These associations are very real; they seriously affect quality of life and they need to be managed as part of treatment. The strongest but not only associations noted so far are anxiety disorders, orthostatic tachycardia, and low blood pressure, a variety of functional gastrointestinal disorders, and pelvic and bladder dysfunction.
These additional problems need to be evaluated and treated when an HSD is diagnosed. The Ehlers-Danlos Society members are sharing information online and learning from each other in ways that were impossible not very long ago. What is HSD? The Mechanics Joint hypermobility is a term to describe the capability of joints to move beyond the normal range of motion. The pattern and severity of the musculoskeletal involvement should be carefully assessed in order to explore the possibility full-blown hEDS.
Localized joint HSD L-HSD : JH at single joints or group of joints plus one or more secondary musculoskeletal manifestations regionally related to the hypermobile joint s.
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Rheumatology ; 40 : —3. Chronic pain is a manifestation of the Ehlers—Danlos syndrome. J Pain Symptom Manage ; 14 : 88 — Psychosocial functioning in the Ehlers—Danlos syndrome.
Am J Med Genet ; 53 : — Living with the hypermobility syndrome. Rheumatology ; 40 : —9. Murray KJ, Woo P. Benign joint hypermobility in childhood. Rheumatology ; 40 : — Examination of the joints. London: Mosby, : 1 — Heritable disorders of connective tissue. Improving pain by the stabilisation of hyperlax joints. J Orthop Rheumatol ; 9 : 46 — Proprioceptive enhancement for anterior cruciate ligament deficiency. A prospective randomised trial of two physiotherapy regimes. J Bone Joint Surg Br ; 76 : —9.
Evaluation of a cognitive behavioural programme for rehabilitating patients with chronic pain. Br J Gen Pract ; 43 : —8. When the heart has to work extra hard just to circulate blood, it brings the entire body to the verge of a fight-or-flight reaction, requiring very little to set off panic.
Eccles hypothesizes that these patients might benefit in particular from beta blockers, drugs that ease anxiety by reducing symptoms of the body's fight-or-flight response. She hopes that future studies will investigate such targeted treatments for double-jointed people. In the meantime, the findings are an important reminder for clinicians to consider the possibility that a patient's mental disorder could have purely physical origins.
Tori Rodriguez is a journalist and psychotherapist based in Atlanta. Already a subscriber? Sign in. Thanks for reading Scientific American. Create your free account or Sign in to continue. This report presents the first successful linkage study in a unique three-generation Belgian family in which EDS-HT segregates with autosomal dominant inheritance pattern.
In order to make the clinical assessment in this family as accurate as possible, the same physician Fransiska Malfait was responsible for repeated clinical evaluation and history taking.
In addition to assessment of joint hypermobility and musculoskeletal problems, a number of clinical signs, indicative of generalized connective tissue fragility, were registered. These were helpful for determining the phenotype in individuals who were ambiguous on the joint phenotype alone.
After exclusion of a number of candidate genes, a suggestive candidate locus was identified, which segregates with the EDS-HT phenotype. The highest two-point LOD score of 4. A haplotype of marker alleles segregated with the phenotype and critical meiotic recombinants placed the EDS-HT predisposition gene within an 8. Moreover, the absence of linkage for the identified locus in several other EDS-HT families underscores the genetic heterogeneity of the disorder. Four of the protein-coding genes located within this region were considered potentially promising candidate genes for EDS-HT.
BMP1 belongs to secreted metalloproteinases and was first described as a procollagen C-proteinase for types I—III procollagen but is also responsible for the cleavage of multiple other substrates e. Biallelic defects in BMP1 were recently described as the cause of a severe recessive variant of the brittle bone disorder Osteogenesis imperfecta [ 22 ]. Investigation of these genes with Sanger sequencing did not result in the identification of pathogenic alterations segregating with the phenotype.
In a next step, WES was performed for two affected sisters. The applied variant filtering strategy narrowed the number of shared heterozygous alterations down to a single missense variant in the LZTS1 gene which was found to segregate with the disease phenotype.
LZTS1 is a tumor suppressor gene implicated in several human cancers. It is expressed in different normal tissues Supplementary Figure S2 and was shown to be involved in cell cycle regulation through prevention of Cdc25C degradation thereby regulating Cdk1 activity [ 23 ]. In addition to its role in cancer, LZTS1 was also shown to be important during neuronal development [ 24 ]. This revealed the presence of three additional LZTS1 variants. It has been previously reported that the LZTS1 gene and its protein contain features resembling those of transcription factors, which makes it tempting to speculate that LZTS1 could have a role in modulating gene transcription and thereby affect the expression of genes encoding connective tissue molecules [ 28 ].
At present, however, we have no conclusive evidence for an exact function of LZTS1 in connective tissue biology and further studies are necessary to confirm the pathogenic role of the identified sequence alterations. It should also be noted that, as the majority of disease-causing mutations reside within the protein-coding part of the genome, our study focused on the exonic part of the candidate interval, thereby omitting the interrogation of important noncoding regions, such as deep intronic regions, promoter sequences, and other regulatory and conserved sequences that reside within the candidate interval and which can also contain disease-causing alterations.
Collectively, these issues can lead to false negative results and can mask the true underlying cause. Efforts towards the identification of genes underlying joint hypermobility syndromes such as EDS-HT and BJHS are important in order to gain better insights into the clinical phenotypes, their natural history, and the underlying pathogenic basis.
This will improve early recognition and diagnosis of joint hypermobility and lead to a more logical classification of the hypermobility syndromes. Understanding the genetic basis of joint hypermobility syndromes will moreover enhance our understanding of normal connective tissue biology and homeostasis and of mechanisms underlying EDS and joint mobility.
The authors declare that there is no conflict of interests regarding the publication of this paper. The authors would like to thank the families for their cooperation. Supplementary Table 1: Candidate genes, their chromosome localization and markers that were used for linkage analysis. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Academic Editor: Ralf Lichtinghagen. Received 15 Jun Revised 01 Sep Accepted 10 Sep Published 04 Oct Abstract Joint hypermobility is a common, mostly benign, finding in the general population. Materials and Methods 2.
TMJ: temporomandibular joint. Table 1. Clinical characteristics of affected and unaffected family members. Figure 1. Pedigree of the three-generation Belgian family. The genotypes of 5 markers within and surrounding the linked region on chromosome 8 are depicted.
An arrow indicates the proband. Individuals included in the initial genome-wide linkage screen are indicated with an asterisk. Affected and unaffected individuals are indicated with a black or white pictogram, respectively, whereas a grey pictogram with a question mark points to a patient for whom the phenotype was not clear unknown. Marker 0 0. Table 2. Two-point LOD scores for microsatellite markers on the 8pp The identified candidate interval. Table 3. Ranking of the candidate genes according to different gene prioritization tools with functionally interesting candidates indicated in bold.
Ser — — — —. Table 4. Supplementary Figure S1: Overview of the candidate region.
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