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

Key Data

< swipe to see entire table >
Synonyms Sarcoma breast leukemia and adrenal gland cancer syndrome
Gene product PHOX2B
Function Proliferation regulation of immature sympathetic neurons
Heredity Autosomal dominant
Prevalence Along with ALK mutations, around 1-2% of neuroblastoma patients
Genotype-phenotype correlation 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).

Penetranz Probably around 50%
< swipe to see entire table >


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 the detection of 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 the ganglioneuroma or malignant like the 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 that are rotated towards the back.

Therapeutic Considerations

Treatment is in accordance with the treatment guidelines of the neuroblastoma study.

Surveillance Recommendations

Surveillance Recommendations

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.

Additional Information

Open Clinical Trials / Registries

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with a PHOX2B-related predisposition to neuroblastic tumors. We will add new information as it becomes available.