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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. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
[Lysyl-Hydroxylase Deficiency, EDS VI, EDS Kyphoscoliotic Form, EDS Type VI, Ehlers-Danlos Syndrome Type VI. Includes: Ehlers-Danlos Syndrome Type VIA, Nevo Syndrome]
Disease 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 muscle hypotonia at birth; progressive scoliosis, present at birth or within the first year of life; and scleral fragility and 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.
Diagnosis/testing. 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 an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatography (HPLC) (a highly sensitive and specific test) and/or assay of lysyl hydroxylase enzyme activity in skin fibroblasts. Molecular genetic testing of PLOD1, the only gene known to be associated with EDS, kyphoscoliotic form, is available.
Management. Treatment of manifestations: management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed; physical therapy to strengthen large muscle groups; control of blood pressure to reduce the risk of arterial rupture; treatment with beta blockers as needed to prevent further aortic dilation. Prevention of secondary complications: adequate hydration to prevent oxalic acid nephrolithiasis; 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.
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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Prenatal testing for pregnancies at increased risk is available for families in which the disease-causing mutations are known.
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 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. PLOD1 is the only gene known to be associated with 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, Randolph, Steinmann 2005].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|
| Sequence analysis | PLOD1 sequence variants | Unknown | Clinical
 |
| Deletion/duplication analysis | Intragenic duplication of PLOD1 sequences in intron 9 through intron 16 | ~18% |
To confirm the diagnosis in a proband, perform urinary cross-link analysis; assay lysyl hydroxylase activity.
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.
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 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 in 1972 by Pinnell et al.
Prior to the development of the 1998 VilleFranche classification, EDS, kyphoscoliotic form was known as EDS VI.
Giunta, Randolph, Al-Gazali et al (2005) 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, Randolph, Al-Gazali et al 2005; Giunta, Randolph, Steinman 2005].
Carrier frequency is estimated to be 1:150.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 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. The diagnosis of EDS, kyphoscoliotic form can be confirmed by biochemical analysis of urinary Pyr/Dpyr cross-links and lysyl hydroxylase activity assay.
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] to distinguish it from EDS VIA, the kyphoscoliatic type discussed in this GeneReview, 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 ratios of urinary pyridinolines and lysyl hydroxylase enzyme activity [Al-Hussain et al 2004].
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
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.
Hydration should be maintained to prevent oxalic acid nephrolithiasis.
Individuals with mitral valve prolapse should follow standard American Heart Association guidelines for antimicrobial prophylaxis.
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
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Ascorbate therapy has been suggested as a treatment, but its effectiveness has not been biochemically proven.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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.
Ehlers-Danlos syndrome (EDS), kyphoscoliotic form is inherited in an autosomal recessive manner.
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, 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.
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.
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. 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 the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
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 15-18 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
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| PLOD1 | 1p36.3-p36.2 | Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 153454 | PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE; PLOD1 |
| 225400 | EHLERS-DANLOS SYNDROME, TYPE VI |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| PLOD1 | 5351 (MIM No. 153454) | PLOD1 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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. 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).
Recently, the 319G>A polymorphism in exon 3 has been linked to reduced bone mineral density (BMD) [Tasker et al 2006, Yamada et al 2007], as described in Pathologic allelic variants. It has been reported that PLOD1 may be a susceptibility gene for reduced BMD [Tasker et al 2006, Yamada et al 2007]. The 319G>A polymorphism coding for p.Ala99Thr [Yeowell & Walker 2000] (numbering based on GenBank accession number M98252) has been linked to reduced BMD and an increase in the ratio of Pyr/Dpyr cross-links in urine.
Pathologic allelic variants: More than 20 different mutations in PLOD1 have been associated with EDS, kyphoscoliotic form [Yeowell & Walker 2000; Giunta, Randolph, Steinmann 2005; 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 [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 (p.Tyr511X). 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].
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].
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. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Association Francaise des Syndrome d'Ehlers Danlos
34 rue Léon Joulin
37000 Tours
France
Email: m.h.boucand@wanadoo.fr
www.afsed.com
Canadian Ehlers-Danlos Association
28 Waterbury Street
Bolton L7E 1X2
Canada
Phone: 905-951-7559
Fax: 905-761-7567
Email: ceda@rogers.com
www.ehlersdanlos.ca
Ehlers-Danlos National Foundation
3200 Wilshire Blvd
Suite 1601 South Tower
Los Angeles CA 90010
Phone: 800-956-2902; 213-368-3800
Fax: 213-427-0057
Email: staff@ednf.org
www.ednf.org
Ehlers-Danlos Support Group
PO Box 337
Aldershot GU12 6WZ
United Kingdom
Phone: 01252 690940
Email: director@ehlers-danlos.org
www.ehlers-danlos.org
National Library of Medicine Genetics Home Reference
Ehlers-Danlos syndrome
Medline Plus
Ehler-Danlos Syndrome
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Beat Steinmann, MD (2008-present)
Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (1999-2008)
Heather N Yeowell, PhD (2005-present)
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
