An ALK-related predisposition to neuroblastic tumors (OMIM #613014) is due to a heterozygous germline mutation of the anaplastic lymphoma kinase (ALK) gene and predisposes to the development of neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, specifically during infancy and childhood. It is also possible for tumors to develop in the adrenal glands and in the region of the sympathetic ganglia.

Key Data

< swipe to see entire table >
Synonym Predispostion to neuroblastoma
Gene ALK (anaplastic lymphoma kinase)
Gene product ALK tyrosine kinase receptor
Function Membrane tyrosine kinase, which controls the proliferation of immature sympathetic neurons
Heredity Autosomal dominant
Prevalence Approximately 1-2% of neuroblastoma patients
Genotype-phenotype correlation With the exception of the following three pathogenic variants, there are no known associations between specific ALK mutations and the risk of developing neuroblastoma or the outcome of neuroblastoma.

  • p.Arg1275Gln occurs in approximately 45% of patients carrying an ALK germline mutation and has lowpenetrance (40%).
  • p.Gly1128Ala was detected in a large family and presumed to have low penetrance: 40% of heterozygous mutation carriers developed a neuroblastoma during childhood; while heterozygous adult carriers remained unaffected. Neuroblastomas were not associated with the development of any other aditional tumor types.
  • p.Phe1174Leu was described in a patient who died prematurely.
Penetrance Incomplete; presumed to be approximately 50%
< swipe to see entire table >


Clinical Diagnostic Criteria

The following findings constitute a potential ALK-related predisposition to neuroblastic tumors:

  • Multiple primary neuroblastic tumors occuring synchronously or metachronously

  • A family history of neuroblastoma, ganglioneuroblastoma, or ganglioneuroma

Genetic Diagnostics

The diagnosis “ALK-related predisposition to neuroblastic tumors” is confirmed by the detection of a heterozygous germline ALK mutation that alters the amino acid sequence of the tyrosine kinase domain.

Differential Diagnoses

  • Germline PHOX2B mutation

  • Germline KIF1B mutation

  • Neurofibromatosis type 1

  • Beckwith-Wiedemann syndrome spectrum

Clinical Presentation

Patients with an ALK-related predisposition to neuroblastic tumors are at increased risk of developing the following neuroblastic tumors:

  • Neuroblastoma: malignant tumor with the poorest outcome

  • Ganglioneuroblastoma: depending on the histological findings, tend to be benign similar to ganglioneuroma or malignant like neuroblastoma

  • Ganglioneuroma: predominantly a benign tumor

The risk of developing neuroblastic tumors is highest during infancy and decreases with increasing age. Tumors occur earlier (on average at 9 months of age) in cases of familial neuroblastoma compared with cases without a familial neuroblastoma predisposition (on average at 2-3 years of age).

In addition, there is a greater risk of developing multiple primary tumors in the case of familial neuroblastoma compared to the non-familial form. These multiple primary tumors may be bilateral adrenal gland tumors or tumors external to the adrenal glands that form in the region of sympathetic ganglia. Tumors may occur synchronously or metachronously.

The outcome of neuroblastic tumors is largely dependent on tumor type, tumor stage, and the effectiveness of therapy and less dependent on the presence of an ALK germline mutation.

Therapeutic Considerations

Treatment is in accordance with the treatment guidelines of the neuroblastoma study. An ALK inhibitor therapy option should be discussed with the study.

Surveillance Recommendations

Surveillance Recommendations

There are no standard recommendations to date. The following is a potential approach for the early detection of neuroblastic tumors in cases where an ALK mutation has been detected:

Clinical examination, ultrasound of the abdomen, measurement of catecholamines, urin VMA, and HVA, X-ray of the thorax (PA and lateral):

  • Every 3 months for children 0-6 years of age

  • Every 6 months for children 6-10 years of age

  • No screening examinations are necessary for children > 10 years of age.

Following the successful treatment of a neuroblastic tumor, the early detection examinations should be continued up to 10 years of age to minimize the risk of developing multiple primary tumors.

Additional Information

Open Clinical Trials / Registries

Support Groups

Unfortunately, we are as yet unaware of any existing self-help groups for patients with an ALK-related predisposition to neuroblastic tumors. We will add any new information in this regard as soon as we learn of it.