Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes

Abstract

The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.

Keywords: Ehlers-Danlos syndrome; hypermobility; musculoskeletal.

FIGURE 1

Section in situ hybridization of EDS genes. Messenger RNA expression of EDS genes on sagittal mouse sections at E14.5. Purple staining reveals expression of mRNAs showing widespread expression of EDS genes in regions of connective tissue development. Numbers correspond to specific anatomical locations (red: neural tissues, teal: craniofacial tissues, yellow: thoracic/abdomen tissues). 1, Roof of midbrain; 2, mesencephalic vesicle; 3, ventral part of midbrain; 4, pons; 5, choroid plexus within central part of lumen of fourth ventricle; 6, dorsal part of medulla oblangata; 7, upper lip; 8, Meckel’s cartilage; 9, dorsal surface of tongue; 10, cartilage primordium of nasal bone; 11, right ventricle of the heart; 12, aortic valve and ascending aorta; 13, mitral valve; 14, cartilage primordium of the palatal shelf; 15, lower thoracic dorsal root ganglion; 16, apical part of caudal lobe of right lung; 17, right dome of diaphragm; 18, diencephalon; 19, median circumvallate papilla/cartilage primordium of basisphenoid bone; 20, evidence of ossification within cartilage primordium of basioccipital bone (cilvus); 21, lumen of urogenital sinus (future bladder); 22, liver; 23, costal cartilage of ribs