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Gilheeney. Rare Dis Orphan Drugs J. 2026;5:15 Page 3 of 4

when gender-affirming therapy is initiated, the dose of the hormonal therapy is adjusted to gradually bring
the levels of either estradiol or testosterone into the range of the affirmed gender. The goal is to mimic
changes associated with puberty over a period of 2-3 years while minimizing and avoiding supraphysiologic
dosing and any potential related side-effects . The classical teaching is that childhood through puberty is a
[2]
vulnerable period of growth for neurofibromas . Of note, Dagalakis et al. reviewed data in adolescents with
[3]
NF-1 progressing through puberty, noting that while correlations between dermal neurofibroma growth and
puberty are present, the same data for plexiform neurofibromas had been previously non-existent. Their
analysis did not demonstrate any relationship between hormonal markers of puberty and changes in tumor
burden . Notably, they are quick to note that their study population differs significantly from the general
[4]
NF-1 population due to some of their patients receiving tumor-directed treatment. While they note an
absence of significant difference in patients receiving treatment versus those not receiving treatment, the
sample size in this single-institution study limits our ability to draw solid inferences.

The 2017 Clinical Practice Guidelines for the Endocrine Treatment of Gender-Dysphoric/Gender
Incongruent Persons does state that “concomitant medical issues that could interfere with treatment… have
been addressed” . Understandably and correctly, their guidelines do not identify any specific medical
[5]
concerns. These same guidelines suggest an in-treatment monitoring frequency of every 3-6 months. Again
understandably, such guidelines cannot and therefore do not take into account the type of patient we present
here. Thus, what would appropriate monitoring be? Is imaging of a greater frequency appropriate? Attention
must also be paid to the fact that hormone levels can have wide intra- and inter-institution variability .
[6]
What does appropriate patient monitoring entail in this situation?

Of further note, the preponderance of the literature available for review in reference to this topic discusses
plexiform neurofibromas and their biology. In vitro studies have shown that the proliferation of Schwann
cells of the NF1 -/- genotype is increased when treated with testosterone at levels similar to those targeted
and achieved in gender-affirming care . What are the other tumor types seen in patients with NF-1. Similar
[7]
data for optic pathway glioma in the NF-1 population does not appear to exist in the published literature. As
it relates to other types of fibromas, there is at least one case report of a transgender male patient assigned
female at birth with a history of multiple endocrine neoplasia type 1 who developed growth of angiofibroma
while receiving gender-affirming care with testosterone . Nonetheless, this represents an entirely different
[8]
tumor biology.

The most recent published data estimate that 0.6% of people over the age of 13 identify as transgender .
[9]
With 1/2000 live births presenting with NF-1, it is possible that a controlled study of these patients would be
difficult at best. Nonetheless, counseling a patient such as this would require an inclusive atmosphere for
discussion with a clinician to determine the best course of action. In conclusion, an inclusive approach to
care for the LGBTQ+ population is integral to good patient care, both as it relates to the doctor-patient
relationship and to medical care itself. Further research regarding the intersection of this population with
that of patients with chronic conditions, including neurofibromatosis, is needed.

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The author contributed solely to the article.

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