Ehlers-Danlos Syndrome, Classic Type, 2

A number sign (#) is used with this entry because Ehlers-Danlos syndrome classic type 2 (EDSCL2) is caused by heterozygous mutation in the collagen alpha-2(V) gene (COL5A2; 120190) on chromosome 2q31.

Rarely, specific mutations in the COL1A1 gene (e.g., R134C, 120150.0059) cause classic EDS.

Description

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are loose-jointedness and fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars (Beighton, 1993). There are both severe and mild forms of classic EDS, previously designated EDS I and EDS II, respectively.

For a general phenotypic description and a discussion of genetic heterogeneity of classic EDS, see 130000.

Clinical Features

The minimal diagnostic features for EDS I used in the study of Wenstrup et al. (1996) were autosomal dominant inheritance, generalized joint laxity, hyperextensible skin with doughy and velvety texture, and the presence of widened atrophic scars. The criterion used to distinguish EDS II from EDS I was the absence of widened atrophic scars in EDS II.

De Felice et al. (2001) studied 4 patients with EDS II and 8 patients with EDS III (130020), the hypermobile type. They concluded that absence of the inferior labial frenulum and the lingual frenulum are characteristics of EDS. Absence of the inferior labial frenulum showed 100% sensitivity and 99.4% specificity; absence of the lingual frenulum showed 71.4% sensitivity and 100% specificity.

Inheritance

Classic EDS is an autosomal dominant disorder (Wenstrup et al., 1996; De Paepe et al., 1997).

Cytogenetics

Prontera et al. (2010) reported a 42-year old Italian man with a complex EDS phenotype caused by a 13.7-Mb de novo heterozygous deletion of chromosome 2q23.3-q31.2 resulting in deletion of the COL3A1 (120180), COL5A2, and myostatin (MSTN; 601788) genes. Loss of function mutations in COL3A1 (120180) and COL5A2 cause vascular (130050) and classic EDS, respectively. Haploinsufficiency for MSTN results in overgrowth of skeletal muscle. Due to the monosomy for MSTN, the patient had 'an exceptional constitutional muscular mass,' without muscle weakness, myalgia, or easy fatigability. He also had no generalized joint hypomobility or recurrent joint dislocation; symptoms of EDS were limited to recurrent inguinal hernias and mild mitral valve prolapse. Prontera et al. (2010) hypothesized that haploinsufficiency for the MSTN allele exerted a protective effect against EDS clinical manifestations in this patient. The findings also indicated that there is direct involvement of muscle damage in EDS and that care of muscle function in these patients may be beneficial.

Molecular Genetics

Michalickova et al. (1998) demonstrated heterozygous mutations in the COL5A2 gene (e.g., 120190.0001) in patients mild and severe classic EDS.

Richards et al. (1998) demonstrated a heterozygous missense mutation in the COL5A2 gene (120190.0003) in a mother and her 2 sons with mild classic EDS.

Malfait et al. (2005) studied fibroblast cultures from 48 patients with classic EDS for the presence of type V collagen defects. Forty-two (88%) were heterozygous for an expressed polymorphic variant of COL5A1, and cDNA from 18 (43%) expressed only 1 COL5A1 allele. In total, 17 mutations leading to a premature stop codon and 5 structural mutations were identified in the COL5A1 and COL5A2 genes. Four patients had COL5A2 mutations (120190.0004-120190.0007). In 3 patients with a positive COL5A1 null-allele test, no mutation was found. Overall, in 25 of the 48 patients (52%), an abnormality in type V collagen was confirmed. Variability in severity of the phenotype was observed, but no significant genotype-phenotype correlations were found. The relatively low mutation detection rate suggested that other genes are involved in classic EDS. Malfait et al. (2005) excluded COL1A1, COL1A2 (120160), and DCN (125255) as major candidate genes for classic EDS, since they could find no causal mutation in these genes in a number of patients who tested negative for COL5A1 and COL5A2.

Symoens et al. (2012) analyzed COL5A1 and COL5A2 in 126 patients with a diagnosis or suspicion of classic EDS. In 93 patients, a type V collagen defect was found, of which 73 were COL5A1 mutations, 13 were COL5A2 mutations, and 7 were COL5A1 null-alleles with mutation unknown. The majority of the 73 COL5A1 mutations generated a COL5A1 null-allele, whereas one-third were structural mutations, scattered throughout COL5A1. All COL5A2 mutations were structural mutations. Reduced availability of type V collagen appeared to be the major disease-causing mechanism, besides other intra- and extracellular contributing factors. All type V collagen defects were identified within a group of 102 patients fulfilling all major clinical Villefranche criteria, that is, skin hyperextensibility, dystrophic scarring, and joint hypermobility. No COL5A1/COL5A2 mutation was detected in 24 patients who displayed skin and joint hyperextensibility but lacked dystrophic scarring. Overall, over 90% of patients fulfilling all major Villefranche criteria for classic EDS were shown to harbor a type V collagen defect, indicating that this is the major, if not the only, cause of classic EDS.