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Genetics of Ehlers-Danlos Syndrome Workup

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
 
Updated: Aug 05, 2015
 

Laboratory Studies

The following laboratory studies may be indicated in patients with Ehlers-Danlos syndrome (EDS):

  • Diagnosis of the vascular type EDS (type IV), arthrochalasia type EDS (type VII A and B), and dermatosparaxis type EDS (type VIIC) requires a skin biopsy. Biochemical studies performed on cultured skin fibroblasts can detect alterations in collagen molecules.
  • Molecular (DNA-based) testing is available for vascular type EDS, arthrochalasia, and dermatosparaxis types.
  • Kyphoscoliosis type EDS (type VI) can be identified by urinary enzyme assay.
  • The remaining types of EDS, classical type EDS, and hypermobility type EDS are identified through clinical examination.
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Imaging Studies

Patients diagnosed with vascular type Ehlers-Danlos syndrome (type IV) have positive findings on various imaging studies, namely CT scans, MRI, ultrasonography, and angiography. The most common imaging abnormalities are arterial aneurysms and arterial dissections, followed by arterial ectasias and arterial occlusions.[26]

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Other Tests

Ultrastructural examination of collagen fibrils may be a useful diagnostic tool to support the diagnosis of classical type Ehlers-Danlos syndrome (EDS) (types I and II), but also for arthrochalasia type EDS (type VII A and B), and to further differentiate the subtypes VIIA and VIIB.[27]

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Histologic Findings

Presently, histopathologic analyses of skin biopsy specimens are nondiagnostic.

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Contributor Information and Disclosures
Author

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Michael Fasullo, PhD Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

Acknowledgements

Melanie G Pepin, MS, CGC Health Services Manager, Collagen Diagnostic Laboratory; Genetic Counselor, Department of Pathology, University of Washington School of Medicine

Disclosure: Nothing to disclose.

G Bradley Schaefer, MD Director of Hattie B Munroe Center for Human Genetics, Department of Pediatrics, Professor, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

Robert D Steiner, MD Executive Director, Marshfield Clinic Research Foundation; Chief Science Officer, Marshfield Clinic; Associate Executive Director, Institute for Clinical and Translational Research, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting; Zacharon Consulting

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Patient with Ehlers-Danlos syndrome. Note the abnormal ability to elevate the right toe. Courtesy of Enrico Ceccolini, MD.
Girl with Ehlers-Danlos syndrome. Dorsiflexion of all the fingers is easy and absolutely painless. Courtesy of Enrico Ceccolini, MD.
Patient with Ehlers-Danlos syndrome mitis. Joint hypermobility is less intense than with other conditions. Courtesy of Enrico Ceccolini, MD.
Table 1. Types of Ehlers-Danlos Syndrome[10, 11]
TypeInheritancePrevious NomenclatureMajor Diagnostic CriteriaMinor Diagnostic Criteria
ClassicalAutosomal dominantTypes I and IIMarked skin hyperextensibility, wide atrophic scars, joint hypermobilitySmooth, velvety skin; easy bruising; tissue fragility; molluscoid pseudotumors (calcified hematomas over pressure points, eg, elbows); subcutaneous spheroids (fat-containing cysts on forearms and shins); joint hypermobility (eg, sprains, dislocations, subluxations); flat feet; muscle hypotonia; gross motor delays; postoperative complications (eg, hernia); manifestations of tissue fragility (eg, hiatal hernia, anal prolapse, cervical insufficiency); positive family history
HypermobilityAutosomal dominantType IIIGeneralized joint hypermobility, affecting both large (elbows, knees) and small (fingers, toes) joints; skin involvement (soft, smooth and velvety)Recurrent joint dislocations and subluxations of shoulder, patella, and temporomandibular joints; chronic joint pain; limb pain; musculoskeletal pain; bruising tendencies; positive family history
Vascular



*Considered most serious EDS type, owing to risk of spontaneous arterial or organ rupture



Autosomal dominantType IVThin, translucent skin, easy to see vasculature through the skin, especially chest and abdomen; arterial/intestinal fragility or rupture; extensive bruising with minor trauma; characteristic facial appearance of large eyes, thin nose, lobeless ears; short stature; thin scalp hairAcrogeria, aging skin; decrease of subcutaneous tissue in the face and extremities; gingival recession; hypermobile small joints; tendon/muscle rupture; clubfoot; early onset varicose veins; arteriovenous fistula; carotid-cavernous fistula; pulmonary conditions, pneumothorax, pneumohemothorax; positive family history; sudden death in close relative
KyphoscoliosisAutosomal recessiveType VI



(Lysyl hydroxylase deficiency-collagen-modifying enzyme)



Generalized joint laxity; severe hypotonia at birth; delayed gross motor development; progressive scoliosis (present at birth); scleral fragility or ocular globe rupture post minor traumaTissue fragility; atrophic scars; easy bruising; spontaneous arterial rupture; marfanoid habitus; microcornea; osteopenia; positive family history (affected sibling)
ArthrochalasiaAutosomal dominantType VII A and BCongenital hip dislocation; severe generalized joint hypermobility; recurrent subluxationsSkin hyperextensibility with easy bruising; tissue fragility with atrophic scars; muscle hypotonia; kyphoscoliosis, mild osteopenia
DermatosparaxisAutosomal recessiveType VIICSevere skin fragility; marked bruising; saggy, redundant skin, especially of the face; scars not atrophicSoft, doughy skin; premature rupture of membranes; hernias (umbilical and inguinal)
Table 2. Molecular Basis of EDS
TypeOld NomenclatureProtein AbnormalityGene AbnormalityChromosome Locus
ClassicalTypes I and IIType V collagen*COL5A1,COL5A2



COL1A1



*9q34.3



2q32.3



17q21.3



HypermobilityType IIIType III collagen



Tenascin-XB



COL3A1



TNXB



2q32.2



6p21.3



VascularType IVType III collagenCOL3A12q32.2
KyphoscoliosisType VILysyl hydroxylase deficiency (some)PLOD11p36.22
ArthrochalasiaType VII A and BType I collagenA: COL1A1



B: COL1A2



17q21.33



7q21.3



DermatosparaxisType VIICN-proteinaseADAMTS25q35.3
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