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Achondroplastic Dwarfism by pengxiuhui


									 Achondroplastic Dwarfism

           Kyle Suddreth

          Medical Genetics

R. Ostrowski, PhD. & L. McNally, M.S.

        Achondroplastic dwarfism is the most common form of short-limbed dwarfism. Subjects

with this disorder have very short stature and average about 4 feet in height. Other characteristics

include a large prominent forehead and a small mid-face. The chances of its occurrence ranges

from 1 in every 15,000 to 1 in every 40,00 live births. When inherited it acts as an autosomal

dominant gene, but roughly 80% of all cases are due to a new mutation. People with

achondroplasia run a higher risk for certain health problems, but in general live normal healthy

lives. If any problems do arise they can be treated and it is even possible to increase the stature of

people with achondroplasia using specific treatments.

        A number of disorders can cause extremely short stature in the afflicted person. Among

these are groups involving primary bone disorders, in which the bones do not grow and develop

as they would in a normal person. Of these conditions, also known as skeletal dysplasias or

chondrodystrophies, achondroplasia is the most common. Its occurrence varies greatly between

different studies due to misdiagnosis, but it generally occurs in 1 out of every 15,000 to 1 out of

every 40,000 live births (Francomano, 1998). Currently there are approximately 10,000

individuals residing in the United States that are afflicted by achondroplasia (Human Growth


        The gene that causes achondroplasia is inherited as an autosomal dominant, which means

that only one parent needs to pass the gene on for their offspring to have the disorder. However,

about seven-eighths of all reported cases are due to a new mutation. The recurrence risk of

achondroplasia in future siblings of achondroplastic children afflicted due to a spontaneous

mutation in parents of normal stature is extremely low; about 2 hundredths of a percent

(McKusick et al., 1996). If a person has achondroplasia they must have a heterozygous genotype

carrying one normal gene and one achondroplasia gene, because homozygous babies carrying two

achondroplasia genes are spontaneously aborted due to major health complications. Since both

parents will contribute one gene to their offspring, if one parent has achondroplasia there is a 50%

chance that any child born will be heterozygous and have achondroplasia. If both parents have

achondroplasia there is still a 50% chance of an achondroplastic child being born, and there is

only a 25% chance that their offspring could inherit two normal genes. The other 25% of their

children are homozygous for achondroplasia and are spontaneously aborted. Therefore the

probability of two achondroplastic parents having a child with achondroplasia is about 66%

(Human Growth Foundation).

        The actual gene that causes achondroplasia is designated FGFR3, which stands for

fibroblast growth factor receptor 3. It is located on the p arm of the fourth chromosome in locus
16.3; 4p16.3. Over 99% of all cases of achondroplasia are caused by a G to A transition at

nucleotide 1138 and a G to C transversion at the same nucleotide. Both of these result in the

same amino acid substitution. The FGFR3 gene has been shown to negatively affect bone growth

in studies, so it can be determined that the mutations causing achondroplasia are gain-of-function

mutations that activate the negative growth control of the FGFR3 pathway (McKusick et al.,


Phenotypic Milestones and Diagnostic Techniques

         Achondroplasia is a very distinctive disease with multiple phenotypes that will or may

appear. Many of the characteristic features of achondroplasia are apparent at birth, which makes

it easy to recognize and diagnose. If there is any doubt to whether or not a child has the disorder

molecular genetic testing of the FGFR3 gene can be performed. The test is more than 99%

accurate, but is normally not necessary. The shortened stature of achondroplastic dwarves is due

to rhizomelic or proximal shortening of the limbs (see Figure 2). Elbow extension and rotation is

limited and hyperextensibility of the knees and many other joints is normal (Francomano, 1998).

As an infant the legs are straight, however, when a child begins to walk the legs will take on a

valgus or knock kneed position. Later on as the child continues to walk and develop, the legs

take on a varus or bow legged appearance (Greenberg Center for Skeletal Displasias).

The typical facial features include a large head with a prominent forehead, a small prominent jaw

which can cause dental crowding, small mid-face with flat nasal bridge, and narrow nasal

passages (see Figure 1). The narrow nasal passages combined with Eustachian tube dysfunction

leads to frequent ear infections, which can lead to hearing loss if treated improperly.

         Infants and children with the disorder may also face respiratory problems. These

problems can be central or obstructive in origin. Problems that are central in origin are due to

foramen magnum compression around the spinal cord, while problems obstructive in origin are

caused by the narrowed nasal passages. The signs pointing toward airway obstruction may

include snoring, sleeping with the neck in a hyperextended position, and apnea or sudden, short
cessation of respiration. A sleep study may be done to determine the cause of airway restriction if

any of these symptoms are present (Greenberg Center for Skeletal Displasias). Approximately

7.5% of infants that are afflicted with achondroplasia die in the first year of life from apnea.

Obstructive apnea may result from mid-face hypoplasia while central apnea is the result of

brainstem compression around the craniocervical junction (Francomano, 1998).

        At birth a thoracolumbar gibbus, or hump, is present, but gives way to lumbar lordosis, or

curvature of the lumbar region of the spine, as the child learns to walk. Mild to moderate

hypotonia is common and development of motor skills is delayed. Intelligence is almost certainly

normal unless hydrocephalus or other central nervous system complications arise. Disproportion

between the base of the skull and the brain can result in internal hydrocephalus, but

hydrocephalus is also caused by increased intracranial venous pressure due to stenosis or

curvature of the sigmoid sinus at the level of the narrowed jugular foramen. The jugular foramen

is a passage between bones in the neck that contains the jugular vein as it passes through the neck

and into the skull. Megalocephaly, or an unusually large head, can also occur, and it has been

speculated that this is another affect of the gene outside of those present in the skeletal structure

(McKusick et al., 1986). The most common problem that occurs in adulthood is lumbosacral

spinal stenosis. In this condition the lumbar section of the spinal cord is abnormally curved and

the nerve roots are compressed producing neurologic symptoms. Initial symptoms are weakness,

tingling, and pain in the legs, but as the condition worsens pain in the lower back and buttocks

sets in. Diagnosis of this problem is made by administering a neurologic exam, SERs (somatic

evoked responses), and CT or MRI scans (Greenberg Center for Skeletal Displasias). Obesity is

also a major problem in achondroplasia, which can contribute to lumbar stenosis or curvature,

joint problems, and possibly lead to early mortality from cardiovascular complications.

Excessive weight gain is manifest in early childhood, and children with achondroplasia have the

same average weight to height ratio as children of normal stature until they are about 75 cm.
After reaching 75 cm the weight to height ratio for those afflicted with achondroplasia greatly

exceeds that of the general population (Francomano, 1998).


        Individuals with achondroplasia face an increased risk of numerous health problems, but

few are fatal and all can be treated. Many health problems simply require close monitoring to

ensure that they do not become problematic. Standardized growth curves for children with

achondroplasia are readily available to monitor the child’s weight, height, and head

circumference to help determine if problems may occur (Greenberg Center for Skeletal

Displasias). Treatments for common problems such as ear infections and dental crowding are

routine and merely need to be performed before these conditions can cause any permanent

damage. Other problems, however, can be more serious and require surgery. Hydrocephalus is

one of the more serious health problems faced by achondroplastic individuals early in life.

Infants should have the size of their head measured regularly to ensure it is not growing at an

increased rate. If other symptoms or tests indicate that the child has hydrocephalus and

intervention is necessary, a ventriculoperitonial shunt can be placed to relieve the fluidic pressure

on the brain (Greenberg Center for Skeletal Displasias). If an individual with achondroplasia has

respiratory problems a variety of procedures may be performed to alleviate them depending on

their cause. If respiratory problems are caused by the reduced size of the opening in the foramen

magnum applying pressure to the spinal cord then foramen magnum decompression surgery is

performed. Problems caused by narrow nasal passages may be treated using tonsillectomy,

adenoidectomy, or tracheostomy placement (Greenberg Center for Skeletal Displasias). In

childhood, orthopedic problems may arise from abnormal curvature to the spine or the legs. If

these conditions are prevalent in any form a simple brace is normally sufficient to correct the

problem; however, this is normally unnecessary because the majority of cases resolve themselves

in time. When orthopedic problems persist despite treatment, surgery may be necessary to correct

them (Human Growth Foundation, 1996). For adults and adolescents the most common problem
is curvature of the lumbar region of the spine compressing the nerve roots: lumbosacral spinal

stenosis. This can be treated with a neurosurgical procedure called a lumbar laminectomy

(Greenberg Center for Skeletal Displasias).

        Although the short stature does not cause any serious medical problems in achondroplasia

a number of procedures have been tested to help bring patients closer to a normal stature. Human

growth hormone therapy is one of these treatments and involves injection of additional growth

hormones into children with achondroplasia. This treatment was first received with skepticism,

but studies have shown that it does have a positive effect on the growth of the patient, especially

during the first year of its use. The actual usefulness of this treatment is unknown and will not be

determined until patients using it reach their full height. Another treatment for short stature is

surgical limb lengthening. Early attempts at this type of procedure were problematic with

complications including pain, infection, and neurologic and vascular failure due to sudden

lengthening. More recent attempts have had more success, but the procedure is still prone to

certain complications (Francomano, 1998).

        The short stature of people with achondroplasia often leads to social as well as health

difficulties. There are numerous support groups for people with short stature to help them to deal

with these difficulties. The most prominent of these organizations is Little People of America.

This organization and others provide valuable support and advice on health problems, social

issues, disability rights, and other important issues. Suitable clothing and adaptive devices are

also offered to help people with short stature live normal lives (Francomano, 1998).
Figure 1. A group of people with achondroplasia who show all of the phenotypical traits for the

disorder (University of Virginia).

Figure 2. A classic example of the rhizomelic or proximal shortening of the bones associated with

achondroplastic dwarfism (South Bank University).

Francomano, C. A. (1998). Gene Reviews: Achondroplasia. Retrieved from Gene Tests-Gene

     Clinics database on the World Wide Web <> (7/7/02)

Greenberg Center for Skeletal Displasias. Achondroplasia. Retrieved from Johns Hopkins

     University database on the World Wide Web

     <> (7/7/02)

Human Growth Foundation (1996). Achondroplasia. Retrieved from on the World

     Wide Web <> (7/7/02)

McKusick, V. A. et al. (1986). Retrieved from the Online Mendelian Inheritance of Man database

     on the World Wide Web <

     post/Omim/dispmim?100800#DESCRIPTION> (7/7/02)

South Bank University. Retrieved from the South Bank University database on the World Wide

     Web <> (7/7/02)

University of Virginia. Retrieved from the University of Virginia database on the World Wide

     Web <> (7/7/02)

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