- Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD more...
Ehlers-Danlos syndrome (EDS) is the name given to a group of more than 10 different inherited disorders; all involve a genetic defect in collagen and connective-tissue synthesis and structure.
Ehlers-Danlos syndrome can affect the skin, joints, and blood vessels. This syndrome is clinically heterogeneous; the underlying collagen abnormality is different for each type. Clinical recognition of the types of Ehlers-Danlos syndrome is important. One type, type IV, is associated with arterial rupture and visceral perforation, with possible life-threatening consequences.
Ehlers-Danlos syndrome is a heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, cutaneous fragility, and hyperextensibility. The collagen defect has been identified in only 6 of the 11 types of Ehlers-Danlos syndrome. Type IV is characterized by a decreased amount of type III collagen. It is autosomal dominant and caused by mutations in the COL3A1 gene that result in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. Types V and VI are characterized by deficiencies in hydroxylase and lysyl oxidase, an important posttranslational modifying enzyme in collagen biosynthesis. Type VII has an amino-terminal procollagen peptidase deficiency. Type IX has abnormal copper metabolism. Type X has nonfunctioning plasma fibronectin.
In Ehlers-Danlos syndrome types I and II, the classic variety, identifying the molecular structure in most individuals who are affected is difficult. Causative mutations may involve the COL5A1, COL5A2, and tenascin-X genes and are implied to be in the COL1A2 gene. Nonetheless, in most families with autosomal dominant Ehlers-Danlos syndrome, the disease appears to be linked to loci that contain the COL5A1 or COL5A2 genes. Although half of the mutations that cause Ehlers-Danlos syndrome types I and II are likely to affect the COL5A1 gene, a significant portion of the mutations result in low levels of mRNA from the mutant allele as a consequence of nonsense-mediated mRNA decay.
Bouma et al evaluated 3 generations in a family with Ehlers-Danlos syndrome type II. The genomic defect was an A(-2)→G substitution at the exon 14 splice-acceptor site. Transmission electron micrographs of type I collagen fibrils in a proband dermal biopsy specimen demonstrated heterogeneity in fibril diameter that was greater than that of a matched control sample. The proband was found to have a greater proportion of both larger and smaller fibrils, and occasional fibrils with a cauliflower configuration were observed.
Wenstrup and associates identified haploinsufficiency of the COL5A1 gene that encodes the proalpha1(V) chain of type V collagen in the classic form of Ehlers-Danlos syndrome. Eight of 28 probands with classic Ehlers-Danlos syndrome who were heterozygous for expressed polymorphisms in COL5A1 had complete or nearly complete loss of expression of one COL5A1 allele. One third of individuals with classic Ehlers-Danlos syndrome were estimated to have mutations of COL5A1 that result in haploinsufficiency. These findings suggest that the normal formation of the heterotypic collagen fibrils that contain types I, III, and V collagen requires the expression of both COL5A1 alleles. Type V collagen mutations are pivotal in classic Ehlers-Danlos syndrome.
Autosomal recessive–type VI Ehlers-Danlos syndrome, also known as the kyphoscoliotic type, is characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. Biochemically, this type is attributed to a deficiency in lysyl hydroxylase (LH), the enzyme that hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines with 2 important functions. The residues are attachment sites for galactose and glucosylgalactose, and they act as precursors of the cross-linking process that gives collagen its tensile strength.
More than 20 mutations are identified in the LH1 gene that contributes to LH deficiency and clinical Ehlers-Danlos syndrome type VI. Yeowell and Walker identified 2 of these mutations in 5 or more unrelated patients: (1) a large duplication of exons 10-16, which arise from a homologous recombination of intronic Alu sequences, and (2) a nonsense mutation, Y511X, in exon 14 of the LH1 gene. Both mutations seem to originate from a single ancestral gene.
Tenascin-X is a large extracellular matrix protein, a deficiency of which causes a clinically distinct recessive form of this syndrome. Thus, factors other than collagens or collagen-processing enzymes may cause this syndrome. This newly described form may be associated with additional anomalies.
A case with colonic perforation in a young girl, with a fatal outcome, was related to a novel mutation of the COL3A1 gene. Crystal structure of human type III, in the structure G991-G1032 cystine knot, shows both 7/2 and 10/3 symmetries.
A novel point mutation has been found in the vascular type of Ehlers-Danlos syndrome. The mutation took place in the second position of exon 24 of COL3A1.
Impaired wound healing is a typical feature of Ehlers-Danlos syndrome, probably for a fibroblast defect. Wound repair can be achieved using exogenous type V collagen.
Ehlers-Danlos syndrome pediatric patients have been shown to have deficiencies in 3 genes of the glutathione S-transferase family (GSTM1, GSTT1, GSTP1). This leads to the generation of reactive oxygen species.
Reduced activity of beta4-galactosyltransferase 7 (beta4GalT-7) is associated with the progeriform Ehlers-Danlos syndrome.
Biallelic mutations in FKBP14 may result in a recessive form of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, hearing loss, and, possibly, an increased risk for vascular complications.
The prevalence of Ehlers-Danlos syndrome is reported to be 1 case in approximately 400,000 people, but mild or incomplete forms appear to be underdiagnosed and more common than other forms.
No racial predominance seems to exist; however, some believe that whites probably are affected more than other races.
The sex-related prevalences are almost equal.
The disease has clinical features (eg, joint mobility, skin extendibility, scarring tendency) that are easily recognizable beginning in early childhood. The other clinical manifestations require more time to become evident. Ehlers-Danlos syndrome is usually diagnosed in young adults.
Type IV Ehlers-Danlos syndrome is a severe form. Patients often have a shortened lifespan because of the spontaneous rupture of a large artery (eg, splenic artery, aorta) or the perforation of internal organs. Surgery can pose life-threatening risks in these patients. Arterial aneurysms, valvular prolapse, and spontaneous pneumothorax are common complications. The prognosis with this type is poor. Sudden death can occur after visceral perforation or after the rupture of a large vessel, most commonly an abdominal and splenic vessel.
The other types are usually not as dangerous, and affected individuals can live a healthy if somewhat restricted life. Type VI is also somewhat dangerous, although it is rare.
Eder J, Laccone F, Rohrbach M, Giunta C, Aumayr K, Reichel C, et al. A new COL3A1 mutation in Ehlers-Danlos syndrome type IV. Exp Dermatol. 2013 Mar. 22 (3):231-4. [Medline].
Schwarze U, Atkinson M, Hoffman GG, Greenspan DS, Byers PH. Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet. 2000 Jun. 66 (6):1757-65. [Medline].
Bouma P, Cabral WA, Cole WG, Marini JC. COL5A1 exon 14 splice acceptor mutation causes a functional null allele, haploinsufficiency of alpha 1(V) and abnormal heterotypic interstitial fibrils in Ehlers-Danlos syndrome II. J Biol Chem. 2001 Apr 20. 276 (16):13356-64. [Medline].
Wenstrup RJ, Florer JB, Willing MC, Giunta C, Steinmann B, Young F, et al. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet. 2000 Jun. 66 (6):1766-76. [Medline].
Sun M, Connizzo BK, Adams SM, Freedman BR, Wenstrup RJ, Soslowsky LJ, et al. Targeted deletion of collagen V in tendons and ligaments results in a classic Ehlers-Danlos syndrome joint phenotype. Am J Pathol. 2015 May. 185 (5):1436-47. [Medline].
Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab. 2000 Sep-Oct. 71 (1-2):212-24. [Medline].
Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001 Oct 18. 345 (16):1167-75. [Medline].
Boudko SP, Engel J, Okuyama K, Mizuno K, Bächinger HP, Schumacher MA. Crystal structure of human type III collagen Gly991-Gly1032 cystine knot-containing peptide shows both 7/2 and 10/3 triple helical symmetries. J Biol Chem. 2008 Nov 21. 283 (47):32580-9. [Medline].
Okamoto O, Ando T, Watanabe A, Sato F, Mimata H, Shimada T, et al. A novel point mutation in type III collagen gene resulting in exon 24 skipping in a case of vascular type Ehlers-Danlos syndrome. Arch Dermatol Res. 2008 Oct. 300 (9):525-9. [Medline].
Viglio S, Zoppi N, Sangalli A, Gallanti A, Barlati S, Mottes M, et al. Wound repair capability in EDS fibroblasts can be retrieved by exogenous type V collagen. ScientificWorldJournal. 2008 Oct 3. 8:956-8. [Medline].
Kuz'mina NS, Shipaeva EV, Semyachkina AN, Vasil'eva IM, Kovalenko LP, Durnev AD, et al. Polymorphism of detoxification genes and cell resistance to mutagens in patients with Ehlers-Danlos syndrome. Bull Exp Biol Med. 2007 Nov. 144 (5):717-21. [Medline].
Murray ML, Yang M, Fauth C, Byers PH. FKBP14-related Ehlers-Danlos syndrome: expansion of the phenotype to include vascular complications. Am J Med Genet A. 2014 Jul. 164A (7):1750-5. [Medline].
Bethea BT, Fitton TP, Alejo DE, Barreiro CJ, Cattaneo SM, Dietz HC, et al. Results of aortic valve-sparing operations: experience with remodeling and reimplantation procedures in 65 patients. Ann Thorac Surg. 2004 Sep. 78 (3):767-72; discussion 767-72. [Medline].
Remvig L, Flycht L, Christensen KB, Juul-Kristensen B. Lack of consensus on tests and criteria for generalized joint hypermobility, Ehlers-Danlos syndrome: hypermobile type and joint hypermobility syndrome. Am J Med Genet A. 2014 Mar. 164A (3):591-6. [Medline].
Castori M, Dordoni C, Morlino S, Sperduti I, Ritelli M, Valiante M, et al. Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet C Semin Med Genet. 2015 Mar. 169C (1):43-53. [Medline].
Yassin OM, Rihani FB. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome. J Clin Pediatr Dent. 2006 Summer. 30 (4):337-41. [Medline].
van Bon AC, Kristinsson JO, van Krieken JH, Wanten GJ. Concurrent splenic peliosis and vascular Ehlers-Danlos syndrome. Ann Vasc Surg. 2009 Mar. 23 (2):256.e1-4. [Medline].
Guala A, Viglio S, Ottinetti A, Angeli G, Canova G, Colombo E, et al. Cutaneous metaplastic synovial cyst in Ehlers-Danlos syndrome: report of a second case. Am J Dermatopathol. 2008 Feb. 30 (1):59-61. [Medline].
Vilisaar J, Harikrishnan S, Suri M, Constantinescu CS. Ehlers-Danlos syndrome and multiple sclerosis: a possible association. Mult Scler. 2008 May. 14 (4):567-70. [Medline].
Perrinaud A, Matos M, Maruani A, Mondon K, Machet L. [Absence of inferior labial or lingual frenula in Ehlers-Danlos syndrome: a new diagnostic criterion?]. Ann Dermatol Venereol. 2007 Nov. 134 (11):859-62. [Medline].
Baba CS, Sharma PK, Deo V, Pal S, Sethuraman G, Gupta SD, et al. Association of Ehlers-Danlos syndrome and solitary rectal ulcer syndrome. Indian J Gastroenterol. 2007 May-Jun. 26 (3):149-50. [Medline].
Savasta S, Crispino M, Valli M, Calligaro A, Zambelloni C, Poggiani C. Subependymal periventricular heterotopias in a patient with ehlers-danlos syndrome: a new case. J Child Neurol. 2007 Mar. 22 (3):317-20. [Medline].
Miles SC, Robinson PD, Miles JL. Ehlers–Danlos syndrome and anorexia nervosa: a dangerous combination?. Pediatr Dermatol. 2007 May-Jun. 24 (3):E1-4. [Medline].
Kundu AK, Chattopadhyay P, Kundu S, Choudhury S. Pregnancy in Ehlers-Danlos syndrome. J Assoc Physicians India. 2006 Dec. 54:938. [Medline].
Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. J Pediatr. 2011 May. 158 (5):826-830.e1. [Medline].
Dordoni C, Ritelli M, Venturini M, Chiarelli N, Pezzani L, Vascellaro A, et al. Recurring and generalized visceroptosis in Ehlers-Danlos syndrome hypermobility type. Am J Med Genet A. 2013 May. 161A (5):1143-7. [Medline].
Hamonet C, Frédy D, Lefèvre JH, Bourgeois-Gironde S, Zeitoun JD. Brain injury unmasking Ehlers-Danlos syndromes after trauma: the fiber print. Orphanet J Rare Dis. 2016 Apr 22. 11:45. [Medline].
Aalberts JJ, van den Berg MP, Bergman JE, du Marchie Sarvaas GJ, Post JG, van Unen H, et al. The many faces of aggressive aortic pathology: Loeys-Dietz syndrome. Neth Heart J. 2008 Sep. 16 (9):299-304. [Medline].
Castori M. Ehlers-Danlos syndrome(s) mimicking child abuse: Is there an impact on clinical practice?. Am J Med Genet A. 2016 May 5. [Medline].
Umekoji A, Fukai K, Hosomi N, Ishii M, Tanaka A, Murakami K, et al. Vascular type of Ehlers-Danlos syndrome associated with mild haemophilia A. Clin Exp Dermatol. 2009 Jan. 34 (1):101. [Medline].
Rombaut L, Malfait F, De Wandele I, Cools A, Thijs Y, De Paepe A, et al. Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Arch Phys Med Rehabil. 2011 Jul. 92 (7):1106-12. [Medline].
Alkadhi H, Wildermuth S, Desbiolles L, Schertler T, Crook D, Marincek B, et al. Vascular emergencies of the thorax after blunt and iatrogenic trauma: multi-detector row CT and three-dimensional imaging. Radiographics. 2004 Sep-Oct. 24 (5):1239-55. [Medline].
Monroe GR, Harakalova M, van der Crabben SN, Majoor-Krakauer D, Bertoli-Avella AM, Moll FL, et al. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1. Am J Med Genet A. 2015 Jun. 167 (6):1196-203. [Medline].
Fernández-Alcantud J, López RC, Osado IR, Castro MR. [Management of anesthesia in vascular-type Ehlers-Danlos syndrome (type IV)]. Rev Esp Anestesiol Reanim. 2008 May. 55 (5):312-3. [Medline].
Jones TL, Ng C. Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome. Int J Obstet Anesth. 2008 Oct. 17 (4):365-9. [Medline].
Faber P, Craig WL, Duncan JL, Holliday K. 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. [Medline].
Sinibaldi L, Ursini G, Castori M. Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers-Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised. Am J Med Genet C Semin Med Genet. 2015 Mar. 169C (1):97-106. [Medline].