PHOX2B Deficiency – Definition

A heterozygous germline mutation in the PHOX2B gene causes a PHOX2B-related predisposition to neuroblastic tumors (OMIM #603851). It favors the development of neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas), Hirschsprung’s disease, and congenital central hypoventilation syndrome (CCHS).

Synonyms:

Sarcoma breast leukemia and adrenal gland cancer syndrome

Gene:

PHOX2B

Gen­e product:

PHOX2B

Function:

Proliferation regulation of immature sympathetic neurons

Pattern of inheritance:

Autosomal dominant

Prevalence:

Along with ALK mutations, around 1-2% of neuroblastoma patients

Genotyp-Phänotyp-Korrelation:

Polyalanine repeat mutations (PARM) in the PHOX2B gene are associated with more severe cases of hypoventilation with CCHS (the longer the polyalanine tract expansion, the more pronounced the hypoventilation) and with neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas).
While missense, frameshift, and truncating mutations in the PHOX2B gene (non-polyalanine repeat mutations, NPARM) are much rarer, they are nevertheless associated with a much higher risk of developing neuroblastic tumors (around 45% compared to 1-2% with PARM).

Penetrance:

Probably around 50%

Overview of the Chapters on This Page:

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

PHOX2B Deficiency – Diagnosis

Clinical Diagnostics

A PHOX2B-related predisposition to neuroblastic tumors is suspected with the following findings:

  • Multiple primary neuroblastic tumors that occur synchronously or metachronously
  • A family history of neuroblastoma, ganglioneuroblastoma, or ganglioneuroma
  • The occurrence of a neuroblastic tumor in combination with CCHS, Hirschsprung’s disease, or another neurocristopathy

Genetic Diagnostics

The diagnosis of a “PHOX2B-related predisposition to neuroblastic tumors” is confirmed by detecting a heterozygous germline mutation in the PHOX2B gene.

Differential Diagnoses

  • Germline mutation of ALK

Clinical Presentation

Patients with a PHOX2B-related predisposition for neuroblastic tumors (especially NPARM) have an increased risk of developing neuroblastic tumors, such as the following:

  • Neuroblastoma: malignant tumor with the worst outcome
  • Ganglioneuroblastoma: depending on the histological findings, tends to be benign like ganglioneuroma or malignant like neuroblastoma
  • Ganglioneuroma: most benign tumor

In addition, there is also an increased risk of developing neurocristopathies, particularly CCHS and Hirschsprung’s disease. In patients with CCHS, the risk of developing a neuroblastic tumor is around 5-10%.

A few patients with a PHOX2B mutation exhibit facial dysmorphia, such as drooping palpebral fissures, a narrow nose, a triangular mouth, or low-lying ears rotated towards the back.

Special Features of Treatment

Treatment follows the guidelines of the neuroblastoma study.

Diagnosis of PHOX2B Deficiency- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Diagnosis of PHOX2B Deficiency- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Recommendations for Early Detection in Your Patients

There are no standard recommendations to date. The following is a possible approach for the early detection of neuroblastic tumors when a PHOX2B mutation has been detected:

Clinical examination, ultrasound of the abdomen, measurement of the catecholamines, VMA, and HVA in the urine, X-ray of the thorax (PA and lateral)

  • Every 3 months for children 0-6 years of age
  • Every 6 months for children 6-10 years of age
  • No screening examinations are necessary for children > 10 years of age.

PHOX2B Deficiency – weitere Informationen

Additional Resources

Unfortunately, we are currently not aware of any support groups for patients with PHOX2B-Deficiency. New information will be added as soon as it becomes available.