Achondroplasia

Achondroplasia is a type of genetic disorder that is a common cause of dwarfism. People with this condition have short stature, usually reaching a full adult height of around 4’0″ (1.2 meters).

Incidence and Prevalence
This condition occurs at a frequency of about 1 in 25,000 to 1 in 40,000 births. Achondroplasia also occurs in all races with equal frequency in males and females.

Clinical Features

Clinical features of the disease:
nonproportional dwarfism (short stature)
shortening of the proximal limbs (termed rhizomelic shortening)
short fingers and toes
a large head with prominent forehead
small mid-face with a flattened nasal bridge
spinal kyphosis (convex curvature) or lordosis (concave curvature)
varus (bowleg) or valgus (knock knee) deformities
frequently have ear infections (due to Eustachian tube blockages), sleep apnea (which can be central or obstructive), and hydrocephalus
Causes

The disorder is a result of an autosomal dominant mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation. FGFR3 normally 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 needs to be present for the disorder to occur. Therefore, a person with achondroplasia has a 50% chance of passing on the gene to their offspring, meaning that there will be a 50% chance that each child will have achondroplasia. Since two copies are fatal, if two people with achondroplasia have a child, there’s a 25% chance of it dying shortly after birth, a 50% chance the child will have achondroplasia, and a 25% chance the child will have a normal phenotype. However, in 3 out of 4 cases, people with achondroplasia are born to parents who don’t have the condition. This is the result of a new mutation.

New gene mutations are associated with increasing paternal age (over 35 years). Studies have demonstrated that new gene mutations are exclusively inherited from the father and occur during spermatogenesis (as opposed to resulting from a gonadal mosaicism). 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. Both of these disorders are also caused by a genetic mutation in the FGFR3 gene.

Diagnosis

Achondroplasia can be detected before birth by the use of prenatal ultrasound. A DNA test can be performed before birth to detect homozygosity, where two copies of the mutant gene are inherited, a condition which is lethal and leads to stillbirths.

Radiologic Findings

A skeletal survey is useful to confirm the diagnosis of achondroplasia. Skull films demonstrate a large skull with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and cuboidal, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch. 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.

The diagnosis can be made on 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.

Treatment

Growth hormone (GH) therapy has been proposed as a possible treatment for the short stature of achondroplasia. However, the people who participated in the studies on the subject have not yet reached adult size, so this type of therapy has unknown results.

Early experience with surgical limb lengthening procedures resulted in a high incidence of complications, but recent experiences have improved results considerably.

New animal studies have demonstrated efficacy of parathyroid hormone-related peptide (PTHrP) replacement.