3. Forgotten Diseases Research Foundation | Ehlers-Danlos Syndrome, Periodontitis (type 8)

Forgotten Diseases Research Foundation

Ehlers-Danlos Syndrome, Periodontitis (type 8)


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. In addition, the easy bruising that is commonly seen in many people with EDS is an indication that capillaries are fragile. 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.



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. Type 8 is very rare, and its prevalence is not known.

EDS is a generally characterized by hypermobile joints and skin. However, these two clinical features are not uniformly prevalent in type 8 and are generally not as severe as they are in other types of EDS. There is also considerable variation in joint hypermobility, with some patients having no hypermobility or hypermobility in a limited number of joints.

Clinical information

Signs and symptoms

The most striking features of EDS 8 are dental and dermatological. Patients tend to have severe periodontal disease and fragile, easily bruised skin, especially on the lower legs. The presence of cigarette paper scars and bruised-looking tibial lesions (called pretibial plaques) are very common in peope with EDS 8. The photos on this page illustrate these problems.

As with all other forms of EDS, the clinical features of EDS 8 overlap with other forms of EDS. In particular, there is some overlap between EDS 8 and the vascular type of EDS. The lack of fragile blood vessels may help distinguish the two (see Differential Diagnosis, below). In general, the following features occur commonly in this form of EDS:

    Signs and symptoms of EDS 8

  • Periodontal disease:
  •     Gum recession (see photos)
        Alveolar bone loss (loss of bone that forms tooth sockets; see photos)
        Loss of permanent teeth (often begins in adolescence; sometimes sooner)
        Inflamed, swollen gums
        Loss of some or all permanent teeth, often at a young age
        Many cavities

  • Easy bruising
  • Brownish-yellowish shin lesions (pretibial plaques; see photo)
  • Fragile skin (lower legs especially; may split with minimal trauma)
  • Flat feet, especially when standing
  • Smooth, velvety skin
  • Loose or stretchy skin (roughly half of patients)
  • Joint hypermobility (may not be extreme; may be limited to the hands)
  • Arachnodactyly (long, slender fingers)
  • A Marfanoid habitus (tall and slender, with arachnodactyly; armspan may be greater than height)
  • Hernia(s)

We found reports of cardiac abnormalities as well. Mitral valve prolapse was the most common reported problem.

Some patients with EDS 8 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 VIII, they include the following:

    Facial features that may occur in EDS 8

  • A triangular face
  • Prominent eyes
  • A distinctive nose (long, with narrow root)
  • Some patients may show premature aging

Diagnosis and Testing

EDS 8 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 70 patients. Sixty, or 86%, had an affected parent. There was no history of an EDS-like disorder in the families in the remaining 10 people.

At this time, no genes have been associated with EDS 8, meaning that no genetic tests can diagnose it. A large study in Sweden implicated a region of chromosome 12 (12p13) with EDS 8 2). Another research group found this connection in a patient from the United States and and a connection between EDS 8 and chromosome 9 in other US patients (3,4). Because of the lack of gene-disease associations, the diagnosis of EDS 8 is primarily clinical, with laboratory tests for collagen being useful for ruling out other forms of EDS.

EDS 8 is generally suspected in patients with periodontal disease, shin lesions such as those pictured here, and fragile, easily bruised skin. In addition, hypermobile joints and stretchy skin occur in EDS 8. While these clinical features are less common in EDS 8 than in most other forms of EDS, their presence, along with periodontal disease and shin lesions is suggestive of EDS 8 (but not definitive; 4). In our survey of the literature, roughly 75% of EDS 8 patients had lax joints and slightly more than half had stretchy skin.

It is important to remember that there is a lot of overlap between the different forms of EDS. As noted above, there is overlap between EDS 8 and the vascular type of EDS (EDS type 4). In particular, periodontal disease has been reported in patients with vascular EDS (see Differential Diagnosis, below; 5). This fact means that, in the absence of laboratory testing, definitive subcategorization of EDS in a patient may be difficult or even impossible.

Differential Diagnosis

The clinical features of the vascular form of EDS overlap with EDS 8. Specifically, a number of clinical features are seen in both:

  • Hyperextensible skin
  • Fragile skin
  • Thin/transluecent skin
  • Easy bruising
  • Joint hypermobility
  • Flat feet
  • Periodontal disease
  • Blood vessel fragility

While most items on the above list are relatively common in both types, the prevalence of periodontal disease is low in the vascular form, and a recent study noted that it is not a good diagnostic indicator for EDS-vascular (5). In addition, the prevalence of blood vessel fragility (apart from fragile capillaries associated with easy bruising) appears to be low in EDS 8. In our analysis of published cases, this problem was mentioned in only one patient out of 20 in which the condition was discussed (6). Thus, these two characteristics may help distinguish the two conditions. In addition, laboratory tests are available for EDS-vascular, which is associated with mutations in the gene COL3A1. Thus, gene sequencing can either make a definitive diagnosis of EDS-vascular or rule it out. 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 it out in any patient suspected of having EDS.

EDS 8 may be distinguished from the kyphoscoliotic type by genetic testing: the kyphoscoliotic form is caused by mutations in PLOD1. In addition, people with the kyphoscoliotic form tend to have severe spinal deformities. These deformities occur in EDS 8, but are not generally so severe as they are in the kyphoscoliotic type.

The classic form of EDS ranges in severity from mild to relatively severe. Like many EDS 8 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. Skin involvement in EDS 8 patients can be severe on the legs, but extreme skin fragility and the lesions commonly seen on the shins of EDS 8 patients do not appear to extend to other parts of the body. Molluscoid pseudotumors or subcutaneous spheroids (see pictures on the classic form page) have not been reported in EDS 8 patients, but occur in more than hlf of EDS-classic patients.

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. Unlike EDS 8, cigaratte paper scars do not appear to be a general feature of the hypermobile form of EDS-H. In our analysis, they were cited in more than 75% of EDS 8 patients.

People with the arthrochalasia type of EDS suffer frequent dislocations, and many are born with hip dislocations. This feature can help distinguish this condition from EDS 8.

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. Rahman N et al. (2003) Ehlers-Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am J Hum Genet 73198-204. Full text on PubMed.
  3. 3. Reinstein E et al. (2011) Ehlers-Danlos type VIII, periodontitis-type: further delineation of the syndrome in a four-generation pedigree. Am J Med Genet Part A 155:742-747. Abstract on PubMed.
  4. 4. Reinstein E et al. (2013) Ehlers-Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features. Eur J Hum Gen 21:233-236. Full text on PubMed.
  5. 5. Ferré FC et al. (2012) Oral phenotype and scoring of vascular Ehlers-Danlos syndrome: a case-control study. BMJ Open 2(2):e000705. doi: 10.1136/bmjopen-2011-00070. Full text on PubMed.
  6. 6. Cikla U et al. (2014) Fatal ruptured blood blister-like aneurysm of middle cerebral artery associated with Ehlers-Danlos yndrome type VIII (periodontitis type). J Neurol Surg Rep 75(2):e210-e213. Full text on PubMed.
  7. 7. Moore MM et al. (2006) Ehlers-Danlos syndrome type VIII: periodontitis, easy bruising, Marfanoid habitus, and distinctive facies. J Am Acad Dermatol 55(2 Suppl):S41-S45. Abstract on PubMed.
  8. 8. Ronceray S et al. (2013) Ehlers-Danlos syndrome type VIII: a rare cause of leg ulcers in young patients. Case Rep Dermatol Volume 2013:Article ID 469505. Full text on PubMed.
  9. 9. Bhat RM et al. (2014) Type VIII - Ehlers Danlos syndrome with café-au-lait macules: a rare variant. Indian J Dermatol 59(3):317. Full text on PubMed.
  10. 10. Bernard B (2005) Image found on the Wikimedia Commons.


Above: Thin, translucent skin in a person with EDS 8. Blood vessels are visible. Source: Reference 8.



Above: Joint hypermobility in a person with EDS 8. Source: Reference 9.





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: Figure legend from original manuscript: Physical (a, c) and dental (b, d) findings
in the proposita's father. Note normal body habitus (a) and pronounced shin discoloration (c).
There is generalized periodontal disease with severe recession and multiple missing teeth (b,d).
Source: reference 4. For license information, hover over photo.


Below: Figure legend from original manuscript: Physical (a+c) and dental (b+d) findings
in the proband. Note normal body habitus (a), nondysmorphic facial features and minimal
shin bruising (c). Several metal restorations are observed on primary teeth (b) as well as
gingival recession and bacterial biofilm accumulation (d). Source: reference 4.
For license information, hover over photo.




Page last modified on 10 March 2017.