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%
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.
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
According to the latests AACR guidelines, the following screening tests for neuroblastoma predisposition are recommended for patients with CCHS and pathogenic variants in PHOX2B that are so-called PARMs (polyalanine repeat mutations) ≥28 repeats or non-PARMs:
Children aged 0-6 years
- Abdominal ultrasound, vanillin mandelic acid and homovanillic acid in urine every 3 months
- Chest x-ray every 6 months
Children aged 6-10 years
- Abdominal ultrasound, vanillin mandelic acid and homovanillic acid in urine every 6 months
- Chest x-ray every 6-12 months
Children >10 years
No screening recommended.
