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Ehlers-Danlos Syndrome, Kyphoscoliotic Form 

[EDS Type VI, Ehlers-Danlos Syndrome Type VI, Lysyl-Hydroxylase Deficiency]

   Authors:  Richard Wenstrup, MD; Heather N Yeowell, PhD

    About the Authors

Summary

Disease characteristics. Ehlers-Danlos syndrome (EDS), kyphoscoliotic form (previously known as EDS VI) is a generalized connective tissue disorder characterized by kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, ocular problems. Intelligence is normal; lifespan may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe.

Diagnosis/testing. EDS, kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies upon the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme activity in skin fibroblasts is also available. Molecular genetic testing of the PLOD1 gene that encodes the enzyme lysyl hydroxylase 1 is available on a research basis.

 
Genetic counseling. EDS, kyphoscoliotic form is inherited in an autosomal recessive manner. Couples who have had one affected child have a 25% chance of having an affected child in each pregnancy. Prenatal testing may be available through laboratories offering custom prenatal testing.
 

Diagnosis

Clinical Diagnosis

The major and minor clinical features of 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 results in a deficiency in hydroxylysine-based pyridinoline crosslinks in types I and III collagen. As a result, crosslinked telopeptides are excreted in urine as byproducts of collagen turnover. Detection of an increased ratio of deoxypyridinoline (Dpyr) to pyridinoline (Pyr) crosslinks in urine quantitated by HPLC is a highly sensitive and specific test for EDS, kyphoscoliotic form. The ratio of crosslinks Dpyr:Pyr is 1:3 in normals, whereas in EDS, kyphoscoliotic form, the ratio is 5:1 [Pasquali et al 1994 , Steinmann et al 1995]. Such testing is clinically available. See

     ·   Enzyme assay. Activity of the enzyme procollagen-lysine, 2-oxoglutarate 5 dioxygenase-1 [Murad & Pinnell 1987] 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. See

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

 Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US . GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work. Listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. â€”ED.

Gene.   PLOD1 is the only gene known to be associated with EDS, kyphoscoliotic form.

Molecular genetic testing: Research

Table 1 summarizes molecular genetic testing for this disorder.

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Genetically Related (Allelic) Disorders

 

No other phenotypes are known to be associated with mutations in the PLOD1 gene.

<!--[endif]-->Clinical Description

 

Natural History

 

A range of clinical severity is observed in individuals with EDS, kyphoscoliotic form for each of the systems below [Wenstrup et al 1989 , Beighton 1992 , 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. 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.

   

• 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 and recurrent pneumonia.

   

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

   

• Recurrent joint dislocations are a common serious problem for affected individuals.

   

• 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 only 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 [Wenstrup et al 1989]. 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.

   

• About 60% of individuals have abnormal scarring, characterized by thinness and widening.

   

• Bruising occurs easily in all individuals and severe bruising occurs in about 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 in 1972 by Pinnell et al .

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

<!--[endif]-->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. Carrier frequency is estimated to be 1/150.

<!--[endif]-->Differential Diagnosis

 

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. â€”ED.

• EDS, kyphoscoliotic form has some overlapping clinical features with other forms of EDS, particularly EDS, classic type and EDS, vascular type . Abnormal wound healing and joint laxity are present in many EDS types. Although all types of EDS have a relatively high risk of scoliosis compared to the general population, scoliosis in EDS, kyphoscoliotic form is usually more severe and of earlier onset than that seen in other EDS types.

   

• Most congenital myopathies present with poor muscle tone and increased range of motion of small and large joints. Joint laxity can be difficult to distinguish from muscle hypotonia, particularly in infants and children. In EDS, kyphoscoliotic form, in which both hypotonia and joint laxity are present, the increased range of motion is often striking. Velvety skin texture may help distinguish EDS, kyphoscoliotic form from congenital myopathies, such as X-linked myotubular myopathy . Unlike spinal muscular atrophy , EDS, kyphoscoliotic form is characterized by normal deep tendon reflexes.

   

• Many syndromic and metabolic disorders include early-onset hypotonia. In these disorders, however, the other manifestations of EDS, kyphoscoliotic form are generally absent, and additional features are usually present.

   

• A rare condition, designated EDS VIB (OMIM 229200), features the clinical phenotype of EDS, kyphoscoliotic type with normal lysyl hydroxylase enzyme activity. Alternative pathways (in addition to lysyl hydroxylation of collagens) may be affected in EDS VIB, suggesting genetic heterogeneity [Walker et al 2004].

   

• Although brittle cornea syndrome, characterized by corneal rupture following minor trauma, is characterized by skin hyperelasticity and joint hypermobility, biochemical analysis reveals normal lysyl hydroxylase enzyme activity [Al-Hussain et al 2004].

   

<!--[endif]-->Management

 

<!--[endif]-->Evaluations at Initial Diagnosis to Establish the Extent of Disease

 

   ·   Musculoskeletal

• Referral to an orthopedic surgeon for management of 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 by echocardiogram at the time of diagnosis or by age five years

   

• Vigilant observation and aggressive control of blood pressure to 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.

   

Treatment of Manifestations

 

   ·  Musculoskeletal

• Regular follow-up by an orthopedic surgeon for management of kyphoscoliosis. Orthopedic surgery is not contraindicated in individuals with EDS, kyphoscoliotic form and can be performed as necessary.

   

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

   

   ·  Cardiovascular

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

   

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

   

Prevention of Primary Manifestations

 

Oral ascorbate may improve urinary excretion of hydroxylysine and also improve muscle strength and wound healing [Elsas et al 1978]. Oral vitamin C, 500 mg per day in young children and up to 10 gm per day in adults, may be beneficial.

Prevention of Secondary Complications

 

Hydration should be maintained to prevent oxalic acid nephrolithiasis [Miller et al 1979].

Surveillance

 

• Routine ophthalmological examination for management of myopia and early detection of glaucoma

   

• Routine examination for inguinal hernia and surgical referral as necessary

   

• It may be advisable to repeat an echocardiogram at five-year intervals even if the initial echocardiogram is normal.

   

Therapies Under Investigation

 

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

<!--[endif]-->Genetic Counseling

 

<!--[endif]-->Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. â€”ED.

<!--[endif]-->Mode of Inheritance

 

EDS, kyphoscoliotic form is inherited in an autosomal recessive manner.

<!--[endif]-->Risk to Family Members

 

This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. â€”ED.

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 the PLOD1 gene.

   

• Heterozygotes are asymptomatic.

   

Sibs of a proband

• At conception, the sibs of a proband with EDS, kyphoscoliotic form have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.

   

• 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.   The sibs of obligate heterozygotes have a 50% chance of being heterozygotes.

Carrier Detection

 

<!--[endif]-->Carriers cannot be detected by biochemical testing or by enzyme assay.

Carrier testing using molecular genetic techniques is not clinically available.

<!--[endif]-->Related Genetic Counseling Issues

 

Family planning.  The optimal time for determination of genetic risk is before pregnancy.

DNA banking.  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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

 

<!--[endif]-->Molecular genetic testing.  Although no laboratories offer routine molecular genetic testing for prenatal diagnosis of EDS, kyphoscoliotic form, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory [Yeowell & Walker 1999 , Yeowell et al 2000]. For laboratories offering custom prenatal testing, see <!--[endif]-->.

Biochemical testing.   At present, prenatal testing by analysis of activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 [Dembure et al 1984] is not clinically available.

<!--[endif]-->Molecular Genetics

 

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. â€”ED.

Normal allelic variants: The PLOD1 gene is approximately 40 kb and consists of 19 exons with an unusually large first intron of 12.5 kb [Heikkinen et al 1994]. The introns are of high homology, generating many potential recombination sites within the gene. Five polymorphic markers have been identified in the PLOD1 gene [Yeowell et al 2000]. These are located at nucleotides 318 (C>T), 319 (G>A), 382 (G>T), 1230 (C>T), and 1656 (A>C) in the coding region and, in the noncoding region, at 2349 (G>A). (Numbering is based on GenBank accession number M98252.)

Pathologic allelic variants: Over 20 different mutations in the PLOD1 gene that are associated with EDS, kyphoscoliotic form have been reported [Yeowell & Walker 2000 , Walker et al 2005]. These mutations are located throughout the gene. The most common mutation, an 8.9-kb duplication of seven exons (exons 10 to 16), is caused by a homologous recombination event between identical 44-bp Alu sequences in introns 9 and 16 [Pousi et al 1994]. The allele frequency of the duplication is 18.3% in probands with EDS, kyphoscoliotic form from 53 families [Heikkinen et al 1997 , Yeowell et al 2005]. The second most common mutation in PLOD1 occurs in exon 14 and results in chain termination at codon 511 for tyrosine (Y511X). The allele frequency of this mutation in EDS probands is 10%. Both mutations have been linked by haplotype analysis to a common ancestral gene [Yeowell & Walker 2000].

Normal gene product: The cDNA for PLOD1 codes for a polypeptide of 727 amino acids including a signal peptide of 18 residues [Hautala et al 1992 , Yeowell et al 1994]. Lysyl hydroxylase 1 exists as a dimer of identical subunits of molecular weight approximately 80-85 kd, depending on the state of glycosylation. The enzyme requires Fe²⁺, <!--[endif]-->-ketoglutarate, O₂, and ascorbate as cofactors. The C-terminal region is well conserved across species and is thought to contain the active site of the enzyme [Yeowell 2002].

Abnormal gene product: Western blot analysis using polyclonal antibody to recombinant LH1 showed, in contrast to EDS VIB, decreased levels of LH1 in two individuals with EDS, kyphoscoliotic form [Walker et al 2004].

<!--[endif]-->Resources

 

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

<!--[endif]-->  Resources Printable Copy <!--[endif]-->

References

 

<!--[endif]-->

Published Statements and Policies Regarding Genetic Testing

 

No specific guidelines regarding genetic testing for this disorder have been developed.

Literature Cited

 

• <!--[endif]-->Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B (2004) 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 124:28-34 [Medline]

   

• <!--[endif]-->Beighton P (1992) The Ehlers-Danlos syndromes. In: Beighton P (ed) McKusick's Heritable Disorders of Connective Tissue. Mosby, St. Louis , pp 189-251

   

• <!--[endif]-->Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998) Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation ( USA ) and Ehlers-Danlos Support Group ( UK ). Am J Med Genet 77:31-7 [Medline]

   

• <!--[endif]-->Dembure PP, Priest JH, Snoddy SC , Elsas LJ (1984) Genotyping and prenatal assessment of collagen lysyl hydroxylase deficiency in a family with Ehlers-Danlos syndrome type VI. Am J Hum Genet 36:783-90 [Medline]

   

• <!--[endif]-->Elsas LJ 2d, Miller RL, Pinnell SR (1978) Inherited human collagen lysyl hydroxylase deficiency: ascorbic acid response. J Pediatr 92:378-84 [Medline]

   

• <!--[endif]-->Freeman RK, Swegle J, Sise MJ (1996) The surgical complications of Ehlers-Danlos syndrome. Am Surg 62:869-73 [Medline]

   

• <!--[endif]-->Hautala T, Byers MG, Eddy RL, Shows TB, Kivirikko KI, Myllyla R (1992) Cloning of human lysyl hydroxylase: complete cDNA-derived amino acid sequence and assignment of the gene (PLOD) to chromosome 1p36.3-p36.2. Genomics 13:62-9 [Medline]

   

• <!--[endif]-->Heikkinen J, Hautala T, Kivirikko KI, Myllyla R (1994) Structure and expression of the human lysyl hydroxylase gene (PLOD): introns 9 and 16 contain Alu sequences at the sites of recombination in Ehlers-Danlos syndrome type VI patients. Genomics 24:464-71 [Medline]

   

• <!--[endif]-->Heikkinen J, Toppinen T, Yeowell H, Krieg T, Steinmann B, Kivirikko KI, Myllyla R (1997) Duplication of seven exons in the lysyl hydroxylase gene is associated with longer forms of a repetitive sequence within the gene and is a common cause for the type VI variant of Ehlers-Danlos syndrome. Am J Hum Genet 60:48-56 [Medline]

   

• <!--[endif]-->Heim P, Raghunath M, Meiss L, Heise U, Myllyla R, Kohlschutter A, Steinmann B (1998) Ehlers-Danlos Syndrome Type VI (EDS VI): problems of diagnosis and management. Acta Paediatr 87:708-10 [Medline]

   

• <!--[endif]-->Miller RL, Elsas LJ, Priest RE (1979) Ascorbate action on normal and mutant human lysyl hydroxylases from cultured dermal fibroblasts. J Invest Dermatol 72:241-7 [Medline]

   

• <!--[endif]-->Murad S and Pinnell SR (1987) Suppression of fibroblast proliferation and lysyl hydroxylase activity by minoxidil. J Biol Chem 262:11973-8 [Medline]

   

• <!--[endif]-->Pasquali M, Dembure PP, Still MJ, Elsas LJ (1994) Urinary pyridinium cross-links: a noninvasive diagnostic test for Ehlers-Danlos syndrome type VI [letter]. N Engl J Med 331:132-3 [Medline]

   

• <!--[endif]-->Pinnell SR, Krane SM, Kenzora JE, Glimcher MJ (1972) A heritable disorder of connective tissue. Hydroxylysine-deficient collagen disease. N Engl J Med 286:1013-20 [Medline]

   

• <!--[endif]-->Pousi B, Hautala T, Heikkinen J, Pajunen L, Kivirikko KI, Myllyla R (1994) 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 55:899-906 [Medline]

   

• <!--[endif]-->Steinmann B, Eyre DR, Shao P (1995) Urinary pyridinoline cross-links in Ehlers-Danlos syndrome type VI [letter]. Am J Hum Genet 57:1505-8 [Medline]

   

• <!--[endif]-->Steinmann B, Royce PM, Superti-Furga A (2002) The Ehlers-Danlos syndrome. In: Royce PM and Steinmann B (eds) Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects. Wiley-Liss , New York , pp 431-523

   

• <!--[endif]-->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 (2005) A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient. J Invest Dermatol 124:914-8 [Medline]

   

• <!--[endif]-->Walker LC, Overstreet MA, Willing MC, Marini JC, Cabral WA , Pals G, Bristow J, Atsawasuwan P, Yamauchi M, Yeowell HN (2004) 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 131:155-62 [Medline]

   

• <!--[endif]-->Wenstrup RJ, Murad S, Pinnell SR (1989) Ehlers-Danlos syndrome type VI: clinical manifestations of collagen lysyl hydroxylase deficiency. J Pediatr 115:405-9 [Medline]

   

• <!--[endif]-->Yeowell HN (2002) Isoforms of lysyl hydroxylase. In: Creighton T (ed) Wiley Encyclopedia of Molecular Medicine. JW Wiley, New York , pp 1980-4

   

• <!--[endif]-->Yeowell HN and Walker LC (1999) Prenatal exclusion of Ehlers-Danlos syndrome type VI by mutational analysis. Proc Assoc Am Physicians 111:57-62 [Medline]

   

• <!--[endif]-->Yeowell HN, Ha V, Clark WL, Marshall MK, Pinnell SR (1994) Sequence analysis of a cDNA for lysyl hydroxylase isolated from human skin fibroblasts from a normal donor: differences from human placental lysyl hydroxylase cDNA. J Invest Dermatol 102:382-4 [Medline]

   

• <!--[endif]-->Yeowell HN and Walker LC (2000) 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 71:212-24 [Medline]

   

• <!--[endif]-->Yeowell HN, Walker LC, Farmer B, Heikinnen J, Myllyla R (2000) 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 16:90 [Medline]

   

• <!--[endif]-->Yeowell HN, Walker LC, Neumann LM (2005) An Ehlers-Danlos syndrome type VIA patient with cystic malformation of the meninges. Eur J Dermatol 15:1-6

   

<!--[endif]-->Author Information

 

Richard Wenstrup, MD
Division of Human Genetics
Cincinnati Children's Hospital Medical Center
Cincinnati

Heather N Yeowell, PhD
Medicine/Dermatology
Duke University Medical Center
Durham

Revision History

 

• 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