Thompson & Thompson Genetics in Medicine, 8th Edition

Case 2. Achondroplasia (FGFR3 Mutation, MIM 100800)

Autosomal Dominant


• Gain-of-function mutations

• Advanced paternal age

• De novo mutation

Major Phenotypic Features

• Age at onset: Prenatal

• Rhizomelic short stature

• Megalencephaly

• Spinal cord compression

History and Physical Findings

P.S., a 30-year-old healthy woman, was 27 weeks pregnant with her first child. A fetal ultrasound examination at 26 weeks' gestation identified a female fetus with macrocephaly and rhizomelia (shortening of proximal segments of extremities). P.S.'s spouse was 45 years of age and healthy; he had three healthy children from a previous relationship. Neither parent has a family history of skeletal dysplasia, birth defects, or genetic disorders. The obstetrician explained to the parents that their fetus had the features of achondroplasia. The infant girl was delivered at 38 weeks' gestation by cesarean section. She had the physical and radiographic features of achondroplasia, including frontal bossing, megalencephaly, midface hypoplasia, lumbar kyphosis, limited elbow extension, rhizomelia, trident hands, brachydactyly, and hypotonia. Consistent with her physical features, DNA testing identified an 1138G>A mutation leading to a glycine to arginine substitution at codon 380 (Gly380Arg) in the fibroblast growth factor receptor 3 gene (FGFR3).


Disease Etiology and Incidence

Achondroplasia (MIM 100800), the most common cause of human dwarfism, is an autosomal dominant disorder caused by specific mutations in FGFR3; two mutations, 1138G>A (≈98%) and 1138G>C (1% to 2%), account for more than 99% of cases of achondroplasia, and both result in the Gly380Arg substitution. Achondroplasia has an incidence of 1 in 15,000 to 1 in 40,000 live births and affects all ethnic groups.


FGFR3 is a transmembrane tyrosine kinase receptor that binds fibroblast growth factors. Binding of fibroblast growth factors to the extracellular domain of FGFR3 activates the intracellular tyrosine kinase domain of the receptor and initiates a signaling cascade. In endochondral bone, FGFR3 activation inhibits proliferation of chondrocytes within the growth plate and thus helps coordinate the growth and differentiation of chondrocytes with the growth and differentiation of bone progenitor cells.

The FGFR3 mutations associated with achondroplasia are gain-of-function mutations that cause ligand-independent activation of FGFR3. Such constitutive activation of FGFR3 inappropriately inhibits chondrocyte proliferation within the growth plate and consequently leads to shortening of the long bones as well as to abnormal differentiation of other bones.

Guanine at position 1138 in the FGFR3 gene is one of the most mutable nucleotides identified in any human gene. Mutation of this nucleotide accounts for nearly 100% of achondroplasia; more than 80% of patients have a de novo mutation. Such de novo mutations occur exclusively in the father's germline and increase in frequency with advanced paternal age (>35 years) (see Chapter 7).

Phenotype and Natural History

Patients with achondroplasia present at birth with rhizomelic shortening of the arms and legs, relatively long and narrow trunk, trident configuration of the hands, and macrocephaly with midface hypoplasia and prominent forehead. They have a birth length that is usually slightly less than normal, although occasionally within the low-normal range; their length or height falls progressively farther from the normal range as they grow.

In general, patients have normal intelligence, although most have delayed motor development. Their delayed motor development arises from a combination of hypotonia, hyperextensible joints (although the elbows have limited extension and rotation), mechanical difficulty balancing their large heads, and, less commonly, foramen magnum stenosis with brainstem compression.

Abnormal growth of the skull and facial bones results in midface hypoplasia, a small cranial base, and small cranial foramina. The midface hypoplasia causes dental crowding, obstructive apnea, and otitis media. Narrowing of the jugular foramina is believed to increase intracranial venous pressure and thereby to cause hydrocephalus. Narrowing of the foramen magnum causes compression of the brainstem at the craniocervical junction in approximately 10% of patients and results in an increased frequency of hypotonia, quadriparesis, failure to thrive, central apnea, and sudden death. Between 3% and 7% of patients die unexpectedly during their first year of life because of brainstem compression (central apnea) or obstructive apnea. Other medical complications include obesity, hypertension, lumbar spinal stenosis that worsens with age, and genu varum.


Suspected on the basis of clinical features, the diagnosis of achondroplasia is usually confirmed by radiographic findings. DNA testing for FGFR3 mutations can be helpful in ambiguous cases but is usually not necessary for the diagnosis to be made.

Throughout life, management should focus on the anticipation and treatment of the complications of achondroplasia. During infancy and early childhood, patients must be monitored for chronic otitis media, hydrocephalus, brainstem compression, and obstructive apnea and treated as necessary. Treatment of patients with brainstem compression by decompression of the craniocervical junction usually results in marked improvement of neurological function. During later childhood and through early adulthood, patients must be monitored for symptomatic spinal stenosis, symptomatic genu varum, obesity, hypertension, dental complications, and chronic otitis media and treated as necessary. Treatment of the spinal stenosis usually requires surgical decompression and stabilization of the spine. Obesity is difficult to prevent and control and often complicates the management of obstructive apnea and joint and spine problems.

Patients should avoid activities in which there is risk for 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.

Both growth hormone therapy and surgical lengthening of the lower legs have been promoted for treatment of the short stature. Both therapies remain controversial.

In addition to management of their medical problems, patients often need help with social adjustment both because of the psychological impact of their appearance and short stature and because of their physical handicaps. Support groups often assist by providing interaction with similarly affected peers and social awareness programs.

Inheritance Risk

For unaffected parents with a child affected with achondroplasia, the risk for recurrence in their future children is low but probably higher than for the general population because mosaicism involving the germline, although extremely rare in achondroplasia, has been documented. For relationships in which one partner is affected with achondroplasia, the risk for recurrence in each child is 50% because achondroplasia is an autosomal dominant disorder with full penetrance. For relationships in which both partners are affected, each child has a 50% risk for having achondroplasia, a 25% risk for having lethal homozygous achondroplasia, and a 25% chance of being of average stature. Cesarean section is required for a pregnancy in which an unaffected baby is carried by a mother with achondroplasia.

Prenatal diagnosis before 20 weeks of gestation is available only by molecular testing of fetal DNA, although the diagnosis can be made late in pregnancy by analysis of a fetal skeletal radiograph (Fig. C-2). The features of achondroplasia cannot be detected by prenatal ultrasonography before 24 weeks' gestation, whereas the more severe thanatophoric dysplasia type 2 (homozygous achondroplasia) can be detected earlier.


FIGURE C-2 Radiographs of a normal 34-week fetus (left) and a 34-week fetus with achondroplasia (right). Comparison of the upper frames shows rhizomelia and trident positioning of the fingers in the fetus with achondroplasia. Comparison of the lower frames illustrates the caudal narrowing of the interpedicular distance in the fetus with achondroplasia versus the interpedicular widening in the normal fetus. Also, the fetus with achondroplasia has small iliac wings shaped like an elephant's ear and narrowing of the sacrosciatic notch. See Sources & Acknowledgments.

Questions for Small Group Discussion

1. Name other disorders that increase in frequency with increasing paternal age. What types of mutations are associated with these disorders?

2. Discuss possible reasons that the FGFR3 mutations 1138G>A and 1138G>C arise exclusively during spermatogenesis.

3. Marfan syndrome, Huntington disease, and achondroplasia arise as a result of dominant gain-of-function mutations. Compare and contrast the pathological mechanisms of these gain-of-function mutations.

4. In addition to achondroplasia, gain-of-function mutations in FGFR3 are associated with hypochondroplasia and thanatophoric dysplasia. Explain how phenotypic severity of these three disorders correlates with the level of constitutive FGFR3 tyrosine kinase activity.


Pauli RM. Achondroplasia. [Available from]

Wright MJ, Irving MD. Clinical management of achondroplasia. Arch Dis Child. 2012;97:129–134.