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ALK-Related Neuroblastic Tumor Susceptibility.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2010 Jan 5 [updated 2015 Apr 9].



ALK-related neuroblastic tumor susceptibility results from heterozygosity for a germline ALK activating pathogenic variant in the tyrosine kinase domain that predisposes to neuroblastic tumors. The spectrum of neuroblastic tumors includes neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. At present there are no data regarding the lifetime risk to an individual with a germline ALK pathogenic variant of developing a neuroblastic tumor. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest that the overall penetrance is around 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.


ALK-related neuroblastic tumor susceptibility is established by identification of a heterozygous germline ALK activating pathogenic variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function.


Treatment of manifestations: Children who develop neuroblastic tumors should be evaluated and treated by a pediatric oncologist at a pediatric cancer center. Treatment for individuals with neuroblastoma and ganglioneuroblastoma who have a germline ALK activating pathogenic variant is the same standard risk-stratified therapy used to treat all neuroblastoma. Ganglioneuromas are typically removed by surgical resection and require no further therapy. Surveillance:Asymptomatic children. Because no data are available as yet on the effect of screening in families with a germline ALK activating pathogenic variant and because tumor surveillance at the population level does not improve neuroblastoma outcome, there is currently no consensus on the proper frequency or type of tumor surveillance for asymptomatic children with a germline ALK activating pathogenic variant. In the absence of published guidelines, some healthcare providers perform the noninvasive measures of physical examination, abdominal ultrasound examination, and measurement of urine catecholamine metabolite levels every 1-2 months in infants age ≤12 months and every 3-4 months in children age ≤10 years; however, less frequent intervals may also be appropriate. After successful treatment of a neuroblastic tumor. Screening for neuroblastoma should continue since children with ALK-related neuroblastoma are at risk of developing multiple primary tumors. Although no consensus exists, some recommend screening until age six years. Evaluation of relatives at risk: It is appropriate to test relatives at risk (i.e., sibs who are younger than age ten years at the time of diagnosis of the proband, as well as sibs born subsequently) for the ALK pathogenic variant found in the proband to identify those for whom early detection of neuroblastoma and initiation of therapy would likely improve quality of life and possibly affect outcome (if therapy is started prior to end organ damage).


ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner, with incomplete penetrance. Some (not all) individuals diagnosed with ALK-related neuroblastic susceptibility have an affected parent who may have had any one of the three neuroblastic tumor types. Although de novo germline pathogenic variants have been reported, the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with ALK-related neuroblastic tumor susceptibility has a 50% chance of inheriting the ALK pathogenic variant; however, the likelihood that a child who inherits the ALK pathogenic variant will develop a neuroblastic tumor is unknown. Prenatal testing for pregnancies at increased risk is possible; however, requests for prenatal testing for conditions which (like ALK-related neuroblastic tumor susceptibility) do not affect intellect and have some treatment available are not common.

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