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ALK-Related Neuroblastoma Susceptibility

Other Names: Familial neuroblastoma


ALK-related neuroblastoma susceptibility is a rare genetic condition in which individuals have a higher chance to develop certain cancerous and noncancerous tumors. It is caused by mutations in the ALK gene which makes a protein called anaplastic lymphoma kinase.

Characteristics of ALK-Related Neuroblastoma Susceptibility
Individuals with ALK-related neuroblastoma susceptibility have an increased chance of developing cancerous (malignant) and noncancerous (benign) tumors. The most aggressive cancerous tumor in this condition is neuroblastoma, the most common cancer to occur in children under 1 year of age. Individuals with this condition also have an increased chance to develop other similar, but less aggressive tumors, including ganglioneuroblastoma and ganglioneuroma. Neuroblastoma is a cancer that occurs when immature nerve cells, called neuroblasts, become abnormal and multiply uncontrollably to form a tumor. If the tumor is surrounded by a cell type called ganglion cells, it may be called a ganglioneuroblastoma, or the more benign, ganglioneuroma. The chance for tumors to develop in individuals with ALK-related neuroblastoma susceptibility is greatest in infancy and decreases by late childhood. Individuals with ALK-related neuroblastoma susceptibility tend to develop tumors at a younger age than those without an inherited predisposition.

Diagnosis/Testing
ALK-related neuroblastoma susceptibility can be diagnosed by genetic testing for a change or mutation in a gene called ALK. The ALK gene is thought to be an oncogene which means that it contributes to how fast cells grow. Mutations in the ALK gene are thought to result in an abnormal version of the anaplastic lymphoma kinase protein which may cause cells to grow uncontrollably. This uncontrolled growth of immature nerve cells is what can cause the neuroblastoma and related tumors in affected individuals. Individuals with neuroblastoma who have a family history of neuroblastoma, or those with multiple neuroblastoma tumors, are more likely to have an ALK gene mutation than individuals with a single tumor and no family history of tumors. About 1-2% of individuals diagnosed with neuroblastoma have a family history of neuroblastoma.

Management/Surveillance
Formal guidelines have not yet been established for screening individuals with ALK-related neuroblastoma susceptibility. However, for children with an ALK gene mutation, screening may include noninvasive techniques such as having ultrasounds of the abdomen (to look for tumors) and/or measuring levels of substances (catecholamines) in the urine. Neuroblastomas can cause the level of catecholamines in the urine to be increased. These tests can be done every 1-2 months in infants and then less frequently (3-4 months) from age 1 to 10 years.
Since there is no consensus on the timing and frequency of screening for individuals with ALK-related neuroblastoma susceptibility, being aware of the signs and symptoms of neuroblastoma is important. General signs and symptoms (irritability, fever, tiredness, pain, loss of appetite, diarrhea, easy bruising, pale skin, dark circles around the eyes) may develop. It is important to keep in mind that when most of these nonspecific symptoms occur in an individual, the symptoms are most often not associated with a cancer or tumor.
For individuals with ALK-related neuroblastoma susceptibility who are diagnosed with neuroblastoma, they should be closely followed by a pediatric oncologist at a pediatric cancer center.

Mode of inheritance
ALK-related neuroblastoma susceptibility is inherited in an autosomal dominant pattern with incomplete penetrance. This means inheriting one ALK mutation is enough for an individual to have an increased chance of developing neuroblastoma, but not everyone with an inherited ALK gene mutation develops cancer. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child.

Risk to family members
The risk to family members depends on whether or not the individual with an ALK gene mutation has a parent with the gene mutation. If a parent also has ALK-related neuroblastoma susceptibility, the risk of having a child with the risk is 50% with each pregnancy. If a parent does not have ALK-related neuroblastoma susceptibility, the risk of other siblings being affected is very low.

Special considerations
Mutations in another gene, called PHOX2B, can also cause susceptibility to neuroblastoma development. Individuals with mutations in the PHOX2B gene are also at an increased risk of developing abnormalities of the colon (Hirschsprung’s disease) and lungs (central hypoventilation).

Resources
Children's Neuroblastoma Cancer Foundation
Genetics Home Reference: Neuroblastoma

References
Bourdeaut, F. et al. (2012)."ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome." European Journal of Human Genetics 20(3): 291-297.
Johnson RH, Park, JR. (Updated 9 May 2013). ALK-Related Neuroblastoma Susceptibility. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.ncbi.nlm.nih.gov/books/NBK24599/. Accessed [07/12/2013].
Mosse, YP. et al. (2008)."Identification of ALK as the major familial neuroblastoma predisposition gene." Nature 455(7215): 930-935.

Created:07/2013

Updated:mm/yyyy

Created by:Kami Wolfe Schneider, MS, CGC

Edited by:Seema Jamal, MSc, LCGC



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