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

EDS dermatosparaxis type is a rare autosomal recessive connective tissue disorder characterized by extreme skin fragility and excessive bruising. It is 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.

Clinical Description

ES dermatosparaxis type is a rare condition, which is characterized by premature rupture of the membranes, large fontanels, umbilical hernia, short stature, redundant lax skin with extreme skin fragility and easy bruising. 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 pigmentation 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. Spontaneous bladder rupture has been reported in some children with this disorder, illustrating the fragility of internal tissues.

Pathogenesis

EDS dermatosparaxis type and the related animal disease dermatosparaxis, are recessively inherited connective tissue disorders, 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. 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 EDS dermatosparaxis type.

Diagnosis

The diagnosis of a cutis laxa syndrome is primarily based on clinical assessment of the typical skin features, and the associated extracutaneous findings. Light microscopy of a skin biopsy, using a Verhoeff-von Giesson stain for elastin, can reveal the absence or disruption of elastic fibers. For Occipital Horn Syndrome (X-linked CL), determining levels of copper and ceruloplasmin is diagnostic. Molecular analysis can help to confirm the diagnosis.

The diagnosis of EDS dermatosparaxis 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 is available on a research basis.

Prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member. Up till now prenatal testing for this type of EDS has never been reported since affected individuals were still too young to start a family.

Treatment

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.