Clinical Diagnosis

The major and minor clinical features of Ehlers-Danlos syndrome (EDS), kyphoscoliotic form have been outlined by Beighton et al [1998].

Major clinical features

• Friable, hyperextensible skin, thin scars, easy bruising

• Generalized joint laxity

• Severe muscle hypotonia at birth

• Progressive scoliosis, present at birth or within the first year of life

• Scleral fragility and rupture of the globe

Minor clinical features

• Widened, atrophic scars

• Marfanoid habitus

• Rupture of medium-sized arteries

• Mild to moderate delay of attainment of gross motor milestones

The presence of three major clinical features is highly suggestive of EDS, kyphoscoliotic form.

Testing

Affected individuals

• Biochemical testing. Deficiency of the enzyme procollagen-lysine, 2-oxoglutarate 5 dioxygenase-1 (PLOD1) results in a deficiency in hydroxylysine-based pyridinoline cross-links in collagens. Detection of an increased ratio of deoxypyridinoline (Dpyr) to pyridinoline (Pyr) cross-links in urine quantitated by high-performance liquid chromatography (HPLC) is a highly sensitive and specific test for EDS, kyphoscoliotic form. The normal ratio of cross-links Dpyr:Pyr is approximately 1:4, whereas in EDS, kyphoscoliotic form, the ratio is approximately 6:1 [Steinmann et al 1995, Al-Hussain et al 2004]. Such testing is clinically available.

• Enzyme assay. Activity of the enzyme PLOD1 can be measured in cultured fibroblasts. In individuals with EDS, kyphoscoliotic form, enzyme activity is below 25% of normal [Yeowell & Walker 2000]. Such testing is clinically available.

Carriers. Carriers cannot be detected by biochemical testing or by enzyme assay.

Molecular Genetic Testing

Gene. PLOD1 is the only gene in which mutation is known to cause EDS, kyphoscoliotic form.

Clinical testing

• Sequence analysis of all exons and flanking intronic sequences

• Deletion/dupliction analysis. An intragenic duplication caused by an Alu-Alu recombination in introns 9 and 16 is the most common mutant allele, with a frequency of 18.3% in 53 families with EDS, kyphoscoliotic form [Yeowell et al 2005]. The duplication can be confirmed in genomic DNA by PCR using duplication-specific primers [Pousi et al 1994, Giunta et al 2005b].

Table 1. Summary of Molecular Genetic Testing used in EDS, Kyphoscoliotic Form

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PLOD1	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion / duplication analysis	Intragenic duplication of sequences in introns 9 through 16	~18%

Testing Strategy

To confirm the diagnosis in a proband, perform urinary cross-link analysis; assay lysyl hydroxylase activity.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in PLOD1, with the exception of linkage of a polymorphism 319 (G>A), coding for p.Ala99Thr, as described in Molecular Genetics.

Natural History

A range of clinical severity is observed in individuals with EDS, kyphoscoliotic form for each of the systems discussed in this section [Steinmann et al 2002].

Prenatal. Pregnancy involving an affected fetus may be complicated by premature rupture of membranes.

Musculoskeletal. Muscle hypotonia with joint laxity is present in neonates. Muscle weakness is common, may be severe with wrist drop, and may lead to upper brachial plexus palsy. Attainment of gross motor milestones may be mildly to moderately delayed, but walking nearly always occurs before age two years; loss of motor milestones does not occur. Intellect is unaffected.

A marfanoid habitus is often striking.

Thoracic scoliosis is common in the neonate. The kyphoscoliosis appears during infancy and becomes moderate to severe in childhood. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.

Clubfoot (equinovarus) deformities are present at birth in approximately 30% of affected individuals.

Recurrent joint dislocations are a common serious problem.

Osteoporosis occurs in all individuals.

Eyes. Ocular fragility, which was observed in the original reports of individuals with procollagen lysyl hydroxylase deficiency [Pinnell et al 1972], is found in a minority of individuals.

High myopia is common.

Most individuals have microcornea, although its clinical significance is unclear.

Glaucoma and retinal detachment also occur.

Cardiovascular. Vascular rupture is the major life-threatening complication in this disorder. In one series, three of ten individuals had vascular rupture. Both aortic dilation/dissection and rupture of medium-sized arteries may occur. The rate of progression of aortic root dilation in EDS, kyphoscoliotic form is not known.

Mitral valve prolapse is common.

Venous ectasis following use of intravenous catheters has been reported [Heim et al 1998].

Skin. All individuals with EDS, kyphoscoliotic form have hyperelastic and easily stretched skin.

An estimated 60% of individuals have abnormal scarring, characterized by thinness and widening.

Bruising occurs easily in all individuals and severe bruising occurs in approximately 50%.

Genotype-Phenotype Correlations

Genotype-phenotype correlations that predict risk for specific complications or clinical severity do not exist.

Penetrance

Penetrance for EDS, kyphoscoliotic form is 100%.

Nomenclature

EDS, kyphoscoliotic form was initially referred to as EDS, oculoscoliotic form after its first description by Pinnell et al [1972].

Prior to the development of the 1998 VilleFranche classification, EDS, kyphoscoliotic form was known as EDS VI.

Giunta et al [2005a] convincingly demonstrated that Nevo syndrome is part of the spectrum of EDS VI; thus, the term Nevo syndrome does not refer to a distinct disorder, but is now incorporated into EDS, kyphoscoliotic form.

Prevalence

EDS, kyphoscoliotic form is rare; the exact prevalence is unknown. A disease incidence of approximately 1:100,000 live births is a reasonable estimate.

Prevalence does not vary by race or ethnicity, although many of the reported and unreported cases originated in Turkey, the Middle East, and Greece [Giunta et al 2005a, Giunta et al 2005b].

Carrier frequency is estimated to be 1:150.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Ehlers-Danlos syndrome (EDS), kyphoscoliotic form, the following evaluations are recommended:

• Musculoskeletal

  • Evaluation for kyphoscoliosis. Photographic and radiologic documentation of the spine is recommended in view of the progressive kyphoscoliosis.

  • Physical therapy evaluation to develop a plan for ongoing therapy to strengthen large muscle groups and prevent recurrent shoulder dislocation

• Cardiovascular. Measurement of aortic root size and assessment of heart valves by echocardiogram at the time of diagnosis or by age five years

• Ophthalmologic. Formal ophthalmologic evaluation at diagnosis for myopia, astigmatism, and potential for retinal detachment

Treatment of Manifestations

Musculoskeletal

• Referral to an orthopedic surgeon for management of kyphoscoliosis is appropriate.

• Orthopedic surgery is not contraindicated in individuals with EDS, kyphoscoliotic form and can be performed as necessary.

• Physical therapy is recommended for older children, adolescents, and adults to strengthen large muscle groups, particularly at the shoulder girdle, and to prevent recurrent shoulder dislocation. Swimming is recommended.

Cardiovascular

• Vigilant observation and control of blood pressure can reduce the risk of arterial rupture.

• Vascular surgery is fraught with danger. Although virtually no surgical literature exists on EDS, kyphoscoliotic form, the review by Freeman et al [1996] on surgical complications of EDS, vascular type is relevant.

• Individuals with aortic dilation may require treatment with beta blockers to prevent further expansion.

Ophthalmologic

• Myopia and/or astigmatism may be corrected by glasses or contact lenses.

• Laser treatment of the retina is indicated in case of imminent detachment.

Prevention of Secondary Complications

Hydration should be maintained to prevent oxalic acid nephrolithiasis.

Individuals with mitral valve prolapse should follow standard American Heart Association guidelines for antimicrobial prophylaxis.

Surveillance

The following are appropriate:

• Routine ophthalmologic examination for management of myopia and early detection of glaucoma or retinal detachment

• Routine examination for inguinal hernia and surgical referral as necessary

• Vigilant observation of blood pressure

• Regular follow-up by an orthopedic surgeon for management of kyphoscoliosis

• Echocardiogram at five-year intervals, even if the initial echocardiogram is normal

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
Phone: 800-334-8571 ext. 24640
Email: gentac-registry@rti.org
Web: gentac.rti.org

Other

Ascorbate therapy has been suggested as a treatment, but its effectiveness has not been biochemically proven.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Ehlers-Danlos syndrome (EDS), kyphoscoliotic form is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in PLOD1.

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband with EDS, kyphoscoliotic form has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an affected individual are obligate heterozygotes.

Other family members. Each sib of an obligate heterozygote is at a 50% risk of being a heterozygote.

Carrier Detection

Biochemical genetic testing. Carriers cannot be detected by biochemical testing or by enzyme assay.

Molecular genetic testing. Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed [Yeowell & Walker 1999, Yeowell et al 2000].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical testing. At present, prenatal testing by analysis of activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is not clinically available.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B. Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet A. 2004;124:28–34. [PubMed: 14679583]
2. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7. [PubMed: 9557891]
3. Freeman RK, Swegle J, Sise MJ. The surgical complications of Ehlers-Danlos syndrome. Am Surg. 1996;62:869–73. [PubMed: 8813174]
4. Giunta C, Randolph A, Al-Gazali LI, Brunner HG, Kraenzlin ME, Steinmann B. Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA). Am J Med Genet A. 2005a;133:158–64. [PubMed: 15666309]
5. Giunta C, Randolph A, Steinmann B. Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab. 2005b;86:269–76. [PubMed: 15979919]
6. Heim P, Raghunath M, Meiss L, Heise U, Myllyla R, Kohlschutter A, Steinmann B. Ehlers-Danlos syndrome type VI (EDS VI): problems of diagnosis and management. Acta Paediatr. 1998;87:708–10. [PubMed: 9686670]
7. Pinnell SR, Krane SM, Kenzora JE, Glimcher MJ. A heritable disorder of connective tissue. Hydroxylysine-deficient collagen disease. N Engl J Med. 1972;286:1013–20. [PubMed: 5016372]
8. Pousi B, Hautala T, Heikkinen J, Pajunen L, Kivirikko KI, Myllyla R. Alu-Alu recombination results in a duplication of seven exons in the lysyl hydroxylase gene in a patient with the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet. 1994;55:899–906. [PMC free article: PMC1918329] [PubMed: 7977351]
9. Steinmann B, Eyre DR, Shao P. Urinary pyridinoline cross-links in Ehlers-Danlos syndrome type VI. Am J Hum Genet. 1995;57:1505–8. [PMC free article: PMC1801424] [PubMed: 8533783]
10. Steinmann B, Royce PM, Superti-Furga A. The Ehlers-Danlos syndrome. In: Royce PM, Steinmann B, eds. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects. New York, NY: Wiley-Liss; 2002:431-523.
11. Tasker PN, Macdonald H, Fraser WD, Reid DM, Ralston SH, Albagha OM. Association of PLOD1 polymorphisms with bone mineral density in a population-based study of women from the UK. Osteoporos Int. 2006;17:1078–85. [PubMed: 16758144]
12. Walker LC, Overstreet MA, Siddiqui A, De Paepe A, Ceylaner G, Malfait F, Symoens S, Atsawasuwan P, Yamauchi M, Ceylaner S, Bank RA, Yeowell HN. A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient. J Invest Dermatol. 2005;124:914–8. [PubMed: 15854030]
13. Walker LC, Overstreet MA, Willing MC, Marini JC, Cabral WA, Pals G, Bristow J, Atsawasuwan P, Yamauchi M, Yeowell HN. Heterogeneous basis of the type VIB form of Ehlers-Danlos syndrome (EDS VIB) that is unrelated to decreased collagen lysyl hydroxylation. Am J Med Genet A. 2004;131:155–62. [PubMed: 15523625]
14. Yamada Y, Ando F, Shimokata H. Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men. Int J Mol Med. 2007;19:791–801. [PubMed: 17390085]
15. Yeowell HN. Isoforms of lysyl hydroxylase. In: Creighton T, ed. Wiley Encyclopedia of Molecular Medicine. New York, NY: JW Wiley; 2002:1980-4.
16. Yeowell HN, Walker LC. Prenatal exclusion of Ehlers-Danlos syndrome type VI by mutational analysis. Proc Assoc Am Physicians. 1999;111:57–62. [PubMed: 9893157]
17. Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab. 2000;71:212–24. [PubMed: 11001813]
18. Yeowell HN, Walker LC, Farmer B, Heikinnen J, Myllyla R. Mutational analysis of the lysyl hydroxylase 1 gene in six unrelated patients affected by Ehlers-Danlos syndrome type VI; prenatal exclusion of this disorder in one family. Human Mutation. 2000;16:90. [PubMed: 10874315]
19. Yeowell HN, Walker LC, Neumann LM. An Ehlers-Danlos syndrome type VIA patient with cystic malformations of the meninges. Eur J Dermatol. 2005;15:353–8. [PubMed: 16172044]

Suggested Reading

1. Abel MD, Carrasco LR. Ehlers-Danlos syndrome: classifications, oral manifestations, and dental considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:582–90. [PubMed: 17052632]
2. Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 205. Available at www.ommbid.com. Accessed 12-27-11.

Author History

Beat Steinmann, MD (2008-present)
Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (1999-2008)
Heather N Yeowell, PhD (2005-present)

Revision History

• 19 February 2008 (me) Comprehensive update posted to live Web site

• 12 July 2005 (me) Comprehensive update posted to live Web site

• 12 March 2003 (me) Comprehensive update posted to live Web site

• 2 February 2000 (me) Review posted to live Web site

• 7 April 1999 (rw) Original submission