Adults with Loeys–Dietz syndrome and vascular Ehlers–Danlos syndrome: A cross‐sectional study of health burden perspectives

The aim is to study adults with vascular Ehlers–Danlos syndrome (vEDS) and Loeys–Dietz syndrome (LDS) with regard to sociodemographic characteristics, perceived vascular‐ and multi‐organ symptom burdens, and health services utilization. This is a cross‐sectional study. In 2018, a postal questionnaire was sent to 71 individuals with genetically verified LDS types 1–4 or vEDS, age ≥ 18 years, recruited through a National Resource Centre for Rare Disorders in Norway. Eighteen patients with vEDS and 34 patients with LDS subtypes 1‐4 participated, the response rate was 74%. Median age was 43.5 (range 18‐68) years, and 58% were women. Median age at diagnosis was 34 years (range: 6–63). Severe vascular‐ and multi‐organ symptom burdens were found, and chronic pain was reported by 79%. Most respondents (87%) had cardiovascular surveillance visits, 58% yearly or more often, and still 29% had no antihypertensive medications. Three quarters communicated diagnosis‐related concerns with their general practitioner. A considerable group (31%) had left work before retirement age. Healthcare professionals should be aware of the spectrum of health burden in adults with vEDS and LDS. A verification of the diagnosis is crucial to counseling, including medical follow‐up, education, and work, and advices on precaution and life style decisions.     

Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date

The Ehlers–Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers–Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.     

Ehlers–Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia

Some variants that cause autosomal‐recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers–Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21‐hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin‐X, an extracellular matrix protein. Two types of CAH tenascin‐X (CAH‐X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH‐X CH‐1 has a TNXB exon 35 120‐bp deletion resulting in haploinsufficiency, and CAH‐X CH‐2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant‐negative effect. We present here three patients with biallelic CAH‐X and identify a novel dominant‐negative chimera termed CAH‐X CH‐3. Compared with monoallelic CAH‐X, biallelic CAH‐X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin‐X function and computational data linking the type of TNXB variant to disease severity.     

Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers–Danlos syndrome

Vascular Ehlers–Danlos syndrome (vEDS) is a connective tissue disorder due to defective type III collagen production and is associated with arterial rupture, spontaneous intestinal perforation, and gravid uterine rupture. Spontaneous pneumothorax and/or hemothorax (P/HTX) also occurs in vEDS patients. The temporal relation of pulmonary manifestations to arterial and intestinal complications in vEDS has not been well described. This was investigated in a multi‐institutional retrospective case series of vEDS patients with confirmatory testing for COL3A1 mutation between 2000 and 2012. Data abstracted included demographics, family histories, presentation, and management of associated complications. Ninety‐six cases (39% males, mean age 38.6 ± 15.5 years, range 8–79) had confirmatory testing for vEDS. P/HTX was documented in 17 (17.7%) cases. Most P/HTX preceded the diagnosis of vEDS (81%). Diagnosis of vEDS was made after arterial or intestinal complications at a mean of 7 years (range 0–26) post the initial P/HTX. In conclusion, spontaneous P/HTX is an early manifestation of vEDS frequently preceding an arterial complication or intestinal perforation. Thus, a spontaneous P/HTX in a young patient should trigger a differential diagnosis that includes vEDS. This should lead to an investigation of other vEDS features and subsequent genetic testing if vEDS features are present.     

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.     

Amniotic band sequence in paternal half‐siblings with vascular Ehlers–Danlos syndrome

Familial amniotic band sequence (ABS) is rare but has been reported in the offspring of mothers with connective tissue disorders. We present a family of two half‐siblings with ABS who share the same biological father. Following a serious vascular event a de novo pathogenic variant in COL3A1 was detected in the father, confirming a diagnosis of vascular Ehlers–Danlos syndrome (vEDS). The same variant was found in both his ABS‐affected children but not in his unaffected child. The amniotic membrane is derived from fetal tissue, type III collagen being a component. As the affected children are paternal half‐siblings, ABS was less likely due to maternal factors. Rather, the amniotic bands may have resulted from decreased type III collagen production as seen in people with vEDS, causing fragility of the amniotic membrane. Consequently, it is important to consider vEDS in patients with ABS.     

Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers–Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis

Bi‐allelic variants in CHST14, encoding dermatan 4‐O‐sulfotransferase‐1 (D4ST1), cause musculocontractural Ehlers–Danlos syndrome (MC‐EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi‐allelic variants in DSE, encoding dermatan sulfate epimerase‐1 (DS‐epi1), in a child with MC‐EDS features, suggested locus heterogeneity for this condition. DS‐epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC‐EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC‐EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1‐ as well as DS‐epi1‐deficient patients. However, in D4ST1‐deficiency, the decorin GAG is completely replaced by CS, whereas in DS‐epi1‐deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.     

Pain and sleep quality in children with non‐vascular Ehlers–Danlos syndromes

The objective of this study was to explore the factors contributing to quality of life in pediatric patients with non‐vascular Ehlers–Danlos syndromes (EDS). Data were analyzed on 41 children with a diagnosis of non‐vascular EDS from the de‐identified data available from the National Institute on Aging (NIA) study of heritable disorders of connective tissue. Children under age 19 years were seen as part of a long‐term evaluation project from 2003 to 2013 on a larger natural history of patients with heritable disorders of connective tissue. Data collected included medical history, physical examination findings, diagnostic study results, and responses on validated questionnaires. We reviewed a sub‐cohort of children with a diagnosis of non‐vascular EDS and explored pain severity and interference via the Brief Pain Inventory, and sleep quality via the Pittsburgh Sleep Quality Index. Pain severity had a strong correlation with pain interference, and both were similar to other disorders that include chronic pain reported in the literature. Sleep quality did not correlate with pain severity or interference, but all patients had poor sleep quality in comparison to historical controls. We conclude that pain and sleep are significant issues in the pediatric non‐vascular EDS population, and future research may be directed toward these issues.     

Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers–Danlos syndrome and related disorders

Ehlers–Danlos syndromes (EDSs) are a group of inherited connective tissue disorders, and among them, classical EDS (cEDS) and hypermobile EDS (hEDS) are the most common. Mitral valve prolapse (MVP) and aortic root dilation (ARD) have previously been reported to occur at an increased frequency within cEDS and hEDS. More recently, a study performed in the pediatric population did not show increased prevalence (Ritter et al., American Journal of Medical Genetics Part A, 173(6), 1467–1472, 2017). The purpose of this study was to review a large population of individuals with cEDS, hEDS, and hypermobility spectrum disorders to determine the frequency of MVP and ARD. A retrospective chart review of 209 individuals with echocardiograms was performed. Overall, 6.4% (13/209) had MVP and 1.6% (3/189) were found to have ARD. Although the presence of MVP is higher than what has been reported in the general population, no patients had severe MVP or required surgical intervention. No patients in this cohort had an aortic root diameter requiring surgical repair. Based on the results of this study and previous studies, routine echocardiograms to assess for valvular diseases and ARD may not be necessary unless warranted by presence of symptoms or family history.     

Single base mutation that substitutes glutamic acid for glycine 1021 in the COL3A1 gene and causes Ehlers–Danlos syndrome type IV

The proposita described here was a 24-year-old woman with an acrogeric form of the Ehlers–Danlos syndrome including a massive dissecting aortic aneurysm. She was found to have a single-base mutation that substituted glutamic acid for glycine at amino acid position 1021 in the triple-helical domain of type III Procollagen. It is the most carboxyterminal single-base mutation characterized to date in the COL3A1 gene. Analysis of medium and cell layer proteins from proposita's cultured skin fibroblasts showed that the mutant protein was poorly secreted, migrated more slowly on a polyacrylamide gel, and was partially unstable at +25°C to brief digestion with trypsin. © 1993 Wiley-Liss, Inc.