PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome
Synonyms: EDS, Kyphoscoliotic Form; EDS Type VI; EDS VI; Ehlers-Danlos Syndrome Type VI; kEDS; Lysyl-Hydroxylase Deficiency
Heather N Yeowell, PhD and Beat Steinmann, MD.
Author Information and AffiliationsInitial Posting: February 2, 2000; Last Revision: October 18, 2018.
Estimated reading time: 20 minutes
Summary
Clinical characteristics.
PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.
Diagnosis/testing.
The diagnosis of PLOD1-related kEDS is established in a proband with typical clinical findings and biallelic pathogenic (or likely pathogenic) variants in PLOD1 identified by molecular genetic testing. If only one or no pathogenic variant is identified, testing for 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) may be necessary for confirmation of the diagnosis.
Management.
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 dilatation.
Prevention of secondary complications: Standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse.
Surveillance: Regular follow up by an orthopedic surgeon for management of kyphoscoliosis; routine examination for inguinal hernia; routine ophthalmologic examination for management of myopia and early detection of glaucoma or retinal detachment; echocardiogram at five-year intervals even if the initial echocardiogram is normal.
Agents/circumstances to avoid: Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports for eye injury concerns.
Pregnancy management: Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries.
Genetic counseling.
PLOD1-related kEDS 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 the PLOD1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, generalized joint hypermobility, skin fragility, and ocular abnormality. Pathogenic variants in PLOD1 cause abnormal collagen biosynthesis resulting in decreased lysyl hydroxylase enzyme activity.
A disorder with a clinically overlapping phenotype known as FKBP14-related kEDS (not addressed in this GeneReview) is distinguished by the presence of myopathy and hearing loss, normal lysyl hydroxylase enzyme activity, and pathogenic variants in FKBP14; see Differential Diagnosis and FKBP14-Related Kyphoscoliotic EDS.
Suggestive Findings
PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) should be suspected in individuals with the following findings (adapted from Malfait et al [2017]):
Major criteria
Minor criteria
Skin hyperextensibility
Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring)
Rupture/aneurysm of a medium-sized artery
Osteopenia/osteoporosis
Blue sclerae, scleral and ocular fragility/rupture
Hernia (umbilical or inguinal)
Pectus deformity
Marfanoid habitus
Talipes equinovarus
Refractive errors (myopia, hypermetropia)
Microcornea
Minimal criteria suggestive of PLOD1-related kEDS
Congenital muscular hypotonia AND
congenital or early-onset kyphoscoliosis; PLUS
Either of the following:
Establishing the Diagnosis
The diagnosis of PLOD1-related kEDS is established in a proband with typical clinical findings and biallelic pathogenic (or likely pathogenic) variants in PLOD1 identified by molecular genetic testing (see Table 1). If only one or no pathogenic variant is identified, additional confirmatory testing (e.g., measuring urinary pyridinolines) may be necessary.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic PLOD1 variants of uncertain significance (or of one known PLOD1 pathogenic variant and one PLOD1 variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PLOD1-related kEDS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited generalized connective tissue disorders are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of PLOD1-related kEDS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
A multigene panel that includes
PLOD1 and other genes of interest (see
Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the phenotype is indistinguishable from many other inherited generalized connective tissue disorders, comprehensive
genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome
View in own window
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|
|
PLOD1
| Sequence analysis 3 | 67% 4 |
| Gene-targeted deletion/duplication analysis 5 | 33% 6 |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Additional Confirmatory Testing
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 is a highly sensitive and specific test for PLOD1-related kEDS. The normal ratio of Dpyr:Pyr cross-links is approximately 0.2, whereas in kyphoscoliotic EDS 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.
Clinical Characteristics
Clinical Description
A range of clinical severity is observed in individuals with PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) for each of the systems discussed in this section [Steinmann et al 2002, Rohrbach et al 2011, Brady et al 2017].
Prenatal. Pregnancy involving an affected fetus may be complicated by premature rupture of membranes.
Musculoskeletal
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.
Gross motor delay (mild to moderate) is common.
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 (associated with generalized joint hypermobility) are a common serious problem.
Osteopenia/osteoporosis occurs in all individuals, but its clinical significance is currently unknown.
Skin
All individuals with PLOD1-related kEDS 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%.
An equal distribution of umbilical and inguinal hernias was reported in 12 affected individuals.
Eyes
Ocular fragility (scleral as opposed to corneal), 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.
Bluish sclerae are a common feature.
High myopia is common.
Many 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. Both aortic dilatation/dissection and rupture of medium-sized arteries may occur. The rate of progression of aortic root dilatation in PLOD1-related kEDS is not known.
Mitral valve prolapse is common.
Venous ectasia following use of intravenous catheters has been reported [
Heim et al 1998].
Penetrance
Penetrance for PLOD1-related kEDS is 100%.
Nomenclature
Kyphoscoliotic EDS (kEDS) 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, kEDS 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 kEDS.
In 2017, the International EDS Consortium proposed a revised EDS classification system. The new nomenclature for EDS, kyphoscoliotic form is kyphoscoliotic EDS, or kEDS [Malfait et al 2017].
Prevalence
PLOD1-related kEDS 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 at 1:150.
Differential Diagnosis
Other forms of Ehlers-Danlos syndrome. Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) has some overlapping clinical features with other forms of EDS, particularly classic EDS and vascular EDS. 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 kEDS is usually more severe and of earlier onset than that seen in other EDS types.
The diagnosis of PLOD1-related kEDS can be confirmed by molecular genetic testing of PLOD1 or biochemical analysis of urinary Dpyr/Pyr cross-links.
Several rare conditions share features of PLOD1-related kEDS but have normal lysyl hydroxylase enzyme activity as indicated by results of the urinary Dpyr/Pyr testing. These include:
Congenital myopathies. 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 kEDS, in which both hypotonia and joint laxity are present, the increased range of motion is often striking. Velvety skin texture may help distinguish kEDS from congenital myopathies such as X-linked myotubular myopathy. Unlike spinal muscular atrophy, kEDS is characterized by normal deep tendon reflexes.
Corneal disorder. Brittle cornea syndrome (BCS) is associated with corneal rupture following minor trauma (OMIM 229200 and 614170). Although this disorder is also 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]. BCS is caused by biallelic pathogenic variants in ZNF469 or PRDM5.
Disorders with early-onset hypotonia. Many syndromic and metabolic disorders include early-onset hypotonia. In these disorders, however, the other manifestations of kEDS are generally absent, and additional features are usually present.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) the following evaluations are recommended if not already completed:
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
Skin. Consultation with a dermatologist to review skin findings and discuss treatment of abnormal wound healing.
Ophthalmologic. Formal ophthalmologic evaluation at diagnosis for myopia, astigmatism, and retinal detachment
Cardiovascular. Measurement of aortic root size and assessment of heart valves by echocardiogram at the time of diagnosis or by age five years
Other. Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Musculoskeletal
Refer to an orthopedic surgeon for management of kyphoscoliosis.
Orthopedic surgery is not contraindicated in individuals with PLOD1-related kEDS 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.
Skin
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.
Ophthalmologic
Cardiovascular
Regular monitoring by a cardiologist
Vigilant observation and control of blood pressure can reduce the risk of arterial rupture.
Vascular surgery is fraught with danger. While virtually no surgical literature exists on
PLOD1-related kEDS, the review by
Freeman et al [1996] on surgical complications of vascular EDS is relevant.
Individuals with aortic dilatation may require treatment with beta-blockers to prevent further expansion.
Prevention of Secondary Complications
Individuals with mitral valve prolapse should follow standard American Heart Association guidelines for antimicrobial prophylaxis.
Surveillance
The following are appropriate:
Regular follow up by an orthopedic surgeon for management of kyphoscoliosis
Routine examination for inguinal hernia and surgical referral as necessary
Routine ophthalmologic examination for management of myopia and early detection of glaucoma or retinal detachment
Regular follow up by a cardiologist to monitor the echocardiogram at five-year intervals, even if the initial echocardiogram is normal
Vigilant observation and control of blood pressure to decrease the risk of arterial rupture
Females should be made aware of complications associated with pregnancy (see Pregnancy Management).
Agents/Circumstances to Avoid
In children with significant joint hyperextensibility, sports that place stress on the joints (e.g., gymnastics, long-distance running) should be avoided.
High-impact sports should be avoided for eye injury concerns.
Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband / at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.
Such an evaluation includes molecular genetic testing if the pathogenic variants in the family are known.
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 miscarriage, 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 with a high-risk perinatologist in attendance.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an affected individual with PLOD1-related kyphoscoliotic EDS are obligate heterozygotes (carriers).
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.
Carrier Detection
Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the PLOD1 pathogenic variants in the family.
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.
Prenatal Testing and Preimplantation Genetic Testing
Once the PLOD1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
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.
Ehlers-Danlos Society - Europe
United Kingdom
Phone: +44 203 887 6132
Ehlers-Danlos Support UK
United Kingdom
Phone: 0208 736 5604; 0800 9078518
The Ehlers-Danlos Society
Phone: 410-670-7577
MedlinePlus
DICE EDS and HSD Global Registry
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.
PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
OMIM Entries for PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome (View All in OMIM)
View in own window
|
153454 | PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE; PLOD1 |
|
225400 | EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 1; EDSKSCL1 |
Gene structure.
PLOD1 is approximately 40 kb and consists of 19 exons with an unusually large (12.5-kb) first intron. The introns are of high homology, generating many potential recombination sites within the gene. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than 39 different pathogenic variants in PLOD1 have been associated with kyphoscoliotic EDS (kEDS) [Yeowell & Walker 2000, Giunta et al 2005b, Walker et al 2005, Brady et al 2017]. These variants are located throughout the gene.
The first and third pathogenic variants have been linked by haplotype analysis to a common ancestral gene [Yeowell & Walker 2000].
Table 2.
PLOD1 Pathogenic Variants Referenced in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Not standard 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 (LH1) 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 decreased levels of LH1 in two individuals with PLOD1-related kEDS [Walker et al 2004].
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
18 October 2018 (aa) Revision: new information on
FKBP14-related kEDS [
Giunta et al 2018]
12 April 2018 (ha) Comprehensive update posted live
24 January 2013 (me) Comprehensive update posted live
19 February 2008 (me) Comprehensive update posted live
12 July 2005 (me) Comprehensive update posted live
12 March 2003 (me) Comprehensive update posted live
2 February 2000 (me) Review posted live
7 April 1999 (rw) Original submission
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