The Laryngoscope
Lippincott-Raven Publishers, Philadelphia
0 1997 The American Laryngological,
Rhinological and Otological Society, Inc.
Familial Occurrence of Unilateral
Vestibular Schwannoma
Nadim B. Bikhazi, MD; William H. Slattery 111, MD; Anil K. Lalwani, MD; Robert K. Jackler, MD;
Paul H. Bikhazi, MD; Derald E. Brackmann, MD
Vestibular schwannoma (VS)may present clin-
ically in one of two forms: sporadic unilateral or
hereditary bilateral. Almost all cases of familial
transmission have been associated with the diag-
nosis of neurofibromatosis type I1 (NF-2). In this
report, we describe nine families (18 individuals)
presenting with unilateral VS without evidence of
NF-2. In four of the nine families, the affected indi-
viduals were of parent-offspring relationship, in
three families they were cousin-cousin, and in the
remaining two families, they were sibling-sibling
and aunt-nephew. No other members of the fami-
lies were diagnosed with NF-2. There was no evi-
dence for gender predilection or genomic imprint-
ing among affected individuals. This study
suggests that familial occurrence of unilateral VS
may be genetically inherited as it occurs more com-
monly than would be estimated by chance alone.
Future genetic studies will elucidate whether oc-
currence of unilateral VS in these families repre-
sents a variable expression of NF-2, chance occur-
rence of unilateral VS in families, or a new genetic
disorder.
Laryngoscope, 107:1176-1180,1997
INTRODUCTION
Vestibular schwannomas (VS) are benign tu-
mors that arise from the vestibular portion of the
eighth cranial nerve and account for more than 80%
of cerebellopontine angle tumors. Unilateral VS
usually occur sporadically but may present in com-
bination with other intracranial tumors as part of
Presented a t the 100th Annual Meeting of The American Laryngo-
logical, Rhinological and Otological Society, Inc., Scottsdale, Arizona, May
12, 1997.
From the Department of Otolaryngology-Head and Neck Surgery,
University of California, (N.B.B., A.K.L., R.K.J., P.H.B.), San Francisco, San
Francisco and The House Ear Institute (w.H.s., D.E.B.),Los Angeles, Cali-
fornia.
Send Correspondence to Rohert K. Jackler, MD, 350 Parnassus Av-
enue #210, San Francisco, CA 94117, U.S.A.
Laryngoscope 107: September 1997
1176
neurofibromatosis type I1 (NF-2). In contrast, bilat-
eral VS occur exclusively in patients with NF-2 and
account for greater than 90% of patients diagnosed
with this syndrome.
Neurofibromatosis type 11, or central neurofi-
bromatosis, is inherited in an autosomal dominant
manner with a high degree of penetrance and occurs
with a prevalence of 1:210,000.1 The NF-2 gene,
which has been localized to chromosome 22q12,2 en-
codes a tumor suppressor product named merlin or
schwannomin.3 Mutations in this gene have been
associated with sporadic VS, NF-2-associated VS,
meningioma, melanoma, breast carcinoma, and ma-
lignant mesotheliomas.3-7 In this study, we describe
nine families (18 individuals) with familial occur-
rence of unilateral VS without other criteria needed
for the diagnosis of NF-2. The clinical characteris-
tics of these patients are detailed and the probabil-
ity that this occurrence represents a new phenotypic
expression of VS is discussed.
MATERIAL AND METHODS
Patients
Families with more than one member with a unilat-
eral VS were retrospectively identified through a chart re-
view of all cases of unilateral VS treated at the University
of California San Francisco (UCSF) from 1985 to 1995. Pa-
tients were also recruited both from an Acoustic Neuroma
Association (ANA) newsletter seeking families with more
than one unilateral VS and the House Ear Institute. After
identification, patients were sent questionnaires regard-
ing characteristics of clinical presentation, tumor size,
treatment, and subsequent follow-up. In addition, the clin-
ical presentation, diagnosis, radiological imaging, and sur-
gical pathology were verified from medical records. Pa-
tients with the diagnosis of NF-2 were excluded from this
study. In the absence of clinical symptoms and negative
family history of NF-2, screening spinal MRI was not ob-
tained.
Bikhazi et al.: Familial Unilateral Vestibular Schwannoma
Inclusionary Criteria
The following criteria were necessary for the diagno-
sis of familial unilateral VS:
1. Histologically confirmed solitary, unilateral VS in
two or more family members.
2. No family members diagnosed with NF-2.
3. No intracranial tumors or contralateral VS on en-
hanced magnetic resonance imaging (MRI).
4. A normal ophthalmologic examination (showing
no evidence of posterior subcapsular cataracts o r
Lisch nodules) documented within the past 5
years in at least one affected family member.
5. No evidence of skin neurofibromas.
Probability Calculation
The frequency with which a family would be expected
to present with more than one family member having VS
was estimated using the combinatorial formula:
P (dr) = (Incidence) X -J!-.-
r!(n-r)!
where P = the probability of occurrence,
n = the number of family members, and
r = the number of vestibular neuromas in one family.
Assumptions in this calculation include the incidence
of sporadic VS to be 1/100,000,~ the average number of
first generational family members to be 20, and the esti-
mated number of families in the U.S. to be 12.5 million.
The probability of occurrence was then calculated for a 10-
year period. The calculated expected incidence was then
compared with the observed number of familial unilateral
VS in the UCSF chart review.
RESULTS
Families
Review of 494 charts of patients with unilateral
VS treated at UCSF from 1985 to 1995 identified
four families who met the inclusionary criteria. Two
additional families were referred from the House
Ear Institute and three families were identified
from ANA newsletter request. Overall, nine families
were identified with more than one member affected
with a unilateral VS in the absence of diagnostic cri-
teria for NF-2. Pedigrees of these families are shown
in Figure 1. The affected individuals were parent-
offspring in four families, first cousins in three other
families, siblings in one family and aunt-nephew in
the remaining family. In pedigree 1,the monozygotic
twin of an affected individual had no evidence of VS
on MRI, suggesting that there is incomplete pene-
trance of the responsible gene in this family. In ad-
dition, there is evidence for incomplete penetrance
in pedigrees 7, 8, and 9 if the VS are inherited in
these families.
Table I summarizes the presenting clinical
characteristics of these 18 patients. The average age
of symptom presentation was 50.3 years (range, 24
to 67 years). Two individuals were deceased at the
Laryngoscope 107: September 1997
time of the study. Of the 18 individuals, 11 are
women and seven are men. The most common pre-
senting symptoms included progressive hearing loss
(56%),vertigo (39%), imbalance (39%),and tinnitus
(28%).None of the patients complained of sensory or
motor disturbance in the extremities. Of the 18 af-
fected individuals, 13 had a normal ophthalmologic
examination within the past 5 years whereas the re-
maining five (two of whom are deceased) had not
seen a n ophthalmologist during this period. There
was an equal side distribution among the 18 tu-
mors. The maximum diameter of the tumor in the
cerebellopontine angle was greater than 3 cm in size
(large tumor) in half of the patients, between 1and
3 cm (medium) in 44% of the cases, and less than 1
cm (small) in 6%.
There was no evidence of genomic imprinting,
which is defined as a gamete-dependent phenotype,
because gender type was equally distributed among
the parent-offspring presentations. An earlier age of
onset of symptoms was noted among subsequent
generations (first generation average = 57.8 years,
second generation average = 35.5 years). Among the
MRI scans obtained postoperatively in 13 patients
ranging in age from 1 to 25 years, none demon-
strated contralateral VS or other intracranial tu-
mors. Five individuals without follow-up scans in-
cluded two who are deceased and three who are in
the early postoperative period (less than 1 year).
Clinical follow-up in this group ranged from 5
months to 27 years, with an average of 7.4 years.
Statistical Results
The incidence of sporadic VS is known to be
1/100,00O/year. Estimating an immediate family
size to be 20 members, the probability of one family
having two VS present during a 10-year period is
1.9/1,000,000. Twenty-four families would be ex-
pected to present with two VS during 10 years.
Given the number of VS during 10 years to be
25,000, the frequency of familial unilateral presen-
tation by chance alone would be approximately
1/1000.A review of UCSF charts found four families
with familial unilateral VS out of 500 charts of VS
patients, for a frequency of 8/1000.
If one considers only families with affected
first-degree relatives, the probability of genetic
transmission is strengthened. When considering
only first-degree relatives, the average family size
would be approximately five (compared with 20)
and the calculated frequency of familial unilateral
presentation by chance alone would be 1/10,000.
This is much lower than the observed frequency of
4/500 noted at UCSF.
DISCUSSION
Classification of VS traditionally has fallen into
two distinct groups: those with sporadic unilateral
Bikhazi et al.: Familial Unilateral Vestibular Schwannoma
1177
&
Pedigree I
Pedigree 4
+ Pedigree 2
Pedigree 5
Pedigree 7 Pedigree 8
presentation and those associated with NF-2. Subtle
differences in clinical presentation and cytological
characteristics between these two groups have been
described. NF-2-associated VS tend to present at a
younger age1 and are of a larger size at clinical pre-
sentation than their sporadic counterparts.9 A ma-
ternal effect, which is defined as the earlier presen-
tation and more rapid progression of VS in
maternally-inherited cases, has also been noted to
occur in NF-2.10 Histologically, VS in NF-2 have foci
of higher cellularity and more lobular growth pat-
terns as compared with their sporadic counter-
parts.11 Although the simplicity of this division of
VS into sporadic and NF-2-associated is practical, it
is not necessarily all-inclusive. This study presents
18 individuals with familial VS who do not meet cri-
teria for NF-2 diagnosis. A thorough review of the
medical literature revealed only one other study
that has noted the familial presentation of unilat-
eral VS in the absence of NF-2.12 In this study of
clinical and audiological profile of 93 patients with
unilateral VS, Neary et al. found two families with
more than one member presenting with unilateral
VS in the absence of NF-2. The relationship among
the affected members was siblings in one family and
first cousins in the second family. The authors high-
light that NF-2 should be considered in these cases
of familial unilateral VS but provide no further data
of other possibilities accounting for this phenotype.
Three possible hypotheses for explaining the fa-
milial occurrence of unilateral VS include the fol-
lowing: 1. a less severe expression of NF-2, 2. a
chance occurrence of two or more sporadic VS
Laryngoscope 107: September 1997
1178
Pedigree 3
Pedigree 6
Fig. 1. Pedigrees of nine families
presenting with more than one uni-
lateral vestibular schwannorna in the
family.
Pedigree 9
within the same family, or 3. an entirely separate
genetic disorder. Neurofibromatosis type I1 is known
to be a clinically heterogeneous disease, and two
separate clinical presentations of NF-2, a mild
(Gardner-Frazier) and a severe (Wishart) form, have
been described.13 Mild presentation is typified by
late onset and slow progression of bilateral VS with
infrequent skin manifestations or other CNS tu-
mors. Conversely, severe presentation is character-
ized by early age of onset, rapid progression, and
multiple CNS tumors in addition to bilateral VS. Pa-
tients with familial unilateral VS thus may repre-
sent a less severe expression of NF-2.
Clinical characteristics of individuals in this
study further supports similarities to NF-2. NF-2-
associated VS tend t o present at larger size as com-
pared with sporadic VS.9 In agreement with this, a
study of sporadic VS in the MRI era noted only 16%
of sporadic VS presented with size greater than 3
cm.14 In this study, 50% of individuals presented
with VS 3 cm or larger. In the largest NF-2 family
known,l5 an earlier age of presentation of VS among
successive generations was described.16 In this
study, the average age of symptom onset of first gen-
eration and second generation individuals was 57.8
years and 35.5 years, respectively. This result could
be explained either by a similar pathogenesis to NF-
2 or by greater awareness leading to earlier diagno-
sis (anticipation bias).
Genetically, it is possible that familial occur-
rence of unilateral VS may result from mutations in
the NF-2 gene that result in less severe NF-2 phe-
Bikhazi et al.: Familial Unilateral Vestibular Schwannoma
 TABLE I.
Characteristics of PatientsWith Familial Unilateral Vestibular Schwannorna.
~~

Age (Y) Side/Size (cm)

Kindred Sex Relationship Current At Presentation At Surgery of Acoustic Neuroma Presenting Symptoms
1A F Sister 51 46 51 Rll.5 HWTTTN
1B F Sister 46 24 25 R13 HWT/FN
2A M Son 37 37 37 u3 FNIFP
2B F Mother 61 54 59 R11.5 HUlM
3A F Daughter 53 44 44 u3 HA
3B M Father 89x 60 61 u3.5 VT/IM
4A M Son 31 30 30 R13.5 HL (sudden)/TN
46 M Father 62 56 56 u3 HWT/TN
5A F Aunt 70 65 66 u3 HUFN
5B M Nephew 47 33 37 w4 HUlM
6A M Father 71 61 64 Rl1.5 HWT
6B F Daughter 47 31 31 RJ2.5 VT
7A F First cousin 65 49 52 u2 HLNT
78 M First cousin 65x 63 NA u1.5 HL
8A F First cousin 68 64 65 u1 HUIM/TN
88 F First cousin 66 60 62 U1.5 IMTTNJHA
9A F First cousin 68 61 62 Rl2.5 HL (sudden)/lM
$6 F First cousin 72 67 67 RJ3.5 IM
NA = not applicable; HL = hearing loss; VT = vertigo; TN = tinnitus; IM = imbalance: FN = facial numbness; FP = facial paralysis; HA = headache:
x = deceased.

notype. Mutations that involve the NF-2 gene have
been observed in 22% to 59% of patients with spo-
radic VS as well as a variety of other t~mors.5~17Re-
cent genotype-phenotype correlation studies sug-
gest that mutations in the NF-2 gene are associated
with variable phenotypic expression. Ruttledge et
al.l* have found that nonsense and frameshift mu-
tations in the NF-2 gene that result in protein trun-
cation are associated with a more severe clinical
presentation of NF-2 (Wishart), whereas missense
mutations that lead to a single amino acid change
in the protein are associated with milder form of
the disease. Their data also show that there is vari-
able phenotypic expression within a family (in-
trafamilial variability): for example, some family
members have bilateral VS, whereas others may
have unilateral VS only even though they all have
the same mutation. Similarly, Parry et al.19 re-
ported that retinal abnormalities were associated
with the more disruptive nonsense or frameshift
mutations in the NF-2 gene; further, their data also
demonstrated intrafamilial variability in clinical
expression. These two studies support the concept
that other factors or genes may contribute to or
modify the clinical phenotype of NF-2. Therefore, it
is quite possible that specific mutations in the NF-
2 locus in combination with the patients genetic
background could lead t o a milder phenotypic ex-
pression and incomplete penetrance seen in our
families.
Our data suggest that the presentation of fa-
milial unilateral VS occurs more frequently than ex-
pected by chance alone. A formula for probability
adjusting for combinations was used to estimate the
number of families expected to present with two VS
in one family. The actual frequency of familial uni-
lateral VS is likely t o be even larger given the poor
knowledge of family history of most patients and in-
complete ascertainment. Selection bias may exist
within the three sources of patients for this study
(UCSF, the House Ear Institute, and the ANAL The
selection bias within this study may include both a
diagnostic bias (a patient with a relative diagnosed
with VS is more likely to be diagnosed with VS) and
a tertiary care referral bias (patients referred to ter-
tiary care facilities may not represent the larger
group of VS patients). The exact impact of these bi-
ases on this small sample of patients cannot be cal-
culated.
Sporadic unilateral VS have not been previ-
ously thought of as a genetically transmissible dis-
ease. This study suggests that unilateral VS may be
inherited in a small subset of patients. If true, this
has important implications for genetic counseling of
patients with unilateral VS. Future genetic analysis
of these patients and longitudinal follow-up of fam-
ily members will clarify the nature of familial uni-
lateral presentation of VS. As a preliminary step in
the genetic study of these families and determining
the role of NF-2 gene in these VS, the patients tu-

Laryngoscope 107: September 1997 Bikhazi et al.: Familial Unilateral Vestibular Schwannoma
1179
mors are being assessed for loss of heterozygosity a t
the NF-2 locus, and the NF-2 gene is being screened
for possible mutations.
CONCLUSION
This study reports nine families with a newly
defined phenotype, familial unilateral VS, who
failed to meet current criteria for the diagnosis of
NF-2. Although age and symptom presentation are
similar t o sporadic VS, 50% of individuals presented
with large tumors (greater than 3 cm). Earlier
symptom presentation was observed in succeeding
generations without any evidence of genomic im-
printing. Familial unilateral VS occurred more com-
monly than would be expected by chance alone. This
phenotype may represent a variable expression of
NF-2 or a new genetic disorder. Further genetic
analysis will help to elucidate this entity.
ACKNOWLEDGMENT
We thank the Acoustic Neuroma Association for
providing patients for this study. In addition, we
thank Michael Baser, PhD, and Dilys Parry, PhD, for
critical review of the manuscript.
BIBLIOGRAPHY
1. Evans, DGR, Huson SM, Donnai D, et al. A genetic study of
type I1 neurofibromatosis in the north west of England
and the UK. I. Prevalence, mutation rate, fitness, and con-
firmation of maternal transmission effect on severity. J
Med Genet 1992a;29:841-6.
2 . Rouleau GA, Wertelecki W, Haines JL, et al. Genetic linkage
of bilateral acoustic neurofibromatosis to a DNA marker
on chromosome 22. Nature 1987;329:246-8.
3. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel
moesin-, ezrin-, radixin-like gene is a candidate for the
neurofibromatosis 2 tumor suppressor. Cell 1993;72:
791-800.
4. Seizinger BR, Martuza RL, Gusella JF. Loss of genes on chro-
mosome 22 in tumorigenesis of human acoustic neuroma.
Nature 1986;322:644-7.
5. Wolff RK, Frazer KA, Jackler RK, et al. Analysis of chromo-
8ome 22 deletions in neurofibromatosis type 2-related tu-
mors. Am J Hum Genet 1992;51:478-85.
6. Bianchi AB, Mitsunaga SI, Cheng JQ, et al. High frequency
Laryngoscope 107: September 1997
1180
of inactivating mutations in the neurofibromatosis type 2
gene (NF2) in primary malignant mesotheliomas. Proc Nat
Acad Sci U S A 1995;92:10,854-8.
7. Ruttledge MH, Sarrazin J, Rangaratnam S, et al. Evidence
for the complete inactivation of the NF2 gene in the ma-
jority of sporadic meningiomas. Nut Genet 1994;6:1 8 0 4 .
8. Tos M, Thomsen J. Epidemiology of acoustic neuromas. J
Laryngol Otol 1994;8:685-92.
9. Short PM, Martuza RL, Huson SM. Neurofibromatosis 2:
clinical features, genetic counselling and management is-
sues, In: Huson SM, Hughes RAC, eds. The Neurofibro-
matoses: A Pathogenetic and Clinical Overview. London:
Chapman and Hall; 1994:41444.
10. Fontaine B, Sanson M, Delattre 0, et al. Parental origin of
chromosome 22 loss in sporadic NF2 neuromas. Genomics
1991;10:280-3.
11. Sobel RA, Wang Y. Vestibular (acoustic) schwannomas: histo-
logic features in neurofibromatosis 2 and in unilateral
cases. J Neuropathol Exp Neurol 1993;52:106-13.
12. Neary WJ, Newton VE,Laoide-Kemp SN, et al. A clinical and
audiological study of patients and families with unilateral
vestibular schwannomas. I. Clinical features of neurofibro-
matosis in patients with unilateral vestibular schwanno-
mas. J Laryngol Otol 1996;110:63440.
13. Eldridge R, Parry DM, Kaiser-Kupfer MI. Neurofibromatosis
11: clinical heterogeneity and natural history in 39 individ-
uals in 9 families and 16 sporadic cases. Proceedings of the
Eighth International Congress on Human Genetics. Am J
Hum Genet 1991;49:133.
14. Selesnick SH, Jackler RK, Pitts LH. The changing clinical
presentation of acoustic tumors in the MRI era. Laryngo-
scope 1993;103:431-6.
15. Gardner WJ, Frazier CH. Bilateral acoustic neurofibromato-
sis: a clinical study and field survey of a family of five gen-
erations with bilateral deafness in thirty-eight members.
Arch Neurol Psycho1 1930;23:266-302.
16. Young DR, Eldridge R, Gardner WJ. Bilateral acoustic neu-
roma in a large kindred. JAMA 1970;214:347-53,
17. Irving RM, Moffat DA, Hardy DG, et al. Molecular genetic
analysis of the mechanism of tumarigenesis in acoustic
neuroma. Arch Otolaryngol Head Neck Surg 1993;119:
1222-8.
18. Ruttledge MH, Andermann AA,Phelan CM, et al. Type of mu-
tation in the neurofibromatosis type 2 gene (NF2) fre-
quently determines severity of disease. A m J Hum Genet
1996;59:331-42.
19. Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al. Germ-
line mutations in the neurofibromatosis 2 gene: correla-
tions with disease severity and retinal abnormalities. A m
J Hum Gene. 1996;59:529-39.
20. Evans DGR, Huson SM, Neary W, et al. A clinical study of
type 2 neurofibromatosis. Quart J Med 1992b;304:603-18.
Bikhazi et al.: Familial Unilateral Vestibular Schwannoma