Inherited connective tissue disorders

Persikov, A. V., Pillitteri, R. J., Amin, P., Schwarze, U., Byers, P. H., and Brodsky, B. (2004). Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum. Mut. 24, 330-337. 

Several inherited connective tissue disorders predispose to arterial dissection and other vascular abnormalities, including aneurysms and vasoocclusive disease. 

Gout. An inherited metabolic disorder occurring especially in men, characterized by a raised but variable blood uric acid level, recurrent acute arthritis of sudden onset, deposition of crystalline sodium urate in connective tissues and articular cartilage, and progressive chronic arthritis. 

Some inherited disorders of connective tissue (Table 3.2) can present with, or be complicated by, arterial dissection or even rupture, intra- and extracranial aneurysm formation. 

Marfan syndrome is genetic disease that involves defects in the connective tissues of the body with the cardinal collection of abnormalities affecting the skeletal, ocular, and cardiovascular systems. It is inherited as an autosomal dominant disorder, meaning that inheriting only one defective gene from either the paternal or maternal side will lead to the disorder. Although the majority of mutations are inherited from one of the parents, approximately 25% of affected individuals develop Marfan syndrome as a result of a new mntation. The prevalence is 1/20,000 and the disorder is inherited with variable expression. This means that each individual may have a different combination of the possible clinical features that characterize the disorder. 

Drockop DJ, Kuivanieni H, Tromp G, Ala-Kokko L. Inherited disorders of connective tissue. In Braunwald E, Fauci AS, Kasper DL et al. Harrison s Principles of Internal Medicine, 15th edn. New York, McGraw-HiU, 2001 2290-300 (specifically 2295-7). 

Several inherited disorders of methionine metabolism (Chapter 17) give rise to exeessive production of homocysteine, HS-CH2-CH2CH(NH3 )COO , and its excretion in urine. The most common form of homocystinuria is due to a deficiency of cystathionine synthase (Chapter 17). A major clinical manifestation of homocystinuria is connective tissue abnormalities that are probably due to the accumulation of homocysteine, which either inactivates the reactive aldehyde groups or impedes the formation of polyfunctional cross-links. 

Osteogenesis imperfecta (01) is an inherited disorder of connective tissue resulting from abnormal quantity and/or quality of type I collagen, the major protein of bone. The phenotypic presentation is enormously varied, ranging from perinatal death to normal lifespan complicated by only a few fractures. Because fractures are a feature of the condition it must be given serious consideration in any child with unexplained fractures. There are four major types in the Sillence classification (Sillence et al. 1979), but it should be noted that there are no strict boundaries. Type IV is an uncommon type of 01 (only 5% of the patients in the Sillence study) with mild to severe bone disease. Patients with this type... 

Alterations of the connective tissue composition of the extracellular matrix are an important feature of various inherited and acquired disorders of soft tissue (Miller 1976). This phenomenon is particularly important in the lung in which elasticity is a vital determinant of function. Interstitial collagen is composed of at least two distinct trimeric polypeptide molecules designated as type 1 and type 111 collagens. Type 1 contains two ai(I) chains and one 02 chain, whereas type 111 contains 3 identical a, (HI) chains. Pulmonary fibroblasts produce more type I... 

Several inherited diseases of connective tissues are known (McKusick, 1966), some of which involve a derangement of glycosaminoglycan metabolism, and, in particular, Hurler s syndrome has been extensively studied in many laboratories (Dorfman, 1966a Dorfman and Matalon, 1969). The disorder expresses itself biochemically as an accumulation of glycosaminoglycans in various tissues (particularly dermatan sulfate and heparan sulfate), and recent work by Fratantoni si al. (1968) and Neufeld and Fratantoni (1970) suggests that there is a defect in degradation of the glycosaminoglycans rather than an overproduction. 

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