Achondroplasia

Achondroplasia is a genetic disorder that results in dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. Other features include an enlarged head and prominent forehead. It does not affect intelligence.EDAR (EDAR hypohidrotic ectodermal dysplasia) Achondroplasia is a genetic disorder that results in dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. Other features include an enlarged head and prominent forehead. It does not affect intelligence. Achondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. In about 80% of cases, this occurs as a new mutation during early development. In the other cases, it is inherited from one's parents in an autosomal dominant manner. Those with two affected genes do not typically survive. Diagnosis is generally based on symptoms but may be supported by genetic testing if uncertain. Treatments may include support groups and growth hormone therapy. Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required. Life expectancy of those affected is about 10 years less than average. The condition affects about 1 in 27,500 people. Rates are higher in Denmark and Latin America. The shortest known adult with the condition is Jyoti Amge at 62.8 centimetres (2 ft 0.7 in). Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3) gene. This gene is mainly responsible for making the protein, fibroblast growth factor receptor 3. This protein contributes to the production of collagen and other structural components in tissues and bones. When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height. In normal development FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. The effect is genetically dominant, with one mutant copy of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth (known as a lethal allele). A person with achondroplasia thus has a 50% chance of passing dwarfism to each of their offspring. People with achondroplasia can be born to parents that do not have the condition due to spontaneous mutation. Achondroplasia can be inherited through autosomal dominance. In couples where one partner has achondroplasia there is a 50% chance of passing the disorder onto their child every pregnancy. In situations where both parents have achondroplasia there is a 50% chance the child will have achondroplasia, 25% chance the child will not, and a 25% chance that the child will inherit the gene from both parents resulting in double dominance and leading to death. Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis; it is theorized that oogenesis has some regulatory mechanism that prevents the mutation from being passed on in females. The frequency of mutations in sperm leading to achondroplasia increase in proportion to paternal age, as well as in proportion to exposure to ionizing radiation. The occurrence rate achondroplasia in the children of fathers over 50 years of age is 1 in 1875 compared to 1 in 15,000 in the general population. There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia. Achondroplasia can be detected before birth by prenatal ultrasound. A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths. Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia. Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.