Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development.
Approximately 1-2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset.
Universal mass screening for neuroblastoma is not indicated but targeted screening of infants at risk of hereditary neuroblastoma with germline ALK or PHOX2B mutations is appropriate.
These findings show that PHOX2B alterations are a rare cause of hereditary neuroblastoma, but disruption of this neurodevelopmental pathway can interfere with transcription-dependent terminal differentiation.
The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma.
The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma.