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Ehlers-Danlos Syndrome, Dermatosparaxis Type

DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, DERMATOSPARAXIS TYPE
Synonymous -
Estimated prevalence -
OMIM 225410
Inheritance Autosomal recessive
Gene (s) ADAMTS2 (A Disintegrin-Like and Metalloproteinase with Thrombospondin Type 1 Motif, 2) (604539)

Definition

Dermatosparaxis EDS (dEDS) is a rare autosomal recessive connective tissue disorder characterized by extreme skin fragility and excessive bruising. It is caused by mutations in ADAMTS2 gene, which lead to deficient activity of procollagen I N-proteinase, the enzyme that excises the N-terminal propeptide in procollagen type I, type II and type III.1

 

Clinical Description

dEDS is a rare condition, which is characterized by premature rupture of the membranes (e.g. spontaneous bladder rupture), umbilical hernia, short stature, redundant lax skin with extreme skin fragility and easy bruising (with formation of large subcutaneous hematomas) and large fontanels. Bleeding problems can occur including severe epistaxis and gum bleeds as well as cerebral hemorrhages. Most patients present a characteristic facies with epicanthic folds, downslanting palpebral fissures, puffy eyelids, blue sclerae, prominent lips, excessive buccal mucosa and micrognathia. Hands and feet, which are usually very short, may have a progeric appearance due to presence of many fine creases on the palms and multiple skin folds around fingers and ankles. During childhood and puberty, increased bruisability and severe skin fragility predominate the clinical picture. Wound healing is not delayed and initial scar formation is only minimal. In the older patients, however, more typical atrophic scarring with hyperpigmentation is seen, probably due to repeated skin tearing, bruising and secondary infections. Joint hypermobility, although not obvious during the first years of life, seems to become more important with age. However, a mild delay in gross motor development occurs frequently. Arterial rupture or aortic dilatation has not been reported so far. Further features are listed below. 2

 

Clinical Criteria3

Major criteria:

  1. Extreme skin fragility with congenital or postnatal skin tears
  2. Characteristic craniofacial features, which are evident at birth or early infancy, or evolve later in childhood
  3. Redundant, almost lax skin, with excessive skin folds at the wrists and ankles
  4. Increased palmar wrinkling
  5. Severe bruisability with a risk of subcutaneous hematomas and hemorrhage
  6. Umbilical hernia
  7. Postnatal growth retardation
  8. Short limbs, hand and feet
  9. Perinatal complications due to connective tissue fragility

Minor criteria

  1. Soft and doughy skin texture
  2. Skin hyperextensibility
  3. Atrophic scars
  4. Generalized joint hypermobility
  5. Complications of visceral fragility (e.g., bladder rupture, diaphragmatic rupture, rectal prolapse)
  6. Delayed motor development
  7. Osteopenia
  8. Hirsutism
  9. Tooth abnormalities
  10. Refractive errors (myopia, astigmatism)
  11. Strabismus

Minimal criteria suggestive for dEDS:

Major criteria 1. and 2. plus either one other major criterion and/or three minor criteria

 

Pathogenesis

dEDS is are recessively inherited connective tissue disorder, caused by a deficient activity of procollagen-I-N-proteinase, the enzyme that excises the N-terminal propeptide in procollagen type I, type II and type III. As a consequence, there is accumulation of pN- procollagen, resulting in polymerization of abnormal collagen fibers that appear thin, irregular, branched and “hieroglyphic” in cross-section with dereased tissue strenght. Homozygous or compound heterozygous mutations in the gene encoding the procollagen-I-N-proteinase ADAMTS-2 (A Disintegrin And Metalloproteinase with ThromboSpondin-like repeats) have been identified in all reported patients with dEDS2,4

 

Diagnosis

The diagnosis of dEDS is made based on the characteristic clinical findings. It can be confirmed by ultrastructural studies of the dermal collagen fibrils, showing the pathognomonic hieroglyphic pattern.

Figure 1. ultrastructural study of dermal collagen fibrils of a patient with  EDS demtaosparaxis type, showing the pathognomonic hieroglyph-like pattern of the fibrils.

Ultrastructural with EDS demtaosparaxi

Biochemical protein-based testing of radioactively labeled procollagen type I from skin fibroblast cultures shows impaired processing of the N-propeptide of type I collagen, with accumulation of pNα1(I) and pNα2(I). Molecular sequence analysis of the ADAMTS2 gene may confirm the diagnosis. Prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member. 

 

Treatment

See article "Ehlers Danlos Syndrome"

Children with EDS dermatosparaxis type should wear protection in the form of pads or bandages over the forehead, knees and shins, in order to avoid skin tears and bruises. Contact sports should be avoided. Dermal wounds should be closed without tension, preferably in two layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scars.
A baseline echocardiogram with aortic diameter measurement is recommended prior to the age of 10 years with follow-up studies timed according to whether an abnormal measurement is found. Awareness for internal complications, such as bladder rupture and possibly vascular rupture is warranted, and invasive interventions, including catheterization and angiography should be performed with the utmost care.

 

 

References

1. Smith LT, Wertelecki W, Milstone LM, Petty EM, Seashore MR, Braverman IM, et al. Human dermatosparaxis: a form of Ehlers-Danlos syndrome that results from failure to remove the amino-terminal propeptide of type I procollagen. Am J Hum Genet. 1992;51(2):235-244.

2. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, et al. The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017;175(1):70-115.

3. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26.

4. Van Damme T, Colige A, Syx D, Giunta C, Lindert U, Rohrbach M, Aryani O, Alanay Y, Simsek-Kiper PÖ, Kroes HY, Devriendt K, Thiry M, Symoens S, De Paepe A, Malfait F. Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type. Genet Med. 2016 Sep;18(9):882-91.