PHOX2B – Neuroblastoma Predisposition

PHOX2B, located on chromosome 4p12, encodes a homeobox transcription factor essential for development of neural crest–derived autonomic neurons. Heterozygous mutations in PHOX2B are established causes of congenital central hypoventilation syndrome and Hirschsprung disease; accumulating data now implicate PHOX2B in hereditary neuroblastoma predisposition. Germline variants have been identified in multiple families with early‐onset neuroblastic tumors, reflecting a shared neurocristopathy spectrum.

Neuroblastoma associated with PHOX2B follows an autosomal dominant inheritance pattern with incomplete penetrance. Segregation has been documented in familial clusters, including a three‐member kindred harboring c.299G>T (p.Arg100Leu) across first-degree relatives (PMID:15949893). A novel missense mutation, c.422G>A (p.Arg141Gln), co-segregated in two affected siblings in a multigenerational neuroblastoma family (PMID:38420445).

At least five unrelated probands have been reported with distinct PHOX2B germline variants, including c.421C>G (p.Arg141Gly) and c.945A>G (p.Ter315Trp) in families with both isolated and syndromic neuroblastoma presentations (PMID:15024693). This variant spectrum encompasses missense, frameshift, and nonstop changes, meeting strong genetic evidence thresholds for disease causation.

Functional studies corroborate a loss-of-function mechanism in neuroblastoma-linked PHOX2B variants. Frameshift and truncation mutants disrupt binding to the neuronal calcium sensor HPCAL1, abrogating neurite outgrowth in neuroblastoma cells (PMID:23873030). Additionally, patient-derived mutant proteins fail to induce target gene expression and terminal differentiation in vitro (PMID:17637745).

Although PHOX2B mutations are rare in sporadic neuroblastoma cohorts (<3%), their consistent identification in familial and syndromic cases, coupled with segregation and functional concordance, reinforces a strong gene-disease association. No substantial refuting evidence has emerged, underscoring a specific role of PHOX2B in hereditary neuroblastoma predisposition.

Collectively, germline PHOX2B variants satisfy ClinGen Strong criteria for neuroblastoma association, supported by multiple segregating pedigrees and concordant experimental data. PHOX2B sequencing is recommended in familial or syndromic neuroblastoma cases to inform risk assessment and guide surveillance.

References

• American journal of human genetics • 2004 • Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. PMID:15024693
• Cancer letters • 2005 • Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. PMID:15949893
• Oncogene • 2008 • Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. PMID:17637745
• Oncogene • 2014 • Mutations that disrupt PHOX2B interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma. PMID:23873030
• Heliyon • 2024 • Identifying a novel PHOX2B gene variant in a neuroblastoma family: A case report. PMID:38420445

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