PHOX2B Germline Mutation and Neuroblastoma: Genetic Evidence

By Nucleati Team
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In the intricate realm of genetics, certain master regulators hold the key to developing and functioning critical systems within our bodies. One such transcription factor, PHOX2B, has emerged as a crucial player in developing the autonomic nervous system and determining neurotransmitter phenotype. This DNA-binding protein, belonging to the paired family of homeobox proteins, functions as a transcription factor localized to the nucleus. Its significance becomes apparent when we explore the diseases associated with mutations in the PHOX2B gene.

Germline mutations in the PHOX2B gene primarily cause congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by impaired autonomic control of breathing, particularly during sleep. Interestingly, genetic analysis has also uncovered a fascinating link between PHOX2B germline mutations and neuroblastoma development, a childhood tumor originating from progenitor cells of the sympathetic nervous system. This finding has brought new light to the understanding of neuroblastoma pathogenesis and provided important insights into the genetic basis of this pediatric cancer.

Table 1 summarizes published case reports illuminating the association between PHOX2B germline mutations and neuroblastoma—these reports present cases where neuroblastoma is present in patients carrying specific mutations in the PHOX2B gene.

Table 1: Published Case Reports of PHOX2B and Neuroblastoma
Patient/Family Gene/Variation Clinical Characteristics HGVS(es) Citation
A familial case of neuroblastoma and a patient associated with Hirschsprung disease (HSCR) and neuroblastoma. Germline mutations of the PHOX2B and NF1 gene Neuroblastoma is a frequent pediatric tumor associated with other congenital malformations such as Hirschsprung disease and central hypoventilation syndrome. Germline mutations in the PHOX2B gene are implicated in both neuroblastoma and Hirschsprung disease. NM_003924.4(PHOX2B):c.552C>T (p.Ser184=), NM_003924.4(PHOX2B):c.676del (p.Ala226fs) PubMed
A family with three first-degree relatives with neuroblastic tumors (two ganglioneuromas and one neuroblastoma) A constitutional PHOX2B mutation. One patient with Hirschsprung's disease developed a multifocal neuroblastoma. Both mutations disrupt the homeodomain of the PHOX2B protein. NM_003924.4(PHOX2B):c.299G>T (p.Arg100Leu) PubMed
Neurocristopathy syndrome patient PHOX2B germline mutation Congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma NM_003924.4(PHOX2B):c.691_698dup (p.Gly234AlafsX78) PubMed
One day old male patient diagnosed with NB-HSCR-CCHS cluster PHOX2B gene deletion NB, HSCR, CCHS; abdominal distention, vomiting, severe apneic episodes NM_003924.4(PHOX2B):c.699_706del8 (p.Gly234ArgfsTer?) PubMed

Building on the evidence from individual case reports (Table 1), we explore case series articles that further validate the association of PHOX2B germline mutations with neuroblastoma. These comprehensive studies offer a broader perspective, analyzing data from multiple patients with neuroblastoma and PHOX2B mutations, reinforcing the significance of this genetic connection.

Table 2: Case Series Articles on PHOX2B and Neuroblastoma
Cohort Setup Outcome HGVS(es) Citation
237 sporadic neuroblastomas and 22 cell lines Phox2B gene mutations in exons 2 and 3 were analyzed. Six frameshift mutations in exons 2 and 3 were found, including one in cell line SK-N-SH. Two patients showed de novo constitutional mutations. NM_003924.4(PHOX2B):721_737dup (p.Ala247GlnfsTer?), NM_003924.4(PHOX2B):284_291del (p.Lys95ThrfsTer80) PubMed
Neuroblastoma cohort Germline mutations in PHOX2B gene Only a few NB families carry PHOX2B mutations, indicating a remarkable genetic heterogeneity of NB. Familial NB cannot be modeled as a Mendelian monogenic trait, but an oligogenic mode of inheritance might explain the existence of different NB loci genetically interacting to cause and/or modify the disease-phenotype. - PubMed
Italian families with recurrence of NB and one family with the occurrence of ganglioneuroblastoma and isolated Hirschsprung disease PHOX2B gene screening No mutation found in PHOX2B gene in families analyzed, suggesting PHOX2B may not be the NB susceptibility gene in these families ~ PubMed
86 individuals with non-syndromic NB (4 cases had a family history of NB) PHOX2B analysis in constitutional DNA PHOX2B mutations are a rare cause of non-syndromic NB. G197D, a missense mutation, was present in a family with multiple individuals with NB but no evidence of autonomic dysfunction. 600delC, a frameshift mutation, was found in an individual with isolated, unifocal NB. NM_003924.4(PHOX2B):c.590G>A (p.Gly197Asp), NM_003924.4(PHOX2B):600delC PubMed
13 NB cell lines and 45 tumours Expression, mutations of coding and promoter sequences, loss of heterozygosity (LOH), or aberrant hypermethylation of PHOX2B No identified mutations but LOH in 10% of cases and aberrant CpG dinucleotide methylation of the 500 bp PHOX2B promoter region in 4/31 tumours and cell lines (12.9%) NM_003924.4(PHOX2B):c.552C>T (p.Ser184=) NM_003924.4(PHOX2B)870C>A (p.Pro290=) PubMed
47 individuals with presumed genetic predisposition to neuroblastoma Germline PHOX2B alterations in hereditary neuroblastomas PHOX2B alterations are a rare cause of hereditary neuroblastoma. Forced overexpression of wild-type PHOX2B suppressed cell proliferation and synergized with all-trans retinoic acid to promote differentiation. Patient-derived mutant PHOX2B constructs retained the ability to suppress cellular proliferation, but were not able to promote differentiation or activate expression of a known PHOX2B target gene in vitro. NM_003924.4(PHOX2B):c.691_698dup (p.Gly234AlafsX78), NM_003924.4(PHOX2B):c.552C>T (p.Ser184=), NM_003924.4(PHOX2B):c.676del (Ala226ArgfsTer83), NM_003924.4(PHOX2B):c.299G>T (p.Arg100Leu), NM_003924.4(PHOX2B):c.741_755del (p.Ala248_Ala252del), NM_003924.4(PHOX2B):c.756_776del (p.Ala253_Ala259del) PubMed

Nucleati Germline Cancer Evidence Base: Our Source of Comprehensive Data

To compile the summary tables of case reports and case series, we relied on the Nucleati Germline Cancer Evidence Base, a reliable repository of evidence in germline cancer genetics. This robust resource presents the most comprehensive and up-to-date information on the association between PHOX2B germline mutations and neuroblastoma.


In conclusion, the discovery of the link between PHOX2B germline mutations and neuroblastoma represents a significant milestone in understanding the genetic basis of neuroblastoma and the crucial role PHOX2B plays in neurodevelopment. As we uncover the intricate connections between genetics and disease, this newfound knowledge paves the way for more targeted and personalized approaches to diagnosing and treating neuroblastoma. The Nucleati Germline Cancer Evidence Base is a powerful tool in unraveling the mysteries of germline mutations and their impact on cancer development, ultimately leading us toward a brighter future in the fight against pediatric cancers.