Background Ehlers–Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. Methods We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers–Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. Results Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely l...

https://www.nejm.org/doi/pdf/10.1056/NEJM200003093421001

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

The cushioning function of large arteries encompasses distension during systole and recoil during diastole which transforms pulsatile flow into a steady flow in the microcirculation Arterial stiffness, the inverse of distensibility, has been implicated in various etiologies of chronic common and monogenic cardiovascular diseases and is a major cause of morbidity and mortality globally The first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins that support the mechanical load, while the second important components are vascular smooth muscle cells (VSMCs), which not only regulate actomyosin interactions for contraction but mediate also mechanotransduction in cell-ECM homeostasis Eventually, VSMC plasticity and signaling in both conductance and resistance arteries are highly relevant to the physiology of normal and early vascular aging This review summarizes current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis We further speculate on the contribution of cellular stiffness along the arterial tree to vascular wall stiffness In addition, this review provides the latest advances in the identification of gene variants affecting arterial stiffening Now that important hemodynamic and molecular mechanisms of arterial stiffness have been elucidated, and the complex interplay between ECM, cells, and sensors identified, further research should study their potential to halt or to reverse the development of arterial stiffness

Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease

Ehlers-Danlos syndrome type IV, the vascular type of Ehlers-Danlos syndromes (EDS), is an inherited connective tissue disorder defined by characteristic facial features (acrogeria) in most patients, translucent skin with highly visible subcutaneous vessels on the trunk and lower back, easy bruising, and severe arterial, digestive and uterine complications, which are rarely, if at all, observed in the other forms of EDS. The estimated prevalence for all EDS varies between 1/10,000 and 1/25,000, EDS type IV representing approximately 5 to 10% of cases. The vascular complications may affect all anatomical areas, with a tendency toward arteries of large and medium diameter. Dissections of the vertebral arteries and the carotids in their extra- and intra-cranial segments (carotid-cavernous fistulae) are typical. There is a high risk of recurrent colonic perforations. Pregnancy increases the likelihood of a uterine or vascular rupture. EDS type IV is inherited as an autosomal dominant trait that is caused by mutations in the COL3A1 gene coding for type III procollagen. Diagnosis is based on clinical signs, non-invasive imaging, and the identification of a mutation of the COL3A1 gene. In childhood, coagulation disorders and Silverman's syndrome are the main differential diagnoses; in adulthood, the differential diagnosis includes other Ehlers-Danlos syndromes, Marfan syndrome and Loeys-Dietz syndrome. Prenatal diagnosis can be considered in families where the mutation is known. Choriocentesis or amniocentesis, however, may entail risk for the pregnant woman. In the absence of specific treatment for EDS type IV, medical intervention should be focused on symptomatic treatment and prophylactic measures. Arterial, digestive or uterine complications require immediate hospitalisation, observation in an intensive care unit. Invasive imaging techniques are contraindicated. Conservative approach is usually recommended when caring for a vascular complication in a patient suffering from EDS type IV. Surgery may, however, be required urgently to treat potentially fatal complications.

/pdf/ehlers-danlos-syndrome-type-iv-1bj8aqmgjx.pdf

Ehlers-Danlos syndrome type IV

Most of the committee members agreed on the material presented Universal adoption of a single system for measuring and recording tendon function will require additional meetings It is suggested that TAM and the Dieter Buck-Gramcko systems be more widely publicized and adopted by various hand surgeons before further discussion

Report of the Committee on Tendon Injuries

Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25 000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.

https://jmg.bmj.com/content/jmedgenet/42/12/881.full.pdf

Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations

Obstetrical problems in patients with Ehlers-Danlos syndrome type IV; a case report.

A multidisciplinary survey of the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with biopsy-proven pseudoxanthoma elasticum (PXE) was undertaken. The major PXE phenotype emerging from this study is very similar in both patient groups and is characterized by severe ophthalmologic manifestations with variable, mild cutaneous and vascular symptoms. In the families with more than one affected relative, segregation analysis is compatible with autosomal recessive inheritance in both groups. It is suggested that the PXE phenotype of these Belgian and Afrikaner patients is distinct from the other recognized PXE subtypes. The phenotypic resemblance in both patient groups raises the question whether a similar genetic mechanism is involved.

Pseudoxanthoma elasticum: Similar autosomal recessive subtype in Belgian and Afrikaner families

Pulse Wave Velocity (P.W.V.) is recorded pneumatically in 27 members of a large family with ecchymotic Ehlers-Danlos syndrome, and compared to registrations in 216 normal subjects. Five relatives, ranging from 3 to 50 years of age, are found to have lowered P.W.V., indicating an increased distensibility of the arterial wall. This might be due to a collagen type III deficiency.

Pulse wave velocity recordings in a family with ecchymotic Ehlers-Danlos syndrome.

The diagnosis of Bartter syndrome was established in a 21 year old female patient, who presented with hypokalaemia and hyperkaluria, alkalosis, hyperreninism, hyperaldosteronism, and decreased fractional chloride reabsorption in the ascending limb of Henle's loop. Her stature was very short (140 cm) with otherwise normal body proportions. At birth, a coloboma of the right eye, dislocation of the left hip, and syndactyly of the second and third toes of the right foot were present. Since the age of 13, -she has suffered from recurrent attacks of gouty arthritis. At the age of 20, she presented with hyperglycaemia and glucosuria for which she had received insulin for one year. Family investigations revealed consanguinity between the parents (F=1/256). Karyotyping was first performed at the age of two, and showed trisomy 3 in 10% of leucocytes. At the age of 21, another cytogenetic evaluation was performed which revealed mosaicism for a normal and a trisomic cell line. In cultured blood leucocytes,

https://jmg.bmj.com/content/jmedgenet/25/5/358.full.pdf

Trisomy 3 mosaicism in a patient with Bartter syndrome.

A familial dermatoglyphic study of 25 syndactyly type I patients and 53 unaffected first-degree relatives showed a significant increase of complex fingertip patterns in the patients and in their relatives as well. An embryonic link between the formation of complex fingertip patterns and syndactyly type I is postulated. The study contributes new data on the hereditary transmission of syndactyly type I which cannot be used for individual genetic counseling. Calculation of the recurrence risk is difficult in view of the reduced penetrance of the gene.

Familial dermatoglyphic analysis in syndactyly type I.

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