Inherited connective tissue disorders are clinically and genetically diverse conditions affecting the skin, joints, and a variety of extracutaneous tissues, including the cardiovascular (CV) system. The nature and severity of the skin phenotype is dependent on the type of mutation as well as the role of the affected protein on dermal structure and function (see Chaps. 15 and 18). The diagnosis of many inherited connective tissue disorders is clinical, although Clinical Laboratory Improvement Amendments (1988) (CLIA)-approved genetic testing is increasingly available. A listing of research laboratories that might offer testing can be found at http://www.genetests.org.
Combined incidence of almost 1 in 5000 persons.
Most commonly autosomal dominant (classical and hypermobile types).
Defects in the Type V collagen gene most commonly cause the classical subtype.
Cutaneous features include varying degrees of skin fragility and hyperextensibility. The classical subtype exhibits soft, velvety skin that bruises easily and wounds that heal as thin, atrophic, gaping scars.
Extracutaneous manifestations include hypermobile joints with frequent dislocations, complications with pregnancy and delivery, and, less commonly, cardiovascular manifestations, particularly aortic root dilation.
Information for patients and professionals at http://www.ehlers-danlos.org and https://www.ehlers-danlos.com/.
A variety of genetically and clinically heterogeneous inherited conditions characterized by varying degrees of skin fragility and hyperextensibility, and joint hypermobility have been collected under the rubric of the Ehlers-Danlos syndromes (EDS). A new classification system published in 20171 attempted to consolidate and simplify existing subgroups (Table 72-1) as well as reconcile new genetic discoveries with existing clinical phenotypes. Major and minor diagnostic criteria were developed for each major subtype of EDS. Despite these revisions, many patients defy clear-cut classification. The spectrum of EDS severity ranges from subtle clinical findings to severe, debilitating disease.
TABLE 72-1The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects ||Download (.pdf) TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects
|CLINICAL EDS SUBTYPE (ABBREVIATION: OMIM #) ||CLINICAL FEATURES ||INHERITANCE ||PROTEIN/(GENE DEFECT) |
|Classical (cEDS:130000 and 130010) ||Hyperextensible skin; easy bruising; wide, atrophic scars; hypermobile joints ||AD ||Collagen Type V/(COL5A1, COL5A2) |
|Classical-like EDS (clEDS: 606408) ||Similar to cEDS but without atrophic scarring; foot deformities; muscle weakness; acrogeria; axonal polyneuropathy ||AR ||Tenascin XB/(TNXB) |
|Cardiac-valvular EDS (cvEDS:225320) ||Similar to cEDS but with severe, progressive, cardiac valvular disease ||AR ||Type I collagen/(COL1A2—biallelic mutations leading to nonsense-mediated messenger RNA decay and loss of pro a2(I) collagen chains |
|Vascular EDS (vEDS:130050) ||Thin, translucent skin with easy bruising; arterial and visceral rupture; typical facies ||AD || |
Major: collagen Type III/(COL3A1)
Rare: Type I collagen/(COL1A1: c.934C>T, p.[Arg312 Cys]; c.1720C>T, p.[Arg574Cys]; c.3227C>T, p.[Arg1093Cys])
|Hypermobile EDS (hEDS: 130020) ||Smooth, velvety skin; joint hypermobility ||AD/AR ||Unclear for most; collagen Type III; tenascin XB/(COL3A1; TNXB)a |
|Arthrochalasia EDS (aEDS: 130060) ||Hyperextensible and fragile skin; severe joint hypermobility; congenital hip dislocation ||AD ||Collagen Type I/(COL1A1...|