ALK-Related Neuroblastic Tumor Susceptibility

Clinical characteristics: ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including 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. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.

Diagnosis/testing: 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.

Management: 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:

1. Asymptomatic children. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every three months between birth and age six years. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every six months between age six years and ten years. Screening beyond age ten years is not indicated.

2. 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. Screening should continue as described above until age ten years.

Evaluation of relatives at risk: It is appropriate to test relatives at risk (i.e., sibs age <10 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).

Genetic counseling: ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner, with reduced penetrance. Some individuals diagnosed with ALK-related neuroblastic susceptibility have an affected parent who may have had any one of the three neuroblastic tumor types. 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 is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.