Diseases

The diagnosis of achondroplasia can be based on the typical physical features, the hallmarks of achondroplasia, evident at birth. Characteristic features are also seen by X-rays, ultrasound, and other imaging techniques. With ultrasound imaging, the diagnosis can sometimes be strongly suspected before birth. The molecular diagnosis of achondroplasia before birth is possible if there is suspicion of the diagnosis or an increased risk (such as when a parent is affected by achondroplasia). In families in which both parents have achondroplasia, prenatal diagnosis may be particularly useful, the aim being to distinguish fatal homozygous achondroplasia (with two copies of the defective gene) from heterozygous achondroplasia (with one copy of the achondroplasia gene) from normal. Diagnosis before birth is accomplished by examining cells obtained by chorionic villus sampling (CVS) or amniocentesis.

Achondroplasia is inherited as an autosomal dominant trait whereby only a single copy of the abnormal gene (mutation) is required to cause achondroplasia. The gene for achondroplasia is fully penetrant, meaning that everyone who possesses it has achondroplasia. No one with the gene escapes achondroplasia. However, there is some variation in expression of the gene, meaning that children with achondroplasia are not carbon copies of each other, although they may look alike to the untutored eye. In only about an eighth of cases is the gene inherited from a parent who has achondroplasia. Rather, about seven-eighths of cases are due to a new mutation (a new change in the gene). This means that most cases of achondroplasia occur sporadically (out of the blue) and are the result of a new mutation in a sperm or ovum of one of the normal- appearing parents. The chance of a new mutation rises with the age of the father. As early as 1912 it was noted that sporadic (new) cases were more often last-born than first-born children. This fits with the fact that the chance of an achondroplastic birth has been shown to increase with paternal age (age of the father).

Achondroplasia is a distinctive condition that usually can be noted at birth.

• The baby with achondroplasia has a relatively long, narrow torso (trunk) with short extremities (arms and legs) and a disproportionate shortening of the proximal (near the torso) segments of the limbs (the upper arms and thighs).
• There is a typically large head with prominence of the forehead (frontal bossing), underdevelopment (hypoplasia) of the midface with cheekbones that lack prominence, and a low nasal bridge with narrow nasal passages.
• The baby's fingers appear short and the ring and middle fingers may diverge, giving the hand a trident (three-pronged) appearance. Most joints can extend more than normal. For example, the knees can hyperextend beyond the normal stopping point. Not all joints are lax in this way. To the contrary, extension and rotation of the elbow are abnormally limited. Hip extension also tends to be limited.
• At birth there is often prominence of the mid-to-lower back with a small gibbus (a hump). With walking, the hump goes away and a pronounced sway (lordosis) of the lumbar region (the lower back) becomes apparent. The lumbar lordosis is persistent into adulthood. The legs are bowed (genu varum).
• The baby exhibits some decrease in muscle tone (hypotonia). Because of the large head, especially compared to rest of the body, and the decreased muscle tone, the child with achondroplasia will run "behind schedule" in reaching the usual motor developmental milestones. The schedule to which an achondroplastic child's development should be compared is not that for all children in the general population, but rather the growth charts and timetable followed by children with achondroplasia.
• Intelligence is generally normal in patients with achondroplasia. Enlargement of the brain (megalencephaly) is common and normal with achondroplasia.

Children and adults with achondroplasia can lead normal lives provided they receive attentive, informed care by their physicians and parents. Considerations in monitoring children with achondroplasia include careful measurements of growth (length/height and weight) and head circumference using curves specially standardized for those with achondroplasia. Knowledgeable pediatric care and periodic orthopedic and neurologic examinations are critical. When special problems complicate achondroplasia, prompt and expert intervention is important. For example:

• The foramen magnum (the large opening under the skull) may need to be surgically enlarged in cases of severe narrowing (stenosis) and compression of the spinal cord. When this opening is too narrow, the blood vessels and nerves are compressed, which can lead to central apnea (loss of breathing control). This is responsible for the risk of sudden death in infants (SIDS) with achondroplasia. The risk of sudden death for infants with achondroplasia is 2% to 5%.
• The back of individuals with achondroplasia can develop a marked sway (lordosis) to the lower back while abnormalities in the mid-back may cause a small hump (kyphosis) in infancy and compression of the spinal cord in adolescence. The spinal cord compression can require surgery to decompress it. Spinal stenosis is the most common medical complication of achondroplasia seen in adulthood.
• Orthopedic procedures may be performed for lengthening of the limb bones and correction of bowed legs (usually after full growth has been achieved).
• Surgery (lumbar laminectomy) is also indicated when spinal stenosis (narrowing) causes symptoms, which tends to be evident in young adults.
• Disproportion between the brain and the base of the skull can sometimes result in hydrocephalus ("water on the brain") which needs to be promptly detected and treated by placement of a shunt to drain the excess fluid.
• The large head with achondroplasia increases the chance of bleeding within the baby's head during vaginal delivery. This should be taken into account in planning the birth and postnatal care, and Cesarean delivery (C-section) may be recommended for a fetus with achondroplasia. The brainstem (which contains a center for controlling respiration) may be compressed in achondroplasia and contribute to abnormal breathing.
• Pregnant women with achondroplasia should have their babies delivered by cesarean section, due to their characteristically small pelvis, and high risk of birth related trauma.
• Middle ear infections (otitis media) are frequent and can lead to mild to moderate hearing loss. Therefore, ear infections should be readily suspected and promptly and fully treated with antibiotics and/or ear tubes.
• Dental crowding is also common. Teeth should be straightened and, if necessary, removed to alleviate this problem.
• Control of obesity is essential, and obesity can be a significant problem in people with achondroplasia. The excessive weight gain usually occurs during childhood. When obesity is present, the back and joint problems that are characteristic of this condition worsen in severity. The child with achondroplasia must not be allowed to become overweight. Adults with achondroplasia should also monitor and control their weight.
• Treatment with human growth hormone, which is still considered experimental, has been preliminarily reported to increase the growth rate after treatment, but studies have not yet demonstrated that adult height is increased by this treatment.

Achondroplasia is caused by mutations in the FGFR3 gene which codes for a protein (fibroblast growth factor receptor 3) that is important for the maintenance of bone and brain tissues. Two specific mutations in this gene are responsible for almost all cases of achondroplasia. These mutations limit the process of ossification, or the formation of bone from cartilage. The FGFR3 gene is located on the short (p) arm of chromosome 4 in chromosome band 4p16.3.

Although most children with achondroplasia do not have an achondroplastic parent but have a new mutant gene for achondroplasia, they can still transmit the gene to their children, and the risk for passing that gene down to a child is 50% in each pregnancy.

People with achondroplasia sometimes have children together. If so, each parent has a 50:50 chance of passing on the gene. Thus, with each conception, there is a 25% chance for an average-size child, a 50% chance for a child (like them) with achondroplasia and a 25% chance for a conception with two achondroplasia genes. The combined presence of two genes for achondroplasia (called homozygous achondroplasia) causes a grievous skeletal disorder that leads to early death from breathing failure due to constriction by a tiny chest cage and neurologic problems from hydrocephalus.

Achondroplasia is a genetic (inherited) condition that results in abnormally short stature and is the most common cause of short stature with disproportionately short limbs. The average height of an adult with achondroplasia is 131 cm (52 inches, or 4 foot 4 inches) in males and 124 cm (49 inches, or 4 foot 1 inch) in females. Although achondroplasia literally means "without cartilage formation," the defect in achondroplasia is not in forming cartilage but in converting it to bone, particularly in the long bones. Achondroplasia is one of the oldest known birth defects. The frequency of achondroplasia is estimated to range from about 1 in 10,000 births in Latin America to about 12 in 77,000 in Denmark. An average figure worldwide is approximately 1 in 25,000 births.