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ALK or PHOX2B – risk management

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Familial neuroblastoma predisposition is an autosomal dominant cancer predisposition due to a heritable pathogenic variant in the ALK gene or the PHOX2B gene.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow-up. 

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

Unaffected individuals under age 18 years with or obligate carrier of:

Exclusion criteria

  • Individuals age 18 years and over 
  • Individuals who tested negative for a familial ALK or PHOX2B pathogenic variant.
Cancer/tumour type Risk for this group by age 20 years General population risk by age 20 years

Neuroblastoma, neuroganglioblastoma or neuroganglioma with:

     - ALK pathogenic variant

     - PHOX2B NPARM*

     - PHOX2B PARM*

 

Variable, up to 45-50%r,r

Variable, up to 40%r

<3%r

 

Unknown

Unknown

Unknown

* Abbreviations: NPARM = non-polyalanine repeat mutation; PARM = polyalanine repeat mutation

There is currently no international consensus on screening. Surveillance protocols have been proposed by expert groups but have not been systematically studied.

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

Cancer/tumour type Recommendations*
Neuroblastoma Surveillance Age Strategy and frequency
0 to 6 years Consider abdominal ultrasound, urine VMA and HVA, and chest x-rays 3 monthly
6 to10 years Consider abdominal ultrasound, urine VMA and HVA, and chest x-rays 6 monthly

Abbreviations: VMA = vanillylmandelic acid; HVA = homovanillic acid
* The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

For children with a PHOX2B variant a referral for respiratory review is recommended for consideration of congenital central hypoventilation syndrome and/or obstructive sleep apnoea. 

Surveillance

There are limited data on the effectiveness of cancer screening in ALK or PHOX2B pathogenic variant carriers. Published recommendations represent expert opinion and are extrapolated from cancer screening studies in the general population. 

Population screening for neuroblastoma (NB) by measuring urinary catecholamine metabolites in newborn, infancy and at 1 year of age was shown to be effective for screening for presymptomatic NB but resulted in a significantly increased incidence of NB, no decrease in NB in children over 1 year of age and no difference in mortality.r,r However, experts suggest that screening using a combination of abdominal ultrasound, urine catecholamines and chest x-rays may be useful in a targeted population of children at increased risk of NB due to a hereditary predisposition.r

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 2

Date Summary of changes
28/09/2022

Protocol discussed at Paediatric cancer genetics reference committee meeting on 23 June 2022. Approved for publication with the following changes made: 

  • Summary: template sentence updated
  • Management of associated health problems: new section added

Approved on 28/09/2022. Changes published on 4/10/2022. Version number increased to V.2. Review in 2 years.

Version 1

Date Summary of changes
19/12/2019 New protocol developed and discussed by the cancer genetics paediatric reference committee at the July 2019 reference committee meeting. Protocol approved for publication as V.1. Review in 2 years.
28/01/2021 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Summary: template sentence added
  • Lifetime risk of cancer table: heading changed to "Lifetime risk of cancer/tumour"
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • "Age to begin" changed to "Age"
  • Support and information: template wording updated

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3735

26 Nov 2022