What is hereditary neuroblastoma (NBL)?

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 shrinking on their own, while others demonstrate a more aggressive course. NBL tumors may originate in the:

• Adrenal glands (small hormone producing organs located on top of each kidney)
• Nerve tissues symmetrically distributed on either side of the spine from the base of the skull to the pelvis

Most cases of neuroblastoma (NBL) occur sporadically, affecting individuals who have no family history of the disease. However, in 1-2 percent of cases, a susceptibility to develop neuroblastoma can be inherited from a parent. Children with familial neuroblastoma have a higher incidence of multiple primary tumors and are diagnosed at a younger age, than their counterparts with the sporadic form of the disease.

The risk of developing the features associated with hereditary neuroblastoma may be passed from generation to generation in a family, but the severity of disease can vary widely between family members.

Causes

A predisposition to hereditary neuroblastoma 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:

• Anaplastic lymphoma kinase (ALK) gene, located on chromosome 2 at position p23
• Paired-like homeobox 2b (PHOX2B) gene, located on chromosome 4 at position p12

Most hereditary neuroblastomas 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:

• Hirschsprung's disease — a condition affecting the large intestine (colon) where nerves are missing from a part of the colon resulting in bowel obstructions or difficulty passing stool
• Decreased esophageal motility — transfer of food from the mouth to the stomach is disrupted or not as efficient as it should be
• Congenital central hypoventilation syndrome (CCHS) — a disorder of the central nervous system where, most dramatically, the automatic control of breathing is absent or impaired

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. However, in some patients with hereditary neuroblastoma, each cell contains only one working copy of either of these genes. 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 neuroblastoma by increasing the proliferation of neural cells, which makes them more likely to become cancerous.

How is hereditary neuroblastoma inherited?

Some individuals with hereditary neuroblastoma 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 child will be the first person in their family to carry this genetic change.

People who carry an alteration in one copy of either ALK or PHOX2B in all the cells of their body have a 50 percent — or one in two chance — of passing this same alteration on to each of their 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's disease and difficulty swallowing.

Sometimes, it is difficult to tell whether a predisposition to hereditary neuroblastoma 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. Individuals who carry an ALK or PHOX2B gene mutation but never acquire these other genetic alterations may be less likely to develop neuroblastoma.