Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Achondropasia

Introduction
Achondroplasia is the most common skeletal dysplasia with an incidence of 1/15,000 to 1/77,000 live births. It is an autosomal dominant disorder with complete penetrance and occurs in all ethnic groups. Eighty to 90% of cases are new mutations and advanced paternal age has been associated with de novo cases. An affected individual has a 50% risk to transmit the disorder to his/her child. The recurrence risk for two unaffected parents is less than 1%, although instances of gonadal mosaicism have been reported.
If both parents are affected, there is a 25% risk for their child(ren) to be homozygous for the achondroplasia allele, resulting in a much more severe phenotype that is usually lethal within the first year of life.
Achondroplasia is caused by a mutation in fibroblast growth factor 3 (FGFR3) on chromosome 4, causing a defect in the maturation of chondrocytes in the cartilage growth plate. Direct mutation analysis is available for prenatal diagnosis or confirmation of equivocal cases.
Clinical Features
The clinical features of achondroplasia include disproportionate short stature with a normal trunk length and rhizomelic shortening of the extremities, macrocephaly, frontal bossing with a depressed nasal bridge, bowing of the lower extremities, trident hands, lumbar lordosis, infantile hypotonia with motor delays, and normal intelligence. Average adult height is 51 inches (130 cm) in males and 48.5 inches (123 cm) in females. The skeletal features of achondroplasia may lead to neurologic, respiratory, orthodontic, skeletal, and psychosocial problems.
Common Medical Complications
Neurologic complications include cervicomedullary junction compression, communicating hydrocephalus, spinal stenosis, and infantile hypotonia. The foramen magnum is relatively small in achondroplasia and may lead to a variety of neurologic abnormalities including apnea, paraparesis or quadriparesis, hydrocephalus, or sudden death. Therefore, it is critical to provide adequate neck support during the first year of life and to perform a thorough neurologic examination at each medical encounter.
Infants should be referred to a pediatric neurosurgeon if there is any evidence of central apnea, reflex asymmetry, extreme hypotonia, or early hand preference. Only on very rare occasions is decompression of the foramen magnum necessary.
Megalencephaly with enlarged ventricles is common in achondroplasia due to anatomic abnormalities of the skull, however, symptomatic hydrocephalus requiring shunting is uncommon. Nonetheless, the head circumference should be measured monthly during the first year of life. A head ultrasound should be obtained if there is an unusually large fontanel, rapidly increasing head circumference, or other signs or symptoms of increased intracranial pressure develop, with referral to a pediatric neurosurgeon as necessary.
Spinal cord compression due to lumbosacral spinal stenosis is the most common neurologic complication of adolescents and adults with achondroplasia. It is exacerbated by lumbar lordosis and may present with a variety of neurologic signs and symptoms including weakness, paresthesias, pain, claudication, urinary or fecal retention or incontinence, abnormal deep tendon reflexes, or sensory loss. It is usually treatable with laminectomy if diagnosed early. Therefore, a thorough neurologic history and examination is required at each medical encounter.
Maneuvers which may prevent or delay the development of this complication include discouragement of early sitting in infancy, avoidance of curled up positions, avoidance of gymnastics and contact sports, and correct posture. Epidural or spinal anesthesia is contraindicated.
The midface hypoplasia, short cranial base, and small foramen magnum characteristic of achondroplasia can lead to a number of respiratory complications including apnea, upper airway obstruction, otitis media, sinusitis, and dental malocclusion. Upper airway obstruction may manifest as excessive sweating, snoring, retractions, compensatory sighs, or choking.
The development of any of the above signs should be evaluated with sleep studies, sensory evoked responses, and/or MRI. Nasal CPAP, tonsillectomy and adenoidectomy, and weight loss have been beneficial in reducing upper airway obstruction.
There is an increased incidence of serous otitis media in achondroplasia due to short eustachian tubes. Therefore, an ear examination should be done with each upper respiratory infection and otitis media should be treated as necessary. Hearing should be tested annually and a formal speech evaluation should occur by two years of age. Sinusitis is also common in achondroplasia due to midface hypoplasia. It should strongly be considered in the differential diagnosis of the febrile child and treated if present.
Other skeletal complications of achondroplasia include low thoracic/high lumbar gibbus, lumbar lordosis, external rotation of the hips, joint stress, leg bowing, disc herniation, osteophyte formation, and short stature. The gibbus abnormality is avoidable by avoiding curled up positions and providing proper back support throughout life. The lumbar lordosis can be minimized by emphasizing correct posture beginning in early childhood. External rotation of the hips usually resolves spontaneously within six months of weight bearing. Leg bowing occurs due to fibular overgrowth but usually does not require treatment. If it interferes with walking, an orthopedic referral may be indicated.
Other Medical Considerations
Short stature is the most significant problem for people with achondroplasia. Achondroplasia growth charts are available. Experimental limb lengthening procedures and growth hormone therapy have been tried in some patients, however, most people learn to adapt their environment to foster independence. Adaptations include lowering faucets and light switches, use of a step stool to keep feet from dangling when sitting, use of step stools, an extended wand for toileting, and adaptations of toys for short limbs.
Obesity occurs in approximately one-third of patients with achondroplasia and often develops by mid to late childhood. It may exacerbate lumbar lordosis, spinal stenosis, obstructive apnea, and other respiratory problems. A person with achondroplasia may only need half of the calories of an average-size individual of the same age. Nutritional counseling and regular exercise should begin in early childhood.
While achondroplasia does not affect fertility, pregnant women are considered high risk. Respiratory compromise is common during the third trimester and baseline pulmonary function studies should be done before pregnancy to aid in evaluation and management. Pelvic insufficiency necessitates Cesarean section under general anesthesia since the epidural approach is contraindicated.

Conclusion

The vast majority of people with achondroplasia have normal intelligence and lead healthy, independent, and productive lives. However, the presence of short stature can cause a number of psychosocial problems. Many families find it beneficial to interact with other families and children with achondroplasia through local and national support groups. Two national support groups are:

Little People of America
P.O. Box 9897
Washington, D.C. 20026
(888) LPA-2001
or (214) 388-9576

The Billy Barty Foundation
929 W. Olive Ave.,
Suite C
Burbank, CA 91506
(818) 953-5410

Reference:
Health Supervision for Children With Achondroplasia. Committee on Genetics, Pediatrics 95 (3): 443-451, 1995

Contributed by Joanne Milisa, MS (NM) and Peggy Pearson, MD (AZ)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table of Contents:
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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