NF and Marfan Syndrome Flashcards
Neurofibromatosis Type-1
incidence is 1/4,000; half of all cases are due to a new mutation in the NF-1 gene at 17q11.2; Meaning suspect case is first member of family affected. Presents as Cafe au lait macules or skinfold freckling.
Neurofibromatosis Type 2
1) incidence is 1/40,000 (much rarer than NF-1)
2) Chromosomal and molecular identification: NF-2 condition due to mutations in the Merlin gene, located at 22q12, which codes for a tumor suppressor protein in Schwann cells
3) symptoms of tinnitus, hearing loss, and balance dysfunction.
Marfan syndrome
Incidence is 1/5,000;
2) Chromosomal and molecular identification: condition due to mutations in the fibrillin (FBN-1) gene, located at 15q21.1. Fibrillin is an extracellular matrix protein that forms insoluble microfibrils, providing a scaffold for the deposition of elastin in connective tissue. Contributes to the strength of connective tissues in certain areas of the body
3) Presents with skeletal, cardiovascular, optic and dural symptoms
Explain why dominant negative mutations in the fibrillin gene can result in more severe phenotypes, relative to individuals who have nonsense/frameshift mutations leading to their Marfan syndrome.
A nonsense/frameshift mutation, resulting in a truncated polypeptide that fails to associate with other (normal) monomers to disrupt the assembly of microfibrils, would exhibit a less severe phenotype than a missense mutation resulting in a dominant negative product.
Describe the inheritance and modifying factors of Neurofibromatosis Type 1.
Autosomal Dominant Inheritance, Complete Penetrance, variable expressivity, and pleiotrophic.
How is Neurofibromatosis Type 1 diagnosed?
Patient must have at least 2 of its symptoms. Cafe-au-lait macules, skinfold freckling, Neurofibroma, optic gliomas (tunnel vision, headache), Lisch nodules, Osseous lesion or thinning of long bone cortex with or without a false joint, 1st degree relative diagnosed with NF-1
Explain the clinical process if someone presents with a single symptom of Neurofibromatosis Type 1 but has a parent that has been diagnosed.
The patient is diagnosed with NF-1 and is at risk for optic glioma, osseus lesions, and a high likelihood of learning disability (possibly macrocephaly). The product of NF-1 gene, neurofibronin 1, is a tumor supressor that downregulates Ras in the MAP kinase pathway. Mutations in NF-1 results in overgrowth syndrome NF-1 diagnosis should lower your threshold for investigation of symptoms.
Carefully consider the results of genetic tests when looking for NF-1
Due to the various types of mutations that can affect neurofibromin expression and/or function, disease causing mutations can only be detected in the NF-1 gene in 70% of individuals with clinically confirmed NF-1. If a patient tests negative, it does not rule out a diagnosis!
What is the inheritance pattern and modifying factors of NF-2.
Autosomal dominant inheritance, complete penetrant, variable expressivity.
What are the clinical manifestations of NF-2?
Bilateral eighth nerve vestibular schwannomas confirm diagnosis. If a first degree relative is diagnosed with NF-2., the patient is diagnosed.
Describe the Merlin gene testing.
Tests only detect 65% of the time. If someone is diagnosed, then family members are tested for hearing and brain/spinal cord issues. Obviate carriers get annual MRI’s and testing as well.
