Neurofibromatosis Type Two
by Sally Petrella
In a large Italian-American family first studied in 1992 (Narod 487), seven
young adult cousins were seen at a clinic for hearing impairment and brown
skin marks. The brown skin marks or "cafe au lait" spots are characteristic
of an inherited dominant disorder called neurofibromatosis (NF) that predisposes
individuals to develop swellings in the nerves called neurofibromas (Clayman
722-723). This family has a history of deafness and brain tumors: six of
the seven cousins have or had a parent affected by one or both and they
all shared a grandfather who was deaf and died from a brain tumor.
There are two types of neurofibromatosis: one affecting peripheral nerves
and one affecting the central nervous system. Neurofibromatosis type one
(NF1), also known as vonRecklinghausen or Peripheral NF is the most common
neurofibromatosis (1/3000) and is characterized by skin marks, optic nerve
gliomas and bony abnormalities (Rouleau 575). The less common (1/37,000)
neurofibromatosis type two (NF2) or Central Bilateral Acoustic NF is associated
with central nervous system tumors especially affecting both of the auditory
nerves, as well as brain and spinal cord tumors and posterior capsular lens
opacities (Bourn 69). Bilateral vestibular schwannomas (BVS) or unilateral
vestibular schwannomas in a patient or in a patient's first degree relative
are the hallmark of NF2 and are sufficient for diagnosis (Narod 487).
Small tumors in the fatty schwann cells covering the auditory nerves were
found in the cousins of this family. This information combined with the
cafe au lait skin marks and the family history of hearing impairment and
brain tumors led doctors to suspect this family had familial NF2.
In 1987, linkage studies confirmed the distinction between NF1 and NF2 when
NF1 was mapped to chromosome 17 and NF2 to chromosome 22. The NF2 gene was
isolated in 1993 by several groups of researchers through the use of positional
cloning and genetic linkage and deletion mapping analyses of affected individuals.
A CA repeat polymorphism associated with the mutant allele was often used
as a marker for the gene (Narod 486-487).
The NF2 gene is a tumor suppressor gene and encodes a 595-amino acid protein
called merlin or schwannomin. Merlin is an acronym for moesin-ezrin-radixin-like
protein, a family of proteins that play a role in cell surface dynamics
and structure by linking the cytoskeleton to components of the plasma membrane
(Bianchi 10854). In NF2, there is a nonsense or splice site mutation or
frameshift deletions and insertions leading to truncated forms of merlin.
In 1995, Ruttledge et al. searched for a connection between the type of
mutation in the NF2 gene and the severity of the disease. NF2 had previously
been subdivided into two forms: the severe Wishart type and the more mild
Gardner type. The Wishart type has an early onset, usually before age 25,
a rapid course and multiple other tumors in addition to BVS. Wishart individuals
undergo repeated surgeries and rarely survive past 50. The Gardner type
is mild, has a later onset, progresses slowly and rarely has tumors other
than BVS (Ruttledge 331). Ruttledge et al. discovered a correlation between
protein truncating mutations (80% nonsense or frameshift causing deletion/insertion)
and the severe Wishart type whereas the mild Gardner type is usually found
in cases of single codon alterations, splice-site mutations, missense and
3-bp insertions (Ruttledge 341).
Our case study family was one of 73 families studied by Ruttledge et al.
in 1995 (Ruttledge 331). The 1995 study pinpointed a 200 base pair insertion
in the intron between exons 15 and 16 in eight affected family members and
four at-risk individuals (Ruttledge 339). The family had been diagnosed
with the mild Gardner type of NF2 because of the late onset of BVS and the
lack of non-BVS tumors. Locating the causal mutation in a noncoding intron
region fit with the hypothesis that less severe mutations result in less
severe manisfestations. It is possible to have both types within a family
yet all family members studied fit the Gardner type diagnosis. Since this
mutation is in a splice site, partial splicing could cause the increased
use of the normal gene, resulting in a more normal type of individual (Ruttledge
340) and helping to explain incomplete penetrance in some individuals who
obviously inherited the mutation.
NF2 is incompletely penetrant and shows variation in its expression. Four
of the seven affected cousins in this family came from one family with a
father who had the disease. Since each sibling had a 50% chance of inheriting
the defective gene, the probability of all four of them inheriting the gene
is 1/16 or 0.0625. The fact that the mutant NF2 gene can be incompletely
penetrant further reduces the likelihood that all four would both inherit
the gene and exhibit the mutation. Because this is such an unlikely occurrence
and the family had no unaffected offspring, perhaps the mother was also
affected. The other possibility is that both of the father's genes were
mutated. Either of these is possible since 50% of NF2 cases are due to new
mutations (Narod 494).
There are two individuals in this family in whom the mutant NF2 gene appears
nonpenetrant. One of these is in the first filial generation (individual
II4) and is unaffected yet he has a son with the disease. Narod et al. mentioned
that this individual did have progressive deafness though it could have
been occupational in origin and he died in his fifties. Although this individual
never had a confirmed BVS, his phenotype remains ambiguous as he was never
tested (Narod 487). The other seemingly nonpenetrant family member is in
the same generation as the seven cousins and already has a son with the
disorder. This nonpenetrance is probably due to the mildness of the Gardner
type and the partial splicing effect of this family's particular mutation.
Neurofibromatosis is a genetic disease that currently has no cure, the only
therapy involves treatment of symptoms. Treatment consists of removal of
harmful tumors and is most effective if done early in the growth stage of
the tumor. Since NF2 is incompletely penetrant and age of onset can be late,
early screening is important in affected families. The CA repeat polymorphism
is the most commonly used test for the mutant NF2 gene but is not completely
reliable because it is ten map units from the NF2 gene and recombination
occurs 10% of the time giving a false reading. This test is still fairly
reliable for NF2 diagnosis in combination with pedigree analysis but it
will not diagnose the NF1 disorder because NF1 does not share the same locus
Families with a known history of NF2 need to be carefully screened and would
benefit from genetic counseling if they choose to have children. Individual
III10 has been diagnosed with NF2 and married a man who also has NF2. Their
child has a 25% chance of not inheriting the mutation. The fact that the
mother comes from a family where there are no unaffected offspring may decrease
the chances further of having an unaffected child. Her mother, though she
does not exhibit the phenotype, could also have the mutation, making individual
III10 homozygous and giving her child a 100% chance of inheriting the mutation.
Testing her mother (individual II7) for the CA repeat polymorphism would
help to clear this up.
Like all cancers, NF2 has no known cure. Genetic analysis techniques have
improved dramatically over the past ten years and it is only recently that
we have had the technology available to pinpoint the mutant gene and discover
the types of mutations causing dysfunction in its encoded protein. Until
we learn how to repair these mutations in the DNA or in the resulting protein,
we are capable only of testing for the mutation, genetic counseling of affected
individuals to try to avoid its inheritance, and treatment of symptoms.
We have come far in our understanding of all the complex interactions involved
in gene regulation and cancer, yet there is still so much to be learned.
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Frequency of Inactivating Mutations in the Neurofibromatosis Type 2 Gene
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Type 2 Tumor-suppressor Gene, Giving Rise to Widely Different Clinical Phenotypes
in Two Unrelated Individuals." American Journal of Human Genetics.
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Narod, Steven A., Dilys M. Parry, Jillian Parboosingh, et al. "Neurofibromatosis
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Rouleau, Guy A., Philippe Merel, Mohini Lutchman, et al. "Alteration
in a New Gene Encoding a Putative Membrane-organizing Protein Causes Neurofibromatosis
type 2." Nature. Vol. 363, 10 June 1993.
Ruttledge, Martin H., Anne A. Andermann, Catherine M. Phelan, et al. "Type
of Mutation in the Neurofibromatosis Type 2 Gene (NF2) Frequently Determines
Severity of Disease." American Journal of Human Genetics. 59: 331-342,
Wolff, Roger K., Kelly A. Frazer, Robert K. Jackler, et. al. "Analysis
of Chromosome 22 Deletions in Neurofibromatosis Type 2-Related Tumors."
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