Clinical-Genomic Analysis of 1261 Patients with Ehlers-Danlos Syndrome Outlines an Articulo-Autonomic Gene Network (Entome).

Systematic evaluation of 80 history and 40 history findings diagnosed 1261 patients with Ehlers-Danlos syndrome (EDS) by direct or online interaction, and 60 key findings were selected for their relation to clinical mechanisms and/or management. Genomic testing results in 566 of these patients supported EDS relevance by their differences from those in 82 developmental disability patients and by their association with general rather than type-specific EDS findings. The 437 nuclear and 79 mitochondrial DNA changes included 71 impacting joint matrix (49 COL5), 39 bone (30 COL1/2/9/11), 22 vessel (12 COL3/8VWF), 43 vessel-heart (17FBN1/11TGFB/BR), 59 muscle (28 COL6/12), 56 neural (16 SCN9A/10A/11A), and 74 autonomic (13 POLG/25porphyria related). These genes were distributed over all chromosomes but the Y, a network analogized to an 'entome' where DNA change disrupts truncal mechanisms (skin constraint, neuromuscular support, joint vessel flexibility) and produces a mirroring cascade of articular and autonomic symptoms. The implied sequences of genes from nodal proteins to hypermobility to branching tissue laxity or dysautonomia symptoms would be ideal for large language/artificial intelligence analyses.

A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes.

A substantial fraction of the 15% with double-jointedness or hypermobility have the traditionally ascertained joint-skeletal, cutaneous, and cardiovascular symptoms of connective tissue dysplasia and its particular manifestation as Ehlers-Danlos syndrome (EDS). The holistic ascertainment of 120 findings in 1261 EDS patients added neuro-autonomic symptoms like headaches, muscle weakness, brain fog, chronic fatigue, dyspnea, and bowel irregularity to those of arthralgia and skin laxity, 15 of these symptoms shared with those of post-infectious SARS-CoV-2 (long COVID-19). Underlying articulo-autonomic mechanisms guided a clinical qualification protocol that qualified DNA variants in 317 genes as having diagnostic utility for EDS, six of them identical (F2-LIFR-NLRP3-STAT1-T1CAM1-TNFRSF13B) and eighteen similar to those modifying COVID-19 severity/EDS, including ADAMTS13/ADAMTS2-C3/C1R-IKBKG/IKBKAP-PIK3C3/PIK3R1-POLD4/POLG-TMPRSS2/TMPRSS6-WNT3/WNT10A. Also, contributing to EDS and COVID-19 severity were forty and three genes, respectively, impacting mitochondrial functions as well as parts of an overlapping gene network, or entome, that are hypothesized to mediate the cognitive-behavioral, neuro-autonomic, and immune-inflammatory alterations of connective tissue in these conditions. The further characterization of long COVID-19 natural history and genetic predisposition will be necessary before these parallels to EDS can be carefully delineated and translated into therapies.

Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities.

PURPOSE OF REVIEW: Dysautonomia refers to the dysfunction of the autonomic nervous system and encompasses a wide variety of autonomic symptoms and disorders. The most common autonomic disorders are postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS), and orthostatic hypotension (OH), which may be encountered in clinical practice as part of a triad of dysautonomia, hypermobility spectrum disorders (HSD), and mast cell activation syndrome (MCAS). Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms. Diagnostic criteria, pathophysiologic mechanisms, and therapeutic considerations in patients with migraine and comorbid dysautonomia, HSD, and MCAS are reviewed. RECENT FINDINGS: Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS. In clinical setting, dysautonomia, HSD, and MCAS may present a diagnostic and therapeutic challenge in patients with migraine and require a high index of suspicion on the part of the neurologist. Diagnosis and treatment of these complex disorders in patients with migraine is essential to comprehensive patient-centric care, reduced symptom burden, and improved functional impairment secondary to both migraine and comorbidities.

ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders.

Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders.

Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-ß Signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-ß signaling, and will discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases.

Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural-functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.

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.

Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1.

Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.

Evaluating the efficacy of a long-read sequencing-based approach in the clinical diagnosis of neonatal congenital adrenocortical hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders predominantly characterized by impaired corticosteroid synthesis. Clinical phenotypes include hypoadrenocorticism, electrolyte disturbances, abnormal gonadal development, and short stature, of which severe hyponadrenocorticism and salt wasting can be life-threatening. Genetic analysis can help in the clinical diagnosis of CAH. However, the 21-OHD-causing gene CYP21A2 is arranged in tandem with the highly homologous CYP21A1P pseudogene, making it difficult to determine the exact genotypes using the traditional method of multiplex ligation-dependent probe amplification (MLPA) plus Sanger sequencing or next-generation sequencing (NGS). We applied a long-read sequencing-based approach termed comprehensive analysis of CAH (CACAH) to 48 newborns with CAH that were diagnosed by clinical features and the traditional MLPA plus Sanger sequencing method for retrospective analysis, to evaluate its efficacy in the clinical diagnosis of neonatal CAH. Compared with the MLPA plus Sanger sequencing method, CACAH showed 100 % consistency in detecting SNV/indel variants located in exons and exon-intron boundary regions of CAH-related genes. It can directly determine the cis-trans relationship without the need to analyze parental genotypes, which reduces the time to diagnosis. Moreover, CACAH was able to distinguish different CYP21A1P/CYP21A2 and TNXA/TNXB chimeras, and detect additional variants (CYP21A2 variants c.-121C > T, c.*13G > A, c.*52C > T, c.*440C > T, c.*443 T > C, and TNXB variants c.12463 + 2 T > C, c.12204 + 5G > A). We also identified the TNXB variant c.11435_11524 + 30del alone instead of as a part of the TNXA/TNXB-CH-1 chimera in two newborns, which might be introduced by gene conversion. All of these characteristics enabled clinicians to better explain the phenotype of subjects and manage them more effectively. CACAH has a great advantage over the traditional MLPA and Sanger sequencing methods, showing substantial potential in the genetic diagnosis and screening of neonatal CAH.

Creatine Monohydrate as an Effective Supplement for Muscular Fatigue in an Ehlers-Danlos Patient.

Patients with Ehlers-Danlos syndrome (EDS) frequently report symptoms such as chronic pain and muscular fatigue that can heavily impact their quality of life. The treatment for many of the physical symptoms of EDS is focused on supportive care, which may include physical therapy and exercise programs. However, many patients will experience difficulty in deriving benefits from these activities due to significant pain and fatigue from physical activity. We report a case of a 39-year-old female with a history of EDS whose physical capabilities were severely impacted by their chronic pain and fatigue symptoms. After little progress was made with their current treatment plan of analgesics, manual therapy, exercise, and physical therapy, the patient was supplemented with creatine monohydrate due to its studied benefits in muscular strength and endurance for athletes. Following supplementation, the patient reported significant benefits in their muscular fatigue symptoms, allowing them to engage in daily activities and exercises more effectively. This case demonstrates a potential addition to the treatment of EDS that can improve a patient's quality of life.

Two-stage free latissimus dorsi flap for the management of a voluminous enterocutaneous fistula in a patient with Ehlers-Danlos syndrome: a case report.

Background: Ehlers-Danlos syndrome (EDS) is a rare genetic disorder that causes abnormal collagen structure and production, seriously impacting the quality of connective tissues. Reconstructive surgery can be challenging in affected patients, and additional precautions should be taken for microsurgical transfers. Case Description: This case aimed to describe the management of a 27-year-old man with vascular EDS and a history of heavy smoking who developed a voluminous enterocutaneous fistula after multiple abdominal surgeries. Due to the high surgical risk of flap failure resulting from the patient's condition, the large full-thickness abdominal defect, and the lack of locoregional reconstructive options, a two-stage free latissimus dorsi flap reconstruction was performed. A left myocutaneous free latissimus dorsi flap (sized 10 cm × 25 cm) was transferred and anastomosed to the left superficial femoral artery and the proximal part of the rerouted greater saphenous vein. The flap was folded, sutured to itself, and left in place for 8 days. Once the flap's viability was confirmed, complete small bowel liberation with resection of the enterocutaneous fistula and end-to-end primary anastomosis were performed by the visceral surgeons. The latissimus dorsi flap was unfolded and moved cephalically to cover the defect. No complications were reported on the flap. A fistula recurrence occurred on postoperative day 9 but was successfully addressed within 6 weeks using a combination of nasogastric tube aspiration, somatostatin, antibiotics, and negative pressure therapy. Follow-up at 6 months showed complete wound healing with no further complications. Conclusions: This report suggests the two-stage free flap transfer strategy to manage a voluminous full-thickness abdominal wall defect in a patient with vascular EDS. This approach allowed for optimal tissue coverage and full abdominal restoration while minimizing the risk of complications.

Comorbidities of Rural Children and Adolescents with Migraine and without Migraine.

(1) Background: Migraine is associated with comorbidities that are common in the general rural pediatric population. The purpose of this study is to evaluate the differences in the occurrence of comorbidities between rural children and adolescents with and without migraine. (2) Methods: A cross-sectional, secondary data analysis using electronic medical records of 1296 patients (53.8% females, aged 12.4 ± 3.2) was completed. Mann-Whitney U test was used to detect the difference in the number of comorbidities between the two groups. Chi-square test was used to identify the differences in the number of comorbidities, which were classified as low (0-1 comorbidities), medium (2-3 comorbidities), and high (4 or plus comorbidities) degree of comorbidities. (3) Results: Significant differences were found between those children and adolescents with migraine vs. those without for depression (p < 0.0001), anxiety (p < 0.0001), and Ehlers-Danlos Syndrome (EDS; p = 0.0309). A marginally significant difference was found between those children and adolescents with migraine (47.2%; n = 306) vs. those without (42.1%; n = 273) for unhealthy weight (p = 0.0652). Approximately 40% of the migraineurs had 2-3 comorbidities, whereas 32% of the non-migraineurs had 2-3 comorbidities (p = 0.0003). (4) Conclusions: Findings demonstrate the importance of identifying comorbidities associated with rural pediatric migraine in order to develop effective treatment strategies that optimize patient outcomes.

Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.

Ehlers-Danlos syndrome type arthrochalasia (aEDS) is a rare genetic disease characterized by severe generalized joint hypermobility, bilateral congenital hip dislocation, skin hyperextensibility, muscle hypotonia, and mild dysmorphic features. It is an autosomal dominant connective tissue disease causing defects in collagen, associated with two genes, COL1A1 or COL1A2. Only about 42 cases have been published worldwide. Treatment is currently symptomatic and focuses on increasing the quality of life of these patients, as there is no curative treatment. The main objective of the review was to update information on Ehlers-Danlos syndrome type arthrochalasia from scientific publications. The review report was carried out in accordance with the criteria of the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) review protocol, by searching Orphanet, OMIM, PubMed, and Scopus, as well as free sources. A total of 20 articles were analyzed, which, after analysis, provide an updated report that aims to establish a solid starting point for future lines of research.

In vivo N-Terminomics Highlights Novel Functions of ADAMTS2 and ADAMTS14 in Skin Collagen Matrix Building.

A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2 and ADAMTS14 were originally known for their ability to cleave the aminopropeptides of fibrillar collagens. Previous work using N-terminomic approach (N-TAILS) in vitro led to the identification of new substrates, including some molecules involved in TGF-ß signaling. Here, N-TAILS was used to investigate the substrates of these two enzymes in vivo, by comparing the N-terminomes of the skin of wild type mice, mice deficient in ADAMTS2, in ADAMTS14 and in both ADAMTS2 and ADAMTS14. This study identified 68 potential extracellular and cell surface proteins, with the majority of them being cleaved by both enzymes. These analyses comfort their role in collagen matrix organization and suggest their implication in inflammatory processes. Regarding fibrillar collagen, this study demonstrates that both ADAMTS2 and ADAMTS14 are involved in the processing of the aminopropeptide of alpha1 and alpha2 type V collagen. It also revealed the existence of several cleavage sites in the Col1 domain and in the C-propeptide of type I collagens. In addition to collagens and other extracellular proteins, two major components of the cell cytoskeleton, actin and vimentin, were also identified as potential substrates. The latter data were confirmed in vitro using purified enzymes and could potentially indicate other functions for ADAMTS2 and 14. This original investigation of mouse skin degradomes by N-terminomic highlights the essential role of ADAMTS2 and ADAMTS14 in collagen matrix synthesis and turnover, and gives clues to better understand their functions in skin pathophysiology. Data are available via ProteomeXchange with identifier PXD022179.

Gastric perforation leading to the diagnosis of classic Ehlers-Danlos syndrome: a case report.

BACKGROUND: Ehlers-Danlos syndrome is a clinically and genetically heterogeneous group of heritable connective tissue disorders caused by a defect in collagen synthesis and structure. The vascular subtype (Ehlers-Danlos syndrome IV) is reported to be associated with a higher incidence of gastrointestinal perforations. The most reported site of perforation is the colon, followed by the small bowel. Perforation of the stomach is very rare, and there are no reported cases to date of classic types I and II. CASE PRESENTATION: We present the case of a 14-year-old Saudi girl who visited our emergency department with abdominal pain and vomiting. Initially, she was diagnosed with gastroenteritis and discharged once her condition stabilized. After 48 hours, she developed severe abdominal pain with recurrent vomiting and peritonitis evident on clinical examination. Initial abdominal x-ray failed to show any free air; however, enhanced computed tomography revealed free air and contrast extravasation in the proximal gut. During exploratory laparotomy, a large perforation was found on the anterior wall of the stomach due to the underlying ischemia. The posterior wall had ischemic mucosa with an intact healthy serosa. A free-hand partial gastrectomy was performed to resect all ischemic parts of the stomach. Detailed examinations and laboratory workup were carried out after the surgery to figure out the possible underlying cause. The clinical findings during the physical examination supported marfanoid features. Marfan's syndrome and related disorders sequencing panel was requested, and Deoxyribonucleic acid (DNA) samples were sent. Given results were supporting the diagnosis of classical Ehlers-Danlos syndrome, the patient was labeled as a case of Ehlers-Danlos syndrome. During the postoperative period, she developed a wound infection that was managed successfully with vacuum-assisted closure dressing. She recovered well without gastrointestinal sequelae in the 4 years of follow-up. CONCLUSIONS: Heritable systemic connective tissue diseases must be given serious consideration in young patients with unusual spontaneous perforation. Such patients might develop life-threatening conditions that require immediate intervention. Hence, correct and timely diagnosis is important to prepare for the anticipated complications.

Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome.

Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) features. We investigated a 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS. Whole-exome sequencing identified two COL5A1 missense variants in trans configuration: NM_000093.5:c.[1588G>A];[4135C>T], NP_000084.3:p.[(Gly530Ser)];[(Pro1379Ser)]. Functional assays demonstrated a significant decrease of collagen α1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband. Interestingly, both parents manifested very subtle EDS signs, such as atrophic scars, recurrent bone fractures, colonic diverticulosis, varicose veins, and osteoarthritis. Our findings emphasize the involvement of COL5A1 in the predisposition to vascular phenotypes and provide novel insights on the c.1588G>A variant, whose functional significance has not been definitely established. In fact, it was previously reported as both "disease modifying", and as a biallelic causative mutation (with heterozygous individuals showing subtle clinical signs of cEDS). We speculated that the c.1588G>A variant might lead to overt phenotype in combination with additional genetic "hits" lowering the collagen α1(V) chain expression below a hypothetical disease threshold.

Implications of Ehlers-Danlos Syndrome in a Patient With Mayer-Rokitansky-Küster-Hauser Syndrome.

BACKGROUND: Ehlers-Danlos syndromes (EDS) are a heterogenous group of connective tissue disorders characterized by defective collagen production. Patients with EDS have lax and fragile connective tissue in their joints, skin, blood vessels, and hollow organs. This can lead to, among other complications, joint hypermobility, aneurysms, organ prolapse, and musculoskeletal chronic pain. Given that patients with vaginal agenesis, which occurs with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, often require vaginal dilation as part of their treatment, tissue elasticity and fragility are important considerations. This case report aims to describe the intersection of MRKH and EDS and its impact on vaginal dilation. CASE: A 16-year-old girl with joint hypermobility and type III EDS presented with primary amenorrhea and a karyotype of 46 XX. Magnetic resonance imaging confirmed an absent uterus, cervix, and upper vagina. Physical examination showed Tanner V breasts and Tanner IV pubic hair, and an external genital examination revealed a blind-ending, 1-cm vaginal dimple. The patient was diagnosed with MRKH. Following her diagnosis, she received vaginal dilation instruction and returned for follow-up 2 months later, having quickly progressed to the largest vaginal dilator without symptoms of bleeding, pain, or dysuria. In that timeframe, her vaginal dimple had increased from 1 cm to 7-8 cm in depth, a rate much faster than is typically seen. Because of this rapid progress, a urogenital examination was performed. There was no evidence of urethral abnormality, perforation, or vaginal prolapse. SUMMARY AND CONCLUSION: Recognition of EDS in patients with Müllerian anomalies has important implications for safe and effective vaginal dilation. All patients using vaginal dilation to lengthen the vagina require education on the technique. This need is heightened in patients with EDS in order to prevent accidental dilation of the urethra due to their tissue elasticity, to avoid tissue prolapse, and to prevent the theoretical risk of vaginal perforation.

Ultrastructure study of skin fibroblasts in patients with Ehlers-Danlos Syndrome (EDS): preliminary results.

AIM OF THE STUDY: To investigate, in vivo and in vitro, the fibroblast-to-myofibroblast transition in patients with hypermobile Ehlers-Danlos Syndrome (EDS). To analyze the dermis of patients with classical form of EDS (cEDS) and with hEDS, to identify qualitative and/or quantitative differences in ECM component and ultrastructural changes in collagen. MATERIALS AND METHODS: Seven subjects, aged over 18, two with cEDS and five with hEDS underwent two skin biopsy. One sample was prepared for transmission electron microscopy (TEM), the other for immunofluorescence. The diameter of collagen fibers was measured with TEM. Fibrils were analyzed in four patients: the two with cEDS and two with hEDS. For each patient, the diameter of n=250 collagen fibrils was measured. αSMA was used as specific marker for myofibroblast to highlight their presence in vivo in the skin of patients with hEDS. RESULT: IF observation could not assess an increased expression of αSMA in hEDS patients, which showed no statistical difference compared to classic form patients. The major result from the analysis of TEM images is the clear difference in ECM composition between the two forms of EDS: ECM in hEDS is optically more dense and more prominently composed of elastic fibers. CONCLUSION: Our study provides the following important evidence: 1) the absence in vivo of dermal fibroblasts in patients with hEDS, demonstrated by αSMA negativity; 2) the presence of statistically significant changes in the diameter of collagen fibrils between the classic and the hypermobile forms.

Severe Peripheral Joint Laxity is a Distinctive Clinical Feature of Spondylodysplastic-Ehlers-Danlos Syndrome (EDS)-B4GALT7 and Spondylodysplastic-EDS-B3GALT6.

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.

Recurrent Depression and Borderline Personality Disorder in a Patient with Ehlers-Danlos Syndrome.

Ehlers-Danlos syndrome is a group of connective tissue disorders that most commonly causes joint hypermobility, skin hyperextensibility, and tissue fragility. Patients diagnosed with Ehlers-Danlos syndrome (EDS) frequently suffer from chronic pain and other comorbid conditions. In addition, there is an increased incidence of psychiatry conditions in this patient population, such as anxiety, depression, and personality disorders. We present the case of a 25-year-old female who presented to a community hospital with frequent thoughts of suicide and major depression. She was previously diagnosed with Ehlers-Danlos syndrome, borderline personality disorder, and major depressive disorder. The patient was treated with a selective serotonin reuptake inhibitor (SSRI) and gabapentin for pain associated with EDS. However, she was still suicidal and was admitted upon evaluation. Subsequently, she was prescribed lithium in order to augment the effects of the SSRI and reduce her risk of suicide. In addition to pharmacotherapy, patients with these conditions should consider enrolling in some type of therapy.