ALK-Related Neuroblastic Tumor Susceptibility

Excerpt

Clinical characteristics: ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Neuroblastomas are a more malignant tumor and ganglioneuromas a more benign tumor. Depending on the histologic findings, ganglioneuroblastomas can behave in a more aggressive fashion, like neuroblastomas, or in a benign fashion, like ganglioneuromas. The overall penetrance of a germline ALK pathogenic variant is approximately 50%, 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 by molecular genetic testing.

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 neuroblastomas and ganglioneuroblastomas 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: In asymptomatic children and after successful treatment of neuroblastic tumors: abdominal ultrasound and urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every three months and physical examination and chest radiograph every six months between birth and age six years; physical examination, abdominal ultrasound, and measurement of urine catecholamine metabolite levels every six months and chest radiograph every six to 12 months between ages six and ten years. Screening beyond age ten years is not indicated.

Evaluation of relatives at risk: It is appropriate to test relatives at risk (e.g., 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 neuroblastomas 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. Some individuals diagnosed with ALK-related neuroblastic susceptibility inherited a pathogenic variant from a heterozygous parent. Because of reduced penetrance, a parent may have a germline ALK activating pathogenic variant without having developed a neuroblastic tumor. Some individuals diagnosed with ALK-related neuroblastic tumor susceptibility have the disorder as the result of a de novo germline activating pathogenic variant; the proportion of probands who have 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. The likelihood that a child who inherits the pathogenic variant will develop a neuroblastic tumor is unknown, though the penetrance is estimated to be around 50%. Once the germline ALK activating pathogenic variant has been identified in an affected family member, genetic testing of at-risk asymptomatic relatives and prenatal/preimplantation genetic testing are possible.