Causes of Hypochondroplasia
In some cases, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history of the disorder. According to researchers, such cases typically represent new (sporadic) genetic changes (mutations) that may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutations). Investigators have noted increased age of the father (advanced paternal age) in some instances of apparently sporadic hypochondroplasia.

Familial cases of the disorder have also been reported. In such instances, the disorder has autosomal dominant inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.

Researchers indicate that hypochondroplasia often appears to result from specific mutations of a gene known as "fibroblast growth factor receptor-3" (FGFR3). The FGFR3 gene is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered. Therefore, chromosome 4p16.3 refers to band 16.3 on the short arm of chromosome 4.

Researchers also have found that different mutations of the same gene (i.e., FGFR3) may cause achondroplasia, indicating that hypochondroplasia and achondroplasia are allelic disorders. (An allele is one of two or more alternative forms of a gene that may occupy a particular chromosomal location.) Achondroplasia is a more severe form of short-limbed dwarfism that may be characterized by certain features similar to those seen in hypochondroplasia. (For further information, please see the "Related Disorders" section of this report below.)

Genetic analysis has revealed that some individuals with hypochondroplasia do not have currently identified mutations of the FGFR3 gene. In such cases, researchers suggest that the disorder may result from mutations of different disease genes (genetic heterogeneity) or, possibly, from other, currently undetected FGFR3 gene mutations. Further research is necessary to learn more about the underlying genetic causes of hypochondroplasia.