Forgotten Diseases Research Foundation

Ehlers-Danlos Syndrome, Kyphoscoliotic (type 6)


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 joint laxity that is common in EDS puts patients at high risk for joint dislocations and subluxations. These problems can be painful, and in some cases, debilitating. Surgical procedures have been used to improve skeletal stability and improve quality of life; for examples and reviews, see references 2-4.

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.



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 kyphoscoliotic type (EDS-K) is very rare, and although exact figures are not known, the Gene Review article at the right estimates that it occurs in one birth per 100,000.

Clinical information

Signs and symptoms

The most striking feature of EDS-K is kyphoscoliosis. This problem is often present at birth and otherwise tends to develop at early ages. It often progresses to a point of striking severity (see photos below). In addition, EDS-K patients often have wideset eyes and downslanting palpebral fissures (their eyelids slant downward from the center to the outside; for an example, see the photo of the patient at the right. Other facial features include wide-set eyes and fleshy swelling of facial tissues (this latter problem appears to occur in the patient at right).

The most common signs and symptoms associated with EDS-K are as follows:

    Signs of EDS-Kyphoscoliotic type

  • Joint laxity/hypermobility
  • Hyperelastic/stretchy skin that appears normal after being released
  • Smooth, velvety skin
  • Skin that bruises easily
  • Abnormal spinal curvature that may present at birth
  • Severe neonatal muscular hypotonia (floppiness)
  • Delays in motor development
  • Flat feet or clubfeet
  • Osteopenia (bone loss as measured by low bone density, but not low enough to be called osteoporosis)
  • Joint dislocations or subluxations
  • Sunken chest
  • Myopia/nearsightedness that may be severe
  • Small corneas
  • Glaucoma
  • Blue sclerae (see photo below)
  • Hearing loss
  • Weakness, including a weak cry as an infant

In addition, a minority of EDS-K patients have intellectual disabilities. Fragile/ruptured blood vessels also occur in a minority of EDS-K patients. Readers may wish to consult a review about EDS-6 that contains descriptions of 15 patients (5).

Diagnosis and Testing

EDS-K is an autosomal recessive disorder caused by mutations in the gene PLOD1. The term autosomal recessive means that a defective copy of the gene must be inherited from each parent. PLOD1 codes for the enzyme lysyl hydroxylase 1, which is important for collagen formation and stabilization. Gene sequencing can confirm the diagnosis, as can an assay of lysyl hydroxylase activity in skin fibroblasts. Alternatively, there is also a urine test that uses high-performance liquid chromatography (HPLC). This test looks for an increased ratio of deoxypyridinoline to pyridinoline crosslinks and may be relatively inexpensive compared to sequencing, and is non-invasive compared to a skin biopsy for the enzyme assay. For a list of labs that perform testing, see the links at right.

Differential Diagnosis

Other forms of EDS.The differential diagnosis for EDS-K includes all the other forms of EDS. The forms of EDS most similar to EDS-K include EDS-spondylocheirodysplasia, FKBP14-related EDS, and EDS VIB. In these conditions, lysyl hydroxylase activity (see previous section) is normal. Additionally, EDS-K overlaps with the vascular (type 4) and classic (types 1 and 2) forms of EDS. Laboratory testing can give a definitive diagnosis of EDS-K. However, clinically, scoliosis in EDS-K tends to be more severe than it is in the other forms and its onset is usually earlier than in the vascular and classic forms, as well.

Brittle cornea syndrome (BCS). BCS is another connective tissue disorder. BCS patients often suffer corneal ruptures after minor eye trauma and corneal degeneration (keratoconus). Like EDS patients and EDS-K patients in particular, they may also have blue sclerae, joint hypermobility, hyperelastic skin, and hearing loss. Laboratory testing can distinguish EDS-K from BCS.

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.

A number of congenital muscle disorders feature hypotonia, and EDS-K may be confused with them in very young patients. These disorders include X-linked myotubular myopathy and spinal muscular atrophy. The velvety skin and striking joint hypermobility in EDS-K may help distinguish these other disorders from one another. In addition, deep tendon reflexes are abnormal in the muscle disorders, but are normal in EDS-K.



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. Cole AS et al. (2000) Recurrent instability of the elbow in the Ehlers-Danlos syndrome. A report of three cases and a new technique of surgical stabilisation. J Bone Joint Surg Br 82(5):702-704. Full text from publisher.
  3. 3. Weinberg J et al. (1999) Joint surgery in Ehlers-Danlos patients: results of a survey. Am J Orthop 28(7):406-409. Abstract on PubMed.
  4. 4. Shirley ED et al. (2012) Ehlers-Danlos syndrome in orthopaedics. Etiology, diagnosis, and treatment implications. Sports Health 4(5):394-403. Full text on PubMed.
  5. 5. Rohrbach M et al. (2011) Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis 6:46. doi: 10.1186/1750-1172-6-46. Full text on PubMed.
  6. 6. Kariminejad A et al. (2010) Ehlers-Danlos syndrome type VI in a 17-year-old Iranian boy with severe muscular weakness - a diagnostic challenge? Iran J Pediatr 20(3):358-362. Full text on PubMed.
  7. 7. Canpolat M et al. (2014) Ehlers-Danlos Syndrome Type VI: A case report. Turk J Pediatr Dis 2:101-104. Full text.
  8. 8. SamuelEDS94 (2013) Photograph on the Wikimedia Commons.

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Above: Left. Severe kyphoscoliosis in the patient pictured at the top right on this page.
Right. The same patient's right knee, showing scars and hyperkeratosis follicularis.
Note that the scars in EDS-K do not necessarily resemble scars seen in other forms of EDS.
See reference 2.



Below: Severe kyphoscoliosis in a patient with EDS-K. See reference 3 for details.



Below:The eye of a patient with EDS-K. Note the patient's blue sclerae. This
patient also had congenital glaucoma, severe myopia, and corneal abnormalities.
See the original photo and caption here.




Below: Joint hypermobility in an 18-year-old EDS patient. People with
EDS generally have hypermobilities in many joints (elbows, wrists, fingers,
feet, knees, back etc.). Photo from reference 8.




Page last modified on 10 March 2017.