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Special Feature
November 2001

Pathological Case of the Month

Arch Pediatr Adolesc Med. 2001;155(11):1275-1276. doi:10.1001/archpedi.155.11.1275

Diagnosis and Discussion: Ehlers-Danlos Syndrome—Classical Type

Figure 1. Skin hyperextensibility in a 10-year-old girl.

Figure 2. Electron micrograph of the patient's skin shows collagen fibrils in cross sections with "flowerlike" servated contours, so-called composite fibrils (arrows) (magnification ×36 000).

Figure 3. Collagen fibrils of the patient's skin in longitudinal sections (magnification ×36 000). Arrows indicate broadened and twisted ropes.

A heterogeneous group of heritable connective tissue disorders characterized by skin hyperextensibility, tissue fragility, and articular hypermobility is summarized as Ehlers-Danlos syndrome (EDS). In 1997, classification of EDS was revised and simplified.1 Six types of EDS were defined based on clinical features (major and minor criteria) and biochemical and molecular findings.1 For diagnosis of a specific type of EDS, the presence of 1 or more major criteria is necessary, complemented by positive findings on laboratory tests when possible. The major criteria have high diagnostic specifity because they are infrequent in other conditions or in healthy people. Minor criteria have lower diagnostic specifity, but the presence of 1 or more minor criteria contributes to the diagnosis of a specific type.1

This patient fulfills all the major diagnostic criteria for the diagnosis of the classical type of EDS, showing skin hyperextensibility, widened atrophic scars as a manifestation of tissue fragility, and joint hypermobility. The classical type of EDS—described in the old Berlin classification2 as EDS I in severe cases or as EDS II if moderate severity was observed—has an autosomal dominant inheritance. Moreover, we found 7 of 9 minor criteria of the classical type in this patient: smooth, velvety skin (+); molluscoid pseudotumors (+); subcutaneous spheroids (−); complications of joint hypermobility (eg, pes planus) (+); muscle hypotonia/delayed gross motor development (−); easy bruising (+); manifestations of tissue extensibility and fragility (+); surgical complications (+); and positive family history (+). Specific advice for the diagnosis of skin hyperextensibility, tissue fragility, and easy bruising despite normal coagulation status are described.3 Joint hypermobility should be assessed using the Beighton scale.4

The diagnosis of EDS was confirmed in our patient and her father for the first time when the girl was 10 years old. The diagnosis of skin hyperextensibility in young children can be difficult and delayed because of the abundance of subcutaneous fat.1 Early diagnosis would help to prevent additional complications (eg, by avoiding injury and using fibrin glue after injury).

Within the dermis of patients with EDS, differential ultrastructural abnormalities of collagen fibrils can be found by electron microscopy.5 By light microscopy, in our patient and her father, the epidermis was normal but the dermal connective tissue was loosely packed. Only small collagen bundles could be found, and generally the amount of collagen was diminished compared with the elastic structures. By electron microscopy, many aberrant collagen fibrils became obvious, beginning in the papillary dermis and increasing in number within the reticular dermis. These composite collagen fibrils with enlarged "flowerlike" cross sections and ropelike longitudinal sections are characteristic, but not specific, for the classical types of EDS.5 However, the combination of clinical symptoms and the pattern of ultrastructural collagen changes is highly specific for classical EDS.1,5 Abnormal electrophoretic mobility of the proα1(V) or proα2(V) chains of type V collagen as well as genetic linkage to intragenic markers of the COL5A1 and COL5A2 genes and mutations in the respective genes can be found in several but not most patients with the classical type of EDS.3,6-8 The kyphoscoliotic type of EDS (EDS VI in the old classification), however, can be excluded by a normal ratio (6:1) of hydroxylysyl-pyridinoline to lysyl-pyridinoline in urine.9

The new classification of EDS includes clinical and laboratory findings that are useful for diagnosis of the classical type of EDS, although there is still considerable clinical and ultrastructural heterogeneity among patients.

Accepted for publication July 1, 1999.

Corresponding author: Christof Dame, MD, Children's Hospital, University of Bonn, Adenauerallee 119, D-53113 Bonn, Germany (e-mail:

Beighton  PDe Paepe  ASteinmann  BTsipouras  PWenstrup  RJ Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997.  Am J Med Genet. 1998;7731- 37Google ScholarCrossref
Beighton  PDe Paepe  ADanks  D  et al.  Intenational nosology of heritable disorders of connective tissue.  Am J Med Genet. 1988;29581- 594Google ScholarCrossref
Steinmann  BRoyce  PMSuperti-Furga  A The Ehlers-Danlos syndrome. Royce  PMSteinmann  Beds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects. New York, NY Wiley-Liss Inc1993;351- 407Google Scholar
Beighton  PGrahame  RBird  H Hypermobility of Joints. 2nd ed. Berlin, Germany Springer-Verlag1989;1- 182
Hausser  IAnton-Lamprecht  I Differential ultrastructural aberrations of collagen fibrils in Ehlers-Danlos syndrome types I-IV as a means of diagnostics and classification.  Hum Genet. 1994;3394- 407Google Scholar
Byers  PH Ehlers-Danlos syndrome: recent advances and current understanding of the clinical and genetic heterogeneity.  J Invest Dermatol. 1994;10347S- 52SGoogle ScholarCrossref
De Pape  ANuytinck  LHausser  IAnton-Lamprecht  INaeyaert  JM Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II.  Am J Hum Genet. 1997;60547- 554Google Scholar
Michalickova  KSusic  MWilling  MCWenstrup  RJCole  WG Mutations of the α2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome I.  Hum Mol Genet. 1998;7249- 255Google ScholarCrossref
Acil  YVetter  UBrenner  RMüller  PKBrinckmann  J Ehlers-Danlos syndrome type VI: cross-link pattern in tissue and urine sample as a diagnostic marker.  J Am Acad Dermatol. 1995;33522- 524Google ScholarCrossref