Achondroplasia

Excerpt

Clinical characteristics: Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, genu varum, kyphosis, and spinal stenosis.

Diagnosis/testing: Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals. In individuals in whom there is diagnostic uncertainty or who have atypical findings, identification of a heterozygous pathogenic variant in FGFR3 by molecular genetic testing can establish the diagnosis. Confirmatory molecular genetic testing may aid in obtaining targeted therapy.

Management: Targeted therapy: Vosoritide, a C-type natriuretic peptide (CNP) analog, can increase height velocity in individuals with achondroplasia and is approved from birth until growth plates close.

Treatment of manifestations: Additional treatment for short stature may include extended limb lengthening; suboccipital decompression as indicated for signs and symptoms of craniocervical junction compression; management of hydrocephalus per neurosurgeon; treatment of restrictive pulmonary disease per pediatric pulmonologist; routine immunizations to prevent respiratory disease; adenotonsillectomy, positive airway pressure, and, rarely, tracheostomy to correct obstructive sleep apnea; aggressive management of frequent otitis media including long-lasting pressure-equalizing tubes for middle ear dysfunction; speech therapy; evaluation and treatment by an orthopedist if progressive bowing of the legs arises; spinal surgery may be needed for severe, persistent kyphosis; surgery to correct spinal stenosis in symptomatic adults; standard treatments for obesity; modification in the school and work setting to optimize function; support in socialization and school adjustment.

Surveillance: Infants and children should be seen at a minimum of every six to 12 months. Monitor height, weight, and head circumference using growth curves standardized for achondroplasia; neurologic examinations monitoring for signs of cervical myelopathy; evaluation of developmental milestones throughout infancy and childhood using achondroplasia-specific standards; assess for manifestations of restrictive pulmonary disease throughout infancy; monitor for signs and symptoms of sleep apnea; follow-up hearing evaluation by age approximately one year and then annually through early childhood; assess for middle ear problems throughout childhood; clinical assessment for bowed legs and kyphosis, with radiographic evaluation and referral to an orthopedist if necessary. Adults should be seen every three to five years. In adults, clinical history and neurologic examination to screen for spinal stenosis; assessment of pain; monitor for hearing loss; assess for signs/symptoms of obstructive sleep apnea; monitor blood pressure; track weight and counsel regarding obesity; and discuss social adjustment at each visit.

Agents/circumstances to avoid: Rear-facing car seats should be used as long as possible to avoid injury from motor vehicle accident. Automatic baby swings should also be avoided because of head and neck movement in the swings. Avoid soft-back infant seats and front carriers without a firm back to prevent kyphosis. Avoid activities in which there is risk of injury to the craniocervical junction, such as collision sports; use of a trampoline; diving from diving boards; vaulting in gymnastics; and hanging upside down from the knees or feet on playground equipment.

Pregnancy management: Pregnant women with achondroplasia must undergo cesarean section delivery because of small pelvic size. A consultation with a pulmonologist is recommended in early pregnancy due to slightly increased risk of respiratory failure.

Genetic counseling: Achondroplasia is inherited in an autosomal dominant manner. Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as the result of a de novo pathogenic variant. Approximately 20% of individuals with achondroplasia have at least one parent with achondroplasia. If both parents are of average stature, the risk to sibs of a proband of having achondroplasia is very low but appears to exceed that of the general, comparable population because of the possibility of parental gonadal mosaicism. If an individual with achondroplasia has a reproductive partner of average stature, each child has a 50% chance of having achondroplasia. If an individual with achondroplasia has a reproductive partner with achondroplasia, each child has a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a life-limiting condition). If an individual with achondroplasia has a reproductive partner with a different dominantly inherited skeletal dysplasia, each child has a 25% chance of having average stature, a 25% chance of having the same skeletal dysplasia as the father, a 25% chance of having the same skeletal dysplasia as the mother, and a 25% chance of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. Once the FGFR3 pathogenic variant has been identified in a family member with achondroplasia, prenatal and preimplantation genetic testing are possible.