Skin fragility and wound management in Ehlers- Danlos Syndrome: a report by the Ehlers Danlos Syndrome society skin working group.

The Ehlers-Danlos Syndromes (EDS) are a heterogenous group of heritable connective tissue disorders, characterised by joint hypermobility, skin hyperextensibility and generalised tissue fragility. In all types of EDS skin wound healing is impaired to a variable degree. Additional support through wound management plans may help to improve these outcomes, however, there is paucity of evidence regarding clinical management of skin fragility and wounds in EDS. This paper aims to review current evidence and provide recommendations for management of skin wounds in EDS types. Preventative measures to avoid skin injury are strongly recommended, including avoidance of high impact sport and use of appropriate protection such as shin guards. Bruising is common and some types of EDS are associated with haematoma formation with management including compression bandages and consideration of pharmacological therapy. Skin fragility and tears should be managed with a focus on protection of remaining tissue, avoidance of wound tension and low adherence dressings to avoid further injury. This paper provides clear recommendations to address skin management for this group of patients. It highlights the lack of good quality published data to support treatment decisions.

Oral characteristics in adult individuals with periodontal Ehlers-Danlos syndrome.

AIM: Periodontal Ehlers-Danlos syndrome (pEDS) is a monogenic type of Ehlers-Danlos syndrome characterized by periodontal destruction at a young age. The present study aimed to document the oral phenotype of pEDS based on prospective clinical investigations. MATERIALS AND METHODS: Thirty-five adult individuals from 13 families with a clinically and genetically confirmed diagnosis of pEDS underwent a systematic oral assessment. RESULTS: Periodontitis stage 3 or 4 or edentulism due to periodontal destruction were diagnosed in 94% of the individuals. First permanent tooth loss was reported at the age of 21.5 years (median; range 13-43 years). Deep periodontal pockets were infrequent, with 94% measuring <4 mm. However, there was increased clinical attachment loss (CAL) averaging 8 mm (range 4-13 mm), and the probability of being edentate between the age of 35 and 44 years was 28-47% compared with less than 0.25% of the general population. Radiographic anomalous findings were only found in a portion of subjects and consisted of fused roots of maxillary second molars (81%), root hypoplasia (57%), taurodontism (26%) and tooth rotation of premolars (67%). As such, radiographic findings are not considered common characteristics of pEDS. CONCLUSIONS: Characteristic oral traits of pEDS in adults are severe CAL with shallow probing depths and marked gingival recession. This is complemented by a lack of attached gingiva. These indications need to be paralleled by genetic analyses to diagnose pEDS unambiguously.

Arterial complications in classical Ehlers-Danlos syndrome: a case series.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders with several recognised types. Patients with a type of EDS have connective tissue abnormalities resulting in a varying degree of joint hypermobility, skin and vascular fragility and generalised tissue friability. Classical EDS (cEDS) typically occurs as a result of dominant pathogenic variants in COL5A1 or COL5A2. The cardinal features of cEDS are hyperextensible skin, atrophic scarring and joint hypermobility. Arterial complications are more characteristically a feature of vascular EDS although individual cases of arterial events in cEDS have been reported. METHODS: A cohort of 154 patients with a clinical diagnosis of cEDS from the UK was analysed. RESULTS: Seven patients (4.5%) with a diagnosis of cEDS (four pathogenic, one likely pathogenic and two variants of uncertain significance in COL5A1) who had experienced arterial complications were identified. Arterial complications mostly involved medium-sized vessels and also two abdominal aortic aneurysms. No unique clinical features were identified in this group of patients. CONCLUSION: There is a possible increased risk of arterial complications in patients with cEDS, although not well-defined. Clinicians need to be aware of this possibility when presented with a patient with an arterial complication and features of cEDS. Long-term management in families with cEDS and a vascular complication should be individually tailored to the patient's history and their family's history of vascular events.

Classical-like Ehlers-Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility.

PURPOSE: Currently, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature. We report on the clinical and molecular characteristics of 20 additional patients with clEDS to expand knowledge and to enable improved management of this rare genetic disorder. METHODS: Patients diagnosed with clEDS by the national EDS service in the UK (n = 21) and abroad (n = 1) were asked for consent for publication of their clinical and molecular data. RESULTS: Of 22 patients, 20 consented. All patients had typical features of clEDS: joint hypermobility, easy bruising, and skin hyperextensibility without atrophic scars. Importantly, 3/20 patients experienced gastrointestinal complications consisting of small or large bowel ruptures and one esophageal rupture. Other notable observations included two separate occurrences of spontaneous compartment syndrome, suspicion of nonaccidental injury due to significant bruising, and significant clinical variability regarding the debilitating effect of joint dislocations. CONCLUSIONS: We propose a predisposition to tissue fragility, particularly of the gastrointestinal tract in patients with clEDS. As such, clinical and molecular confirmation of this diagnosis is essential. It is recommended to follow up these patients closely to understand the natural history to develop better recommendations for management.

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.

Are early pregnancy complications more common in women with hyperemesis gravidarum?

Ultrasound evaluation is usually requested for women presenting with hyperemesis gravidarum (HG) in early pregnancy. This is to check viability as well as to diagnose multiple pregnancies and exclude gestational trophoblastic disease (GTD). The aim of this retrospective case control study was to evaluate the early pregnancy outcomes in women with HG and to compare them with an asymptomatic control group. 790 women referred with HG between 2002 and 2014 were matched for gestational age and maternal age with an asymptomatic patient attending for a reassurance or dating scan. A higher proportion of women with HG had ongoing pregnancies compared with controls and conversely, embryonic demise was less frequent in the HG group. The risk of twin pregnancy was doubled in the HG group compared to controls. There was no evidence of an increase in the prevalence of GTD. There appears to be a limited role for ultrasound in women who present with HG alone.

Case report: Two individuals with AEBP1-related classical-like EDS: Further clinical characterisation and description of novel AEBP1 variants.

Introduction: AEBP1-related classical-like EDS (clEDS type 2) is a rare type of Ehlers-Danlos syndrome (EDS) that was first reported in 2016. There are overlapping clinical features with TNXB-related classical-like EDS (or clEDS type 1), including skin hyperextensibility, joint hypermobility, and easy bruising. There are currently nine reported individuals with AEBP1-related clEDS type 2. This report confirms previous findings and provides additional clinical and molecular data on this group of individuals. Materials and methods: Two individuals (P1 and P2), with features of a rare type of EDS, were clinically assessed in the London national EDS service and underwent genetic testing. Results: Genetic testing in P1 revealed likely pathogenic AEBP1 variants: c.821del:p. (Pro274Leufs*18) and c.2248T>C:p. (Trp750Arg). In P2 pathogenic AEBP1 variants, c.1012G>T:p. (Glu338*) and c.1930C>T:p. (Arg644*) were identified. Discussion: These two individuals increased the reported number of individuals with AEBP1-related clEDS to 11 (six females and five males). There are shared features with previously reported individuals, including hypermobility (11/11), skin hyperextensibility (11/11), presence of atrophic scarring (9/11), and easy bruising (10/11). In P1, a chronic right vertebral artery dissection, mild dilatation of the splenic artery, aberrant subclavian artery, and tortuous iliac arteries were observed at the age of 63 years. Cardiovascular disease has been reported, including mitral valve prolapse (4/11), peripheral arterial disease (1/11), and aortic root aneurysm requiring surgical intervention (1/11). Hair loss has been reported in 6/11 individuals (five females and one male), only one of which was documented to have a formal diagnosis of androgenetic alopecia, while other individuals were described as having thinning of hair, male pattern hair loss, or unspecified alopecia. Conclusion: The clinical features of individuals with AEBP1-related EDS have not been fully elucidated yet. Hair loss is present in 6/11 individuals with AEBP1-related clEDS and appears to be a feature of this condition. This is the first time hair loss has been formally reported as a characteristic feature in a rare type of EDS. Cardiovascular surveillance seems warranted in this condition because 2/11 individuals have evidence of arterial aneurysm and/or dissection. Further descriptions of affected individuals are necessary to update diagnostic criteria and management guidelines.

Case report and discussion: Pre-implantation genetic diagnosis with surrogacy in vascular Ehlers-Danlos syndrome.

Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant inherited connective tissue condition, characterized by generalized tissue fragility with an increased risk of arterial dissection and hollow organ rupture. In women with vEDS, pregnancy and childbirth carry significant risks of both morbidity and mortality. The Human Fertilisation and Embryology Authority has approved vEDS for pre-implantation genetic diagnosis (PGD), given the potential for life-limiting complications. PGD avoids implantation of embryos that are affected by specific disorders by carrying out genetic testing (either for a familial variant or whole gene) and selecting unaffected embryos prior to implantation. Case: We present an essential clinical update to the only published clinical case of a woman with vEDS undergoing PGD with surrogacy, initially through stimulated in vitro fertilization (IVF) and in vitro maturation (IVM) and subsequently through natural IVF. Discussion: In our experience, a subset of women with vEDS do wish to have biological, unaffected children through PGD despite being aware of the risks of pregnancy and delivery. Given the clinical heterogeneity in vEDS, these women could be considered on a case-by-case basis for PGD. Controlled studies with comprehensive patient monitoring evaluating the safety of PGD are essential to equitable healthcare provision.

Absence of Collagen Flowers on Electron Microscopy and Identification of (Likely) Pathogenic COL5A1 Variants in Two Patients.

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does not and presents with a vascular complication. This case report highlights the significant intrafamilial variability within the cEDS phenotype and demonstrates that patients with pathogenic COL5A1 variants can have an absence of collagen flowers on TEM skin biopsy analysis. This has not been previously reported in the literature and is important when evaluating the significance of a TEM result in patients with clinically suspected cEDS and underscores the relevance of molecular analysis.