Neuroblastoma (NBL) is a cancer of developing nerve cells that mainly affects infants and young children. The disease shows a wide range of clinical behaviors, with some tumors regressing spontaneously while others demonstrate a more aggressive course.
NBL tumors may originate in the:
Most hereditary neuroblastoma (NBL) occur sporadically, affecting individuals who have no family history of the disease. However, in about 1 to 2 percent of cases, a susceptibility to develop hereditary neuroblastoma (NBL) can be inherited from a parent. Compared to patients with the sporadic form of the disease, individuals with familial neuroblastoma have a higher incidence of multiple primary tumors and are diagnosed at a younger age.
The risk to develop the features associated with hereditary neuroblastoma (NBL) may be passed from generation to generation in a family, but the severity of disease can vary widely between family members.
A predisposition to hereditary neuroblastoma (NBL) is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.
There are two genes that are often altered in patients with familial neuroblastoma:
Most hereditary neuroblastoma (NBL) are caused by alterations in the ALK gene. PHOX2B-related neuroblastomas are far less common, and typically occur in patients with other disorders of neural crest development such as:
Both the ALK and PHOX2B genes produce proteins that are critical for normal nervous system development.
With the exception of egg and sperm cells, each cell of the body normally has two working copies of both the ALK and PHOX2B genes. In some patients with hereditary NBL, however, each cell contains only one working copy of either ALK or PHOX2B. While the second copy is present, it is altered so that it does not function properly. ALK and PHOX2B mutations are believed to contribute to the development of NBL by increasing the proliferation of neural cells, which makes them more likely to become cancerous.
Some individuals with hereditary neuroblastoma (NBL) inherit an altered copy of either ALK or PHOX2B from a parent who carries the same genetic mutation. In the remaining patients, the susceptibility to develop neuroblastoma results from the development of a “new” mutation in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change.
Individuals who carry an alteration in one copy of either ALK or PHOX2B in all the cells of their body have a 50 percent, or 1 in 2 chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy have an increased risk of developing neuroblastoma, or in the case of PHOX2B, the additional features associated with congenital central hypoventilation syndrome (CCHS), such as Hirschsprung disease and decreased esophageal motility.
Sometimes, it is difficult to tell whether a predisposition to hereditary neuroblastoma (NBL) was inherited from a parent. This is because some individuals with ALK or PHOX2B mutations never develop neuroblastoma. Although the basis for this phenomenon is not understood, it is believed that while mutations in ALK or PHOX2B can cause abnormal cell proliferation, additional genetic alteration(s) are necessary for a tumor to form. Thus, individuals who carry an ALK or PHOX2B gene mutation but never acquire these other genetic alterations may be less likely to develop neuroblastoma. However, an individual with an ALK or PHOX2B mutation who does not develop neuroblastoma still has a 50 percent, or 1 in 2 chance of passing this same alteration on to each of his or her children who may then go on to develop disease.
A detailed review of an individual’s medical and family history becomes important in diagnosing hereditary neuroblastoma (NBL). A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates whether other family members have developed neuroblastoma or other disorders of neural crest cell development. If the pattern of clinical features is suggestive of hereditary neuroblastoma (NBL), the physician or counselor may recommend that genetic testing be performed.
In order to confirm on a molecular level that an individual has hereditary neuroblastoma, he or she can undergo genetic testing:
Hereditary neuroblastoma genetic test results can also provide important information for other family members. If a mutation responsible for neuroblastoma is identified in the affected individual, at-risk relatives (first or second degree relatives) can be tested for the same genetic alteration.
A person with hereditary neuroblastoma who does not wish to pass this disease on to future children has several options, including:
Before one can proceed with prenatal testing or PGD, an ALK or PHOX2B mutation must be identified in a parent with familial neuroblastoma. Using either method, a parent can work with a genetic counselor and/or physician to decide whether to carry the pregnancy to term or to end the pregnancy.
Individuals with an altered ALK or PHOX2B gene are at increased risk to develop neuroblastoma. The risk of tumor formation is highest in infancy, and decreases by late childhood. Currently, it is believed that approximately 50 to 60 percent of individuals with an ALK alteration will develop neuroblastoma. While a neuroblastoma can range from low risk to high risk, there is no way to predict how the disease will manifest in individuals with an ALK alteration.
There is no published information about cancer risks in adults who carry an ALK or PHOX2B gene mutation. However, carrier adults who never had neuroblastoma may still be at increased risk to develop tumors later in life, as is the case with other familial cancer syndromes.
At this time, there are no established guidelines for cancer screening in children with an ALK or PHOX2B mutation, but the following methods are generally recommended:
American Cancer Society
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The Children’s Hospital of Philadelphia Research Institute: The Maris Laboratory and Research Program
Gene Reviews- ALK-related neuroblastoma susceptibility
Written by: Sarah Thornton, MS
Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012