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PHOX2B: a diagnostic cornerstone in neurocristopathies and neuroblastomas
  1. Mei-Lan Windels1,
  2. Fleur Cordier1,
  3. Jo Van Dorpe1,2,
  4. Liesbeth Ferdinande1,
  5. David Creytens1,2
  1. 1 Department of Pathology, Ghent University Hospital, Ghent, Belgium
  2. 2 Cancer Research Institute Ghent (CRIG), Ghent University Hospital, Ghent University, Ghent, Belgium
  1. Correspondence to Dr David Creytens, Pathology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium; david.creytens{at}


Paired-like homeobox 2B (PHOX2B) is a gene essential in the development of the autonomic nervous system. PHOX2B mutations are associated with neurocristopathies—Hirschsprung disease (HSCR) and congenital central hypoventilation syndrome (CCHS)—and peripheral neuroblastic tumours. PHOXB2 plays an important role in the diagnostics of these conditions.

Genotyping of a PHOX2B pathogenic variant is required to establish a diagnosis of CCHS. In HSCR patients, PHOX2B immunohistochemical staining has proven to be a valuable tool in identifying this disease. Furthermore, PHOXB2 is a predisposition gene for neuroblastoma, in which PHOX2B immunohistochemical staining can be used as a highly sensitive and specific diagnostic marker. The utility of PHOX2B immunohistochemistry in pheochromocytoma and paraganglioma has also been studied but yields conflicting results.

In this review, an overview is given of PHOX2B, its associated diseases and the usefulness of PHOX2B immunohistochemistry as a diagnostic tool.

  • Pathology, Surgical
  • Pediatrics
  • Pathology, Molecular

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  • Handling editor Vikram Deshpande.

  • Contributors M-LW, FC and DC performed the writing of the paper and made the figures. M-LW, FC, JVD, LF and DC performed the study concept, design and review of the paper. All authors read and approved the final paper.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests One of the coauthors (DC) is an editor for the Journal of Clinical Pathology. The other authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.