Many different genetic conditions can affect the skeletal system. Mutations can occur in genes that influence the development of collagen, fibroblast growth factor receptors, lysosomal enzymes and other substances in the body. Some of these disorders occur sporadically as the result of a new gene mutation, while others are inherited from parents who are carriers of--or affected with--the same condition.
Connective Tissue Disorders
Connective tissue disorders are inherited conditions that impair the development of bones, teeth, skin and organ tissues. Many connective tissue disorders are caused by mutations in genes responsible for the formation of collagen, one of the main building blocks of bone.
One example of a connective tissue disorder is osteogenesis imperfecta (OI). People with OI suffer multiple bone fractures, and may also have short stature, abnormal tooth development, hearing loss and other health problems. There are seven types of OI, with different inheritance patterns. Six are inherited in an autosomal dominant manner, and one is autosomal recessive. An autosomal dominant condition is one in which a person needs only one copy of a gene mutation to develop the condition. Each child of a parent with an autosomal dominant condition has a 50 percent chance of inheriting the gene mutation and, therefore, the condition. Some people with no family history of an autosomal dominant condition develop the condition as the result of a new, spontaneous gene mutation. An autosomal recessive condition is one in which a person must inherit two copies of a gene mutation--one from each parent--to develop the condition. When both parents are carriers of an autosomal recessive condition, meaning they each carry one copy of a gene mutation, each of their children has a 25 percent chance of inheriting both mutations and developing the condition.
Skeletal Dysplasias
Skeletal dysplasias are conditions in which the bones of the skeleton fail to develop properly, often resulting in short stature and sometimes early death. Many skeletal dysplasias result from mutations in genes responsible for fibroblast growth factor receptors (FGFRs). FGFRs are largely expressed in developing bone, so FGFR abnormalities lead to abnormal bone formation. The most common skeletal dysplasia, caused by a mutation in FGFR3, is achondroplasia. Individuals with achondroplasia have disproportionately short limbs, relatively large heads, spinal stenosis (narrowing of the spinal column) and characteristic facial features. The spinal stenosis can be particularly dangerous, increasing the risk for paralysis and early death from spinal cord compression.
According to a study published in a 2000 issue of "Endocrine Review," more than 90 percent of achondroplasia cases are sporadic and are strongly associated with paternal age. This means that most of the time, neither of the parents of a person with achondroplasia has the condition, and that a new, spontaneous gene mutation in the egg or sperm caused the condition. As a man gets older, the chance that one of his sperm will undergo a mutation that could cause a skeletal dysplasia increases.
Lysosomal Storage Disorders
Lysosomal storage disorders are inherited metabolic diseases that result in the abnormal buildup of various materials in the body's cells. Lysosomes are cell components which contain enzymes that break down various substances. Genetic mutations can cause the enzymes in the lysosomes to not function properly, and then toxic materials can accumulate, causing a progressive disease. Many organ systems can be affected by lyososomal storage disorders, including the skeletal system, central nervous system and heart. According to a 2009 article in the journal "Pediatrics," there are more than 50 known lysosomal storage disorders, with a combined incidence of one case per 1,500 to 7,000 live births.
A subtype of lysosomal storage disorders, mucopolysaccharidosis (MPS) involves the abnormal storage of substances called mucopolysaccharides in the body's cells. There are several types of MPSs, and most are inherited in an autosomal recessive manner. MPS can cause progressive skeletal dysplasia (abnormal growth) of all bones; in the most severe forms, linear growth ceases at about three years of age.
References
- Gene Reviews: Osteogenesis Imperfecta
- "Endocrine Review"; The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasia, Muenke craniosynostosis and Crouzon syndrome with acanthosis nigricans; Z. Vajo, et al.; 2000
- "Pediatrics"; Lysosomal storage disorders in the newborn; O. Staretz-Chacham, et al.; April 2009
