Achondroplasia is an autosomal dominant genetic disorder in which the proliferation of chondrocytes is reduced at the epiphyseal plate. This condition results in dwarfism of the extremities and trunk.

Achondroplasia has an incidence of 1 in 15,000 to 1 in 40,000 live births and affects all ethnic groups.

Children with achondroplasia have a much higher mortality rate than the general population. A large percentage of these deaths are believed to be related to spinal cord compression. Because of the danger of sudden death, it is important that these children be treated as soon as possible to correct the problem.

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 often causes compression of the brainstem at the craniocervical junction in approximately 10% of the 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 unexpectadly during their first year of life because of brainstem compression (central apnea) or obstructive apnea. Other medical complications include obesity, 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.

Increase in the level of the protein's expression. Expression is on the FGFR3 gene.

A genetic disorder in which the proliferation of chondrocytes is reduced at the epiphyseal plate. This condition results in dwarfism of the extremities and trunk.

Increased growth at the epiphyseal plate and its replacement by bone in children is controlled by the pituitary hormone, somatotrophin.

Somatotrophin controls the synthesis of the liver hormone somatomedin C, which stimulates chondrocytes at the epiphyseal plate of long bones.

Mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation.

FGFR3 normally has a negative regulatory effect on bone growth

In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.

Achondroplasia, the most common cause of human dwarfism, is an autosomal dominant disorder caused by specific mutations in FGFR3. Two mutations (a G to C mutation and a G to A mutation on the first base of the triplet codon) account for more than 99% of cases of achondroplasia, and both result in the Gly380Arg substitution.

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 signalling 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. De novo mutations of FGFR3 guanine 1138 occur exclusively in the father's germline and increase in frequency with advanced paternal age (usually greater than 35 years).

Occasionally, congenital issues lead to a condition called foramen magnum stenosis, in which the opening at the inferior portion of the skull is not large enough for the spinal cord to easily pass through. This most often happens in conjunction with achondroplasia.

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 their 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, 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.

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 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.

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

Prenatal diagnosis before 20 weeks of gestation is available only by molecular testing of fetal DNA, althrough the diagnosis can be made late in pregnancy by analysis of a fetal skeletal radiograph. The features of achondroplasia cannot be detected by prenatal ultrasonography before 24 weeks' gestation, whereas the more severe thantophoric dysplasia can be detected earlier.

Increase in the level of the protein's expression. Expression is on the FGFR3 gene.

A genetic disorder in which the proliferation of chondrocytes is reduced at the epiphyseal plate. This condition results in dwarfism of the extremities and trunk.

Increased growth at the epiphyseal plate and its replacement by bone in children is controlled by the pituitary hormone, somatotrophin.

Somatotrophin controls the synthesis of the liver hormone somatomedin C, which stimulates chondrocytes at the epiphyseal plate of long bones.

Mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation.

FGFR3 normally has a negative regulatory effect on bone growth

In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.

Achondroplasia, the most common cause of human dwarfism, is an autosomal dominant disorder caused by specific mutations in FGFR3. Two mutations (a G to C mutation and a G to A mutation on the first base of the triplet codon) 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 signalling 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. De novo mutations of FGFR3 guanine 1138 occur exclusively in the father's germline and increase in frequency with advanced paternal age (usually greater than 35 years).

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 often causes compression of the brainstem at the craniocervical junction in approximately 10% of the 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 unexpectadly during their first year of life because of brainstem compression (central apnea) or obstructive apnea. Other medical complications include obesity, 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 their 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, 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.

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 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.

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

Prenatal diagnosis before 20 weeks of gestation is available only by molecular testing of fetal DNA, althrough the diagnosis can be made late in pregnancy by analysis of a fetal skeletal radiograph. The features of achondroplasia cannot be detected by prenatal ultrasonography before 24 weeks' gestation, whereas the more severe thantophoric dysplasia can be detected earlier.

Occasionally, congenital issues lead to a condition called foramen magnum stenosis, in which the opening at the inferior portion of the skull is not large enough for the spinal cord to easily pass through. This most often happens in conjunction with achondroplasia.

Children with achondroplasia have a much higher mortality rate than the general population. A large percentage of these deaths are believed to be related to spinal cord compression. Because of the danger of sudden death, it is important that these children be treated as soon as possible to correct the problem.