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PHOX2B gene

Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

PHOX2B Gene: Overview and Associated Health Conditions

The PHOX2B gene is critical for the development of the autonomic nervous system, and specific mutations in this gene are linked to congenital central hypoventilation syndrome and neuroblastoma.

Normal Function

The PHOX2B gene provides instructions for making a protein that is essential during prenatal development. The PHOX2B protein supports the formation of nerve cells (neurons) and regulates their maturation process, known as differentiation, which allows neurons to carry out specific functions.

During neuron development, this protein is active in the neural crest, 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 vital body functions such as:

  • Breathing
  • Blood pressure
  • Heart rate
  • Digestion

Additionally, neural crest cells give rise to many tissues in the face and skull, as well as 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 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 identified as causes of congenital central hypoventilation syndrome (CCHS). This condition is characterized by shallow breathing (hypoventilation), particularly during sleep, which typically begins in infancy.

Affected individuals often experience other issues 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, a condition known as Hirschsprung disease, which results 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. These mutations 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.

These mutations are believed to interfere with the PHOX2B protein's role in supporting neuron formation and differentiation, especially within the autonomic nervous system. Consequently, bodily functions controlled by this system—including regulation of breathing, heart rate, blood pressure, and body temperature—are inconsistent in individuals with 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 allows cells to grow and divide uncontrollably to form a tumor.

In most cases, these genetic changes are acquired during a person's lifetime and are 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.
  • 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. These additions or deletions change the sequence of amino acids in the PHOX2B protein. All of these types of mutations have been found in both familial and sporadic neuroblastoma. The mutations are believed to interfere with the PHOX2B protein's role in supporting neuron differentiation, resulting in an excess of immature neurons that 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

The PHOX2B gene is found on chromosome 4.

Frequently Asked Questions

CCHS is suspected when an infant shows abnormal breathing patterns, especially during sleep, and may have associated autonomic dysfunction. Diagnosis involves a sleep study (polysomnography) to assess ventilation, blood gas analysis, and genetic testing for PHOX2B mutations. A detailed autonomic function test panel can also help confirm the diagnosis.
Patients typically require lifelong ventilatory support, such as continuous positive airway pressure (CPAP) or mechanical ventilation during sleep. Regular monitoring of heart rate, blood pressure, and temperature is essential. Many patients benefit from a multidisciplinary care team that includes pulmonologists, cardiologists, neurologists, and sleep specialists to adjust ventilation settings and manage autonomic symptoms.
While no diet can cure CCHS, maintaining a balanced diet with adequate protein supports overall health. Patients should avoid extreme temperature changes and strenuous exercise that could trigger autonomic instability. Structured, moderate exercise under medical supervision can improve cardiovascular fitness, but activity plans should be individualized.
Individuals with pathogenic PHOX2B mutations have an increased risk of developing neuroblastoma, especially in early childhood. Routine abdominal ultrasounds or MRI scans every 6–12 months during the first 5 years of life are recommended for early detection. Prompt evaluation of any abdominal mass or unexplained symptoms is critical for early intervention.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.