Achondroplasia

Achondroplasia dwarfism occurs as a sporadic mutation in approximately 85% of cases (associated with advanced paternal age) or may be inherited in an autosomal dominant genetic disorder that is a common cause of dwarfism. If both parents of a child have achondroplasia, and both parents pass on the mutant gene, then it is very unlikely that the homozygous child will live past a few months of its life. The disorder itself is caused by a change in the DNA for fibroblast growth factor receptor 3 which causes an abnormality of cartilage formation. Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3½ inches) for males and 123 cm (4 feet, ½ inch) for females.

The prevalence is approximately 1 in 25,000.

Causes
In normal circumstances, 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.

People with achondroplasia have one normal copy of the fibroblast growth factor receptor 3 gene and one mutant copy. Two copies of the mutant gene are invariably fatal before or shortly after birth. Only one copy of the gene has to be present for the disorder to occur. Therefore, a person with achondroplasia has a 50% chance of passing on the gene to his or her offspring, meaning that there will be a 50% chance that each child will have achondroplasia. Since it is fatal to have two copies (homozygous), if two people with achondroplasia have a child, there is a 25% chance of the child dying shortly after birth, a 50% chance the child will have achondroplasia, and a 25% chance the child will have an average phenotype. People with achondroplasia can be born to parents that do not have the condition. This is the result of a new mutation.

New gene mutations leading to achondroplasia are associated with increasing paternal age (over 35 years old). 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 hinders the mutation from originally occurring in females (although females are still readily able to inherit and pass on the mutant allele). More than 99% of achondroplasia is caused by two different mutations in the fibroblast growth factor receptor 3 (FGFR3). In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution (Bellus et al. 1995, Shiang et al. 1994, Rousseau et al. 1996). About 1% of cases are caused by a G to C point mutation at nucleotide 1138.

There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.

Diagnosis
Achondroplasia can be detected before birth by the use of 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.

Radiologic findings
A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed".

The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.''

Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy.

Treatment
At present, there is no known treatment for achondroplasia, even though the cause of the mutation in the growth factor receptor has been found. Therapies and diagnostic methodologies are likely to be looked into and developed.

Although used by those without achondroplasia to aid in growth, human growth hormone does not help people with achondroplasia. However, if desired, the controversial surgery of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.

Usually, the best results appear within the first and second year of therapy. After the second year of GH therapy, beneficial bone growth decreases. Therefore, GH therapy is not a satisfactory long term treatment.

Epidemiology
Achondroplasia is one of several congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and  thanatophoric dysplasia. This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births. However, another study at the same time found a rate of 1 per 10,000.