Paired-like homeobox 2b (PHOX2B), also known asneuroblastoma Phox (NBPhox), is aprotein that in humans is encoded by the PHOX2Bgene located onchromosome 4.[5]
It codes for ahomeodomain 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 peripheralautonomic nervous system.Neuroblasts are derived from sympathoadrenal lineageneural crest cells and therefore require and constitutively express PHOX2B. PHOX2Bimmunohistochemical staining, as a marker of neural crest derivation, has been shown to be sensitive and specific for undifferentiatedneuroblastoma, 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 theenteric nervous system),ROHHAD, and tumours of thesympathetic 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.
Organisations involved in researching Phox2B include those concerned with Congenitial Central Hypoventilation Syndrome. These include Keep Me Breathing[11] based in the UK and The CCHS Network based in the USA. The CCHS Network held a scientific conference in September 2023, which covered significant research into Phox2B and CCHS with Keep Me Breathing presenting, too.[12]
^Bielle F, Fréneaux P, Jeanne-Pasquier C, Maran-Gonzalez A, Rousseau A, Lamant L, et al. (August 2012). "PHOX2B immunolabeling: a novel tool for the diagnosis of undifferentiated neuroblastomas among childhood small round blue-cell tumors".The American Journal of Surgical Pathology.36 (8):1141–1149.doi:10.1097/PAS.0b013e31825a6895.PMID22790854.S2CID25924210.
^Hung YP, Lee JP, Bellizzi AM, Hornick JL (November 2017). "PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours".Histopathology.71 (5):786–794.doi:10.1111/his.13288.PMID28640941.S2CID19123236.
^Warren M, Matsuno R, Tran H, Shimada H (March 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, Tillack C, Diegelmann J, Pfennig S, et al. (March 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".The American Journal of Gastroenterology.104 (3):665–672.doi:10.1038/ajg.2008.65.PMID19262523.S2CID7144509.
Liu CP, Li XG, Lou JT, Xue Y, Luo CF, Zhou XW, et al. (September 2009). "Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China".Journal of Pediatric Surgery.44 (9):1805–1811.doi:10.1016/j.jpedsurg.2008.12.009.PMID19735829.
Repetto GM, Corrales RJ, Abara SG, Zhou L, Berry-Kravis EM, Rand CM, et al. (January 2009). "Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene".Acta Paediatrica.98 (1):192–195.doi:10.1111/j.1651-2227.2008.01039.x.PMID18798833.S2CID4979994.
Jennings LJ, Yu M, Zhou L, Rand CM, Berry-Kravis EM, Weese-Mayer DE (December 2010). "Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers".Diagnostic Molecular Pathology.19 (4):224–231.doi:10.1097/PDM.0b013e3181eb92ff.PMID21051998.S2CID10071866.
Tu E, Bagnall RD, Duflou J, Lynch M, Twigg SM, Semsarian C (March 2010). "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus".Human Pathology.41 (3):392–400.doi:10.1016/j.humpath.2009.08.020.PMID20004937.
Hammel M, Klein M, Trips T, Priessmann H, Ankermann T, Holzinger A (September 2009). "Congenital Central Hypoventilation Syndrome due to PHOX2b gene defects: inheritance from asymptomatic parents".Klinische Padiatrie.221 (5):286–289.doi:10.1055/s-0029-1220941.PMID19707990.S2CID206295649.
Lee P, Su YN, Yu CJ, Yang PC, Wu HD (February 2009). "PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood".Chest.135 (2):537–544.doi:10.1378/chest.08-1664.PMID19201717.
Wu HT, Su YN, Hung CC, Hsieh WS, Wu KJ (April 2009). "Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants".Human Mutation.30 (4):655–660.doi:10.1002/humu.20929.PMID19191321.S2CID22257861.
Serra A, Häberle B, König IR, Kappler R, Suttorp M, Schackert HK, et al. (October 2008). "Rare occurrence of PHOX2b mutations in sporadic neuroblastomas".Journal of Pediatric Hematology/Oncology.30 (10):728–732.doi:10.1097/MPH.0b013e3181772141.PMID19011468.S2CID32426671.
Rudzinski E, Kapur RP (2010). "PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus".Pediatric and Developmental Pathology.13 (4):291–299.doi:10.2350/09-07-0682-OA.1.PMID19888871.S2CID34088649.
