Congenital central hypoventilation syndrome (CCHS) is a disorder that affects normal breathing. People with this disorder take shallow breaths (hypoventilate), especially during sleep, resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. Ordinarily, the part of the nervous system that controls involuntary body processes (autonomic nervous system) would react to such an imbalance by stimulating the individual to breathe more deeply or wake up. This nervous system reaction is impaired in people with CCHS. They must be supported with a machine to help them breathe (mechanical ventilation) or a device that stimulates a normal breathing pattern (diaphragm pacemaker). Some affected individuals need this support 24 hours a day, while others need it only at night.

Symptoms of CCHS usually become apparent shortly after birth when affected infants hypoventilate upon falling asleep. In these infants, a lack of oxygen in the blood often causes a bluish appearance of the skin or lips (cyanosis). In some milder cases, CCHS may not become apparent until later in life.

In addition to the breathing problem, people with CCHS may have difficulty regulating their heart rate and blood pressure, for example, in response to exercise or changes in body position. They also have decreased perception of pain, low body temperature, and occasional episodes of heavy sweating.

People with CCHS may have additional problems affecting the nervous system. About 20 percent of people with CCHS have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon. (Some researchers refer to the combination of CCHS and Hirschsprung disease as Haddad syndrome.) Some affected individuals develop learning difficulties or other neurological problems. People with CCHS are also at increased risk of developing certain tumors of the nervous system called neuroblastomas, ganglioneuromas, and ganglioneuroblastomas.

Additionally, individuals with CCHS usually have eye abnormalities, including a decreased response of the pupils to light. People with CCHS, especially children, may have a characteristic appearance with a short, wide, somewhat flattened face often described as "box-shaped."

In CCHS, life expectancy and the extent of any intellectual disabilities depend on the severity of the disorder, timing of the diagnosis, and the success of treatment.

Mutations in a gene called PHOX2B cause CCHS. The PHOX2B gene provides instructions for making a protein that is important during development before birth. The PHOX2B protein helps support the formation of nerve cells (neurons) and regulates the process by which the neurons mature to carry out specific functions (differentiation). The protein is active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells migrate to form parts of the autonomic nervous system, many tissues in the face and skull, and other tissue and cell types.

PHOX2B gene mutations that cause CCHS are believed to interfere with the PHOX2B protein's role in supporting neuron formation and differentiation, especially in the autonomic nervous system. As a result, bodily functions that are controlled by this system, including regulation of breathing, heart rate, blood pressure, and body temperature, are inconsistent in CCHS.

Normal Function

The PHOX2B gene provides instructions for making a protein that is important during development before birth. The PHOX2B protein helps support the formation of nerve cells (neurons) and regulates the process by which the neurons mature to carry out specific functions (differentiation). During neuron development, the protein is active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells migrate to form parts of the autonomic nervous system, which controls body functions such as breathing, blood pressure, heart rate, and digestion. Neural crest cells also give rise to many tissues in the face and skull, and other tissue and cell types.

The protein produced from the PHOX2B gene contains two areas where a protein building block (amino acid) called alanine is repeated multiple times. These stretches of alanines are known as polyalanine tracts or poly(A) tracts.

Health Conditions Related to Genetic Changes

Congenital central hypoventilation syndrome

More than 75 mutations in the PHOX2B gene have been found to cause congenital central hypoventilation syndrome (CCHS). This condition is characterized by shallow breathing (hypoventilation), especially during sleep, that typically begins in infancy. Affected individuals often have other problems involving the autonomic nervous system, including difficulty regulating heart rate, blood pressure, and body temperature. Some people with CCHS also have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon.

Most PHOX2B gene mutations that cause CCHS add extra alanines to the second polyalanine tract in the PHOX2B protein. This type of mutation is called a polyalanine repeat expansion. The mutations that cause CCHS typically increase the number of alanines from 20 to 25 or more. Other types of PHOX2B gene mutations have been identified in 8 to 10 percent of individuals with this disorder.

PHOX2B gene mutations that cause CCHS are believed to interfere with the PHOX2B protein's role in supporting neuron formation and differentiation, especially in the autonomic nervous system. As a result, bodily functions that are controlled by this system, including regulation of breathing, heart rate, blood pressure, and body temperature, are inconsistent in CCHS.

Neuroblastoma

Several mutations in the PHOX2B gene have been identified in people with neuroblastoma, a type of cancerous tumor composed of immature neurons (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations allow cells to grow and divide uncontrollably to form a tumor. In most cases, these genetic changes are acquired during a person's lifetime, called somatic mutations. Somatic mutations are present only in certain cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent. Both types of mutation occur in neuroblastoma. Somatic mutations in the PHOX2B gene increase the risk of developing sporadic neuroblastoma, and inherited mutations in the PHOX2B gene increase the risk of developing familial neuroblastoma.

In some people with neuroblastoma, mutations in the PHOX2B gene change a single protein building block (amino acid) in the PHOX2B protein. Other affected individuals may have an addition or deletion of several DNA building blocks (nucleotides) in the PHOX2B gene. Addition or deletion of nucleotides changes the sequence of amino acids in the PHOX2B protein. All of these types of mutations have been found in familial and sporadic neuroblastoma. The mutations are believed to interfere with the PHOX2B protein's role in supporting neuron differentiation, which results in an excess of immature neurons and leads to neuroblastoma.

Some people with PHOX2B gene mutations have both neuroblastoma and Hirschsprung disease. PHOX2B gene variations affect the autonomic nervous system and tissues that grow from the neural crest, resulting in an increased risk of developing both of these disorders.

Other Names for This Gene

• NBLST2
• NBPhox
• neuroblastoma paired-type homeobox protein
• neuroblastoma Phox
• paired like homeobox 2b
• paired mesoderm homeobox 2b
• paired-like homeobox 2b
• Phox2b
• PHOX2B homeodomain protein
• PHX2B_HUMAN
• PMX2B

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

More than 90 percent of cases of CCHS result from new mutations in the PHOX2B gene. These cases occur in people with no history of the disorder in their family. Occasionally an affected person inherits the mutation from one affected parent. The number of such cases has been increasing as better treatment has allowed more affected individuals to live into adulthood and start families.

About 5 to 10 percent of affected individuals inherit the altered gene from an unaffected parent who has a PHOX2B gene mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism. A parent with mosaicism for a PHOX2B gene mutation may not show any signs or symptoms of CCHS.

CCHS is a relatively rare disorder. More than 1,000 individuals with this condition have been identified. Researchers believe that some cases of sudden infant death syndrome (SIDS) or sudden unexplained death in children may be caused by undiagnosed CCHS.