Abstract
The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescent-onset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood. To date, thirteen different EDS types have been recognized, stemming from genetic defects in 20 different genes. While initial biochemical and molecular analyses mainly discovered defects in genes coding for the fibrillar collagens type I, III and V or their modifying enzymes, recent discoveries have linked EDS to defects in non-collagenous matrix glycoproteins, in proteoglycan biosynthesis and in the complement pathway. This genetic heterogeneity explains the important clinical heterogeneity among and within the different EDS types. Generalized joint hypermobility and skin hyperextensibility with cutaneous fragility, atrophic scarring and easy bruising are defining manifestations of EDS; however, other signs and symptoms of connective tissue fragility, such as complications of vascular and internal organ fragility, orocraniofacial abnormalities, neuromuscular involvement and ophthalmological complications are variably present in the different types of EDS. These features may help to differentiate between the different EDS types but also evoke a wide differential diagnosis, including different inborn errors of metabolism. In this narrative review, we will discuss the clinical presentation of EDS within the context of inborn errors of metabolism, give a brief overview of their underlying genetic defects and pathophysiological mechanisms and provide a guide for the diagnostic approach.
Highlights
The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescentonset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood
The lone exception are the congenital anomalies of the kidney and urinary tract sometimes observed in musculocontractural Ehlers–Danlos syndromes (EDS) [7]
There is a higher risk of preterm delivery due to premature rupture of the membranes in some types of EDS and especially in classical type of EDS (cEDS), Vascular EDS (vEDS) and dermatosparaxis EDS, if the fetus is affected [8,9,10]
Summary
Absent N-propeptide cleavage of both pro-α(I)-chains α2-chain of type I procollagen. Deficiency of the molecular chaperone (possibly) leads to premature interaction and accumulation of collagen molecules in the endoplasmic reticulum. Soft, velvety and/or translucent skin, mild skin hyperextensibility, easy bruising, hernia developmental dysplasia of hip, scoliosis, arachnodactyly, hypermobility of distal joints, pes planus, hallux valgus, mild finger contractures, fractures, osteopenia/osteoporosis hypotonia in infancy (usually mild) blue sclerae, frontal bossing, high palate, depressed nasal bridge and/or prominent chin. The diagnosis of the more common and autosomal dominant types (classical (cEDS), hypermobile (hEDS) and vascular EDS (vEDS)) may be missed in childhood due to the presence of only subtle signs of connective tissue fragility that are common in the general population (e.g., joint hypermobility, easy bruising, varicose veins, etc.) This contrasts greatly with most inborn errors of metabolism (IEM) that manifest themselves after a symptom-free period in the first months or years of life [6]. What follows is a concise per system overview of the EDS phenotype keeping a differential diagnosis with the IEM in mind (Table 2)
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