Achondroplasia

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Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

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Synonyms and Keywords: ACH; Achondroplastic dwarfism

Overview

Achondroplasia is known as one of the most common forms of skeletal dysplasia that causes dwarfism. It is a rare genetic disorder characterized by specific features such as:

• Short stature (usually shorter than 4 feet 6 inches)
• An unusually large head (macrocephaly) with a notable forehead (frontal bossing) and flat (depressed) nasal bridge;
• Short arms
• Short legs
• Short hands with fingers that represent a “trident” or three-pronged position during extension
• Prominent abdomen (due to specific curve of the spine)
• Prominent buttocks (due to inward curve of the spine)

Achondroplasia occurs due to a specific changes (mutations) of a gene known as fibroblast growth factor receptor 3 (FGFR3).

Achondroplasia appears to affect males and females equally. The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births.

Historical Perspective

The noun dwarf stems from Old English dweorg, originally referring to a being from Germanic mythology—a dwarf—that dwells in mountains and in the earth, and is associated with wisdom, smithing, mining, and crafting. Nowadays. the terms "dwarf", "little person", "LP", and "person of short stature" are now generally considered acceptable by most people affected by these disorders. However, the plural "dwarfs" as opposed to "dwarves" is generally preferred in the medical context, possibly because the plural "dwarves" was popularized by author J.R.R. Tolkien, describing a race of characters in his The Lord of the Rings books resembling Norse dwarfs. "Midget", whose etymology indicates a "tiny biting insect", came into prominence in the mid-19th century after Harriet Beecher Stowe used it in her novels Sunny Memories of Foreign Lands and Old Town Folks where she described children and an extremely short man, respectively. Later some people of short stature considered the word to be offensive because it was the descriptive term applied to P. T. Barnum's dwarfs used for public amusement during the freak show era. It is also not considered accurate as it is not a medical term or diagnosis, though it is sometimes used as a slang term to describe those who are particularly short, whether or not they have dwarfism. Meanwhile, the specific term for describing a person with notable shorter stature has historically been ambiguous, and has developed euphemistically over the past centuries.

In art, literature, and movies, dwarfs are rarely depicted as ordinary people who are very short but rather as a species apart. Artistic representations of dwarfism can be found on Greek vases and other ancient artifacts, including ancient Egyptian art in which dwarfs are likely to have been seen as a divine manifestation, with records indicating they could reach high positions in society.

- 3000 BC in ancient Egypt: The typical depiction of a dwarf in Egyptian art is pragmatic because we can found a normally grown torso and head, but visibly shortened and slightly bent arms and legs. Those similarity point to achondroplasia and hypochondroplasia as the conditions responsible for the dwarfism of the individual.

Depictions of dwarfism are also found in European paintings and many illustrations. Many European paintings (especially Spanish) of the 16th–19th centuries depict dwarfs by themselves or with others.

Velázquez – Bufón don Sebastián de Morra (Museo del Prado, c. 1645) image courtesy of wikipedia

Classification

Pathophysiology

Causes

Differentiating Achondroplasia from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications, and Prognosis

Diagnosis

Treatment

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.
• Spinal kyphosis (convex curvature of the spine) or lordosis (concave curvature of the spine)

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
• 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.

• Shortening of tubular bones with a normal shaft caliber
• Short phalanges
• Squared iliac wings and narrow sacroiliac notch: champagne glass
• Fingers widely opposed and equal length: trident hands
• Enlarged skull vault and mandible
• Small foramen magnum
• Decreased lumber interpediculate distance and narrow spinal canal

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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

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