Ehlers-Danlos Syndrome, Dermatosparaxis Type

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2019-09-22
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A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome dermatosparaxis type (EDSDERMS) is caused by mutation in the gene encoding the procollagen protease ADAMTS2 (604539) on chromosome 5q35.

Description

Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.

Clinical Features

Lichtenstein et al. (1973) reported 2 patients with severe joint hyperextensibility and mild stretchability and bruisability of the skin similar to that seen in dermatosparaxis in cattle. Other clinical features in the patients included short stature, epicanthal folds, depressed nasal bridge, and micrognathia. Cultured fibroblasts showed decreased activity of procollagen peptidase. Lichtenstein et al. (1973) concluded that the clinical manifestations were related to impaired enzymatic conversion of procollagen to collagen due to an enzyme defect.

Nusgens et al. (1992) reported an affected 2-year-old girl with dysmorphic facial features and soft skin. She had large-appearing eyes and thickened eyelids, small stature, and lack of ossification of cranial bones. Easy bruising was noted at the end of the first year, and she developed a left occipital fracture with massive hematoma following a minor fall. EDS was suspected on the basis of blue sclerae and soft, velvety, hyperextensible skin. She also had marked bruising and open wounds following minor trauma, and suturing was not possible due to the extreme fragility of the skin. Surgical removal of a large umbilical hernia was performed at the age of 20 months; the excised skin could be torn by hand. The parents were unrelated and phenotypically normal. Electron microscopy of skin samples demonstrated altered polymers seen as hieroglyphic pictures, accumulation of type I p-N-alpha-1 and p-N-alpha-2 polypeptides in the dermis, and absence of processing of these polypeptides in fibroblast cultures, similar to that observed in animal models of dermatosparaxis. The authors postulated a deficiency of procollagen I N-proteinase. Nusgens et al. (1992) noted that the clinical manifestations of EDS VIIC were different from those of EDS VIIA (130060) and VIIB, in which the clinical picture is dominated by joint laxity and subluxations. The skin fragility EDS VIIC can be as severe as that observed in the dermatosparactic calves. Thus, the clinical picture is that of dermatosparaxis and not that of arthrochalasis multiplex congenita.

Wertelecki et al. (1992) provided clinical details of the 2 patients reported by Smith et al. (1992). The authors emphasized the large fontanels and wide sagittal and metopic sutures, blue sclerae, micrognathia, and umbilical hernia. Electron microscopic examination of the skin showed collagen sheets rather than fibrils, and characteristic distortions resembling hieroglyphics.

Petty et al. (1993) reported a patient with dermatosparaxis, emphasizing marked skin fragility and laxity, blue sclerae, increased bruisability, micrognathia, umbilical hernia, and growth retardation. The patient was a male infant born at 35 weeks' gestation after premature rupture of the membranes. He presented at birth with large full-thickness groin fissures, large fontanels, umbilical hernia, and dental laminal cysts. The diagnosis of dermatosparaxis was made by electron microscopic findings consisting of characteristic small, irregular, and circular collagen fibers in the skin.

Reardon et al. (1995) described a case of dermatosparaxis in a 15-year-old girl and noted that 3 previously reported patients with this disorder died before the age of 3 years. Easy bruising, severe skin laxity and fragility, extensive scar formation, and joint laxity were the main clinical manifestations in their patient. Her soft, doughy skin was easily stretchable, but did not recoil. Electron microscopy showed typical hieroglyphic figures upon cross-section of collagen fibrils.

Malfait et al. (2004) reported a 5-year-old boy with dermatosparaxis-type EDS and provided follow-up of 2 previously reported patients at the ages of 7 and 12 years. All had characteristic facial features, including large fontanels in infancy, puffy eyelids, epicanthal folds, downslanting palpebral fissures, and micrognathia. Skin was soft, doughy, and redundant. They had short limbs, hands, feet, fingers, and toes. Two patients had spontaneous bladder rupture and 1 had rupture of the diaphragm following vomiting. Orofacial features included gingival hyperplasia, hypodontia, microdontia, and tooth discoloration. Deciduous dentition showed abnormal morphology of the molars and enamel attrition. Skin bruising, skin tearing, and joint hypermobility increased with age.

Colige et al. (2004) reported a boy with EDS dermatosparaxis type confirmed by genetic analysis (604539.0003). At birth, there was rupture of the umbilical cord and generalized edema with swollen eyelids. Craniofacial features included short forehead, flat supraorbital ridges, broad nasal root, wide nares, large mouth, micrognathia, hypodontia, gingival hyperplasia, and hypertrichosis. He had short hands, arms, and legs. Other features included joint hypermobility, easy bruising, fragile skin, and blue sclera. In vitro studies showed impaired aminocollagen processing.

Bar-Yosef et al. (2008) reported an infant of Ashkenazi Jewish origin with EDS dermatosparaxis type confirmed by genetic analysis (604539.0001). He was delivered preterm by cesarean due to fetal heart decelerations and with multiple congenital nontraumatic skull fractures and intracranial hemorrhage. Eight days prior to delivery the mother was admitted to the hospital with premature rupture of the membranes. He died at age 145 days due to sepsis. Family history indicated that the paternal and maternal grandparents originated in Belarus.

Van Damme et al. (2016) reported 5 new patients from 4 unrelated families with the dermatosparaxis type of EDS, bringing the total of molecularly characterized patients to 15. Three of these patients displayed a phenotype that was milder than previously reported. Among the 5 newly reported patients, only 1 had preterm birth, and none exhibited severe neonatal complications. All had a large fontanel and blue sclerae, but only 1 had eyelid edema and blepharochalasis, which was a common feature in previously reported cases. Umbilical hernia was present in all 5 of the newly reported patients and in 14 of 15 patients overall. Van Damme et al. (2016) suggested updated diagnostic criteria, including major diagnostic criteria of severe skin fragility; sagging, redundant skin; easy bruising; and a typical facial gestalt that is congenital and/or postnatal and progressive, with swelling of the periorbital soft tissue, blue sclerae, downslanting palpebral fissures, epicanthal folds, micrognathia, delayed fontanel closure, and dental anomalies. Suggested minor diagnostic criteria included postnatal growth restriction, short limbs with short hands and feet, joint hypermobility, umbilical hernia, and congenital or postnatal visceral and vascular fragility. The authors noted that arterial rupture and aortic dilatation had not been reported.

Pathogenesis

Minor et al. (1986) examined cell lines from 3 new Ehlers-Danlos syndrome variants showing decreased processing of procollagen. In 1, a structural defect in the alpha-2(I) chain was demonstrated, consistent with EDS VIIB. In the other 2, the collagen chains appeared to be normal, and procollagen N-proteinase activity appeared to be decreased.

Smith et al. (1992) identified possible humans case of procollagen protease deficiency on the basis of electron microscopic changes showing a 'hieroglyphic' appearance of the collagen identical to that seen in cattle with dermatosparaxis (Lapiere et al., 1971).

Smith et al. (1992) identified 2 children with soft, lax, and fragile skin which on transmission electron microscopy was found to contain twisted, ribbon-like collagen fibrils characteristic of dermatosparaxis. The skin from 1 child was shown to contain collagen precursors with amino-terminal extensions. Cultured fibroblasts from both children failed to cleave the amino-terminal propeptides from both alpha chains of type I procollagen. Extracts of normal cells cleaved normally the type I procollagen synthesized by cells from both children, demonstrating that the enzyme, not the substrate, was defective.

Molecular Genetics

Colige et al. (1999) identified mutations in the ADAMTS2 gene causing EDS type VIIC in the 6 known affected individuals and also in 1 strain of dermatosparactic calf. Five of the individuals with EDS type VIIC were homozygous for a gln225-to-ter substitution (604539.0001). Four of these 5 patients were homozygous at 3 downstream polymorphic sites. The sixth patient was homozygous for a trp795-to-ter substitution (604539.0002). In the dermatosparactic calf, the mutation was a 17-bp deletion that changed the reading frame of the message.

In 2 unrelated patients with EDS type VIIC, Colige et al. (2004) identified homozygosity or compound heterozygosity for mutations in the ADAMTS2 gene (see, e.g., 604539.0003).

Van Damme et al. (2016) identified 3 novel homozygous loss-of-function mutations and 1 compound heterozygous mutation in ADAMTS2 in 5 patients from 4 unrelated families with dermatosparaxis-type EDS.

Nomenclature

Nusgens et al. (1992) referred to this disorder as Ehlers-Danlos syndrome type VIIC, reserving EDS VIIA and EDS VIIB for the disorders resulting from defects in the procollagen alpha-1 and alpha-2 polypeptides, respectively. McKusick (1979) had previously used the designations VII-A1 and VII-A2 for VII-A and VII-B, and VII-B instead of VII-C for deficiency of procollagen peptidase.

Animal Model

EDS type VIIC has been demonstrated in cattle (Lapiere et al., 1971), sheep (Fjolstad and Helle, 1974), and the Himalayan cat (Counts et al., 1980; Holbrook et al., 1980).