STUDY OF THE DISEASE

ACHONDRAPLASIA
I. Definition and Etiology
Achondroplasia is a form of short-limbed dwarfism. The word achondroplasia literally means "without cartilage formation." Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. However, in achondroplasia the problem is not in forming cartilage but in converting it to bone (a process called ossification), particularly in the long bones of the arms and legs. Achondroplasia is similar to another skeletal disorder called hypochondroplasia, but the features of achondroplasia tend to be more severe.

II. Etiology
Achondroplasia is the most common chondrodysplasia occurring, with the frequency of 1 in 15,000-40,000 worldwide. The prevalence rate has been calculated as 0.5-1.5 cases per 10,000 births and the mutation rate 1.72-5.57 x 10-5 per gamete per generation. The disorder is inherited in an autosomal dominant manner with complete penetrance - but over 80% of cases are spontaneous mutations. Incidence increases with paternal age. Mutations in the FGFR3 gene cause achondroplasia. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. Two specific mutations in the FGFR3 gene are responsible for almost all cases of achondroplasia. Researchers believe that these mutations cause the FGFR3 protein to be overly active, which interferes with skeletal development and leads to the disturbances in bone growth seen with this disorder. Achondroplasia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. About 80 percent of people with achondroplasia have average-size parents; these cases result from new mutations in the FGFR3 gene. In the remaining cases, people with achondroplasia have inherited an altered FGFR3 gene from one or two affected parents. Individuals who inherit two altered copies of this gene typically have a severe form of achondroplasia that causes extreme shortening of the bones and an underdeveloped rib cage. These individuals are usually stillborn or die shortly after birth from respiratory failure.

III. Manifestations
All people with achondroplasia have short stature. The average height of an adult male with achondroplasia is 131 centimeters (4 feet, 4 inches), and the average height for adult females is 124 centimeters (4 feet, 1 inch). Characteristic features of achondroplasia include an average-size trunk, short arms and legs with

particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head (macrocephaly) with a prominent forehead. Fingers are typically short and the ring finger and middle finger may diverge, giving the hand a three-pronged (trident) appearance. People with achondroplasia are generally of normal intelligence.

IV. Health Complications

Health problems commonly associated with achondroplasia include episodes in which breathing slows or stops for short periods (apnea), obesity, and recurrent ear infections. In childhood, individuals with the condition usually develop a pronounced and permanent sway of the lower back (lordosis) and bowed legs. Some affected people also develop abnormal front-to-back curvature of the spine (kyphosis) and back pain. A potentially serious complication of achondroplasia is spinal stenosis, which is a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord. Spinal stenosis is associated with pain, tingling, and weakness in the legs that can cause difficulty with walking. Another uncommon but serious complication of achondroplasia is hydrocephalus, which is a buildup of fluid in the brain in affected children that can lead to increased head size and related brain abnormalities.

V. Prognosis
Life expectancy is normal in the majority of cases. Overall cognitive scores are normal but some children may exhibit mild deficits in visual-spatial tasks. Final height varies between 80 cm and 150 cm. Death in the first year of life can occur due to pressure on the spinal cord, caused by abnormalities at the craniocervical junction. The mortality rate in achondroplastic infants is 2-5%.

VI. Prevention
Genetic counseling may be helpful for prospective parents when one or both have achondroplasia. However, because achondroplasia most often develops spontaneously, prevention is not always possible. If there is a family history of achondroplasia and you plan to have children, you may find it helpful to speak to your health care provider. Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.

VII. Treatment and Management A. Medical Management

The availability of somatotropin (recombinant human growth hormone) has revolutionized the treatment of short stature. Growth hormone is currently being used to augment the height of patients with achondroplasia. The greatest acceleration in growth velocity is seen during the first year of treatment and in those with the lowest growth velocities before treatment. However, no long-term studies exist to determine final height, nor do any randomized controlled studies exist to justify prolonged treatment with growth hormone in patients with short stature. A young age at initiation of therapy (1-6 y) is recommended for maximum benefits.

B. Surgical Management

Spinal canal stenosis

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Wide, multilevel laminectomies extending to the pedicles and lateral recesses with foraminotomies may be necessary. Extradural removal of herniated disc material is performed as necessary. The length of decompression usually extends from the lower thoracic spine to the sacrum to prevent recurrence. Maintaining the integrity of facet joints is necessary to prevent postlaminectomy instability. If instability does occur, anterior fusion may be necessary. The extent of the laminectomies is important to obtain successful results. It should be 3 levels cephalad to the proximal extent of compression, distal to the second sacral level, and lateral to the facet joints. The results of this more extensive approach are encouraging.

Thoracolumbar kyphosis
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Treatment of thoracolumbar kyphosis consists of mere observation for the child who has not begun to walk because spontaneous resolution frequently occurs. Reports exist that demonstrate the efficacy of early prohibition of unsupported sitting. If wedging of the apical vertebra persists after independent ambulation (typically wedging of 12th thoracic or 1st lumbar vertebra), an extension-type thoracolumbosacral orthosis should be used. If the thoracolumbar kyphosis persists and measures greater than 30 at age 5 years, then surgery should be performed. Surgery is usually in the form of combined anterior and posterior fusion. Posterior instrumentation generally is not recommended, due to the narrow canal size. Any instrumentation placed in the canal, such as hooks or sublaminar wires, is contraindicated due to the marked stenosis and decreased subarachnoid fluid space. If kyphosis is associated with a neurologic deficit such as paraplegia, laminectomy alone is not indicated because it can destabilize the spine further. Treatment should consist of anterior cord decompression with strut grafting and posterior fusion.

Genu varum
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Surgical correction of genu varum may be required. It may be in the form of proximal tibiofibular osteotomy or proximal and distal fibular epiphysiodesis. Osteotomy is performed when rapid correction of symptomatic deformity is required. It can be performed through small incisions without internal fixation, with long-leg cast immobilization for 6 weeks. Limb lengthening Limb lengthening of the upper and lower extremities is promoted in Europe. However, the Little People of America (LPA) and Dwarf Athletic Association of America (DAAA) are generally opposed to these procedures (see Patient Education, below). If lengthening is to be performed, any existing angular deformities should be corrected simultaneously. With the current techniques of distraction osteogenesis, 30 cm of length can be gained. Gradual lengthening of the osteotomy callous (callostasis) or through the epiphyseal plates (chondrodiastasis) can be obtained using monolateral frames or Ilizarov ring fixators. The 6-segment lengthening (femur, tibia, humerus) can be performed as staged procedures in various sequences. A potential exists for major complications during 6-segment lengthening. Neurologic injury has been reported in 35% of procedures. Foot drop, vascular compromise, soft-tissue contractures, loss of motion, knee subluxation, infection, psychological changes, and death have been reported with extensive lengthening procedures.

Foramen magnum decompression (neurosurgery)

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Narrowing of the foramen magnum may result in a variety of neurologic problems in the first several years of life. Significant improvement of severe neurologic symptoms has been reported with foramen magnum decompression and C1 laminectomy. However, prophylactic surgery is not recommended. Ventriculoperitoneal shunts are indicated for patients with rapidly progressive head enlargement, increased intracranial pressures, or neurologic signs and symptoms. Neurosurgery is also indicated for other neurologic abnormalities, such as Chiari malformation.

C. Other Managements

Weight, height and occipitofrontal circumference should be measured in the first year of life. Upper to lower segment ratio should be monitored. Dental treatment for crowding of teeth. Management of frequent middle ear infections. Treatment of obstructive sleep apnoea, eg adenotonsillectomy, weight loss and continuous positive airway pressure. Measures to control obesity should be initiated as appropriate. Growth hormone therapy is still experimental. Anti-inflammatory drugs may be helpful in patients with degenerative joint disease. Delivery of pregnant women should be by Caesarean section.