Introduction
The Ehlers-Danlos Syndromes (EDS) are a group of genetic connective tissue disorders that vary in each patient based on the variant of EDS. Prior to the 2017 International Classification for the Ehlers-Danlos Syndromes Publication, EDS was classified into six major subtypes based on how each syndrome was characterized. Currently, the EDS can be classified into thirteen different subtypes (A-F), each with a distinct set of signs, symptoms, or hallmarks to work as the criteria for classifying whether or not the patient has a condition in EDS. However, the thirteen distinct subtypes are differentiated based on their underlying genetic causes. Most commonly, syndromes in the EDS family manifest themselves in the patient through joint hypermobility, tissue fragility, and skin hyperextensibility. Furthermore, the diagnosis criteria of EDS has notable overlap in the diagnosis criteria in various other connective tissue disorders — thus proving it to be difficult to correctly diagnosis every variant of EDS or even differentiate them from other connective tissue disorders.
Identification of EDS or other hypermobility spectrum disorders is largely based on family history and genetic testing. Once diagnosed, there is no cure for the EDS but there exist several different treatments to avoid the possibility of organ or vessel rupture (Vascular Ehlers-Danlos Syndrome) or other complications that are specific to each variant of the EDS.
Epidemiology
Internationally, more than 1.5 million individuals are currently diagnosed with EDS. More specifically, EDS has a population frequency of 1 in 5,000-10,000 — when accounting for all of its major types. However, the occurrence of EDS in the international population depends on which one of the six main Villefranche Nosology classifications is diagnosed. The more specific types of EDS have been logged by the Ehlers-Danlos Society (from most prevalent to least prevalent): Hypermobility-type EDS (type 3), Classical-type EDS (types 1 and 2), and Vascular-type EDS (type 4). The rarest EDS types have also been observed in the international population — Kyphoscoliosis-type EDS (type 6), arthrochalasia-type EDS (type 7A and 7B), dermatosparaxis EDS (type 7C), and dermatosparaxis-type EDS. Hypermobility-type EDS is the most common type of EDS, and it occurs in 1 in 10,000-15,000 people in the international population. Conversely, Vascular-Type EDS is considered the most serious type of EDS, and it occurs in 1 in 100,000-250,000 people in the international population.
In terms of mortality with patients with EDS, there is not a general trend of reduced life expectancy as a result of EDS. There is an exception with vascular-type EDS — which affect the patients in the manifestation of smaller diameter arteries and a ruptured gastrointestinal tract. Vascular-type EDS is a particularly dangerous condition for an individual to have during pregnancy, since incidents of uterine rupture have been reported – thus endangering the health of the unborn child and of the mother.
Diagnostic Criteria
There are several different types of tests that can be performed by the doctor onto the suspected EDS patient to test if the patient has a condition that is part of EDS or has a different hypermobility/connective tissue disorder. These tests include: skin biopsies, genetic tests, and echocardiograms. A skin biopsy will be able to identify any and all collagen defects or more specifically, abnormalities in collagen production. To do a skin biopsy, a small sample of skin is removed and then primarily analyzed under a microscope. Furthermore, genetic tests can be conducted if the child is being born through in vitro fertilization – which allows medical professionals to take a DNA test to examine for any defective genes or abnormalities that could potentially lead to a variant form of EDS.
In most cases of EDS, gene abnormalities will lead to the patient manifesting some sort of recognizable symptoms that could aid the doctor in diagnosing the EDS. The symptoms of classic EDS include loose joints, overly elastic skin, velvety skin, and muscle fatigue. Thus, doctors may use these hallmarks of conditions in EDS to make a preliminary diagnosis and then follow up with the tests described above.
Pathophysiology
The inheritance pattern of the conditions in EDS varies by their classification, although they are all inherited, heterogenous, connective-tissue disorders. The forms of EDS with an autosomal dominant pattern of inheritance include: classical, vascular, arthrochalasia, periodontal, and hypermobile. Having an autosomal dominant inheritance pattern means that if the individual will develop the disorder with only one copy of the abnormally altered gene. It is also possible for these EDS variants to be obtained through de novo gene mutations – meaning that spontaneous genetic mutations will occur to cause the abnormality without any previous history of the disorder in their family.
The forms of EDS with an autosomal recessive pattern include: classical-like, dermatosparaxis, cardiac-vascular, kyphoscoliotic, spondylodysplasia, and musculocontractural. For an individual with a condition with an autosomal recessive inheritance pattern, two copies of the abnormal gene must be inherited in order to exhibit the disorder. Parents of individuals with an autosomal recessive EDS usually have one copy of the abnormal gene each. Moreover, the parents will likely not exhibit any of the hallmarks of conditions in EDS (i.e. hypermobility). A variant of EDS known as myopathic type, is an exception to the generalized autosomal recessive or autosomal dominant classification of EDS. Individuals with myopathic EDS can have an inheritance pattern of autosomal dominant or autosomal recessive.
A collagen defect is characteristic of at least six of the several different variants of EDS. For example, type IV EDS (the vascular form) has been shown to be characterized by a significantly decreased about of type III collagen. This deficiency is likely the result of mutations in the COL3A1 gene – which is responsible for maintaining the structural integrity of the connective tissue in the arteries, intestines, and uterine. Other examples include types V and VI, which are characterized by decreased amounts of the enzymes hydroxylase and lysyl oxidase – both of which are crucial posttranslational modifying enzymes in the synthesis of collagen.