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Growth Disorders - Endocrine Disorders, Skeletal Dysplasias, Excessive Growth

differences genetic clinical mutations cartilage collagen achondroplasia

Growth, which usually refers to skeletal growth since it determines final adult height, is an extremely complex process. As such, it is susceptible to a wide range of genetic and physiologic disturbances. Indeed, growth is adversely affected by many if not most chronic diseases of childhood, through many different mechanisms.

Skeletal growth depends on hormonal signals for regulation. It also requires the production of adequate amounts of cartilage, because most bone forms within a model or template made from cartilage. Primary disorders of growth, that is, disorders in which growth is intrinsically affected, therefore fall into two major categories: disorders of the endocrine (hormone) system and disorders of the growing skeleton itself (skeletal dysplasias). Many of the former and most of the latter are genetic disorders.

Growth Factor Receptor Mutations.

The prototype of the skeletal dysplasias is achondroplasia, which is one of a graded series of dwarfing disorders that result from activating mutations of fibroblast growth factor receptor 3 (FGFR3). Achondroplasia is the most common form of dwarfism that is compatible with a normal life span, while thanatophoric dysplasia, which lies at the severe end of the spectrum of FGFR3 disorders, is the most common lethal dwarfing condition in humans. Both are characterized by the shortening of limbs, especially proximal limb bones, and a large head with a prominent forehead and hypoplasia (reduction of growth) of the middle face. The mildest disorder in this group is hypochondroplasia, in which patients exhibit mild short stature and few other features.

All of the disorders in this group result from heterozygous mutations of FGFR3. Except for the lethal thanatophoric dysplasia, they are inherited as autosomal dominant traits. The vast majority of mutations arise anew, during sperm formation (spermatogenesis), and especially in older fathers. FGFR3 is a very mutable (easily mutated) gene and there are certain extremely mutable regions within the gene where disease-causing mutations cluster.

There is a very strong correlation between clinical phenotypes and specific mutations. In fact, essentially all patients with classic features of achondroplasia have the same amino acid substitution in the receptor. The mutations that cause these disorders enhance the transduction of signals through FGFR3 receptors in chondrocytes in growing bones. This inhibits the proliferation of these cells that is necessary for linear growth to occur.

A six-year-old girl with achondroplasia (right) stands beside her younger, not quite four-year-old brother. Features of achondroplasia evident in the girl include small stature, short arms and legs, relatively large head size, and subtle differences of facial features.

Cartilage Matrix Protein Mutations.

Another major class of skeletal dysplasias result from mutations of genes that encode cartilage matrix proteins such as collagen types II, IX, X, and XI, and cartilage oligomeric matrix protein (COMP). The type II collagen mutations cause a spectrum of autosomal dominant disorders called spondyloepiphyseal dysplasias because they primarily affect the spine (spondylo) and the ends of growing limb bones (epiphyses). They range in severity from lethal before birth to extremely mild. In addition to dwarfism that affects the trunk more than the limbs, patients with these disorders develop precocious osteoarthritis of weight-bearing joints such as the hips and knees. Many patients have eye problems that reflect disturbances of type II collagen in the vitreous portion of the eye.

Mutations of COMP cause two clinically distinct disorders: pseudo-achondroplasia and multiple epiphyseal dysplasia. Both are inherited as autosomal dominant disorders, have onset after birth, and are dominated by osteoarthritis of hips and knees. Dwarfism is severe and skeletal deformities are common in pseudoachondroplasia.

Cartilage collagens and COMP are multimeric molecules, that is, they are composed of multiple subunits, three for collagens and five for COMP. Like a square wheel on a car, the products of mutant alleles interfere functionally with the products of normal alleles when they combine during molecular assembly, a so-called dominant negative effect. Most collagen mutations are thought to act through this mechanism to reduce the number of collagen molecules in cartilage matrix, which in turn alters the ability of cartilage to function as a template for bone growth.

Similar types of mutations occur in genes encoding type I collagen, which is the principal matrix protein of bone. These mutations lead to osteogenesis imperfecta (OI), which is a spectrum of disorders of varying severity. The hallmark of OI is bone fractures, although patients often have blue sclerae (the "whites" of the eye), fragile skin, and dental problems that reflect the widespread distribution of type I collagen in many connective tissues.

Hardy-Weinberg Equilibrium - Basic Concepts, Assumptions Of The Hardy-weinberg Model, Allele Frequencies Remain The Same Between Generations [next] [back] Genotype and Phenotype - Alleles, Polymorphisms, And Mutations, Dominant, Codominant, And Recessive Genes, Multiple Alleles And Pleiotropy

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