What is a PHOX2B-related predisposition to neuroblastic tumors?

A PHOX2B-related predisposition to neuroblastic tumors is caused by a genetic alteration in the PHOX2B gene and is associated with the increased likelihood of tumors developing in autonomic (i.e. not consciously controllable) nerve tissue. The tumors involved are neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. In addition, there is an increased risk of developing Hirschsprung’s disease and congenital central hypoventilation syndrome (CCHS). The terms Hirschsprung’s disease and CCHS are explained below.

How is PHOX2B-related predisposition to neuroblastic tumors diagnosed?

Clinical Diagnostics

The existence of an PHOX2B-related predisposition to neuroblastic tumors is suspected in a person who exhibits the following:

  • Multiple neuroblastic tumors that occur either at the same time or at different times

  • The occurrence of a neuroblastoma, ganglioneuroblastoma, or ganglioneuroma in more than one family member

  • The occurrence of a neuroblastic tumor in combination with CCHS or Hirschsprung’s disease (see below)

Genetic Diagnostics

The diagnosis of a “PHOX2B-related predisposition to neuroblastic tumors” is confirmed by detection of a mutation – or genetic change – in the PHOX2B gene.

Other Clinical Features

Patients with a PHOX2B-related predisposition to neuroblastic tumors are at increased risk of developing neuroblastic tumors, such as the following:

  • Neuroblastoma: This is a malignant tumor that arises from autonomic (i.e. not consciously controllable) nerve tissue and has the worst outcome of the tumors described here. Neuroblastomas can occur in the spinal region, in the head and neck area, and in the chest, abdominal, and pelvic area along the autonomic nerve paths and where there are clusters of autonomic nerve cells. The symptoms vary greatly depending on the location and range from pain to shortness of breath, from urinary tract and intestinal problems to paralysis.

  • Ganglioneuroblastoma: These tumors can either be benign, in the case of ganglioneuromas, or malignant, as in the case of neuroblastomas. They are usually found in the region of the spine, the trunk, or in the posterior chest area.

  • Ganglioneuroma: This is usually a benign tumor that arises from autonomic (i.e. not from consciously controllable) nerve tissue. Ganglioneuromas mainly occur in the spinal region, in the chest, head, and neck area, and in the adrenal glands. While these tumors are often asymptomatic, they can also trigger pain or breathing difficulties.

In addition, there is an increased risk of developing congenital central hypoventilation syndrome (CCHS). This congenital disease of the nervous system is associated with disruption or absent control of autonomic respiration, which is usually more pronounced during sleep than when awake.

Another disease that occurs with PHOX2B mutations is Hirschsprung’s disease, also called congenital megacolon. In this disease, a lacking neural supply in parts of the big intestine causes a constriction in a section of the bowel, leading to considerable constipation. The ensuing backup of feces results in the bowel section above the constricted point to expand, leading to flatulence and vomiting.

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

Wie hoch ist das Krebsrisiko?

Liegt bei einem Patienten eine Mutation, also genetische Veränderung im PHOX2B-Gen vor, so hängt die Wahrscheinlichkeit, einen neuroblastischen Tumor zu entwickeln, von der Art der zugrundeliegenden Mutation ab. Bei den sogenannten Nicht-Polyalanin Repeat Mutationen beträgt das Risiko etwa 50%, bei den Polyalanin Repeat Mutationen ist es hingegen deutlich niedriger. Besprechen Sie dieses Thema bei der genetischen Beratung.

If a patient has a mutation – or genetic change – in the PHOX2B gene, the probability that a neuroblastic tumor will develop depends on the type of underlying mutation. With non-polyalanin repeat mutations, the risk is 50%; with polyalanin repeat mutations, the risk is much lower. Discuss this issue during a genetic consultation.

What causes PHOX2B-related predisposition to neuroblastic tumors?

Die PHOX2B-bedingte Prädisposition für neuroblastische Tumore beruht auf einer Mutation, also einer genetischen Veränderung des PHOX2B-Gens. Dieses Gen kodiert für das PHOX2B-Protein. Dieses Protein kontrolliert die Vermehrung und Entwicklung unreifer Nervenzellen. Liegt nun das Gen in einer veränderten Form vor, wird auch das Protein nicht mehr richtig hergestellt und kann seine Funktion nicht korrekt ausführen, wodurch es folglich zur Entstehung von Tumoren kommt.

Is there a treatment?

Patients with PHOX2B-related neuroblastic tumors should be treated in a pediatric oncology hospital, where the procedure will also be coordinated with the principal investigator of the neuroblastoma study.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

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

A clinical examination, abdominal ultrasound, measurement of the catecholamines (neurotransmitters of the autonomic nervous system) vanillylmandelic acid and homovanillic acid in the urine, X-rays of the lungs

  • 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.

Self-Care and Support

What should I pay special attention to?

With congenital central hypoventilation syndrome and Hirschsprung’s disease, symptoms already occur directly after or during the first few days after birth. In the case of CCHS, these symptoms include disrupted breathing, usually more pronounced during sleep, and in the case of Hirschsprung’s disease symptoms include the absence of meconium evacuation, irregular bowel movements, and vomiting. With both problems, it is very important to consult a pediatrician.

If other symptoms, complaints, or anomalies occur in addition to one of the above-mentioned diseases or if there is a known PHOX2B mutation, you should also consult a doctor to clarify whether there is a neuroblastic tumor.

Support Groups and Additional Information

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.