Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown. METHODS: Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) <0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology. RESULTS: Heterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD. CONCLUSIONS: We demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways.

Long-read sequencing identifies an SVA_D retrotransposon insertion deep within the intron of ATP7A as a novel cause of occipital horn syndrome.

BACKGROUND: SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A. METHODS: We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses. RESULTS: A 2.8 kb insertion was detected deep within the intron of the patient's ATP7A gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago. CONCLUSION: This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

Molecular alterations due to Col5a1 haploinsufficiency in a mouse model of classic Ehlers-Danlos syndrome.

Type V collagen is a regulatory fibrillar collagen essential for type I collagen fibril nucleation and organization and its deficiency leads to structurally abnormal extracellular matrix (ECM). Haploinsufficiency of the Col5a1 gene encoding α(1) chain of type V collagen is the primary cause of classic Ehlers-Danlos syndrome (EDS). The mechanisms by which this initial insult leads to the spectrum of clinical presentation are not fully understood. Using transcriptome analysis of skin and Achilles tendons from Col5a1 haploinsufficient (Col5a1+/-) mice, we recognized molecular alterations associated with the tissue phenotypes. We identified dysregulation of ECM components including thrombospondin-1, lysyl oxidase, and lumican in the skin of Col5a1+/- mice when compared with control. We also identified upregulation of transforming growth factor ß1 (Tgf-ß) in serum and increased expression of pSmad2 in skin from Col5a1+/- mice, suggesting Tgf-ß dysregulation is a contributor to abnormal wound healing and atrophic scarring seen in classic EDS. Together, these findings support altered matrix to cell signaling as a component of the pathogenesis of the tissue phenotype in classic EDS and point out potential downstream signaling pathways that may be targeted for the treatment of this disease.

Comprehensive Assessment of Nutrition and Dietary Influences in Hypermobile Ehlers-Danlos Syndrome-A Cross-Sectional Study.

INTRODUCTION: Disorders of gut-brain interaction (DGBI) are common in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder (hEDS/HSD). Food is a known trigger for DGBI symptoms, which often leads to dietary alterations and, increasingly, nutrition support. We aimed to explore dietary behaviors and influencing factors in patients with hEDS/HSD. METHODS: In a cross-sectional study, patients with hEDS/HSD were recruited from Ehlers-Danlos Support UK (nontertiary) and tertiary neurogastroenterology clinics to complete questionnaires characterizing the following: dietary behaviors, nutrition support, DGBI (Rome IV), gastrointestinal symptoms, anxiety, depression, avoidant restrictive food intake disorder (ARFID), mast cell activation syndrome, postural tachycardia syndrome (PoTS), and quality of life. We used stepwise logistic regression to ascertain which factors were associated with dietary behaviors and nutrition support. RESULTS: Of 680 participants (95% female, median age 39 years), 62.1% altered their diet in the last year and 62.3% regularly skipped meals. Altered diet was associated with the following: reflux symptoms ( P < 0.001), functional dyspepsia ( P = 0.008), reported mast cell activation syndrome ( P < 0.001), and a positive screen for ARFID, specifically fear of eating and low interest ( P < 0.001). Approximately 31.7% of those who altered their diet required nutrition support. The strongest predictor of requiring nutrition support was a positive screen for ARFID, specifically fear of eating (OR: 4.97, 95% CI: 2.09-11.8, P < 0.001). DISCUSSION: Altered diet is very common in the patients with hEDS/HSD we studied and influenced by functional dyspepsia, reflux symptoms, and ARFID. Those with ARFID have a 4-fold increased risk of requiring nutrition support, and therefore, it is paramount that psychological support is offered in parallel with dietary support in the management of DGBI in hEDS/HSD.

National registry insights on genetic aortopathies and thoracic endovascular aortic interventions.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.

Mast cell activation and nutritional disorders in patients with hypermobility.

PURPOSE OF REVIEW: Individuals with joint hypermobility disorders are increasingly referred to gastroenterology services for support with the investigation and management of gastrointestinal complaints. Individuals can present with a myriad of complex coexisting diagnoses, the inter-relationship of which is unclear. This review discusses the proposed association between hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) with disorders of mast cell activation and provides an overview of gastrointestinal symptoms and nutritional outcomes in this patient cohort. RECENT FINDINGS: It is unclear whether a true association between hEDS/HSD and mast cell activation disorders exists. There is a high prevalence of nonspecific gastrointestinal symptoms in individuals with hEDS/HSD and patients may be at risk of macro-nutrient and micro-nutrient deficiencies, although the current evidence base is limited. SUMMARY: We advocate a pragmatic approach to the investigation and management of gastrointestinal symptoms in patients with hEDS/HSD. This centres on excluding organic pathology, discussing the overlap with disorders of gut-brain interactions, trialling evidence-based therapies targeting individual symptoms, and supporting nutritional deficiencies where present via the least invasive approach. Engagement with a broad multidisciplinary team is also important to support the holistic needs of this patient cohort.

Patient experiences of receiving a diagnosis of hypermobile Ehlers-Danlos syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) presents with a wide range of clinical symptoms and comorbidities that impact quality of life. The diagnosis is challenging and often delayed due to the heterogeneity of the disease and lack of diagnostic biomarkers, which adds to the disease burden by affecting patients' psychosocial adaptation and overall well-being. Previous studies have revealed that healthcare professionals and the public have a limited understanding and familiarity with the condition, which leads to disapproval and skepticism that greatly impact patients' social spheres and welfare. While physical manifestations have been widely discussed, the psychosocial impact and the importance of receiving a diagnosis have not been fully studied in the current literature. This survey study investigated the impact of diagnosis in hEDS patients, selected from the University of Miami's hEDS registry. Survey questions were formulated based on clinical expertise and literature review. Descriptive statistics, Mann-Whitney test, and Spearman's correlation were used for data analysis. The median age at symptom presentation was 10 years, with a median gap of 4 years before the initial medical evaluation. On average, it took 10 years to receive a diagnosis of hEDS. Nearly all participants (95.2%) expressed receiving a diagnosis as "important" or "highly important," with 81.9% agreeing that it helped them cope with their condition better, 76.8% could better manage their symptoms, and felt more in control of their long-term care. Participants mostly had a positive emotional reaction and experienced an improvement in the support they were receiving from their caregivers and healthcare providers after receiving a diagnosis of hEDS. This study demonstrates that receiving a diagnosis could positively impact the patient's support, quality of care, and overall well-being.

Longitudinal echocardiography in pediatric patients with hypermobile Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root Z-scores >2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no Z-score >3.0. Subsequent studies (n = 68) found statistically significant decline in aortic root Z-scores. Repeat echocardiography in those with initial aortic root Z-score >2.0 (n = 10) demonstrated a decline in Z score <2.0 in seven. On final examination, 9/225 (4.0%) had a Z-score >2.0, not statistically different from the general population. No aortic dissection occurred in first- or second-degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS.

Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers-Danlos syndrome: A retrospective cross-sectional study from an Italian reference center.

The most common conditions with symptomatic joint hypermobility are hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Diagnosing these overlapping connective tissue disorders remains challenging due to the lack of established causes and reliable diagnostic tests. hEDS is diagnosed applying the 2017 diagnostic criteria, and patients with symptomatic joint hypermobility but not fulfilling these criteria are labeled as HSD, which is not officially recognized by all healthcare systems. The 2017 criteria were introduced to improve diagnostic specificity but have faced criticism for being too stringent and failing to adequately capture the multisystemic involvement of hEDS. Herein, we retrospectively evaluated 327 patients from 213 families with a prior diagnosis of hypermobility type EDS or joint hypermobility syndrome based on Villefranche and Brighton criteria, to assess the effectiveness of the 2017 criteria in distinguishing between hEDS and HSD and document the frequencies of extra-articular manifestations. Based on our findings, we propose that the 2017 criteria should be made less stringent to include a greater number of patients who are currently encompassed within the HSD category. This will lead to improved diagnostic accuracy and enhanced patient care by properly capturing the diverse range of symptoms and manifestations present within the hEDS/HSD spectrum.

The impact of Marfan syndrome and Ehlers-Danlos syndrome on the risk of penile fracture in patients between 18 and 45 years.

BACKGROUND: Despite knowledge of the pathophysiology and clinical complications of connective tissue diseases (CTD), little is known regarding their impact on men's sexual health disorders. AIM: To investigate the prevalence of penile fracture (PF) in patients with Ehlers-Danlos Syndrome (EDS) and Marfan syndrome (MFS) in comparison with disease-free controls between 18 and 45 years of age. METHODS: A multicenter, international, electronic health record network (TriNetX) was queried to identify adult male patients (between 18 and 45 years) with or without EDS and MFS between 1993 and 2023 using ICD-10 codes. The prevalence of PF was compared between patients with and without the diseases of interest. Prevalence ratios (PR) were generated with 95% confidence intervals. OUTCOME: Prevalence of PF in patients with EDS and MFS when compared to disease-free controls. RESULTS: The number of patients with EDS, MFS, and control groups was 8060, 8642, and 20 184 547, respectively, with a mean age of 27.8 ± 7.58, 28.6 ± 7.4, and 31.6 ± 8.04 years. Men with EDS had a higher prevalence of PF (PR 30.18, 95% CI [17.08-53.19]; P < 0.0001). Similarly, men with MFS had a higher prevalence of PF (PR 23.4, 95% CI [12.6-43.7]; P < 0.0001). CLINICAL IMPLICATIONS: This study demonstrates an association between CTD and men's sexual health disorders. It may be important to counsel such men about the risks of PF. STRENGTHS AND LIMITATIONS: This is the largest study to date to demonstrate an association between CTD and men's sexual health disorders. While the large sample sizes in this study contribute to the robustness of the findings, the study is limited by the use of a claims-based dataset, which does not provide further details about disease course and complications, and the use of a univariate analysis only. CONCLUSIONS: Patients with EDS and MFS are possibly at an elevated risk for PF. Due to the limitations of the TriNetX database, the analysis was limited to a univariate one, thus limiting the ability to control for confounders and limiting the generalizability of these findings. Further prospective research is needed to corroborate these findings.

Reviewing hereditary connective tissue disorders: Proposals of harmonic medicolegal assessments.

Hereditary connective tissue disorders (HCTDs) are a heterogeneous group of inherited diseases. These disorders show genetic mutations with loss of function of primary components of connective tissue, such as collagen and elastic fibers. There are more than 200 conditions that involve hereditary connective tissue disorders, while the most known are Marfan syndrome, Osteogenesis Imperfecta, and Ehlers-Danlos syndromes. These disorders need continuous updates, multidisciplinary skills, and specific methodologic evaluations sharing many medicolegal issues. Marfan syndrome and Ehlers-Danlos syndromes show a high risk of early sudden death. As a consequence of this, postmortem genetic testing can identify novel genotype-phenotype correlations which help the clinicians to assess personalized cardiovascular screening programs among the ill subjects. Genetic testing is also essential to identify children suffering from Osteogenesis Imperfecta, especially when a physical abuse is clinically suspected. However, this is a well-known clinical problem even though there are still challenges to interpret genetic data and variants of unknown significance due to the current extensive use of new genetic/genomic techniques. Additionally, the more significant applications and complexities of genomic testing raise novel responsibilities on the clinicians, geneticists, and forensic practitioners as well, increasing potential liability and medical malpractice claims. This systematic review provides a detailed overview on how multidisciplinary skills belonging to clinicians, medicolegal consultants, radiologists, and geneticists can cooperate to manage HCTDs from autopsy or clinical findings to genetic testing. Thus, technical aspects need to be addressed to the medicolegal community since there is no consensus works or guidelines which specifically discuss these issues.

Microvascular status and skin thickness in adults with hypermobile Ehlers-Danlos syndrome: a pilot investigation.

OBJECTIVES: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterised by joint hypermobility, chronic musculoskeletal pain, and skin abnormalities and easy bruising. Morphological and functional microvascular status has not yet been studied in hEDS, and dermal thickness (DT) has been poorly investigated. METHODS: The aim of the study was to investigate the microvascular morphology by nailfold videocapillaroscopy (NVC), peripheral blood perfusion (PBP) by laser speckle contrast analysis (LASCA), and DT by high-frequency skin ultrasound (22 MHz probe) in adults with hEDS compared to sex- and age-matched controls. RESULTS: Microhaemorrhages were found more prevalent and the capillary number per linear millimetre at the nailfold was slightly higher in hEDS patients than in controls, as well as the NVC score for abnormal shaped capillaries was slightly lower (less abnormal shaped capillaries) in hEDS patients than in controls, even if this was not statistically significant. PBP was comparable between hEDS patients and controls. The DT resulted generally lower in hEDS patients than controls with significant values limited to feet and thorax (p=0.04). A statistically significant positive correlation was observed between the Beighton score and the score for microhaemorrhages (r=0.4, p=0.05), as well as between the Beighton score and DT (r≥0.5, p≤0.02) at the level of feet and thorax. CONCLUSIONS: Our study detected in hEDS patients a normal microvascular function at rest and a suitable capillary morphology but with increased microvascular fragility. The dermal thickness seems thinner in hEDS patients than in controls in most skin areas, with strong statistically significance at the level of feet and thorax.

Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. METHODS: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. RESULTS: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. CONCLUSION: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Complex trauma sequelae: Mycobacterium goodii and Priestia endophytica Hardware infection in a patient with Ehlers-Danlos syndrome.

A 26-year-old man with Ehlers-Danlos syndrome, recurrent otitis externa, and chronic otitis media sustained a left lower extremity amputation and open femur fracture with internal hardware fixation after a motor vehicle collision in Arizona. He presented to the emergency department at our institution with severe left leg pain and purulent discharge despite receiving two unidentified antibiotics upon discharge. Evaluations revealed an abscess and malunion of the femur. Initial cultures yielded scant Priestia endophytica, leading to daptomycin treatment. His condition worsened until Gram-positive bacilli identified as Mycobacterium goodii, a rare nosocomial mycobacterial species, were found. Significant improvement occurred with appropriate antibiotics. This case highlights the challenges in diagnosing and managing M. goodii infections in immunocompromised patients with orthopedic complications and notes P. endophytica as a previously unreported, possibly opportunistic human pathogen.

Vascular Ehlers-Danlos syndrome and pregnancy: A systematic review.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder associated with an elevated risk of vascular, uterine and digestive complications. Managing pregnancy in this context can be a challenge. OBJECTIVES: To systematically review the literature data on the complications in pregnancy associated with vEDS. SEARCH STRATEGY: We searched the Pubmed Medline and Embase databases for articles using the following terms "vascular Ehlers-Danlos syndrome" or "vEDS" AND "pregnancy". SELECTION CRITERIA: Women with vEDS. DATA COLLECTION AND ANALYSIS: We searched the PubMed® MEDLINE® database for publications evaluating obstetric outcomes in women with vEDS. MAIN RESULTS: A total of 121 publications were screened, with six (accounting for 412 pregnancies) included in our review. Of the women included in this sample, 30% were infertile. The miscarriage rate was 13.8% (57/412) and 8.8% of the live births were premature. Obstetric anal sphincter injuries occurred in 11.3% (23/203) of the deliveries. The maternal mortality rate per pregnancy was 5.7%. CONCLUSIONS: Women with vEDS present an elevated risk of uterine rupture, vascular events, digestive events and death during pregnancy. Women appear to be most at risk during the peripartum period; to avoid expulsive efforts, a caesarean section should be scheduled at 37 weeks of gestation.

Digenic FLNA and UCHL1 variants resulting in a complex phenotype.

AIM: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. METHODS: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. RESULTS: Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. CONCLUSIONS: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.

High prevalence of gastrointestinal disorders in a large cohort of patients with joint hypermobility.

The gastrointestinal (GI) manifestations in children with hypermobile Ehlers-Danlos syndrome/joint hypermobility syndrome (hEDS/JHS) are not well described. We investigated the prevalence of GI disorders in children and young adults with hEDS/JHS through a single-center retrospective review. Demographic data, clinical history, symptoms, and diagnostic studies were reviewed. Of 435 patients with hEDS/JHS, 66% were females (age 5-28 years). We noted a high prevalence of constipation (61%), dysphagia (32%), dyspepsia and/or gastroparesis (25%), eosinophilic esophagitis (EoE) (21%), and celiac disease (4%) in our cohort. Upper endoscopy and gastric emptying scans had the highest yield to detect abnormalities. Motility studies were abnormal in 31% of the 80 patients who underwent them. Dysphagia symptoms are significantly associated with EoE. Thirty-three percent of dysphagia patients had EoE, versus 16% of non-dysphagia patients (p < 0.001). Screening hEDS/JHS patients for GI issues should be routine, with further investigations and referrals guided by identified symptoms.

Relationship Between Psychological Trauma and Irritable Bowel Syndrome and Functional Dyspepsia in a Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Patient Population.

BACKGROUND: There is frequent overlap between and the connective tissue diseases Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome (JHS/EDS) and disorders of the gut-brain interaction (DGBIs). AIMS: Because not all JHS/EDS patients develop DGBIs, we sought to determine whether secondary environmental triggers may lead to development of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in patients with JHS/EDS. METHODS: We sent electronic surveys to 253 patients from a JHS/EDS support group, with responses collected over one year. IBS and FD were diagnosed by the Rome IV criteria, with additional validated assessments of adverse childhood experiences (ACEs) and traumatic stressors according to DSM-V criteria. We compared clinical and psychological characteristics of JHS/EDS patients with and without DGBIs using univariable and multivariable analyses. RESULTS: We enrolled 193 JHS/EDS patients, of whom 67.9% met Rome IV criteria for IBS. The IBS and JHS/EDS overlap group reported significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without IBS. FD was found in 35.2% of patients and was associated with significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without FD. CONCLUSIONS: We found that JHS/EDS patients with IBS and FD overlap reported significantly more traumatic exposures and ACEs compared to JHS/EDS patients without overlapping IBS or FD. JHS/EDS patients may have increased susceptibility to DGBIs, with traumatic life experiences and/or ACEs acting a secondary environmental trigger driving the subsequent development of DGBIs.

The need for primary care providers in the clinical management of hypermobility spectrum disorders and ehlers-danlos syndrome: a call to action.

Patients with joint-hypermobility and joint-hypermobility spectrum disorders (HSD), including hypermobile Ehlers-Danlos Syndromes (EDS) present numerous co-morbid concerns, and multidisciplinary care has been recommended. The complexity of these patient's needs and increased demand for medical services have resulted in long delays for diagnosis and treatment and exhausted extant clinical resources. Strategies must be considered to ensure patient needs are met in a timely fashion. This opinion piece discusses several potential models of care for joint-hypermobility disorders, several ways in which primary providers can be involved, and argues that primary providers should be an essential and integrated part of the management of these patients, in collaboration with multidisciplinary teams and pediatric subspecialists. We review several strategies and educational opportunities that may better incorporate primary providers into the care and management of these patients, and we also discuss some of the limitations and barriers that need to be addressed to improve provision of care. This includes establishing primary care physicians as the medical home, providing initial diagnostic and treatment referrals while connecting patients with specialty care, and collaboration and coordination with multi-disciplinary teams for more complex needs. Several barriers exist that may hamper these efforts, including a lack of available specialty trainings for providers interested in providing care to patients with EDS and HSD, a lack of expertly derived consensus guidelines, and limited time resources in extant primary care practices. Also, primary providers should have an active voice in the future for the further consideration and development of these presented strategies.