Forgotten Diseases Research Foundation

Ehlers-Danlos Syndrome, Arthrochalasia (Types 7A & 7B)


Ehlers-Danlos syndrome is a condition that affects connective tissue --- particularly, collagen. Collagen is an abundant structural protein found in muscles, tendons, skin and bones. It can be thought of as both holding the body together and strengthening it.

There are many subtypes of EDS. Although there are many differences between them, two clinical features occur in all forms of EDS. The first is joint hypermobility (often called loose or double joints). People with EDS can often move their joints in ways that are impossible for most unaffected people (see the photograph on this page). However, many people without EDS have loose joints, and having joint hypermobility does not mean that person has a medical disorder. The second clinical feature that occurs in every form of EDS is hyperextensible (stretchy) skin. In some forms (classic and kyphoscoliotic, for example), this feature is nearly universal. In our literature survey for our software tool, we found that stretchy skin occured in less than half of people with the hypermobile and vascular forms, more than half of patients with the periodontitis type, and in a large majority of people with the arthrochalasia type (>80%).

Joint laxity/hypermobility is usually assessed with a scoring system called the Beighton score, which was developed in the early 1970s (1). This simple system scores a person's ability to move a joint past certain angles. The highest score is 9 points, and higher scores mean greater joint laxity. Generally speaking, scores of 4 or higher (at any time, past or present) in persons under age 50 indicate joint hypermobility. Many EDS patients have scores of 8 or 9, although many have lower scores, and a minority do not have hypermobile joints. Interested readers may wish to see a basic description of the scale with photographs or a more technical description.

The EDS syndromes as a group also have a classification system. This sytem is called the Villefranche classification. Villefrance uses descriptive terms for different types of EDS (e.g. vascular, kyphoscoliotic). These terms are the formally accepted names for each type of EDS. Before the Villefanche classification, the different forms of EDS were numbered (type 1, type 2, etc). These numbers are still in common use today. As a result, we have included them here. Type 8 is officially referred to as the periodontitis type of EDS, but continues to be generally referred to as type VIII in the literature. We will use the numbered term here (though with the numeral 8).

The Villefranche system classifies the different forms of EDS based on clinical and, when possible, molecular criteria. Unfortunately, some forms of EDS have not yet been associated with mutations in any genes. In addition, different disorders can be caused by mutations in the same genes. The situation can be complex, but research aimed at fully understanding it is ongoing.

Tissue fragility is another common feature of EDS. This problem is very serious in the vascular type of EDS; patients with this form of EDS are at high risk for spontaneous ruptures of large blood vessels and bowel perforations. Surgery on a person with this type of EDS must be performed with great care as a result of this problem. People with the hypermobile form are also prone to blood vessel ruptures, they though tend to occur in the small blood vessels of these patients. Tissue fragility can also lead to hernias and problems in pregnancy. Fragile skin is also a common manifestation of EDS, especially in people with the classic, kyphoscoliotic, and periodontitis types.

EDS affects women more commonly than men. We decided to count the number of male and female patients while we were characterizing six different types of EDS for our diagnostic aid software. Altogether, we analyzed data from ~1,100 patients. Sex information was available for 1,075. The table below shows that although more EDS patients are women in each type of EDS, the female:male ratio varies between each type. For example, females dominated the individuals reported with the hypermobility type, while males comprised a substantial minority of kyphoscoliotic and arthrochalasia patients. The distribution was roughly even in EDS type 8. However, the low number of case reports for these three types of EDS may have affected the outcome of this small analysis.



Above: Percentages of male and female patients with different types of EDS. Source: V. Natale & FDRF.



In our analysis of case histories for our diagnostic tool, we believe that we analyzed all or nearly all reported cases of the arthrochalasia type of EDS (56 total, with care taken not to analyze the same patient twice). The diagnosis in 48/56 of these patients had been confirmed by molecular or biochemical methods, with 5 of the 7 unconfirmed cases being the well-accepted original cohort of five patients (2). Thus, the total number of reported patients for this type of EDS is significantly higher than previous estimates of 27 and 40 (3, 4).

According to NIH's Genetics Home Reference (see link at right), the prevalence of all forms of EDS is roughly 1 in 5,000 worldwide. The arthrochalasic type (EDS-A) is very rare, and exact prevalence figures are not known.

If EDS is a condition characterized by hypermobile joints, the arthrochalasia type represents the extremes of joint hypermobility in EDS. Dislocations were a universal problem in all case histories of EDS-A, with congenital hip dislocations occuring in all but one patient in whom skeletal condition at birth was reported. In addition, the joints in affected individuals were typically so loose, they were reported to dislocate or sublux with minimal handling or disturbance. Surgical corrections of hip dislocations were sometimes required (5-8; list not comprehensive). The surgeries were not always successful (9), and multiple operations were sometimes required (10,11).

Clinical information

Signs and symptoms

The arthrochalasia type is a very rare form of EDS. Its most striking feature is recurrent dislocations, including, most notably, congenital dislocations of the hip (for example, see reference 12). As noted above, all EDS-A case histories to date report recurrent joint dislocations and subluxations, with a tendency for them to happen easily. These problems may be evident on ulstrasonography performed during the fetal period.

As with all other forms of EDS, the clinical features of EDS-A overlap with other forms of EDS. The extreme joint hypermobility combined with frequent dislocations and certain facial and other features may help distinguish EDS-A from other types of EDS (see Differential Diagnosis, below). In general, the following features occur commonly in this form of EDS:

    Signs and symptoms of EDS-A

  • Joint hypermobility
  • Recurring joint dislocations or subluxations
  • Congenital hip dislocation
  • Flat feet, especially when standing
  • Bunions
  • Clubfeet
  • Abnormal curvature of the spine
  • Smooth, velvety skin
  • Loose or stretchy skin
  • Easy bruising (see photo at right)
  • Redundant/extra skin (especially on the hands and feet; may also bunch up in folds)
  • Criss-cross pattern on the palms and soles of the feet
  • Hypotonia (low muscle tone; often accompanied by weakness)
  • Hernia(s)
  • Bone fractures in a minority of patients

It is possible that a criss-cross pattern on the skin, when accompanied by other signs of EDS, is suggestive of EDS-A (3). Unfortunately, it is difficult to make a definite determination about this statement, given the rarity of the condition and the relatively few published case reports.

Some patients with the arthrochalasia form of EDS have distinctive facial features. These features are not as obvious, common, or numerous as they are in patients with other forms of EDS, such as vascular EDS. However, awareness of the constellation of facial features associated with each type may help with diagnosis. In EDS-A, they include the following:

    Facial features that may occur in the arthrochalasia form EDS

  • Wideset eyes
  • Blue sclerae
  • Micrognathia (small jaw)
  • Retrognathia (receding lower jaw)
  • Prominent or protruding forehead (frontal bossing)
  • Macrocephaly (head is large for age or body size)

The girl in the photograph at the top right has some of these features (wideset eyes, a prominent forehead, and a history of macrocephaly).

EDS types 7A and 7B

The arthrochalasia form of EDS comprises what were initially classified as two forms of EDS: subtypes 7A and 7B. These subtypes were named according to which gene was mutated (see below). According the literature on EDS-A, the two forms are clinically indistinguishable (5). No genotype/phenotype correlations are known at this time.

Diagnosis and Testing

Arthrochalasic EDS is an autosomal dominant disorder. This term means that it is usually passed from one affected parent to a child. However, it can also occur sporadically in a person without an affected parent. In our analysis, information on the family history of EDS or EDS-like connective tissue disease was available for 50 patients. Of this group, only 17, or 34%, had an affected parent.

Mutations in one of two collagen genes can cause EDS-A; the genes are COL1A1 and COL1A2. These genes encode two proteins that, together, form type 1 collagen. Each gene forms a different chain on the final protein. In EDS-A patients, mutations in either gene generally occur in exon 6 (see Differential Diagnosis below for more information on the importance of this point). Type I collagen is the most abundant collagen in humans. It is found in scar tissue, which explains why some EDS-A patients have abnormal scars and problems with wound healing. It also occurs in bones, tendons, and ligaments. Ligaments connect bone to bone and have an important role in maintaining joint stability.

In our analysis, mutation was known in 49. We found that 10 of them (~20%) had mutations in COL1A1, while 39 (~80%) had mutations in COL1A2.

In addition, mutations in the gene COL1A1 account for a small minority of cases of classic EDS. Mutations in COL1A1 are associated with a number of other medical conditions, including osteogenesis imperfecta and Caffey disease. Mutations in COL1A2 are also associated with osteogenesis imperfecta, as well as with the cardiac valvular form of EDS. This latter condition is rarer than EDS-A and is an autosomal recessive disorder (both parents must pass a copy of the mutated gene to their child).

The initial diagnosis of EDS-A is based on the clinical features of hip dislocation (especially if present at birth), hypotonia, and some or all of the facial features noted above. A criss-cross pattern on the palms and/or soles of the feet is also suggestive of this disorder. Patients may also have Wormian bones (see x-rays and photos below). This abnormality has been reported in nine patients out of ten surveyed, and although the sample size is small, further investigation may reveal that it is a common feature of EDS-A.

Laboratory testing may help confirm a diagnosis, with the caveats noted under Differential Diagnosis below. There are two general methods of testing. The first is to characterize collagen I aminoterminal propeptides in cultured fibroblasts. The second is to perform sequence analysis of exon 6 in the COL1A1 or COL1A2 genes. The second method may be less invasive.

It is important to remember that there is a lot of overlap between the different forms of EDS and between EDS-A and osteogenesis imperfecta. This fact means that, in the absence of laboratory testing, accurate subcategorization of EDS in a patient may be difficult or even impossible.

Differential Diagnosis

Osteogenesis imperfecta (OI) can also be caused by mutations in type 1 collagen. The clinical features of OI vary. The severe forms are progressive and degenerative, and may involve underdeveloped rib cages and lungs, and early lethality. They are unlikely to be confused with EDS-A. However, the mild forms overlap with EDS-A. An example is OI type 1, which is now called classic non-deforming OI with blue sclerae. People with this type of OI suffer bone fractures as a result of minor or no trauma (e.g. diapering an infant). Fractures can occur in the newborn period or early infancy, but more usually tend appear when a child begins to walk (and fall). They continue through adolescence and then tend to abate. However, they may begin to occur again after menopause in women or after age 40 in men. In addition, OI patients can have lax joints, low muscle, and skin that bruises easily. As the name of the condition says, the whites of a patient's eyes are frequently blue or grey-ish. This is also the case with many EDS-A patients. Height and teeth may be affected in both OI and EDS-A. Thus, the two disorders are very similar. It is possible that they may be the same condition.

Mild OA can be caused by mutations in COL1A1 or COL1A2. Given that mutations in the same gene are involved in both conditions, it is possible that EDS-A is a mild form of OI. For example, in a literature review using the OI mutations database (13), we found a patient with mutations in exon 6 of COL1A1 who had diagnosed with OI type 1. In addition, researchers have also found patients with mutations in COL1A1 and a disorder described as combined OI/EDS7 (14).

Other forms of EDS. The differential diagnosis for EDS-A also includes all the other types of EDS. All forms of EDS involve joint hypermobility, and most also feature very soft, lax skin, as well as a variety of internal problems that result from weak or loose connective tissue (e.g. hernias, spinal column deformities, flat feet). However, some forms of EDS are more severe than others.

EDS-A may be distinguished from the rare vascular and kyphoscoliotic types by genetic testing: the vascular form is caused by mutations in COL3A1, and the kyphoscoliotic form is caused by mutations in PLOD1. In addition, these conditions are generally (although not always) much more severe than the arthrochalasic form. Patients with vascular EDS have a particular facial phenotype that is not shared by classic type patients, and those with the kyphoscoliotic form tend to have severe spinal deformities. EDS-A patients may also have spinal deformities, however. Note also that EDS-vascular patients are prone to spontaneous ruptures of large blood vessels that may be fatal. For this reason, clinicians may wish to use genetic testing to definitively rule out this form of EDS in any patient suspected of having EDS.

The classic form of EDS ranges in severity from mild to relatively severe. Like EDS-A patients, classic EDS patients have hypermobile joints and stretchy skin. Some features may help distinguish the two disorders. Most importantly, classic EDS patients tend to have severe skin involvement that can be disfiguring, while EDS-A patients do not. Alternatively, classic EDS patients do not tend to suffer the serious and recurrent joint dislocations that are universal in EDS-A. Dislocations do occur in people with the classic form of EDS (roughly half of patients, according to our analysis). However, the constancy of the problem in EDS-A and the presence of congenital hip dislocations may be a distinguishing factor.

The hypermobile form of EDS (EDS-H) is a relatively mild form of EDS. As its name implies, joint hypermobility is the primary feature of this form of EDS. The skin in EDS-H patients is typically not as stretchy as it is in patients with the other forms of EDS, although exceptions apply. Atrophic scars also do not appear to be a general feature of the hypermobile form of EDS-H. They appear to occur in roughly half of EDS-A patients.

Overall, joint hypermobility occurs in a variety of medical conditions, and many people without a medical condition have lax joints. In fact, when not part of a disorder, hypermobile joints confer an advantage in sports such as gymnastics and ice skating, as well as in certain forms of dance.

Marfan syndrome. Most medical conditions involvong lax joints are relatively easy to distinguish from EDS, but some are not. Marfan syndrome is an example. Like EDS, Marfan syndrome is a connective tissue disorder and patients have lax joints. Marfan patients generally have a body type called a Marfanoid body habitus. This term means that a person is tall and slender, with long arms, hands, fingers, legs, feet and toes. A Marfanoid body habitus occurs in a minority of EDS-H patients, but it does not appear to be generally associated with classic EDS. The Marfan Foundation has many photographs of Marfan patients of different ethnicities. Unlike EDS patients, Marfan patients do not appear to have fragile skin and blood vessels.

Cutis laxa. Superficially, the stretchy skin found in most forms of EDS may be confused with cutis laxa type 1 and type 2, as stretchy skin is also a feature of these conditions. However, the skin in cutis laxa patients tends to sag and does not return to its normal position after being extended. Cutis Laxa patients often have a prematurely aged appearance.



References

  1. 1. Beighton P et al. (1973) Articular mobility in an African population. Ann Rheum Dis 32(5):413-418. Full text on PubMed.
  2. 2. Hass J & Hass R (1958) Arthrochalasis multiplex congenita; congenital flaccidity of the joints. J Bone Joint Surg Am 40-A(3):663-674. Abstract available through publisher.
  3. 3. Klaassens M et al. (2012) Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood. Clin Genet 82(2):121-130. Full text on PubMed.
  4. 4. Melis D et al. (2012) Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type? Ital J Pediatr 38:65. doi: 10.1186/1824-7288-38-65. Full text on PubMed.
  5. 5. Giunta C et al. (1999) Ehlers-Danlos syndrome type VII: Clinical features and molecular defects. J Bone Joint Surg Am 81(2):225-238. Abstract on PubMed.
  6. 6. Giunta C et al. (2008) The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. Am J Med Genet A 146A(10):1341-1346. Abstract on PubMed.
  7. 7. D'Alessio M et al. (1991) Characterization of a COL1A1 splicing defect in a case of Ehlers-Danlos syndrome type VII: further evidence of molecular homogeneity. Am J Hum Genet 49(2):400-406. Full text on PubMed.
  8. 8. Cole WG et al. (1987) The clinical features of Ehlers-Danlos syndrome type VII due to a deletion of 24 amino acids from the pro alpha 1(I) chain of type I procollagen. J Med Genet 24(11):698-701. Full text on PubMed.
  9. 9. Byers PH et al. (1997) Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagens. Am J Med Genet 72(1):94-105. Abstract on PubMed.     Full text from authors.
  10. 10. Vasan NS et al. (1991) A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype. Am J Hum Genet 48(2):305-317. Full text on PubMed.
  11. 11. Wirtz MK et al. (1987) Ehlers-Danlos syndrome type VIIB. Deletion of 18 amino acids comprising the N-telopeptide region of a pro-alpha 2(I) chain. J Biol Chem 262(34):16376-16385. Full text from publisher.
  12. 12. Carr AJ et al. (1994) The clinical features of Ehlers-Danlos syndrome type VIIB resulting from a base substitution at the splice acceptor site of intron 5 of the COL1A2 gene. J Med Genet 31(4):306-311. Full text on PubMed.
  13. 13. Osteogenesis Imperfecta Variant Database
  14. 14. Cabral WA et al. (2005) Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Anat Physiol 280(19):19259-19269. Full text from publisher.
  15. 15. Barclay-Smith E (1909) A rare condition of Wormian ossifications. J Anat Physiol 43(Pt 3):277-278. Full text on PubMed.
  16. 16. Sobotta J. (1914) Atlas and text-book of human anatomy. Philadelphia: W. B. Saunders Company.


Above: A swan-neck deformity induced by a girl with EDS-A. Source: Reference 4.










This website is certified by Health On the Net Foundation. 
	  Click to verify. This site complies with the HONcode standard for trustworthy health information: verify here.


Above: Left. An 18-month-old boy with EDS-A. Note the position of his right foot. This
boy was not able to maintain an upright posture because of joint hypermobility and
hypotonia. Right: joint hypermobility in the same boy. Source: reference 5. For
license information, hover over photo.


Above: Wormian bones (arrow) in the skull of a young person with EDS-A. Wormian bones
are extra bones that occur within the sutures in the cranium. See below for more examples.
Source: reference 5. For license information, hover over photo.

Below: Left. Wormian bones in the skull of a 21-year-old man who died of tuberculosis.
Other details of his condition were not known. Right: a skull without Wormian bones.
Sources: references Barclay-Smith and Sobotta.




Page last modified on 10 March 2017.