Achondroplasia
Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Achondroplasia is a type of autosomal dominant genetic disorder that is a common cause of dwarfism.
Pathophysiology
Achondroplasia 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 (Homozygous) are fatal, 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 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
Symptoms
- Frequent ear infections (due to Eustachian tube blockages)
- Sleep apnea (which can be central or obstructive)
Physical Examination
General
- Nonproportional dwarfism (short stature)
- Achondroplastic dwarfs have short stature , with an average adult height of 131 cm (4 feet 3.8 inches) for males and 123 cm (4 feet 0.6 inches) for females.
HEENT
- Hydrocephalus may be present
- A large head with prominent forehead
- Small midface or midface hypoplasia
- Flattened nasal bridge
Extremities
- Shortening of the proximal limbs (termed rhizomelic shortening)
- Short fingers and toes
- spinal kyphosis (convex curvature) or lordosis (concave curvature)
- varus (bowleg) or valgus (knock knee) deformities
Laboratory Findings
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. Other indicators of achondroplasia include slow motor movement and low muscle tone (hypotonia). One result of low muscle tone is that walking doesn't occur until between 24 and 36 months. Because of short stature, obesity is often associated with the condition. Children often have middle ear infections (otitis media) because of abnormal drainage of the tube from the middle ear to the throat due to the abnormal skull structure. To help with the drainage many children have a surgical procedure to place tubes in their ears. Because of abnormal skull structure, overcrowding of the teeth occur and malocclusion often results, which makes oral hygiene difficult.
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 vertabral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wingsare 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.
More obvious signs are a prominent forehead, flat nose bridge, protruding jaw, and crowded teeth.
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.
Treatment
At present, there is no actual treatment for achondroplasia.
Although used by those without achondroplasia to aid in growth, growth hormone won't help people with achondroplasia. However, if desired, the controversial surgery (among dwarfs) of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.
References
- Azouz, E. M., Teebi, A. S., Chen, M.-F., Lemyre, E., and P. Glanc. "Achondroplasia, Hypochondroplasia, and Thanatophoric Dysplasia: Review and Update [Bone Dysplasia Series]," Canadian Association of Radiologists Journal 50(3): 185. June 1999. PMID 99334125
- Mueller, Robert F and Ian D. Young. Emery's Elements of Medical Genetics, 11th ed. (2001). ISBN 0-443-07125-X
- Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A., Leder, P. (1996) Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth, Cell, 84, 911-921
- Webster, M.K., Donoghue, D.J. (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia, The EMBO Journal, 15(3), 520-527
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