Pierre Robin sequence is a set of abnormalities affecting the head and face, consisting of a small lower jaw (micrognathia), a tongue that is placed further back than normal (glossoptosis), and blockage (obstruction) of the airways. Most people with Pierre Robin sequence are also born with an opening in the roof of the mouth (a cleft palate). This feature is not generally considered necessary for diagnosis of the condition, although there is some disagreement among doctors.

Some people have the features of Pierre Robin sequence as part of a syndrome that affects other organs and tissues in the body, such as Stickler syndrome or campomelic dysplasia. These instances are described as syndromic. When Pierre Robin sequence occurs by itself, it is described as nonsyndromic or isolated. Approximately 20 to 40 percent of cases of Pierre Robin sequence are isolated.

This condition is described as a "sequence" because one of its features, underdevelopment of the lower jaw (mandible), sets off a sequence of events before birth that cause the other signs and symptoms. Specifically, having an abnormally small jaw affects placement of the tongue, and the abnormally positioned tongue can block the airways. In addition, micrognathia and glossoptosis affect formation of the palate during development before birth, which often leads to cleft palate.

The combination of features characteristic of Pierre Robin sequence can lead to difficulty breathing and problems eating early in life. As a result, some affected babies have an inability to grow and gain weight at the expected rate (failure to thrive). In some children with Pierre Robin sequence, growth of the mandible catches up, and as adults these individuals have normal-sized chins.

Changes in the DNA near the SOX9 gene are the most common genetic cause of isolated Pierre Robin sequence. It is likely that changes in other genes, some of which have not been identified, are also involved in the condition. Doctors speculate that nongenetic factors, for example conditions during pregnancy that restrict growth of the jaw, may cause some cases of isolated Pierre Robin sequence.

The SOX9 gene provides instructions for making a protein that plays a critical role in the formation of many different tissues and organs during embryonic development. The SOX9 protein regulates the activity of other genes, especially those that are important for development of the skeleton, including the mandible.

The genetic changes near the SOX9 gene that are associated with isolated Pierre Robin sequence are thought to disrupt regions of DNA called enhancers, which normally regulate the activity of the SOX9 gene. These changes reduce SOX9 gene activity. As a result, the SOX9 protein cannot properly control the genes essential for normal development of the lower jaw, causing micrognathia, and consequently, glossoptosis, airway obstruction, and, often, cleft palate.

Normal Function

The SOX9 gene provides instructions for making a protein that plays a critical role during embryonic development. The SOX9 protein is especially important for development of the skeleton and plays a key role in the determination of sex before birth. The SOX9 protein attaches (binds) to specific regions of DNA and regulates the activity of other genes, particularly those that control skeletal development and sex determination. On the basis of this action, the SOX9 protein is called a transcription factor.

Health Conditions Related to Genetic Changes

Campomelic dysplasia

More than 70 mutations involving the SOX9 gene have been found to cause campomelic dysplasia, a disorder that affects skeletal development, sex determination, and other processes in the body and is often life-threatening in the newborn period. Most cases of campomelic dysplasia are caused by mutations within the SOX9 gene. These mutations prevent the production of the SOX9 protein or result in a protein with impaired ability to function as a transcription factor. About 5 percent of cases are caused by chromosome abnormalities that occur near the SOX9 gene. These chromosome abnormalities disrupt regions of DNA called enhancers that normally regulate the activity of the SOX9 gene. All of these genetic changes prevent the SOX9 protein from properly controlling the genes essential for normal development of the skeleton, reproductive organs, and other parts of the body. Abnormal development of these structures causes the signs and symptoms of campomelic dysplasia.

Individuals with milder forms of campomelic dysplasia are more likely to have chromosome abnormalities near the SOX9 gene rather than mutations within the gene.

Isolated Pierre Robin sequence

Genetic changes that occur near the SOX9 gene cause some cases of isolated Pierre Robin sequence. Individuals with this condition have a small lower jaw (micrognathia) and a tongue that is placed further back than normal (glossoptosis), which can block the airways. Most affected individuals are also born with an opening in the roof of the mouth (a cleft palate). These cases of Pierre Robin sequence are described as isolated because they occur without other signs and symptoms.

The genetic changes associated with isolated Pierre Robin sequence are thought to disrupt enhancer regions that normally regulate the activity of the SOX9 gene during development of the lower jaw, which reduces SOX9 gene activity. As a result, the SOX9 protein cannot properly control the genes essential for normal jaw development, causing micrognathia. Underdevelopment of the lower jaw affects placement of the tongue and formation of the palate, leading to glossoptosis and, often, cleft palate.

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Other Names for This Gene

• SOX9_HUMAN
• SRA1
• SRY (sex determining region Y)-box 9
• SRY (sex-determining region Y)-box 9 protein
• SRY box 9
• transcription factor SOX9

Genomic Location

Isolated Pierre Robin sequence is usually not inherited. It typically results from new (de novo) genetic changes and occurs in people with no history of the disorder in their family. When the condition is inherited, it follows an autosomal dominant pattern, which means one copy of the DNA alteration in each cell is sufficient to cause the disorder.

Syndromic Pierre Robin sequence is inherited in the same pattern as the condition it is associated with.

Isolated Pierre Robin sequence affects an estimated 1 in 8,500 to 14,000 people.