Six-month-old girl with dysmorphic appearance referred for genetic evaluation. Child is a product of a fraternal twin pregnancy; born at 41 weeks gestational age. Mother, age 32, received no prenatal care. Paternal age, 41 years.
Large head, unusual facial features, and a disproportionate body noted at birth. Cranial ultrasonogram normal at birth. Motor milestones delayed for a 6-month-old infant.
Well-appearing, happy infant. Weight, 5.5 kg (fifth percentile); height, 60.5 cm (under the fifth percentile). Occipitofrontal circumference, 47.5 cm (1.5 cm greater than 98th percentile). Anterior fontanel large: extends halfway down forehead. Posterior fontanel open. Low nasal bridge with prominent forehead (frontal bossing). Long narrow trunk with short arms and legs. Redundant skin folds on limbs. Short fingers and "trident" hands. Mild lumbar curvature of spine.
Infant is unable to hold her head up when prone. Able to roll back-to-front. Unable to "tripod" or sit without support.
This patient presents with the clinical features seen in infants with achondroplasia (A, B). This genetic syndrome is the most common form of short-limb dwarfism.1,2 It is marked by a large cranium, characteristic facial features, and disproportionate short stature with shortening of the proximal limbs (rhizomelia).1,2-4
WHAT'S YOUR DIAGNOSIS?
ETIOLOGY AND PREVALENCE
Achondroplasia is a genetic syndrome inherited as a Mendelian autosomal dominant disorder with complete penetrance.1 Autosomal dominant disorders are inherited when 1 copy of the different gene is passed on from parent to child or if a denovochange occurs in a person for the first time.
In autosomal dominant syndromes, the gene is located on any of the autosomes (chromosomes 1 to 22), but not on the sex chromosomes (X or Y). The dominant gene that causes achondroplasia is located on chromosome 4 (4p16.3).1,5 About 88% of cases of achondroplasia result from a new dominant mutation in that person. Advanced paternal age (older than 40 years) increases the risk of de novo dominant mutations.1 The syndrome is caused by a change in genetic information for the fibroblast growth factor receptor-3 gene (FGFR3).1,3,4 Prenatal molecular genetic testing is available to detect a mutation in the FGFR3 for high-risk families.5 Prenatal ultrasonography in the third trimester can also assist in making the diagnosis.4,5
Current literature cites achondroplasia in a range of 1:15,000 to 1:40,000 live births.1,5 The average worldwide prevalence is estimated to be 1:25,000 live births. The syndrome occurs equally in both girls and boys; ethnic variation in frequency has been reported.6,7
Characteristic features are present at birth. Hypotonia may be seen in infancy and early childhood. Delayed motor skills seen within the first year of life are attributed to the large cranium and poor muscle tone. There is an increased risk of infant death (from obstructive apnea) or central apnea (from cervical spine abnormalities, such as craniocervical junction compression).1,5 Clinical features of persons with achondroplasia include:
•General: disproportionate short stature. Average adult height in males, 131 ± 5.6 cm; average adult height in females, 124 ± 5.9 cm.
•HEENT: large cranium (macrocephaly), megaloencephaly, prominent forehead (frontal bossing), low nasal bridge, midface hypoplasia, dental malocclusion and crowding.
•Body: small thoracic cage, long narrow trunk.
•Extremities: shortened humeri and femurs (rhizomelia), redundant skin folds on arms and legs, short "trident" hands (ring and middle fingers diverge, giv- ing the hand a 3-pronged [trident] appearance), limit- ed elbow and hip extension, hyperextensibility of the knees, bowing of the legs (genu varum).
•Musculoskeletal: exaggerated lumbar lordosis in ambulators, lumbar kyphosis.
•Neurologic: normal intelligence, delayed motor milestones.1,3-5
DIAGNOSIS AND TREATMENT
Characteristic clinical features and radiographic findings are diagnostic of achondroplasia in infants.1,4 In newborns, radiographic findings include a large cranium with a small foramen magnum, narrow interpediculate distance of the caudal spine, a squared appearance to the iliac bones with small sacrosciatic notches, and shortened ribs and tubular bones (eg, humeri and femurs).5,8 In newborns with atypical findings, molecular genetic testing can detect the FGFR3 mutation in 99% of cases.5
Specialized height for weight curves and developmental screening tests are available for patients with achondroplasia.1,4,6
Presently, there is no reliable treatment available to promote linear growth in these patients. Growth hormone treatment has not been successful in increasing height. Surgical intervention to lengthen arms and legs has been tried; however, it is not a standard of care because of risk of complications.
The mainstay of treatment is to prevent and treat the complications associated with achondroplasia that can arise in infancy.9 A small foramen magnum increases the risk of hydrocephalus. Recurrent otitis media caused by midface hypoplasia poses a risk of conductive hearing loss and delayed speech development. A small thoracic cage can lead to upper airway obstruction and respiratory difficulties. Obstructive sleep apnea syndrome with risk of cor pulmonale also occurs. Spinal stenosis and disk compressions can cause neurologic sequelae that require surgical decompression.1,4,5
Life expectancy for patients with achondroplasia is within normal limits. Adults are able to lead independent and productive lives.4 Patients are of normal intelligence unless CNS complications are present. Obesity is a concern in older patients, especially because of the associated comorbidity issues of spinal curvature and/or stenosis, joint problems, and risk of cardiovascular compromise.1 For many affected patients, psychosocial issues arise from the difficulty of living with short stature in today's society.4
A LESSON FOR THE CLINICIAN
Achondroplasia is identifiable at birth. Pediatricians and family practitioners need to recognize this form of short-limb dwarfism so that pertinent medical concerns can be promptly addressed. Support groups and organizations--such as Little People of America, Human Growth Foundation, and the March of Dimes--are invaluable resources. These organizations can help patients with achondroplasia and their caregivers and can educate medical personnel about syndromes of short stature.