PHOX2B analysis in non‐syndromic neuroblastoma cases shows novel mutations and genotype–phenotype associations

McConville, Carmel; Reid, Stuart; Baskcomb, Linda; Douglas, Jenny; Rahman, Nazneen

doi:10.1002/ajmg.a.31278

Cited by 47 publications

(38 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found two mutations in neuroblastoma-derived cell lines (one previously described (van Limpt et al, 2004)), and these may serve as good models for future functional investigations. We did not see any mutations in unselected primary neuroblastoma DNAs, consistent with the relatively low mutation frequency seen in other studies (van Limpt et al, 2004;McConville et al, 2006). Taken together, our result that germline mutations of PHOX2B are rarely found even in cases with clear genetic predisposition is perhaps not surprising since published and ongoing genetic linkage analyses in our lab have not identified a major predisposition locus at 4p13, the chromosomal location of the PHOX2B gene (Maris et al, 2002).…”

Section: Discussionsupporting

confidence: 91%

“…Whereas the majority of PHOX2B mutations in CCHS patients are triplet expansion mutations predicted to extend the second polyalanine tract in the C-terminal portion of the protein, mutations in neuroblastomas tend to be missense alterations in highly conserved regions or nonsense mutations that lead to a truncated protein and absent second polyalanine motif (Amiel et al, 2003;Weese-Mayer et al, 2003;Matera et al, 2004;Mosse et al, 2004;Trochet et al, 2004;van Limpt et al, 2004;McConville et al, 2006). We therefore sought to understand how these neuroblastoma-specific mutations might influence tumorigenesis and whether PHOX2B might play a role in neuroblastoma progression in the absence of coding-region mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygote germline alterations in PHOX2B have recently been identified in patients with familial neuroblastoma (Mosse et al, 2004;Trochet et al, 2004). In addition, PHOX2B mutations have also been discovered in sporadic cases of neuroblastoma, usually (but not always) in association with HSCR and/or CCHS (van Limpt et al, 2004;McConville et al, 2006).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

et al. 2007

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

et al. 2007

View full text Add to dashboard Cite

“…Larger PARMs would be detected by whole-exome sequencing, but may not be detected by gene panels. Although PHOX2B mutations are most often associated with CCHS and/or Hirschsprung disease, germline PHOX2B mutations have also been observed in some patients with NB in the absence of CCHS and/or Hirschsprung disease (86).…”

Section: Inactivating Mutations In Phox2bmentioning

confidence: 99%

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Kamihara

Bourdeaut

Foulkes

et al. 2017

Clinical Cancer Research

187

137

View full text Add to dashboard Cite

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.

show abstract

“…Mcconville et al identifi ed two PHOX2B mutations (600delC, a frameshift mutation and G197D, a missense mutation) as a rare cause of non-syndromic neuroblastoma, which indicates that the underlying PHOX2B mutational mechanism infl uences the risk of tumor and suggests that the position of missense mutations may infl uence the resulting phenotype. 6 We report an infant with CCHS who presented with central sleep apnea, which was fi rst demonstrated by polysomnography (PSG) when the infant was 5 months old. She was heterozygous for the novel 590delG mutation of PHOX2B.…”

Section: A S E R E P O R T Smentioning

confidence: 99%

A Case of Congenital Central Hypoventilation Syndrome with a Novel Mutation of the PHOX2B Gene Presenting as Central Sleep Apnea

Amimoto

Okada

Nakano

et al. 2014

Journal of Clinical Sleep Medicine

View full text Add to dashboard Cite

Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by abnormal autonomic control of breathing resulting in hypoventilation. We report an infant girl with CCHS who presented with central sleep apnea, which was fi rst demonstrated by polysomnography when the infant was 5 months old. She was heterozygous for the novel 590delG mutation of PHOX2B, which is classifi ed as a non-polyalanine repeat mutation (NPARM). This mutation is considered to be associated with a relatively mild phenotype. 2-4 Subsequently, Weese-Mayer and colleagues identifi ed mutations in exon 3 of the PHOX2B gene in all patients with the CCHS phenotype.5 Currently, identifi cation of a PHOX2B mutation is required to confi rm the diagnosis of CCHS. CCHS patients characteristically demonstrate alveolar hypoventilation with diminutive tidal volumes and monotonous respiratory rates during sleep, and in severe cases, also during wakefulness.5 Affected individuals have diffuse autonomic nervous system dysregulation (ANSD), with anatomical manifestations such as the risk of tumor development. Mcconville et al. identifi ed two PHOX2B mutations (600delC, a frameshift mutation and G197D, a missense mutation) as a rare cause of non-syndromic neuroblastoma, which indicates that the underlying PHOX2B mutational mechanism infl uences the risk of tumor and suggests that the position of missense mutations may infl uence the resulting phenotype. We report an infant with CCHS who presented with central sleep apnea, which was fi rst demonstrated by polysomnography (PSG) when the infant was 5 months old. She was heterozygous for the novel 590delG mutation of PHOX2B. REPORT OF CASEThe patient was a 5-month-old girl delivered by Cesarean section performed for obstructed labor at 40 weeks of gestation without any other complication during pregnancy and delivery. The Apgar scores were 8 at 1 min and 9 at 5 min. She was born to healthy parents without consanguinity: a 33-year-old father and a 23-year-old mother. No relatives of either parent suffered from sleep disorders. Three of the infant's grandparents had undergone surgery under anesthesia without any problems of respiratory management. Neither the parents nor the siblings showed any signs of Hirschsprung disease, tumors of neural crest origin, or other symptoms suggestive of ANSD.The patient was admitted to NICU because of frequent episodes of respiratory arrest for a few seconds at the onset of sleep on the day of birth. There were no rales or heart murmurs. The muscle tone was good. Venous blood gas analysis revealed a PvCO 2 of 32.7 mm Hg in room air. There were no abnormalities on x-ray examination of the chest/abdomen, examination of the cerebrospinal fl uid, or ultrasound examination of the brain and heart. The patient was discharged from the NICU one month after birth under home oxygen therapy; supplemental oxygen by nasal cannula (2 L/m) during sleep with SpO 2 monitoring was prescribed at discharge. She was brought to the hospital in which she was born at 5 months of age wi...

show abstract

PHOX2B analysis in non‐syndromic neuroblastoma cases shows novel mutations and genotype–phenotype associations

Cited by 47 publications

References 13 publications

Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

A Case of Congenital Central Hypoventilation Syndrome with a Novel Mutation of the PHOX2B Gene Presenting as Central Sleep Apnea

Contact Info

Product

Resources

About