Diagnostic Considerations

These include the following:

Stickler syndrome
Cutis laxa (elastolysis)
TGFBR-related phenotype (transforming growth factor beta receptor–related phenotype)
Ehlers-Danlos–like syndrome due to tenascin-X deficiency (OMIM #606408)
Neuromuscular disease
Ehlers-Danlos/osteogenesis imperfecta overlap syndromes
Vasculitis^[32]

Differential Diagnoses

Cutis Laxa (Elastolysis)
Hypotonia
Louys-Dietz Syndrome
Marfan Syndrome
Menkes Disease
Williams Syndrome

Workup

Castori M. Ehlers-Danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol. 2012. 2012:751768. [QxMD MEDLINE Link]. [Full Text].
Scheper MC, Nicholson LL, Adams RD, Tofts L, Pacey V. The natural history of children with joint hypermobility syndrome and Ehlers-Danlos hypermobility type: a longitudinal cohort study. Rheumatology (Oxford). 2017 Apr 18. [QxMD MEDLINE Link].
Parapia LA, Jackson C. Ehlers-Danlos syndrome--a historical review. Br J Haematol. 2008 Apr. 141(1):32-5. [QxMD MEDLINE Link].
Beighton P. The Ehlers-Danlos syndromes. McKusick VA, Beighton P, eds. McKusick's Heritable Disorders of Connective Tissue. 5th ed. Mosby-Year Book; 1993. 189-93.
Tschernogobow A. Ein fall von cutis laxa. Jahresber Ges Med. 1892. 27:562.
McKusick VA. Heritable Disorders of Connective Tissue. The CV Mosby Company. St. Louis, MO: 1972.
Gawthrop F, Mould R, Sperritt A, et al. Ehlers-Danlos syndrome. BMJ. 2007 Sep 1. 335(7617):448-50. [QxMD MEDLINE Link].
[Guideline] Rice SG. Medical conditions affecting sports participation. Pediatrics. 2008 Apr. 121(4):841-8. [QxMD MEDLINE Link].
Robinow M, Bennett RL. Ehlers-Danlos Syndrome. Arthritis Foundation. March 21, 2011. [Full Text].
Childs SG. Musculoskeletal manifestations of Ehlers-Danlos syndrome. Orthop Nurs. 2010 Mar-Apr. 29(2):133-9; quiz 140-1. [QxMD MEDLINE Link].
Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD. Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. J Biol Chem. 2002. 277 (6):4223–4231.
Plopper G. Lewin B, Cassimeris L, Lingappa V, Plopper G. The extracellular matrix and cell adhesion, in Cells. Sudbury, MA: Jones and Bartlett; 2007.
Beighton P, De Paepe A, Steinmann B, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998 Apr 28. 77(1):31-7. [QxMD MEDLINE Link].
Levy H, Tinkle B. Medical Resource Guide. Ehlers-Danlos National Foundation. 2010.
Rombaut L, Malfait F, Cools A, de Paepe A, Calders P. Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type. Disabil Rehabil. 2010 Feb 15. [QxMD MEDLINE Link].
Chen CW, Jao SW. Images in clinical medicine. Ehlers-Danlos syndrome. N Engl J Med. 2007 Sep 13. 357(11):e12. [QxMD MEDLINE Link].
Kim ST, Cloft H, Flemming KD, Kallmes DF, Lanzino G, Brinjikji W. Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Ehlers-Danlos Syndrome. J Stroke Cerebrovasc Dis. 2017 Aug. 26 (8):1678-82. [QxMD MEDLINE Link].
Adham S, Billon C, Legrand A, et al. Spontaneous Cervical Artery Dissection in Vascular Ehlers-Danlos Syndrome: A Cohort Study. Stroke. 2021 Mar 1. STROKEAHA120032106. [QxMD MEDLINE Link].
Juul-Kristensen B, Rogind H, Jensen DV, et al. Inter-examiner reproducibility of tests and criteria for generalized joint hypermobility and benign joint hypermobility syndrome. Rheumatology (Oxford). 2007 Dec. 46(12):1835-41. [QxMD MEDLINE Link].
Beighton PH Horan F. Orthopedic aspects of the Ehlers-Danlos syndrome. J Bone Joint Surg [Br]. 1969. 51:444-453.
Merke DP, Chen W, Morissette R, Xu Z, Van Ryzin C, Sachdev V, et al. Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013 Feb. 98(2):E379-87. [QxMD MEDLINE Link]. [Full Text].
Nygaard RH, Jensen JK, Voermans NC, et al. Skeletal muscle morphology, protein synthesis and gene expression in Ehlers Danlos Syndrome. J Appl Physiol (1985). 2017 Jun 8. jap.01044.2016. [QxMD MEDLINE Link].
Byers PH, Belmont J, Black J, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017 Mar. 175 (1):40-7. [QxMD MEDLINE Link].
Voermans NC, van Engelen BG. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI). Neuromuscul Disord. 2008 Nov. 18(11):906; author reply 907. [QxMD MEDLINE Link].
Bar-Yosef O, Polak-Charcon S, Hoffman C, Feldman ZP, Frydman M, Kuint J. Multiple congenital skull fractures as a presentation of Ehlers-Danlos syndrome type VIIC. Am J Med Genet A. 2008 Dec 1. 146A(23):3054-7. [QxMD MEDLINE Link].
Solomons J, Coucke P, Symoens S, Cohen MC, Pope FM, Wagner BE, et al. Dermatosparaxis (Ehlers-Danlos Type VIIC): Prenatal Diagnosis Following a Previous Pregnancy With Unexpected Skull Fractures at Delivery. Am J Med Genet A. 2013 May. 161(5):1122-5. [QxMD MEDLINE Link].
Mataix J, Banuls J, Munoz C, et al. Periodontal Ehlers-Danlos syndrome associated with type III and I collagen deficiencies. Br J Dermatol. 2008 Apr. 158(4):825-30. [QxMD MEDLINE Link].
OMIM. Online Mendelian Inheritance in Man. Available at http://www.omim.org. Accessed: July 10, 2013.
Giunta C, Elcioglu NH, Albrecht B, et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008 Jun. 82(6):1290-305. [QxMD MEDLINE Link].
Giunta C, Elcioglu NH, Albrecht B, et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008 Jun. 82(6):1290-305. [QxMD MEDLINE Link]. [Full Text].
Gotte M, Spillmann D, Yip GW, et al. Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (beta4GalT-7) deficient form of Ehlers-Danlos syndrome. Hum Mol Genet. 2008 Apr 1. 17(7):996-1009. [QxMD MEDLINE Link].
Molloy ES, Langford CA. Vasculitis mimics. Curr Opin Rheumatol. 2008 Jan. 20(1):29-34. [QxMD MEDLINE Link].
Shalhub S, Byers PH, Hicks KL, et al. A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis. J Vasc Surg. 2019 Jul 25. [QxMD MEDLINE Link].
Zilocchi M, Macedo TA, Oderich GS, et al. Vascular Ehlers-Danlos syndrome: imaging findings. AJR Am J Roentgenol. 2007 Sep. 189(3):712-9. [QxMD MEDLINE Link].
Giunta C, Chambaz C, Pedemonte M, Scapolan S, Steinmann B. The arthrochalasia type of Ehlers-Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. Am J Med Genet A. 2008 May 15. 146A(10):1341-6. [QxMD MEDLINE Link].
Faber P, Craig WL, Duncan JL, et al. The successful use of recombinant factor VIIa in a patient with vascular-type Ehlers-Danlos syndrome. Acta Anaesthesiol Scand. 2007 Oct. 51(9):1277-9. [QxMD MEDLINE Link].
Mast KJ, Nunes ME, Ruymann FB, Kerlin BA. Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms. Br J Haematol. 2009 Jan. 144(2):230-3. [QxMD MEDLINE Link].
Kakadia N, Kanaki NS. Ehlers Danlos syndrome: an overview. J. Chem. Pharm. Res. 2011. 3(3):98-107. [Full Text].
Yis U, Dirik E, Chambaz C, et al. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI). Neuromuscul Disord. 2008 Mar. 18(3):210-4. [QxMD MEDLINE Link].
Esaka EJ, Golde SH, Stever MR, Thomas RL. A maternal and perinatal mortality in pregnancy complicated by the kyphoscoliotic form of Ehlers-Danlos syndrome. Obstet Gynecol. 2009 Feb. 113(2 Pt 2):515-8. [QxMD MEDLINE Link].
Larson CM, Stone RM, Grossi EF, Giveans MR, Cornelsen GD. Ehlers-Danlos Syndrome: Arthroscopic Management for Extreme Soft-Tissue Hip Instability. Arthroscopy. 2015 Jul 18. [QxMD MEDLINE Link].
Leistritz DF, Pepin MG, Schwarze U, Byers PH. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet Med. 2011 Aug. 13(8):717-22. [QxMD MEDLINE Link].

Media Gallery

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.

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Table 1. Types of Ehlers-Danlos Syndrome ^{[13, 14]}

Type	Inheritance	Previous Nomenclature	Major Diagnostic Criteria	Minor Diagnostic Criteria
Classical	Autosomal dominant	Types I and II	Marked skin hyperextensibility, wide atrophic scars, joint hypermobility	Smooth, 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
Hypermobility	Autosomal dominant	Type III	Generalized 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 dominant	Type IV	Thin, 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 hair	Acrogeria, 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
Kyphoscoliosis	Autosomal recessive	Type 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 trauma	Tissue fragility; atrophic scars; easy bruising; spontaneous arterial rupture; marfanoid habitus; microcornea; osteopenia; positive family history (affected sibling)
Arthrochalasia	Autosomal dominant	Types VIIA and VIIB	Congenital hip dislocation; severe generalized joint hypermobility; recurrent subluxations	Skin hyperextensibility with easy bruising; tissue fragility with atrophic scars; muscle hypotonia; kyphoscoliosis, mild osteopenia
Dermatosparaxis	Autosomal recessive	Type VIIC	Severe skin fragility; marked bruising; saggy, redundant skin, especially of the face; scars not atrophic	Soft, doughy skin; premature rupture of membranes; hernias (umbilical and inguinal)

Table 2. Molecular Basis of EDS

Type	Old Nomenclature	Protein Abnormality	Gene Abnormality	Chromosome Locus
Classical	Types I and II	Type V collagen	COL5A1,COL5A2 COL1A1*	*9q34.3 2q32.3 17q21.3
Hypermobility	Type III	Type III collagen Tenascin-XB	COL3A1 TNXB	2q32.2 6p21.3
Vascular	Type IV	Type III collagen	COL3A1	2q32.2
Kyphoscoliosis	Type VI	Lysyl hydroxylase deficiency (some)	PLOD1	1p36.22
Arthrochalasia	Types VIIA and VIIB	Type I collagen	A: COL1A1 B: COL1A2	17q21.33 7q21.3
Dermatosparaxis	Type VIIC	N-proteinase	ADAMTS2	5q35.3

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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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