eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Achondroplasia
Updated: Aug 14, 2009
Introduction
Background
Achondroplasia, a nonlethal form of chondrodysplasia, is the most common form of short-limb dwarfism. It is inherited as a mendelian autosomal dominant trait with complete penetrance. Approximately 80% of cases are due to new or de novo dominant mutations with a mutation rate estimated to be 0.000014 per gamete per generation. Salient phenotypic features include disproportionate short stature, megalencephaly, a prominent forehead (frontal bossing), midface hypoplasia, rhizomelic shortening of the arms and legs, a normal trunk length, prominent lumbar lordosis, genu varum, and a trident hand configuration.
Height for females with achondroplasia (mean/standard deviation [SD]) compared to normal standard curves. The graph is based on information from 214 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Height for males with achondroplasia (mean/2 standard deviations [SDs]) compared to normal standard curves. The graph is based on information from 189 males. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Mean growth velocities (solid line) for males (top) and females (bottom) with achondroplasia compared to normal growth velocity curves. Dashed lines indicate third percentile, mean, and 97th percentile. Data are from 26 males and 35 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Upper and lower segment lengths for males (top) and (bottom) with achondroplasia (mean/standard deviation [SD]). Data are from 75 males and 95 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Head circumference for females with achondroplasia compared to normal curves (dashed lines). Data are from 145 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Head circumference for males with achondroplasia compared to normal curves (dashed lines). Data are from 114 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al. Standard growth curves for achondroplasia. J Pediatr. 1978 Sep; 93(3): 435-8.
Pathophysiology
Achondroplasia is caused by mutations in the fibroblast growth factor receptor-3 (FGFR3) gene. At present, FGFR3 is the only gene known to cause achondroplasia. This gene has been mapped to chromosome 4, band p16.3 (4p16.3). All causal mutations occur at the exact same location within the gene; hence molecular testing by targeted mutational analysis is easily done and interpreted. The mutations (G1138A, G1138C) cause an increased function of the FGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production.
The nucleotide G1138A and G1138C mutations of FGFR3 account for 99% of the mutations resulting in a specific point mutation, hence an amino acid substitution. About 98% of cases have the G1138A mutation resulting from a G-to-A point change. One percent of cases have a G-to-C point change at nucleotide 1138, causing the G1138C mutation. A rare missense mutation (Lys650Met) in the tyrosine kinase region of FGFR3 causes a disorder termed severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) . See Differentials.
Frequency
United States
Frequency has not been documented in the United States.
International
Frequency is believed to be 1 case per 15,000-40,000 births worldwide. In 1986, Orioli et al reported on the frequency of all skeletal dysplasias in a study population of 349,470 live births and stillbirths.1 Based on their study, the prevalence rate for achondroplasia was estimated to be 0.5-1.5 cases per 10,000 births and the mutation rate to be 1.72-5.57 x 10-5 per gamete per generation.
Mortality/Morbidity
Sudden death within the first year of life is attributed to abnormalities at the craniocervical junction causing spinal cord compression. Central apnea occurs due arterial compression at the cervical level of the foramen magnum. The small foramen magnum present in these patients may also cause a high cervical myelopathy.
The risk of sudden death for infants with achondroplasia is 2-5%. This risk can be minimized with appropriate assessment of the craniocervical junction, which includes a thorough neurological history and examination, neuroimaging (either CT scanning or MRI), and polysomnography. If neurological abnormalities are detected, referral to medical center with neurosurgical consultation services is indicated.
Caregivers should use an infant carrier with a firm back that gives good neck support and to use a rear-facing car seat for travel as long as possible. Use of mechanical swings and carrying slings should be avoided to limit the potential for uncontrolled head movement.
Thoracolumbar kyphosis occurs in most infants with achondroplasia. Severe kyphosis is related to unsupported sitting of the infant before adequate trunk muscle strength has developed. Angular deformities of the extremities, premature degenerative joint disease, and spinal disorders are common clinical features.
Cervical instability is present in a large number of patients. Great care must be taken with manipulation of the neck, as would occur for preparation of intubation in general anesthesia. Uncontrolled neck movements could cause significant neurological compromise with spinal cord compression.
Obesity, when present, aggravates the morbidity related to lumbar stenosis, nonspecific joint problems, and cardiovascular risks. Based on the weight/height (W/H) curves developed by Hunter et al for boys and girls with achondroplasia, the mean W/H curve in children with achondroplasia matches the control curve until the children reach 75 cm in height. Beyond 75 cm, the weight in children with achondroplasia increases disproportionately to height. The Quetelet index or body mass index (BMI=W/H2) can be used to estimate weight excess in children ages 3-6 years; after that, the Rohrer index (RI=W/H3) should be used for children and adolescents ages 6-18 years.
Respiratory disorders are seen frequently, including apnea and abnormalities of gas exchange. Studies report that as many as 75% of children with achondroplasia have a pathologic apnea index (>30 episodes). Brainstem compression may contribute to central apnea whereas obstructive apnea may be due to midface structural abnormalities such as hypoplasia.
Severe upper airway obstruction occurs in less than 5% in children with achondroplasia. Tonsillectomy and adenoidectomy do not help resolve this obstruction very well in children with achondroplasia. Hypotonicity, a narrow trunk with a small thoracic cage and adenotonsillar hypertrophy all contribute to confining the airway and causing upper airway obstruction.
Children with achondroplasia who have respiratory dysfunction and obstructive sleep apnea (OSA) detected by polysomnography have associated cognitive deficits, as evident in children with OSA within the general population. Restrictive pulmonary disease, with or without restrictive airway disease, occurs in less than 5% of children younger than 3 years old. This risk is greater for those who live at higher elevations.
A study of school-aged children with achondroplasia reported CT findings, including kinking of the medulla and neuroanatomic abnormalities consistent with arrested hydrocephalus, including enlarged ventricles and hypoplasia of the corpus callosum. These CT findings are similar to those seen in children with compensated, unshunted hydrocephalus. The hydrocephalus may be due to increased intracranial venous pressure secondary to stenosis of the sigmoid sinus at the level of the narrowed jugular foramina.
Although their overall cognitive scores are within normal, children with achondroplasia may show mild deficits in visual-spatial tasks. This deficit has been identified in children with arrested hydrocephalus.
Motor milestones are usually delayed for the first year of life due to a large cranium and poor overall muscle tone (hypotonia). Language development is normal, if no conductive hearing loss is present.
Race
No documented race predilection is noted.
Sex
Males and females are equally affected.
Clinical
History
Achondroplasia is primarily due to a de novo mutation; however, some parents who are affected are heterozygous for either the G1138A or G1138C mutation. Identifying families members at risk is helpful in addressing medical treatment plans, offering genetic counseling with options for genetic testing, and providing educational materials and emotional support.
Once the diagnosis of achondroplasia is made, obtain the following history to avoid serious complications:
- A history of pain, ataxia, incontinence, and apnea may be due to cervicomedullary compression. Cord compression can cause respiratory arrest and progressive quadriparesis. Indications for surgery to release the compression include brisk reflexes, a small foramen magnum, and central hypopnea.
- Obtain a careful history for recurrent otitis media to prevent conductive hearing loss which can be the cause of language delays.
- A history of sleep disturbances2 and increased head size may indicate neurologic and respiratory complications.
Physical
- Neurologic findings
- Hypotonia in infancy and early childhood
- Delayed motor milestones
- Normal intelligence with possible minor deficit in visual-spatial tasks
- Craniofacial features:
- Large calvarial bones in contrast to the small cranial base and facial bones
- True megalencephaly (large head) with frontal bossing
- Midface hypoplasia
- Dental malocclusion and crowding
- Skeletal features:
- Disproportionate short stature: The average adult male height is 131 ± 5.6 cm; the average adult female height is 124 ± 5.9 cm (approximately 4 ft for both men and women).
- Normal trunk length that appears long and narrow, small thoracic cage
- Rhizomelic shortening of the proximal limbs with redundant skin folds
- Brachydactyly and trident hand configuration: A marked separation between the ring and middle fingers giving the hand a 3-pronged appearance.
- Thoracolumbar gibbus (lumbar kyphosis) in infancy, which is replaced by an exaggerated lumbar lordosis once ambulation begins
- Hyperextensibility of most joints, especially the knees.
- Limited elbow extension and rotation
- Genu varum (bow legs)
- Radiographic findings
- Contracted skull base
- Progressive interpedicular narrowing in the lumbar spine region
- Short pedicles which can cause spinal stenosis
- Short femoral neck and metaphyseal flaring
- Dysplastic ilium, narrow sacroiliac groove, flat-roofed acetabula
Causes
- Advanced paternal age (age >35 y) is identified as a risk factor in de novo cases of achondroplasia, suggesting that factors influencing DNA replication or repair during spermatogenesis may predispose men to the occurrence of G1138 FGFR3 mutations.
More on Achondroplasia |
 Overview: Achondroplasia |
| Differential Diagnoses & Workup: Achondroplasia |
| Treatment & Medication: Achondroplasia |
| Follow-up: Achondroplasia |
| Multimedia: Achondroplasia |
| References |
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Further Reading
Keywords
achondroplasia, short stature, chondrodysplasia, chondrodystrophy, skeletal dysplasia, osteochondrodysplasia, disproportionate short stature, short-limb dwarfism, hypotonia in infancy, megalencephaly, occipitofrontal circumference, OFC, midface hypoplasia, prominent forehead, frontal bossing, rhizomelic limbs, trident hands, brachydactyly, thoracolumbar gibbus, lumbar kyphosis, caudal narrowing of interpedicular spaces, lumbar lordosis, 4p16.3, fibroblast growth factor receptor-3 gene, FGFR3 gene, paternal age effect, autosomal dominant, treatment, diagnosis
