Anauxetic dysplasia is a disorder characterized by extremely short stature (dwarfism) and other skeletal abnormalities, an unusually large range of joint movement (hypermobility), dental problems, and distinctive facial features. Mild intellectual disability can also occur in this disorder.

People with anauxetic dysplasia have dwarfism with unusually short limbs for their height (disproportionate short stature) beginning before birth. Dislocation of the bones at the top of the spine (atlantoaxial subluxation) can also occur in this disorder, and may cause pinching (compression) of the spinal cord. As a result, affected individuals may experience neurological symptoms including pain, tingling, numbness, coordination problems, weakness, and paralysis. In severe cases, the spinal cord compression may lead to paralysis of the muscles needed for breathing, which can be life-threatening during early childhood.

Other skeletal abnormalities in anauxetic dysplasia include a barrel-shaped chest and a rounded upper back that also curves to the side (kyphoscoliosis). Without surgical correction, the kyphoscoliosis can constrict the lungs and cause difficulty breathing. People with anauxetic dysplasia can also have an exaggerated curvature of the lower back (hyperlordosis), dislocation of the hips, and soles of the feet that are rounded outward (rocker-bottom feet).

Typical facial features in anauxetic dysplasia include closely spaced eyes (hypotelorism), a flat or sunken appearance of the middle of the face (midface hypoplasia), an unusually large tongue (macroglossia), and a protruding chin (prognathism). Affected individuals can also have fewer teeth than normal (hypodontia).

Anauxetic dysplasia can be caused by mutations in the RMRP gene. Unlike many genes, the RMRP gene does not contain instructions for making a protein. Instead, a molecule called a noncoding RNA, a chemical cousin of DNA, is produced from the RMRP gene. Several proteins attach (bind) to this RNA molecule, forming an enzyme complex called mitochondrial RNA-processing endoribonuclease, or RNase MRP.

The RNase MRP enzyme is thought to be involved in several important functions in the cell, including processing ribosomal RNA. This form of RNA is associated with cell structures called ribosomes, which assemble protein building blocks (amino acids) into proteins.

The RMRP gene mutations that cause anauxetic dysplasia alter the noncoding RNA produced from the gene, and the RNase MRP enzyme containing the altered noncoding RNA is impaired in its ribosomal RNA processing function. Although the specific mechanism is unknown, impairment of this function likely disrupts skeletal development, leading to the signs and symptoms of anauxetic dysplasia.

Mutations in at least one gene that provides instructions for making a protein component of the RNase MRP enzyme complex can also cause anauxetic dysplasia.

Normal Function

Unlike many genes, the RMRP gene does not contain instructions for making a protein. Instead, a molecule called a noncoding RNA, a chemical cousin of DNA, is produced from the RMRP gene. Several proteins attach (bind) to this RNA molecule, forming an enzyme called mitochondrial RNA-processing endoribonuclease, or RNase MRP.

The RNase MRP enzyme is thought to be involved in several important processes in the cell. For example, it likely helps copy (replicate) the DNA found in the energy-producing centers of cells (mitochondria). The RNase MRP enzyme also processes ribosomal RNA, which is required for assembling protein building blocks (amino acids) into functioning proteins. In addition, this enzyme helps control the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion.

Health Conditions Related to Genetic Changes

Anauxetic dysplasia

At least four RMRP gene mutations have been identified in people with anauxetic dysplasia, a disorder characterized by severe short stature (dwarfism) and other skeletal abnormalities. The RMRP gene mutations that cause anauxetic dysplasia alter the noncoding RNA produced from the gene, and the RNase MRP enzyme containing the altered noncoding RNA is impaired in its ribosomal RNA processing function. Although the specific mechanism is unknown, impairment of this function likely disrupts skeletal development, leading to the signs and symptoms of anauxetic dysplasia.

Cartilage-hair hypoplasia

More than 100 mutations that cause cartilage-hair hypoplasia have been identified in the RMRP gene. Approximately 90 percent of cases of this disorder result from a mutation in which the DNA building block (nucleotide) guanine is substituted for the nucleotide adenine at position 70 in the RMRP gene (written as 70A>G). This mutation is found in almost all known affected individuals in the Amish population, approximately 92 percent of affected individuals of Finnish descent, and about half of affected individuals in other populations.

Mutations in the RMRP gene likely result in the production of a noncoding RNA that cannot bind to some of the proteins that are normally part of the RNase MRP enzyme complex. These changes are believed to affect the activity of the enzyme, which interferes with its important functions within cells. Impaired RNase MRP enzyme complex causes dwarfism, skeletal abnormalities, abnormal immune system function (immune deficiency), elevated cancer risk, sparse hair growth (hypotrichosis), and other signs and symptoms of cartilage-hair hypoplasia.

Other disorders

RMRP gene mutations, including some of the same mutations that cause cartilage-hair hypoplasia (described above), may result in a similar disorder known as metaphyseal dysplasia without hypotrichosis. This condition is characterized by short stature and skeletal abnormalities that are usually less severe than those seen in cartilage-hair hypoplasia. Individuals with metaphyseal dysplasia without hypotrichosis do not have any changes in the structure or appearance of their hair, but they may have immune deficiency and an increased risk of developing cancer. It is unknown why the same mutations may cause both of these conditions. Together with anauxetic dysplasia (described above), they are often referred to as cartilage-hair hypoplasia spectrum disorders, with anauxetic dysplasia as the most severe form and metaphyseal dysplasia without hypertrichosis on the mild end of the spectrum.

Other Names for This Gene

• CHH
• NME1
• RMRPR
• RRP2

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Anauxetic dysplasia is a very rare disorder; its prevalence is unknown.