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Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14 Page 7 of 15

reduction is meaningful to them. Given that destructive treatments completely eliminate the tumor,
resulting in flat skin, a drug therapy that only partially reduces the size of a CN may or may not be
acceptable to the patient population as a whole.

THE GENETICS OF CN SEVERITY REMAINS POORLY UNDERSTOOD
There are many subclassifications of CNs based on their dermal vs. subdermal location, gross anatomy, and
histopathology; however, the shared underlying mechanism for tumorigenesis is considered constant across
different tumors and individuals: loss of the wild-type NF1 allele, leading to complete/near-complete
deficiency of translated neurofibromin protein. Mutations affecting the NF1 ultrastructure or pathologic
gene alterations directly targeting the Protein Kinase C (PKC) domain may impact CN severity, at least in
[40]
certain ethnic populations . Additional congenital polymorphisms or mutations may influence overall CN
burden, whereas somatically acquired genetic alterations could contribute to individual tumor
heterogeneity. There are a few causative NF1 mutations known to be associated with the phenotype and
number of CNs. For example, microdeletion of the NF1 gene results in an extreme disease phenotype
[41]
characterized by a heavy burden of CNs , while several other mutations have been identified that are
associated with a reduced incidence of CNs [42-45] . However, in the vast majority of patients, a specific
pathogenic germline mutation does not adequately predict CN features. The literature surrounding this
question has been unequivocal that individuals within the same family with the same NF1 alteration can
exhibit disparate cutaneous manifestations. In contrast to this well-accepted discordance between genotype
and phenotype, the author’s clinical experience suggests that the general burden and appearance of
cutaneous and subcutaneous neurofibromas within families are often similar. The generation of databases
documenting quantitative features of CNs will help future research to hone in on genetic and environmental
[46]
modifiers of CN clinical presentation .

Multiple evidence-driven hypotheses have sought to determine the cell of origin that initiates CNs through
Knudson’s “Second Hit” in the remaining wild-type NF1 gene. Loss of function of the intact NF gene can
occur through mutations in coding and noncoding regions as well as deletions, and are not always
detectable using standard gene sequencing, which may explain why dual hits are not identified in all
CNs [47,48] . Chromosomal aberrancies resulting from deletions and amplifications are commonly identified in
cutaneous neurofibromas including recurrent losses in chromosomes 1, 2q, 3p, 4p, 5q, 6q, 7q, 12q, 19p, and
20p, and gains in chromosomes 2p and 8q .
[49]

LABORATORY MODELS OF CNS ARE IMPERFECT
Although innovations in pharmacotherapy for plexiform neurofibromas have greatly benefited from
preclinical research, a truly anthromimetic animal model for CNs has only recently become available. Early
genetically engineered NF1 heterozygous mouse models failed to recapitulate the characteristic symptoms
[50]
of NF1 . Later, conditional knockout mice with biallelic NF1 deletion in specific embryonic
subpopulations of neural crest-derived Schwann cells were able to reproduce certain features of NF1 but did
not develop the characteristic skin tumors . Spontaneous NF1-like veterinary syndromes occur in canine
[51]
[51]
and bovine animals, but not in rodents . It has been hypothesized that the many years required to develop
tumors in humans cannot be modeled by a rapid cycling mammal with a relatively brief life expectancy,
such as the mouse. Porcine models have been developed for multiple medical conditions, as pig physiology
and lifespan more closely mimic that of humans. In 2018, genetically altered NF1 +/R1947X Ossabaw minipigs
were developed that spontaneously developed large diffuse mass-like cutaneous neurofibromas in ~40% of
pigs at 4 months of age . The same year, another group published a NF1 +/ex42del Yucatan mini-swine model
[52]
[53]
in which 44% of animals develop cutaneous tumors of the neck between 11-17 months of age . Both
models exhibited this non-discreet morphology with continuous enlargement in contrast to the nodular