Genetic Syndromes
Most pediatric brain tumors are sporadic, but development of a brain tumor can be linked to the following hereditary disorders:
Neurofibromatosis
- Autosomal dominant congenital disorder
- Associated with central nervous system tumors.
- Two types of neurofibromatosis, NF1 and NF2.
Also called von Recklinghausen's Neurofibromatosis.
Hamartoneoplastic syndrome:
- hamartomas are localized tissue proliferations with faulty differentiation
- mixture of component tissues
- potential towards neoplasia
- embryonic origin of dysgenetic tissues involved in NF1 is ectoblastic
Autosomal dominant with almost complete penetrance and is one of the most frequent genetically inheritable disease
- 30/105 newborns
- 1 /200 mentally handicapped persons
- highly variable expressivity:
- very mild to very severe
- expressivity is also age-related
The NF1 gene:
- Mapped to chromosome 17q11.2.
- Encodes for Neurofibromin protein which is expressed in many tissues, including brain, kidney, spleen, and thymus.
- Neurofibromin belongs to a family of GTPase-activating proteins that down regulate a proto-oncogene, p21-ras, an important determinant of cell growth and regulation (tumor suppressor gene).
The clinical diagnosis of neurofibromatosis is based on the presence of at least two of the following criteria:
NIH criteria for NF1 (Patients must have more then two of the following):
Six or more café-au-lait macules larger than 5 mm in greatest diameter in prepubertal persons and larger than 15 mm in greatest diameter in postpubertal persons |
Two or more neurofibromas of any type or one plexiform neurofibroma |
Freckling in the axillary or inguinal region |
Optic glioma |
Two or more Lisch nodules (iris hamartomas) |
A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis |
A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria |
- Neurofibromas are benign tumors that are comprised of a mixture of Schwann cells, fibroblasts, and mast cells. They may be cutaneous (soft fleshy tumors arising from cells in the peripheral nerve sheath, mostly on trunk), subcutaneous (firm, tender nodules along the course of peripheral nerves) or nodular plexiform (complex clusters along proximal nerve roots and major nerves).
- 15-20% of children with neurofibromatosis develop central nervous system neoplasms, usually as gliomas of the visual pathway or low-grade astrocytomas of the diencephalon, cerebral hemispheres, or posterior fossa.
- 5% of patients with NF develop a malignant neoplasm.
Resources:
Neurofibromatosis type 1 (NF1) at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
- (NF2) is an autosomal dominant disorder.
- Due to a mutation in the NF2 gene, a tumor suppressor gene on chromosome 22 which encodes a membrane cytoskeletal protein called merlin or schwannomin involved in actin-cytoskeleton organization.
- Pathognomonic radiologic findings are bilateral acoustic neuromas (schwannomas).
- Low grade astrocytomas, multiple meningiomas, and occasional ependymomas are also encountered in children with NF2.
Resources:
Neurofibromatosis type 2 (NF2) at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Tuberous Sclerosis
- Hereditary autosomal dominant disorder associated with:
- Cutaneous acneiform lesions
- Angiofibromas
- Mental retardation
- Renal insufficiency
- The TSC1 gene maps to chromosome 9q34 while the TSC2 gene to chromosome 16 and encode for the proteins tuberin and hamartin.
- Increased risk of indolent SubEpendymal Giant cell Astrocytoma (also called SEGA)
- Increased risk of benign CNS conditions:
- Cortical tubers
- White matter heterotopia (dysplastic and dysmyelinated white matter lesions)
- Subependymal nodules
Tuberous Sclerosis (TSC) at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Li-Fraumeni syndrome
- Autosomal dominant.
- Germline mutation of the p53 tumor suppressor gene (70% of families have a mutation of the p53 gene on chromosome 17).
- Associated with an increased incidence of CNS astrocytomas in children.
- Young adults with this syndrome have an increased incidence of breast cancer, sarcomas, and brain tumors. There is also an increased risk of leukemia, and adrenocortical cancer occurring before the age of 45.
Li-Fraumeni Syndrome at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Gorlin Syndrome
- Also called nevoid basal cell carcinoma (NBCC) syndrome
- increased risk of medulloblastoma in NBCC syndrome.
- NBCC syndrome presents with multiple organ abnormalities known to be the consequence of abnormalities in the PTCH gene.
Resources:
Naevoid basal cell carcinoma syndrome at the Atlas of Genetics and Cytogenetics in Oncology and Haematology.
Von Hippel-Lindau
- Hereditary cancer syndrome
- Autosomal dominant disorder with high penetrance (penetrance increases with age)
- Predisposes to the development of multiple benign and malignant tumors
- CNS and retinal hemangioblastomas:
- commonest neoplasms (70% of patients)
- multiple tumors often present
- Renal cell carcinoma:
- occurs in up to 75% of patients
- Pheochromocytomas
- Pancreatic tumors:
- multiple cysts and serous cystadenomas most common
- neuroendocrine tumors (10 - 15%)
- Endolymphatic sac tumours:
- low grade papillary adenocarcinoma
- progressive hearing loss
- usually involves cerebellopontine angle and/or the middle ear
- can destroy the temporal bone.
- CNS and retinal hemangioblastomas:
Resources:
Von Hippel-Lindau at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Turcot syndrome
- Autosomal dominant hereditary cancer syndrome.
- Turcot syndrome is characterized by polyps of the colon (Familial adenomatous polyposis and Hereditary nonpolyposis colorectal cancer)
- Increased risk of brain tumors (medulloblastomas and gliomas)
Turcot syndrome at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Summary Table of Some Hereditary Associations:
| Hereditary Disorder | Disorder Description |
Associated Brain Tumor(s) |
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