Neurofibromatosis Type 2 – Definition
Neurofibromatosis type 2 (NF2), or central neurofibromatosis, is a genetic – or hereditary – disease that typically appears during young adulthood and is associated with the development of benign tumors of the central nervous system. What is characteristic in patients with NF2 is the development of benign tumors of the 8th cranial nerve, typically on both sides, referred to as bilateral vestibular schwannomas and previously called acoustic neuromas as well. Since the 8th cranial nerve is responsible for hearing and equilibrium, these tumors lead to increasing hearing loss and sometimes to impaired balance or an unsteady gait. Other benign tumors, brain tumors, and spinal tumors may occur as well. A decline in visual acuity, triggered by a special form of juvenile cataract, is also characteristic. NF2 is classified as a tumor disposition disease.
Synonyms:
FA
Gene:
22 known FA genes; FANCA (60-70%), FANCC and FANCG (about ~10% each)
Gene products:
repair proteins
Function:
Repair of pathological DNA bridges between complementary DNA strands (inter-strand cross-links, ICL)
Pattern of inheritance:
FANCB – X-linked
FANCR – autosomal dominant
all other subtypes – autosomal recessive
Prevalence:
1:200,000 – 400,000 (homozygous, 10x more common in Ashkenazi Jews and Africans); 1:300 (heterozygous)
Genotype-phenotype correlation:
Patients with mutations in the signaling pathway of “late” FA genes (e.g., FANCD1, FANCB) have a higher cancer risk. Patients with mutations in “early” FA genes have a milder phenotype.
Penetrance:
High, median age of diagnosis 6.5 years; 90% of FA patients are cytopenic by the age of 40
Neurofibromatosis Type 2 – Diagnosis
Procedure in case of clinical suspicion and all congenital bone marrow failures:
- Testing of lymphocytes or fibroblasts (preferably in cases of somatic mosaicism) in culture for increased spontaneous chromosome fragility. By adding DNA-intercalating substances (diepoxybutane (DEB) or mitomycin C (MMC)), an increase in chromosome fragility can be achieved.
- Flow cytometry: Increased cells with G2 arrest
- Molecular genetics (next-generation sequencing -> gene panel analysis)
- Determination of the FA subclass is crucial for estimating the tumor risk in homo- or heterozygous mutation carriers with consecutive recommendations for early detection, e.g., FANCD1 -> BRCA2 mutation, heterozygosity already significantly increases the malignant risk for breast and ovarian carcinomas, homozygosity -> Fanconi anemia
Differential Diagnoses
- SAA, MDS, congenital syndromes with bone marrow failure
- DNA repair defects such as Nijmegen breakage syndrome, Bloom syndrome
Clinical Presentation
Clinical Anomalies
60-70% of FA patients show obvious clinical abnormalities:
- Skeletal malformations of the upper extremity (classically radius and thumb)
- Skin pigmentation changes (hyperpigmentation, hypopigmentation, vitiligo)
- Short stature
- Microcephaly, small eyes, broad nasal root, micrognathia, and epicanthus -> characteristic facial expression in FA patients
- Malformations of the internal organs, primarily kidneys and heart
- Endocrinological disorders (80% of patients):
- Short stature
- hypothyroidism
- reduced glucose tolerance
- Diabetes mellitus
- Hyperinsulinism
- Progressive bone marrow failure beginning in the first decade of life (often the first clinical sign of disease leading to the need for further diagnostics)
- Bi- oder Trizytopenie im Alter von 10 Jahren bei >80%, mit 40 Jahren 90% der FA-Patient:innen (Thrombozyten <100.000/µl, Hb <10g/dl, absolute Neutrophilenzahl <1000/µl)
Tumor Predisposition
Hematology:
- MDS/AML (cumulative incidence at 40 years 30-40%, MDS usually precedes AML; assessment based on morphology (blast proliferation or increase in cellularity despite persistent pancytopenia), cytogenetics and molecular genetics (-7, EVI1 changes, RUNX1 mutations)
Oncology:
- Solid tumors (cumulative incidence at 40 years 28%):
- Squamous cell carcinomas of the head and neck region (risk 500-700 times higher, 65% oral cavity, very aggressive, 2-year survival <50%, wide surgical excision if possible)
- Squamous cell carcinomas in the anogenital region (especially vulvar carcinoma, risk 2000-4000 times higher)
- Liver tumors: mostly only under androgen therapy benign liver adenomas with spontaneous regression after discontinuation of therapy, rarely hepatocellular carcinomas
- Medulloblastomas
- Nephroblastomas
Special Features of Treatment
- Blood transfusions/G-CSF for cytopenias requiring therapy
- Synthetic androgens for progressive bone marrow failure
- Bone marrow transplantation for advanced bone marrow failure or signs of transformation
- Growth hormones for the correction of short stature
- No radiation exposure, if dispensable in case of hypersensitivity to ionizing radiation
- Hypersensitivity to alkylates (cyclophosphamide, ifosfamide, melphalan, mechlorethamine, busulfan, treosulfan, nitrosoureas, procarbazine, and dacarbazine, temozolomide, thiotepa, also platinum derivatives)
- Patient education regarding oral hygiene and monthly oral self-inspection for mucosal changes (or with parental help)
- Avoidance of alcohol and tobacco consumption
- No administration of medication that impairs platelet function, such as non-steroidal anti-inflammatory drugs (e.g., ibuprofen).
Diagnosis of Neurofibromatosis Type 2- 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. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Neurofibromatosis Type 2- 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. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Examination Recommendations According to AACR 2016 and FARF Guidelines
- Hematology
Regular blood count checks, annual bone marrow assessment (KMP and biopsy) based on clinical examination, early referral to a transplant center - Oncology
Semi-annual ENT screening examinations from early adolescence, annual gynecological screening from menarche (see below) - Gynecology
Annual gynecological screening from menarche/13 years, Pap smear as soon as sexually active or from 18 years, HPV vaccination recommended for boys and girls - Immunology
Monitoring of immunoglobulin levels as recommended by the immunologist - Dermatology
Annual dermatological examination from the age of 18 at the latest - Pulmonology
After HSCT: Basic function test with follow-up as required - Gastroenterology
Annual liver function tests, more frequently under androgen therapy - Endocrinology
Annual diabetes test, growth curve - Orthopedics
Testing for bony abnormalities of the forearm and management if necessary - Urology
Basic examination for kidney malformations - Cardiology
Basic examination for heart malformations - ENT
Basic hearing test and regular check-ups every 2-3 years, semi-annual tumor screening from the 2nd decade of life - Dentist
Semi-annual check-ups (clinical, no x-rays)
In this context, please also note the supplementary recommendations of the Fanconi Anemia Registry (download PDF).
