Skin fragility. The skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma. Minor injuries produce gaping defects, and surgical repair or any surgical intervention is accomplished only with great difficulty because of the lack of normal tensile strength.
Structural failure of organ or tissues. The structural defect in connective tissue may lead to serious internal complications, including rupture of the colon and large arteries (vascular EDS); ocular fragility, with rupture of the cornea and retinal detachment (kyphoscoliotic EDS); and diaphragmatic hernias (classical EDS), among others.
The molecular bases for three of the more common variants are as follows:
Deficient synthesis of type III collagen resulting from mutations affecting the COL3A1 gene. This variant, vascular EDS, is inherited as an autosomal dominant disorder and is characterized by weakness of tissues rich in type III collagen (e.g., blood vessels, bowel wall), predisposing them to rupture.
Deficiency of the enzyme lysyl hydroxylase. Decreased hydroxylation of lysyl residues in types I and III collagen interferes with the formation of crosslinks among collagen molecules. As might be expected, this variant (kyphoscoliotic EDS), resulting from an enzyme deficiency, is inherited as an autosomal recessive disorder. Patients typically manifest with congenital scoliosis and ocular fragility.
• Deficient synthesis of type V collagen resulting from mutations in COL5A1 and COL5A2 is inherited as an autosomal dominant disorder and results in classical EDS.
TherearesixvariantsofEDS,allcharacterizedbydefectsincollagensynthesisorassembly.Eachofthevariantsiscausedbyadistinctmutation.
Clinicalfeaturesmayincludefragile,hyperextensibleskinvulnerabletotrauma,hypermobilejoints,andrupturesinvolvingcolon,cornea,orlargearteries.Woundhealingispoor.
Familial hypercholesterolemia is a “receptor disease” caused by loss-of-function mutations in the gene encoding the LDL receptor, which is involved in the transport and metabolism of cholesterol. As a consequence of receptor abnormalities there is a loss of feedback control that normally holds cholesterol synthesis in check. The resulting elevated levels of cholesterol induce premature atherosclerosis and greatly increase the risk of myocardial infarction. Familial hypercholesterolemia is among the most common of mendelian disorders; the frequency of the heterozygous condition is 1 in 500 in the general population. Approximately 7% of the body’s cholesterol circulates in the plasma, predominantly in the form of LDL. As might be expected, the amount of plasma cholesterol is influenced by its synthesis and catabolism, and the liver plays a crucial role in both these processes, as described later. A brief review of the synthesis and transport of cholesterol follows.
Normal Cholesterol Metabolism. Cholesterol may be derived from the diet or from endogenous synthesis. Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa and travel by way of the gut lymphatics to the blood. These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat. The chylomicron remnants, rich in cholesterol, are then delivered to the liver. Some of the cholesterol enters the metabolic pool (to be described), and some is excreted as free cholesterol or as bile acids into the biliary tract. The endogenous synthesis of cholesterol and LDL begins in the liver (