high-quality, randomized trials were needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Sellers, et al. (2018) recently reported, “Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy.” Their mouse study suggested that “increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in.”
Johansen, et al. (2020); Ritelli et al. (2020); Shalhub, et al. (2020) analyzed vEDS data from 11 institutions between the year 2000 and 2015. Data used for this study included family history, clinical features, diagnostic criteria, demographics, and molecular testing results. A total of 173 individuals were identified for the purposes of this study, with 11 excluded because pathogenic COL3A1 variants were not identified. Of the remaining individuals, 86 had been diagnosed with a pathogenic COL3A1 variants, and 76 were diagnosed with only clinical criteria. “Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapses (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). .” This study highlights the importance of genetic testing for a vEDS diagnosis as the symptoms of vEDS overlap with many other disorders and a correct diagnosis is necessary for efficient disease treatment. Further, not all COL3A1 variants are pathogenic, meaning that genetic results must be interpreted by a trained professional.
Using a next-generation sequencing (NGS) multigene panel, Mariath, et al. (2019) identified 11 disease-causing variants of EB in a Brazilian population with an efficiency of 94.3%. Other studies that they have included have calculated efficiencies of 83.5% for a panel with 21 genes, 90% with 49 genes, and 97.7% in 21 genes, where all identified mutations were only in five genes. This conveys the clinical utility of gene variants in EB that could be translated to other connective tissue disorder mutations. In a study done with children with inherited EB, the accuracy of several diagnostic techniques, which included electron microscopy (EM), immunofluorescence mapping (IFM), and clinical provisional diagnosis (CPD) was evaluated. It was found that IFM, EM, and CPD yielded an accuracy of 75%, 75%, and 81.5%, respectively. All genetic components, tissue specimen, and clinical history are all necessary for a confirmed EB diagnosis.
Li, et al. (2021) conducted a study in northwestern China to determine the genotype-phenotype correlation for thoracic aortic aneurysm and dissection via NGS. They screened 15 genes from 212 patients to find that 67 (31.60%) patients in this cohort had a (likely) pathogenic variant, “42 (19.81%) had a variant of uncertain significance (VUS), and 103 (48.58%) had no variant (likely benign/benign/negative),” with 135 reportable variants. With FBN1, a gene implicated in MFS, they found that “patients with truncating and splicing mutations are more prone to developing severe aortic dissection than those with missense mutations, especially frameshift mutations (82.76% vs. 42.86%),” and “the positive rate of genetic testing was higher in TAAD [thoracic aortic aneurysm and dissection] patients with family history than in those without (76.74% vs. 18.94%)”.
Chen, et al. (2021) investigated how genetic testing could aid in avoiding the occurrence of MFS among Chinese families. Using data from 11 families, as well as variant classification and interpretation through pedigree analysis, the researchers were able to support two families who agreed to pre-implantation genetic testing for monogenic diseases (PGT-M) as part of the in vitro fertilization process. They were able to identify 11 potential-disease causing FBN1 variants and found that “nine variants were classified as likely pathogenic/pathogenic variants. Among 11 variants, eight variants were missense and seven of them were located in the Ca-binding EGF-like motifs. Moreover, half of them substituted conserved Cysteine residues.” They also found one splice site variant, one frameshift variant, one synonymous variant, and two de novo variants. All variants were detected by polymerase chain reaction (PCR). Ultimately, the two MFS families were able to give birth to a baby without the FBN1 mutation, as the healthy embryo was selected using haplotype analysis “to deduce the embryo’s genotype by using single nucleotide polymorphisms.” This demonstrated the tangible benefits of genetic testing for eliminating MFS and the development of comorbid conditions among future generations.
Damseh, et al. (2022) conducted a retrospective study using the 2017 EDS classification criteria on 72 pediatric patients who were referred for evaluation of EDS. From this initial cohort, 18 patients met the clinical criteria for an EDS subtype diagnosis, and 15 were confirmed molecularly. 75% (n=54) of the patients also had clinical features that belonged to EDS and other joint hypermobility syndromes, but not a complete qualification of EDS clinical criteria. From those 54 patients, it was discovered that 12 patients (22%) had a molecular genetic diagnosis of EDS. An EDS genetic panel, microarray, whole exome sequencing, single gene sequencing, familial variant testing, and other genetic panels were utilized to confirm genetic based diagnoses of EDS. Of the 15 patients who met clinical criteria and had a positive molecular diagnosis and 12 that did not meet clinical criteria but had a positive molecular diagnosis, 41% had classical EDS, 26% had arthrochalasia EDS, 11% had kyphoscoliotic EDS, and 22% had vascular EDS. The researchers ultimately “observed a correlation between generalized joint hypermobility, poor healing, easy bruising, atrophic scars, skin hyperextensibility, and developmental dysplasia of the hip with a positive molecular result.” This study aided in expanding the scope of the 2017 EDS classifications into the pediatric population and effecting changes to clinical decision making and treatment.
Veatch, et al. (2022) utilized clinical exam data and genetic testing results to understand the phenotypic and genotypic correlation for hereditary connective tissue diseases from 2016-2020. From a cohort of 100 unrelated individuals, the researchers isolated six likely pathogenic, and 35 classified “potentially pathogenic variants of unknown clinical significance.” They found that those with potentially pathogenic variants and pathogenic/likely pathogenic variants of the same genes exhibited similar symptoms, as those with “connective tissue symptoms had suggestive evidence of increased odds of having skin (odds ratio 2.18, 95% confidence interval 1.12 to 4.24) and eye symptoms (odds ratio 1.89, 95% confidence interval 0.98 to 3.66) requiring further studies.” Ultimately, the symptoms were broken up into classes of minimal skeletal symptoms (e.g., limb asymmetry, scoliosis, pes planus), more skeletal than connective tissue (e.g., joint hypermobility, dental defects, repeated ligament and cartilage disease), nervous, or gastrointestinal (e.g., irritable bowel syndrome, food intolerance) symptoms, and more nervous system (e.g., migraines, neuropathy) symptoms. Comprehending the spectrum of phenotypic heterogeneity could guide consequential clinical decision making for surveilling and counseling patients with hereditary connective tissue disorders and their current and future families.