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Page 2 of 9 Lightner. Rare Dis Orphan Drugs J. 2026;5:1

autopsy, he found multiple meningiomas and cranial nerve sheath tumors. Dr. Wishart provided the sentinel
description of neurofibromatosis type 2-related schwannomatosis (NF2-related SWN) in 1822. Mossé and
Cavalié first introduced the terms “peripheral” versus “central” neurofibromatosis in 1897 [1-5] . Despite
differences in tumor locations and presentations, early physicians still considered these to be variations of the
disease described by von Recklinghausen. In their 1940 writing, Dr. Gardner and Dr. Turner even referred to
“an incomplete or abortive form of the disease” .
[6,7]
In 1930, Gardiner and Frazier described a family in which 38 affected individuals suffered progressive
hearing loss, progressive imbalance, and early demise. Autopsies on two of these individuals confirmed
bilateral acoustic schwannomas. The physicians noted that about half of the family members were at risk for
the condition, with no clear gender predilection or evidence of incomplete penetrance. Later reports,
particularly by Moyes, suggested a completely independent autosomal dominant mutation, as most
individuals did not classically follow the description by von Recklinghausen. NF2-related SWN was not
considered an independent entity until 1970, when Dr. Young et al. provided an expanded description of the
original 1930 family. By that point, there were 97 family members spanning nine generations. Affected family
members had two or fewer small café au lait macules, and only two individuals had more than one
subcutaneous nodule .
[5-9]

These descriptions solidified the distinction between von Recklinghausen’s disease and “central”
neurofibromatosis. Genetic linkage analysis localized the NF2 gene to chromosome 22, in contrast to the NF1
gene on chromosome 17 [10-12] . As such, in 1987, the National Institutes of Health formally named NF1 or
“peripheral” and NF2 or “central” neurofibromatosis. It was in 1993 when the NF2 tumor suppressor gene
was identified on the long arm of chromosome 22 .
[13]

The NF2 gene encodes the protein, merlin, which is related to the ezrin-radixin-moesin (ERM) family of
proteins that link plasma membranes and actin filaments. It has widespread effects in the cell and regulates
cell survival, proliferation, and cell-cell interactions in response to multiple pathways in the plasma
membrane and the nucleus. Merlin inhibits downstream pathways of multiple receptor kinases, including
epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), platelet-derived growth factor,
and hepatocyte growth factor. The protein modulates the phosphatidylinositol 3-kinase (PI3K)/protein
kinase B (Akt), rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein
kinase (MAPK)/extracellular signal-regulated kinase (ERK), ras-related C3 botulinum toxin substrate (Rac)/
p21-activated kinase (PAK), wingless-related integration site (Wnt), mammalian target of rapamycin
(mTOR), yes-associated protein (YAP) and Hippo pathways. Merlin may also inhibit LIN28B in the nucleus,
which would downregulate proto-oncogenic proteins such as MYC proto-oncogene, bHLH transcription
factor (MYC) [14,15] .

Clinical findings
The average person sometimes develops symptoms between 18 and 24 years of age, related to neurological
deficits . Almost all individuals are diagnosed with vestibular schwannomas by 30 years of age. Half present
[16]
with meningiomas, and about one-fourth have ependymomas . As opposed to NF1, astrocytomas are
[16]
relatively rare. Vestibular schwannomas cause tinnitus, hearing loss and ataxia. Usually, hearing loss is
progressive; however, it can occur suddenly. Schwannomas can develop on other cranial or peripheral
nerves, but they tend to involve sensory rather than motor nerves. Spinal tumors can be schwannomas or
ependymomas and multiple spinal tumors can be seen. Interestingly, many of the spinal tumors can be
asymptomatic. Meningiomas are usually intracranial in the supratentorial compartment, but they can also be
spinal. Intracranial meningiomas can lead to focal-onset epilepsy. If meningiomas are skull-based, they can
lead to cranial neuropathy, brainstem compression and hydrocephalus. Adults can also develop
mononeuropathy or polyneuropathy, even in the absence of nerve sheath tumors [17,18] .