Paired-like homeobox 2b (PHOX2B), also known as neuroblastoma Phox (NBPhox), is a protein that in humans is encoded by the PHOX2Bgene located on chromosome 4.[5]
It codes for a homeodomain transcription factor. It is expressed exclusively in the nervous system, in most neurons that control the viscera (cardiovascular, digestive and respiratory systems). It is also required for their differentiation.
Essential for the differentiation and survival of sympathetic neurons and chromaffin cells, the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system. Neuroblasts are derived from sympathoadrenal lineage neural crest cells and therefore require and constitutively express PHOX2B. PHOX2B immunohistochemical staining, as a marker of neural crest derivation, has been shown to be sensitive and specific for undifferentiated neuroblastoma, enabling identification where other markers fail to recognize neuroblastoma among various different small round blue cell tumors of childhood.[6][7][8][9]
The diagnostic utility of PHOX2B staining extends to later stages of differentiation. Its strength and specificity can detect the small foci of neuroblastic tumors metastatic to the bone marrow, an identification critical for determining disease staging. PHOX2B staining also overcomes frequent obstacles to neuroblastoma detection in post-treatment samples, which frequently exhibit dense fibrosis, prominent inflammatory infiltrates, and/or diffuse calcification.[10]
Mutations in human PHOX2B cause a rare disease of the visceral nervous system (dysautonomia): congenital central hypoventilation syndrome (associated with respiratory arrests during sleep and, occasionally, wakefulness), Hirschsprung's disease (partial agenesis of the enteric nervous system), ROHHAD, and tumours of the sympathetic ganglia.
In most people, Exon 3 of the gene contains a sequence of 20 polyalanine repeats. An increase in the number of repeats is associated with congenital central hypoventilation syndrome. There may also be other pathogenic mutations further along the gene.
^Hung, Yin P.; Lee, John P.; Bellizzi, Andrew M.; Hornick, Jason L. (2017). "PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours". Histopathology. 71 (5): 786–794. doi:10.1111/his.13288. PMID28640941. S2CID19123236.
^Warren, Mikako; Matsuno, Ryosuke; Tran, Henry; Shimada, Hiroyuki (2018). "Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients". Histopathology. 72 (4): 685–696. doi:10.1111/his.13412. PMID28986989. S2CID3302863.
Glas J, Seiderer J, Pasciuto G, et al. (2009). "rs224136 on chromosome 10q21.1 and variants in PHOX2B, NCF4, and FAM92B are not major genetic risk factors for susceptibility to Crohn's disease in the German population". Am. J. Gastroenterol. 104 (3): 665–72. doi:10.1038/ajg.2008.65. PMID19262523. S2CID7144509.
Liu CP, Li XG, Lou JT, et al. (2009). "Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China". J. Pediatr. Surg. 44 (9): 1805–11. doi:10.1016/j.jpedsurg.2008.12.009. PMID19735829.
Repetto GM, Corrales RJ, Abara SG, et al. (2009). "Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene". Acta Paediatr. 98 (1): 192–5. doi:10.1111/j.1651-2227.2008.01039.x. PMID18798833. S2CID4979994.
Jennings LJ, Yu M, Zhou L, et al. (2010). "Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers". Diagn. Mol. Pathol. 19 (4): 224–31. doi:10.1097/PDM.0b013e3181eb92ff. PMID21051998. S2CID10071866.
Tu E, Bagnall RD, Duflou J, et al. (2010). "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus". Hum. Pathol. 41 (3): 392–400. doi:10.1016/j.humpath.2009.08.020. PMID20004937.
Hammel M, Klein M, Trips T, et al. (2009). "Congenital Central Hypoventilation Syndrome due to PHOX2b gene defects: inheritance from asymptomatic parents". Klin Padiatr. 221 (5): 286–9. doi:10.1055/s-0029-1220941. PMID19707990. S2CID206295649.
Lee P, Su YN, Yu CJ, et al. (2009). "PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood". Chest. 135 (2): 537–44. doi:10.1378/chest.08-1664. PMID19201717.
Wu HT, Su YN, Hung CC, et al. (2009). "Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants". Hum. Mutat. 30 (4): 655–60. doi:10.1002/humu.20929. PMID19191321. S2CID22257861.