Disease Discovery:

The rise of neurofibromatosis type I (NF1) to academic relevancy was born out of discrimination, outcasting, and shame. As written by Siddhartha Mukherjee in The Emperor of All Maladies, “To name an illness is to describe a certain condition of suffering – a literary act before it becomes a medical one. A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering – a traveler who has visited the kingdom of the ill. To relieve an illness, one must begin, then, by unburdening its story.” And this story begins with a man named Joseph Merrick, who, sadly, is more widely known as the “Elephant Man.”

Merrick was born in 1862, and was phenotypically unremarkable at birth. Quickly, by the age of 5, Merrick had begun to develop bony and fleshy tumors around his body, significantly restricting his life.¹ In 1884, Merrick began to be exhibited as “The Elephant Man” in a human oddities show around Europe.¹ Merrick was the spotlight of social entertainment and scientific curiosity. He later would state that the experience made him feel like “an animal in a cattle market.”¹ In 1909, the dermatologist Parkes incorrectly claimed that Joseph Merrick suffered from NF1.² The cultural spotlight led to increased research into NF1 during the 20th century. However, in 1986 it became clear that Joseph Merrick actually had Proteus syndrome, not NF1.² The perpetuation of the false connection between NF1 and the “Elephant Man” increases the burden of those with NF1. In summary, the propulsion of NF1 into academic relevance is a consequence of exploitation and humiliation. The severity of clinical onset sadly makes the social consequences of having this disease inextricable with its clinical consequences. Throughout this study into NF1, it is important to acknowledge these roots, and be reminded of the emotional and social burden that accompanies the onset of disease.

Although the disease became well known in the 20th century, depictions of the disease have been identified in artwork as early as the 13th and 16th centuries.

In figure 1, multiple “goiters” hanging down from the neck can be seen, as well as a deformity of the foot. Furthermore, the inclusion of amphibia with many scales and bumps in this illustration may be reflective of the author’s attempt to describe the person being drawn. The scales on the creatures drawn may be analogous to the way the depicted person looks, potentially indicating the existence of several plexiform neurofibromas.³ The described patient in figure 2 was stated to be Indian, which may be true, but also, this attribution of place must be analyzed through the cultural context in which this description was made. The Renaissance European conception of monsters is based on that of the Greeks, which were races thought to have lived far East, mostly in India.⁴ Therefore, it is worth noting that this early description may be pervaded with racism and discrimination, misconstruing the true geographic origin of this patient. 

Already we see how depictions of patients with NF1 are pervaded with exclusionary sentiment, connected to lowly creatures, and considered as negative anomalies.

The discovery of NF1 is attributed to the German Pathologist Friederich Daniel Von Recklinghausen. In 1882, the German pathologist wrote about two cases of neurofibromatosis, describing the canonical appearance of the disease, and postulating that these tumors grew from connective tissue.⁸ Because of this association, NF1 is also known as Von Recklinghausen’s disease.

Clinical Manifestations

As will be discussed, NF1 is a disease with extreme variability at the genotype and phenotype levels, and correlations between the variabilities have not been elucidated as of yet. The symptoms of NF1 are quite extreme and visible.  Early descriptions of NF1 provide insight into the difficulty of objectively classifying aspects of the disease. In a 1908 case description by authors Morris & Fox, they stated that “[countless] tumors were distributed all over the body,” and categorized the tumors into two types: “soft, almost fluctuating, subcutaneous masses,” and tumors that were firm, “projecting from the surface of the skin.”⁵ This latter type was also noted to be “gelatinous” to the touch. The “type” of tumor differed based on their location on the body.

The phenotypic variability of disease is correlated with severity of disease (as increased onset of symptoms will lead to more severe disease). The most common dermatologic symptoms are discussed below:

Other common, non-dermatologic clinical manifestations of the disease include learning disabilities in children and attention deficit hyperactivity disorder.⁶ 
Diagnosis of NF1 is usually conducted by a physical exam. However, many of the listed features of NF1 are not apparent until the age of five (97% of NF1 patients are diagnosed by eight years old).⁷ The age-dependent nature of disease diagnosis is a major limitation in the current way of testing for NF1. Techniques such as genetic testing have not been implemented as a means of diagnosis due to the wide range of mutations capable of causing NF1. As will be discussed, NF1 is a disease whose effects are exerted via biochemical mechanisms. Therefore, improving the biochemical characterization of the disease will allow for better diagnosis, treatment, and understanding of the disease.

The prognosis of NF1 is quite positive. If there are no outstanding complications, life expectancy of people with NF1 is normal, however, the risk of developing malignant tumors may shorten life span.

There are no treatments for NF1. Tumors that cause patients to experience pain/lose function can be removed. In 2016, Dombi et al. conducted a study on the ability of the selective inhibitor of MEK 1 and 2, selumetinib, to treat NF1.⁷ In mouse models, they found a consistent reduction in tumor volume and a slowing of tumor growth.⁷ When tested on children with severe tumors, these positive results were reproduced.⁷ Currently, selumetinib has been approved to be used in children with severe tumors, as it reduces tumor volume.⁷

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Works Cited

(1) Blatty, D. Joseph Merrick https://www.biography.com/performer/elephant-man-joseph-merrick (accessed 2022 -03 -27).

(2) Legendre, C.-M.; Charpentier-Côté, C.; Drouin, R.; Bouffard, C. Neurofibromatosis Type 1: Persisting Misidentification of the “Elephant Man” Disease. J. Am. Board Fam. Med. 2011, 24 (1), 112–114. https://doi.org/10.3122/jabfm.2011.01.100219.

(3) Madigan, P.; Shaw, R. V. Neurofibromatosis in 13th Century Austria? Neurofibromatosis 1988, 1 (5–6), 339–341.

(4) Madigan, P.; Masello, M. J. Report of a Neurofibromatosis-like Case: Monstrorum Historia, 1642. Neurofibromatosis 1989, 2 (1), 53–56.

(5) Morris, M.; Fox, W. S. Von Recklinghausen’s Disease. Proc. R. Soc. Med. 1908, 1 (Dermatol Sect), 16–17.

(6) Boyd, K. P.; Korf, B. R.; Theos, A. Neurofibromatosis Type 1. J. Am. Acad. Dermatol. 2009, 61 (1), 1–14. https://doi.org/10.1016/j.jaad.2008.12.051.(7) Diagnosing Neurofibromatosis https://nyulangone.org/conditions/neurofibromatosis/diagnosis (accessed 2022 -04 -25).

(7) Dombi, E.; Baldwin, A.; Marcus, L. J.; Fisher, M. J.; Weiss, B.; Kim, A.; Whitcomb, P.; Martin, S.; Aschbacher-Smith, L. E.; Rizvi, T. A.; Wu, J.; Ershler, R.; Wolters, P.; Therrien, J.; Glod, J.; Belasco, J. B.; Schorry, E.; Brofferio, A.; Starosta, A. J.; Gillespie, A.; Doyle, A. L.; Ratner, N.; Widemann, B. C. Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas. N. Engl. J. Med. 2016, 375 (26), 2550–2560. https://doi.org/10.1056/NEJMoa1605943.

(8) Recklinghausen, F. von. Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen: Festschrift zur Feier des fünfundzwanzigjährigen Bestehens des pathologischen Instituts zu Berlin. Herrn Rudolf Virchow; Hirschwald, 1882.

For a complete list of sources used, please access the Annotated Bibliography.