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Page 6 of 15 Brown. Rare Dis Orphan Drugs J. 2025;4:21 https://dx.doi.org/10.20517/rdodj.2025.14

CNS APPEAR IN LATE CHILDHOOD AND CONTINUE TO DEVELOP THROUGHOUT LIFE
CNs typically begin to arise in late childhood or early adolescence and continue to accumulate throughout
the lifetime, affecting 99% of adults with NF1 [31,32] . Their growth is self-limited; in most patients, they reach
an average maximum diameter of ~5 mm, although sizes can range from a few millimeters to 10 cm or
larger. Inter-individual and interfamilial phenotypes can be striking. An 8-year prospective study revealed
that a group-averaged change in CN volume among adults varies in body region but is overall quite modest
3
- on average ~3.5 mm per annum, with the fastest growth seen on the back and abdomen. Similarly, the
average number of new neurofibromas observed was approximately one novel lesion every 4 years during
the 8-year observation period, again with the highest rate of appearance on the back and abdomen . A
[33]
five-year natural history study of CN accumulation is open at the National Institutes of Health, utilizing
whole-body photography to track lesion development, which could provide much-needed data on
predictive factors for CN initiation, growth rates, and variability (ClinicalTrials.gov ID NCT05581511).

Hormones have long been suspected to act as mitogens for cutaneous neurofibromas. This hypothesis was
initially based on the observation that these tumors often appear during early adolescence, a developmental
[34]
stage characterized by high circulating sex hormone levels . Numerous preclinical experiments support a
potential role for hormones in CN tumorigenesis and growth. CNs express hormone receptors, and
Schwann-like tumor cell proliferation in vitro is buttressed by adding hormones to the growth medium [35-37] .
Subjective assessments have also documented that postpartum women retrospectively perceived a faster
growth rate of CNs. However, there are no compelling prospective human data suggesting that either
exogenous or endogenous hormones significantly influence tumor burden or growth rate across different
sexes, or among individuals receiving hormone or anti-hormone therapies. One self-report study noted that
two women receiving depot contraceptives containing high levels of synthetic progesterone believed their
CN growth rate increased during treatment . Therefore, while there is no scientific evidence to support
[38]
avoiding hormone or anti-hormone therapies altogether, women may be advised to consider alternative
forms of contraception rather than depot injections or implants, particularly given similar weak associations
observed with other tumors, such as meningiomas.

CN appearance and volume increase are difficult to assess both clinically and experimentally . There can
[39]
be a high degree of inter-investigator variability on manual measurements, confounded by the use of
different analytic tools (different brands/types of calipers), different methods of measurement (tumor base
vs. largest tumor girth), and the degree of pressure exerted by the calipers on these rubbery/soft, sometimes
inflamed lesions. The moment of nascence of CNs is also difficult to pinpoint, partly because pools of
atypical tumor-like Schwann cells in apparently normal skin could represent a microscopic/primordial form
of CNs, but there is no means to determine their prospective potential for growing into a visible papule.
Retrospective patient report is notably unreliable, and periodic inflammation or differences in lighting may
furthermore alter the investigator’s attention to the presence or size of a tumor.

Future endeavors should strive to identify more CN measures that are independent of human error and
variability. Photography, particularly 3-D photography, together with artificial intelligence (AI) has the
potential to provide a universally accepted objective measure of CN total body burden, but the analytic
software is designed to detect macular lesions with pigmentary differences from surrounding skin, and has
not yet been optimized to automatically detect and measure voluminous and numerous idiochromatic CNs
against a background of potentially abnormal surrounding skin. Furthermore, the research community
would benefit from developing a standardized calibrated caliper device that applies a low, consistent
pressure to CNs to eliminate inconsistencies associated with different tool sizes, manufacturers, weights,
gliding friction, and manually applied pressures. It is important to learn from patients what degree of CN