NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Ehlers-Danlos Syndrome, Kyphoscoliotic Form

Synonyms: EDS, Kyphoscoliotic Form; EDS Type VI; EDS VI; Ehlers-Danlos Syndrome Type VI; Lysyl-Hydroxylase Deficiency

, PhD and , MD.

Author Information
, PhD
Department of Dermatology
Duke University Medical Center
Durham, North Carolina
, MD
Division of Metabolism, Connective Tissue Unit
University Children's Hospital
Zurich, Switzerland

Initial Posting: ; Last Update: January 24, 2013.


Clinical characteristics.

Ehlers-Danlos syndrome (EDS), kyphoscoliotic form (previously known as EDS VI) is a generalized connective tissue disorder characterized by friable, hyperextensible skin, thin scars, and easy bruising; generalized joint laxity; severe muscular hypotonia at birth; progressive scoliosis, present at birth or within the first year of life; and scleral fragility with increased risk of rupture of the globe. Intelligence is normal; life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries and respiratory compromise if kyphoscoliosis is severe.


EDS, kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1, or lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on the demonstration of a markedly increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatography (HPLC) (a highly sensitive, specific, and inexpensive test) and/or assay of lysyl hydroxylase enzyme activity in skin fibroblasts. PLOD1 is the only gene in which mutations are known to cause EDS, kyphoscoliotic form.


Treatment of manifestations: Management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed; physical therapy to strengthen large muscle groups; bracing to support unstable joints; protective pads and helmets during active sports; control of blood pressure to reduce the risk for arterial rupture; treatment with beta blockers as needed to prevent aortic dilation.

Prevention of secondary complications: Standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse.

Surveillance: Routine ophthalmologic examination; routine examination for inguinal hernia; regular follow-up by an orthopedic surgeon; echocardiogram at five-year intervals even if the initial echocardiogram is normal.

Agents/circumstances to avoid: Sports that impact the joints, such as gymnastics or long-distance running.

Pregnancy management: Affected pregnant women may be at increased risk for spontaneous abortions, premature rupture of membranes, and rupture of arteries.

Genetic counseling.

EDS, kyphoscoliotic form is inherited in an autosomal recessive manner. 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. Prenatal testing for pregnancies at increased risk is possible once the disease-causing mutations have been identified in the family.


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.


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 Dpyr:Pyr cross-links is approximately 0.2, whereas in EDS, kyphoscoliotic form, the ratio is approximately 6.0 [Steinmann et al 1995, Al-Hussain et al 2004]. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) can be used to detect faster migration of underhydroxylated collagen chains and their derivatives.
  • 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].

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

Molecular Genetic Testing

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

Clinical testing

Table 1.

Summary of Molecular Genetic Testing used in EDS, Kyphoscoliotic Form

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PLOD1Sequence analysis 4Sequence variantsUnknown
Deletion/duplication analysis 5Intragenic deletions/duplications~18% 6

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a mutation that is present in the indicated gene


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


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]. Deletions of 3 and 5.5 kb have also been reported [Pousi et al 1998, Giunta et al 2009].

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at [Mayer et al 2013 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband, the following testing can be pursued:

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Characteristics

Clinical Description

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, Rohrbach et al 2011].

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


  • Muscular hypotonia with joint laxity is present in neonates. Muscular 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.
  • Osteopenia/osteoporosis occurs in all individuals.


  • 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.
  • Many individuals have microcornea, although its clinical significance is unclear.
  • Glaucoma and retinal detachment also occur.


  • 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].


  • 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 for EDS, kyphoscoliotic form is 100%.


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 (or EDS VIA).

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.


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.

Differential Diagnosis

Ehlers-Danlos syndrome (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 involve a relatively high risk for 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. The diagnosis of EDS, kyphoscoliotic form can be confirmed by biochemical analysis of urinary Dpyr/Pyr cross-links, molecular genetic testing of PLOD1, or lysyl hydroxylase enzyme activity assay.

Several rare conditions (designated here as EDS VIB, EDS VIC, and EDS VID) with overlapping features of EDS, kyphoscoliotic type but with normal lysyl hydroxylase enzyme activity include:

  • EDS VIB, caused by an autosomal recessive deficiency of dermatan-4-sulfotransferase 1 (D4ST-1). EDS VIB is characterized by additional clinical findings including adducted thumbs and feet [Malfait et al 2010].
  • EDS VIC, or EDS-spondylocheirodysplasia (SCD) form, caused by autosomal recessive mutations in the zinc transporter gene, SLC39A13. EDS VIC is characterized by additional clinical findings such as signs of skeletal dysplasia (spondylo) with moderate short stature and characteristic features of the hands (thenar atrophy) (cheiro); the urinary excretion of pyridinolines is changed to a Dpyr/Pyr ratio of approximately 1.0, falling between the ratio in controls and in EDS VIA [Giunta et al 2008].
  • EDS VID, or FKBP14-related EDS, caused by autosomal recessive mutations in FKBP14, the gene which encodes the collagen-specific chaperone FKBP14. EDS VID is characterized by additional clinical findings including myopathy and neurosensorial hearing loss [Baumann et al 2012].

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 muscular 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.

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


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation

Treatment of Manifestations


  • 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.
  • Bracing may be required to support unstable joints.
  • 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.
  • Due to skin fragility, protective pads over knees, shins, and elbows may be helpful in preventing lacerations, particularly in children. The use of helmets in active sports is always advised.


  • 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.


  • 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

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


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

Females should be made aware of complications associated with pregnancy (see Pregnancy Management).

Agents/Circumstances to Avoid

In children with significant joint hyperextensibility, sports which impact the joints such as gymnastics or long-distance running should be avoided.

Evaluation of Relatives at Risk

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

Pregnancy Management

Affected pregnant women may be at increased risk for spontaneous abortions, premature rupture of membranes, and rupture of arteries [Esaka et al 2009]. Two affected women had a total of seven pregnancies resulting in three miscarriages and four healthy children, three of whom were born vaginally at term and one of whom was born at 24 weeks; there were no maternal complications [Steinmann, unpublished]. Delivery should be performed in a medical center.

Therapies Under Investigation

Search 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.


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

Genetic Counseling

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. —ED.

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.

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. Although carriers do tend to have slightly elevated urinary Dpyr/Pyr ratios [Kraenzlin et al 2008], carrier status cannot be reliably ascertained by biochemical testing or by enzyme assay.

Molecular genetic testing. Carrier testing for at-risk family members is possible once the disease-causing 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, are carriers, or are 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Francaise des Syndrome d'Ehlers Danlos
    34 rue Léon Joulin
    Turns 37 000
  • Ehlers-Danlos National Foundation
    1760 Old Meadow Road
    Suite 500
    McLean VA 22102
    Phone: 703-506-2892
  • Ehlers-Danlos Support Group
    PO Box 337
    Aldershot Surrey GU12 6WZ
    United Kingdom
    Phone: 01252 690940
  • Ehlers-Danlos Syndrome Network C.A.R.E.S. Foundation
    PO Box 66
    Muskego WI 53150
    Phone: 262-514-2851
  • National Library of Medicine Genetics Home Reference
  • Medline Plus
  • National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)
    Phone: 800-334-8571 ext 24640

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Ehlers-Danlos Syndrome, Kyphoscoliotic Form: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Ehlers-Danlos Syndrome, Kyphoscoliotic Form (View All in OMIM)


Gene structure. PLOD1 is approximately 40 kb and consists of 19 exons with an unusually large first intron of 12.5 kb. The introns are of high homology, generating many potential recombination sites within the gene. Five polymorphic markers have been identified in PLOD1. These are located at nucleotides 318C>T, 319G>A, 382G>T, 1230C>T, and 1656A>C in the coding region and, in the noncoding region, at 2349G>A (numbering based on GenBank accession number M98252.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 20 different mutations in PLOD1 have been associated with EDS, kyphoscoliotic form [Yeowell & Walker 2000, Giunta et al 2005b, Walker et al 2005]. These pathogenic variants are located throughout the gene.

  • The most common pathogenic variant, 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 [Yeowell et al 2005]. Intragenic deletions are also reported (see Table 1).
  • The second most common mutation in PLOD1 occurs in exon 14 and results in chain termination at codon 511 for tyrosine (p.Tyr511Ter). The allele frequency of this mutation in probands with EDS, kyphoscoliotic form is 10%.

The two mutations have been linked by haplotype analysis to a common ancestral gene [Yeowell & Walker 2000].

Table 2.

PLOD1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The cDNA for PLOD1 codes for a polypeptide of 727 amino acids, including a signal peptide of 18 residues. 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+, α-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].


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;124A:28–34. [PubMed: 14679583]
  2. Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB, Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, Rostásy K, Karall D, Bönnemann CG, Zschocke J, Fauth C. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy and hearing loss. Am J Hum Genet. 2012;90:201–16. [PMC free article: PMC3276673] [PubMed: 22265013]
  3. 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]
  4. Esaka EJ, Golde SH, Stever MR, Thomas RL. A maternal and perinatal mortality in pregnancy complicated by the kyphoscoliotic form of Ehlers-Danlos syndrome. Obstet Gynecol. 2009;113:515–8. [PubMed: 19155940]
  5. Freeman RK, Swegle J, Sise MJ. The surgical complications of Ehlers-Danlos syndrome. Am Surg. 1996;62:869–73. [PubMed: 8813174]
  6. Giunta C, Bürer-Chambaz C, Steinmann B. Novel human pathological mutations. Gene symbol: PLOD1. Disease: Ehlers-Danlos syndrome type VIA, kyphoscoliotic type. Hum Genet. 2009;125:346. [PubMed: 19320026]
  7. Giunta C, Elçioglu NH, Albrecht B, Eich G, Chambaz C, Janecke AR, Yeowell H, Weis MA, Eyre DR, Kraenzlin M, Steinmann B. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome – an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008;82:1290–305. [PMC free article: PMC2427271] [PubMed: 18513683]
  8. 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;133A:158–64. [PubMed: 15666309]
  9. 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]
  10. 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]
  11. Kraenzlin ME, Kraenzlin CA, Meier C, Giunta C, Steinmann B. Automated HPLC assay for urinary collagen cross-links: effect of age, menopause, and metabolic bone diseases. Clin Chem. 2008;54:1546–53. [PubMed: 18653826]
  12. Malfait F, Syx D, Vlummens P, Symoens S, Nampoothiri S, Hermanns-Lê T, Van Laer L, De Paepe A. Musculocontractural Ehlers-Danlos syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat. 2010;31:1233–9. [PubMed: 20842734]
  13. Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlos syndrome types I–VII and variants - update 2012. Eur J Hum Genet. 2013 [PMC free article: PMC3533317] [PubMed: 22892533]
  14. 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]
  15. 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]
  16. Pousi B, Hautala T, Hyland JC, Schröter J, Eckes B, Kivirikko KI, Myllylä R. A compound heterozygote patient with Ehlers-Danlos syndrome type VI has a deletion in one allele and a splicing defect in the other allele of the lysyl hydroxylase gene. Hum Mutat. 1998;11:55–61. [PubMed: 9450904]
  17. Rohrbach M, Vandersteen A, Yiş U, Serdaroglu G, Ataman E, Chopra M, Garcia S, Jones K, Kariminejad A, Kraenzlin M, Marcelis C, Baumgartner M, Giunta C. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis. 2011;6:46. [PMC free article: PMC3135503] [PubMed: 21699693]
  18. 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]
  19. 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.
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. Yeowell HN. Isoforms of lysyl hydroxylase. In: Creighton T, ed. Wiley Encyclopedia of Molecular Medicine. New York, NY: JW Wiley; 2002:1980-4.
  25. 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]
  26. 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]
  27. 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. Hum Mutat. 2000;16:90. [PubMed: 10874315]
  28. 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: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 205.
  3. Burrows NP, Sidhu-Malik N, Yeowell H. Ehlers-Danlos syndromes. In: Irvine A, Hoeger P, Yan A, eds. Harper’s Textbook of Pediatric Dermatology. Chap 142. 3 ed. Hoboken, NJ: Wiley-Blackwell; 2011.

Chapter Notes

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

  • 24 January 2013 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1462PMID: 20301635


  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...