ALK Deficiency – Definition
ALK-related predisposition to neuroblastic tumors (OMIM #613014) is based on a heterozygous germline mutation of the gene for anaplastic lymphoma kinase (ALK). It predisposes to the development of neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, especially in infancy and childhood. It can also lead to the development of tumors of the adrenal glands and tumors in the area of the sympathetic ganglia.
Synonym:
Neuroblastoma predisposition
Gene:
ALK (anaplastic lymphoma kinase)
Gene products:
ALK tyrosine kinase receptor
Function:
Membrane-bound tyrosine kinase that controls the proliferation of immature sympathetic neurons
Inheritance:
autosomal-dominant
Prevalence:
about 1-2% of neuroblastoma patients
Genotype-phenotype correlation:
With the exception of the following three pathogenic variants, there is no known association between certain ALK mutations and the risk of neuroblastoma development or the outcome of neuroblastoma
- p.Arg1275Gln occurs in about 45% of patients with ALK germline mutationsand leads to lower penetrance (40%)
- p.Gly1128Ala was found in a large family and presumably leads to lower penetrance: 40% of heterozygous mutation carriers developed neuroblastoma in childhood, adult heterozygous mutation carriers were healthy. No other tumors besides neuroblastoma developed.
- p.Phe1174Leu was described in a patient who died at an early age
Penetrance:
incomplete; probably by 50%
ALK Deficiency – Diagnosis
Clinical Diagnostics
An ALK-related predisposition to neuroblastic tumors is suspected in the following findings:
- Multiple primary neuroblastic tumors that occur synchronously or metachronously
- Familial occurrence of neuroblastoma, ganglioneuroblastoma or ganglioneuroma
Genetic Diagnostics
The diagnosis of “ALK-related predisposition to neuroblastic tumors” is confirmed by detecting a heterozygous germline mutation of the ALK gene with an altered amino acid sequence of the tyrosine kinase domain.
Differential Diagnoses
- Germline mutation of PHOX2B
- Germline mutation of KIF1B
- Neurofibromatosis type 1
- Beckwith-Wiedemann syndrome spectrum
Clinical Presentation
Patients with an ALK-related predisposition to neuroblastic tumors have an increased risk of developing neuroblastic tumors. These are as follows:
- Neuroblastoma: Malignant tumor with the worst outcome
- Ganglioneuroblastoma: Depending on the histological findings, more benign like ganglioneuroma or malignant like neuroblastoma
- Ganglioneuroma: Mostly benign tumor
The risk of developing neuroblastic tumors is highest in infancy and decreases with increasing age. In familial neuroblastoma, tumors occur earlier (on average at the age of 9 months) than in neuroblastoma without a familial predisposition (on average at the age of 2-3 years).
In addition, there is an increased risk of multiple primary tumors in familial neuroblastoma compared to the non-familial form. These multiple primary tumors can be bilateral adrenal tumors or multiple primary tumors outside the adrenal glands that arise in the area of the sympathetic ganglia. The tumors can occur synchronously or metachronously.
The outcome of neuroblastic tumors is essentially dependent on tumor type, tumor stage, and adequate therapy and less on the presence of an ALK germline mutation.
Special Features of Treatment
Treatment is carried out according to the treatment guidelines of the neuroblastoma study. ALK inhibitor therapy should be discussed in the study.
Diagnosis of "ALK Deficiency" What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of "ALK Deficiency" What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
To date, there are no uniform recommendations. A possible procedure for the early detection of neuroblastic tumors with a known ALK mutation is as follows:
Clinical examination, sonography of abdomen, measurement of catecholamines VMS and HVS in urine, chest X-ray (p.a. and lateral):
- Every 3 months in children aged 0-6 years
- Every 6 months for children aged 6-10 years
- No screening is required for children > 10 years of age.
After successful treatment of a neuroblastic tumor, screening examinations should be continued until the age of 10 years due to the risk of developing multiple primary tumors.
ALK Deficiency- Further Information
Open Clinical Trials/ Registers
Patients can also register for the CPS registry at any time or have this done by their doctors in charge.
