EDS VIA
EHLERS-DANLOS SYNDROME, TYPE VIA, FORMERLY
NEVO SYNDROME
EDS6A, FORMERLY
EHLERS-DANLOS SYNDROME, OCULAR-SCOLIOTIC TYPE
EDS VI
EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE
EDS6
EDS, kyphoscoliotic type
Ehlers-Danlos syndrome, oculoscoliotic type
EDS, oculoscoliotic type
Ehlers-Danlos syndrome type 6A
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998).
Beighton et al. (1998) reported on a ... The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998). Beighton et al. (1998) reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.' The major characteristics of EDS VI are severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe (Beighton et al., 1998). Nevo syndrome, previously thought to be a distinct entity, is identical to EDS type VI (Voermans et al., 2009).
Traditionally, the clinical diagnosis of EDS VI is confirmed by an insufficiency of hydroxylysine on analysis of hydrolyzed dermis and/or reduced enzyme activity in cultured skin fibroblasts (for review, see Steinmann et al., 1993) but can also be ... Traditionally, the clinical diagnosis of EDS VI is confirmed by an insufficiency of hydroxylysine on analysis of hydrolyzed dermis and/or reduced enzyme activity in cultured skin fibroblasts (for review, see Steinmann et al., 1993) but can also be confirmed by the altered urinary ratio of lysyl pyridinoline:hydroxylysyl pyridinoline which is characteristic for EDS VI (Steinmann et al., 1995). Dembure et al. (1984) demonstrated the feasibility of prenatal diagnosis and carrier detection.
In 2 sisters with features somewhat suggestive of the Ehlers-Danlos syndrome, Pinnell et al. (1972) found deficiency of hydroxylysine in collagen with stoichiometric replacement by lysine, and Krane et al. (1972) found deficiency of collagen lysyl hydroxylase. Hydroxylysine ... In 2 sisters with features somewhat suggestive of the Ehlers-Danlos syndrome, Pinnell et al. (1972) found deficiency of hydroxylysine in collagen with stoichiometric replacement by lysine, and Krane et al. (1972) found deficiency of collagen lysyl hydroxylase. Hydroxylysine is important to cross-linking of collagen. Skin collagen was abnormally soluble. Clinical features included severe scoliosis from an early age, recurrent joint dislocations, stretchable skin, premature rupture of fetal membranes, and floppiness in early life, leading to the diagnosis of amyotonia congenita in one. The same patient, aged 9 years, had had one eye enucleated after an automobile accident. McKusick (1966) had a patient who appeared to have the same defect; the distinctive clinical features suggested the mnemonic designation ocular-scoliotic form of EDS. This patient was reported earlier in the ophthalmologic literature (Durham, 1953), and was later studied enzymatically by Sussman et al. (1974). On the basis of this patient, Beighton (1970) raised the possibility of an autosomal recessive form of the Ehlers-Danlos syndrome in which skin and joint changes like those of the dominant form occur but in which serious ocular complications, particularly retinal detachment, are a conspicuous feature. He described an affected brother and normal parents. The brother had 4 unaffected children. The affected female died at the age of 50 years with symptoms typical of acute dissecting aneurysm of the aorta (autopsy was not performed). Studying collagen in a clinically unspecified case of Ehlers-Danlos syndrome, Mechanic (1972) found a deficiency of hydroxylysinonorleucine and other crosslinks and suggested a cross-linkage defect in this disease. The patient studied by Miller et al. (1978) had microcornea but no scoliosis. Vitamin C, 4 g per day (plasma level 0.5-2.0 microg/dL), increased muscle strength, corneal size, and rate of wound healing. Elsas et al. (1978) described a patient with apparent benefit from ascorbic acid. Krieg et al. (1979) studied the affected son of third-cousin parents, both of whom had half-normal amounts of hydroxylysine in dermal collagen. The fetal membrane broke 34 hours before birth. He was limp with flexible kyphosis, very loose joints, and hematomas of the conjunctivae, eyelids, and ears. The diagnosis of EDS and studies of skin biopsy material were made when he was 3 months old. Farag and Schimke (1989) described an Arab brother and sister with the phenotype of EDS VI who also had peripheral polyneuropathy. Both had aortic regurgitation and mitral valve prolapse. The parents were consanguineous. Although Farag and Schimke (1989) suggested that this might be a new form of the Ehlers-Danlos syndrome, they recognized the obvious possibility that these were 2 independent recessive traits in this inbred kindred. Steinmann et al. (1975) described 2 severely affected sibs. Cultured skin fibroblasts were reported to produce hydroxylysine-deficient collagen (8-9% of control values) and extracts of such to display considerably reduced lysyl hydroxylase activity (12-16% of control values); yet in dermis, the reduction in hydroxylysyl residues was only moderate (60-80% of control values). Subsequent studies failed to confirm either the production of underhydroxylated collagen or the deficiency of lysyl hydroxylase activity. In an attempt to understand the cause of the disease, Royce et al. (1989) studied the uptake of ascorbic acid by cultured fibroblasts from these sibs. No abnormality could be found. Thus, decreased availability of ascorbic acid to lysyl hydroxylase in cellula cannot be the explanation for the disorder in these patients. Wenstrup et al. (1989) reviewed the clinical features of 10 patients with lysyl hydroxylase deficiency. The distinctive feature common to all was muscle hypotonia with joint laxity in the newborn period and moderate to severe kyphoscoliosis. They concluded that these patients are at risk for catastrophic arterial rupture. One patient had an intracranial hemorrhage in the perinatal period without evident traumatic delivery or ventilator-dependent respiratory distress syndrome. Another patient had a rupture of a vertebral artery, and 1 had multiple ruptures of the femoral artery and 2 episodes of spontaneous intrathoracic arterial rupture. Remarkably, ocular features were relatively insignificant in the 10 patients reviewed by Wenstrup et al. (1989). One patient was said to have no abnormality, not even myopia; 2 patients had severe myopia, and 7 others had mild to moderate myopia. Three patients, including the 2 patients with severe myopia had corneal diameters measured; all were mildly decreased. One patient had bilateral glaucoma; another had unilateral retinal detachment. Yeowell and Walker (1997) reported a male patient with EDS VI who was born in 1989 to healthy nonconsanguineous parents and was delivered at 38 weeks by cesarean section after a failed eversion to correct the breech position and with known oligohydramnios. He was hypotonic at birth, with multiple contractures of the arms and legs that were considered to be positional. Although he was alert and socially interactive, his general and gross motor development progressed slowly. Kyphoscoliosis was noted early and progressed rapidly. At 9 months, an L5-S1-level spina bifida occulta was identified together with progressive leftward thoracic kyphoscoliosis. Bilateral inguinal hernias were repaired at 3 months; congenital esotropia was corrected at 7 months of age. Since infancy he was observed to have extreme joint hypermobility, soft velvety skin, easy bruisability, and the tendency to develop keloids in response to minor trauma. A highly arched palate was noted as well as increased vertex height of the skull without abnormality of the sutural plates. His academic and personal-social skills were precocious. Heim et al. (1998) described an Iranian patient, the son of consanguineous parents, who developed kyphoscoliosis at the age of approximately 3 years and glaucoma at the age of 10 years. At the age of 13 years he had a marfanoid habitus. He was able to walk only with the upper part of his body bent forward and preferred sitting in a wheelchair. He had microcornea, myopia, brownish sclerae, and tortuous retinal arteries. Salavoura et al. (2006) reported a 4-year-old girl with EDS VI. At birth, she showed neonatal hypotonia, torticollis, dislocation of the shoulders and hips, joint laxity, scoliosis, and talipes equinovarus. At age 4 years, she had severe scoliosis, clumsy and unsteady gait, heart murmur, and thin, hyperelastic skin with easy bruisability. Ocular examination was normal. Biochemical analysis showed an increased urinary lysyl pyridoline/hydroxylysyl ratio. Treatment with high doses of ascorbic acid resulted in improved healing and muscle strength. Nevo et al. (1974) described an inbred Israeli family in which 2 sibs and their cousin had increased growth, kyphosis, prominent forehead, volar edema, spindle-shaped fingers, wrist drop, talipes, hyperbilirubinemia, and generalized hypotonia. Although the authors considered their cases to be an autosomal recessive variant of Sotos syndrome (117550), Cohen (1989) proposed that these patients had a separate entity, which they called the Nevo syndrome. A similar case was reported by Hilderink and Brunner (1995). Their patient, a boy born to consanguineous parents, had neither lens luxation nor aortic dilatation. Al-Gazali et al. (1997) described 2 male patients from unrelated Arab families with features similar to those described by Nevo et al. (1974) but without hyperbilirubinemia. Both had delayed motor development. Cognitive function was normal in one at 2 years 10 months of age. While the other was too young to assess, social responses appeared normal. MRI studies in the older child revealed extreme hyperlordosis of the cervical spine and a wide spinal canal suggestive of dural ectasia. Because the clinical features in patients reported with Nevo syndrome were similar to those of EDS VIA, Giunta et al. (2005) studied 7 patients diagnosed with Nevo syndrome, 2 of whom had been reported by Al-Gazali et al. (1997) and 1 by Hilderink and Brunner (1995), and identified homozygous mutations in the PLOD1 gene in all (see 153454.0001 and 153454.0006). In the 5 patients from whom urine was available, the ratio of total urinary lysyl pyridinoline to hydroxylysyl pyridinoline was elevated compared with that in controls and similar to that observed in patients with EDS VIA. Giunta et al. (2005) concluded that Nevo syndrome is allelic to and clinically indistinguishable from EDS VIA and presented evidence that increased length at birth and wrist drop, in addition to muscular hypotonia and kyphoscoliosis, should prompt the physician to consider EDS VIA earlier than had previously been the case. Voermans et al. (2009) reexamined a male patient, born of first-cousin parents from the Netherlands, who was originally reported by Hilderink and Brunner (1995) and in whom Giunta et al. (2005) identified homozygosity for a deletion in the PLOD1 gene (153454.0006). At the age of 16 years, generalized muscle weakness and mild muscle hypotonia were still present, and the patient had reduced muscle mass. Deep tendon reflexes were symmetrically depressed, vibration sense was reduced in hands and feet bilaterally, and tandem gait was mildly impaired, but position sense of fingers and toes and coordination tests of arms was normal. In addition, he had hyperextensible skin with atrophic scars, contracture of the right elbow, and hypermobility of distal joints. Nerve conduction studies were compatible with a mild sensorimotor axonal polyneuropathy, and electromyography reflected a myopathy. MRI revealed myopathic changes in increase of fat tissue and atrophy of muscles. Needle biopsy of the right quadriceps muscle at 16 years of age showed fibrous and fatty tissue with very few remaining muscle fibers, in contrast to an earlier biopsy at 2 months of age which showed no abnormalities. Voermans et al. (2009) suggested that myopathy or peripheral nerve dysfunction might contribute to the functional decline in adolescence that is observed in patients with EDS VIA, with loss of ambulation in the second or third decade.
In cells from 2 sisters with type VI Ehlers-Danlos syndrome in whom Pinnell et al. (1972) first demonstrated reduced lysyl hydroxylase activity, Hautala et al. (1993) demonstrated homozygosity for a large duplication in the PLOD1 gene, corresponding to ... In cells from 2 sisters with type VI Ehlers-Danlos syndrome in whom Pinnell et al. (1972) first demonstrated reduced lysyl hydroxylase activity, Hautala et al. (1993) demonstrated homozygosity for a large duplication in the PLOD1 gene, corresponding to 7 exons (153454.0002), caused by an Alu-Alu recombination. The same mutation was found by Pousi et al. (1994) in the patient reported by McKusick (1966) and Sussman et al. (1974). Giunta et al. (2005) studied 7 patients diagnosed with Nevo syndrome, 2 of whom had been reported by Hilderink and Brunner (1995) and 1 by Al-Gazali et al. (1997), and found homozygous mutations in the PLOD1 gene in all (see 153454.0001 and 153454.0006). In a child with EDS VI, Salavoura et al. (2006) identified a homozygous deletion in the PLOD1 gene.
The major and minor clinical features of Ehlers-Danlos syndrome (EDS), kyphoscoliotic form have been outlined by Beighton et al [1998]. ...
DiagnosisClinical DiagnosisThe 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. TestingAffected 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 TestingGene. 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 FormView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPLOD1Sequence analysisSequence variants 2UnknownClinical Deletion / duplication analysis 3Intragenic deletions / duplications~18% 41. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.3. 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.4. 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 www.eurogentest.org [Mayer et al 2013 (full text)].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband, the following testing can be pursued:Urinary cross-link analysis to determine the ratio of deoxypyridinoline (Dpyr) to pyridinoline (Pyr) cross-links [Kraenzlin et al 2008]Confirmatory molecular genetic testing of PLOD1 through sequence analysis [Giunta et al 2005b]. If no mutation is identified, deletion/duplication analysis can be pursued.Lysyl hydroxylase activity assay in cultured fibroblastsCarrier 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.Genetically Related (Allelic) DisordersIt has been reported that PLOD1 may be a susceptibility gene for reduced bone mineral density (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 M98252.1) has been linked to reduced BMD and an increase in the ratio of Dpyr/Pyr cross-links in urine.
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]....
Natural HistoryA 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. MusculoskeletalMuscular 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.EyesOcular 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.CardiovascularVascular 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]. SkinAll 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%.
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....
Differential DiagnosisEhlers-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].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with Ehlers-Danlos syndrome (EDS), kyphoscoliotic form, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 consultationTreatment of ManifestationsMusculoskeletal 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.Cardiovascular Vigilant observation and control of blood pressure can reduce the risk of arterial rupture. Vascular surgery is fraught with danger. Although virtually no surgical literature exists on EDS, kyphoscoliotic form, the review by Freeman et al [1996] on surgical complications of EDS, vascular type is relevant. Individuals with aortic dilation may require treatment with beta blockers to prevent further expansion. Ophthalmologic Myopia and/or astigmatism may be corrected by glasses or contact lenses. Laser treatment of the retina is indicated in case of imminent detachment. Prevention of Secondary ComplicationsIndividuals with mitral valve prolapse should follow standard American Heart Association guidelines for antimicrobial prophylaxis.SurveillanceThe 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 AvoidIn children with significant joint hyperextensibility, sports which impact the joints such as gymnastics or long-distance running should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAffected 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 InvestigationSearch 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.OtherAscorbate therapy has been suggested as a treatment, but its effectiveness has not been biochemically proven.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPLOD11p36.22Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1PLOD1 @ LOVDPLOD1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 153454PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE; PLOD1 225400EHLERS-DANLOS SYNDROME, TYPE VI; EDS6Normal allelic variants. 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). Pathologic 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 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]. 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.Tyr511*). 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1533C>Gp.Tyr511*NM_000302.3 NP_000293.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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].