In contrast to endocrine growth disorders, the hallmark of the skeletal dysplasias ("-plasia" means "growth") is disproportionate short stature. In other words, the limbs are disproportionately shorter than the trunk or vice versa. These disorders result from mutations of genes whose products are required for normal skeletal development. In most cases they are involved in endo-ossification bone chondral ossification, the process by which the skeleton grows through the
?formation production of the cartilage template that is converted into bone. The mutated genes encode cartilage and bone extracellular matrix proteins, growth factors, growth factor receptors, intracellular signaling molecules, transcription factors, and other molecules whose functions are needed for bone growth.
Growth Factor Receptor Mutations. The prototype of the skeletal dysplasias is achondroplasia, which is one of a graded series of dwarfing dis-fibroblast undifferenti- orders 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.
heterozygous character- 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.
phenotypes observable There is a very strong correlation between clinical phenotypes and characteristics of an 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 chondrocytes cells that through FGFR3 receptors in chondrocytes in growing bones. This inhibits form cartilage the proliferation of these cells that is necessary for linear growth to occur.
ized by possession of two different forms (alleles) of a particular gene
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.
osteoarthritis a degenerative disease causing inflammation of the joints
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