I am writing this towards the end of August (2023) and would like to use this occasion to recognize a milestone: the 40th anniversary of my involvement in neurofibromatosis. On August 11, 1983, I sent a memo to staff at Boston Children’s Hospital announcing the formation of a Neurofibromatosis Clinic. In this blog I will reflect on how I got involved in NF and make some points on how things have changed and some of what I’ve learned.

A few weeks before sending the memo I was called into the office of the chief of the Boston Children’s Hospital Division of Genetics, Dr. Park Gerald. I was a first-year trainee, doing a combined residency in child neurology and fellowship in genetics. He asked if I was interested in establishing a clinical program for NF patients, given that the disorder is a genetic condition that largely affects the nervous system. He was asking in part because the chief of plastic surgery at the time, Dr. Joseph Murray, had expressed concern that his group was conducting surgery on NF patients, but no one was following them for general medical surveillance. 

At the time, I had seen a few (probably five or fewer) NF patients as part of my training and had attended one lecture on the topic (given by Dr. Judith Bader, one of the co-founders of the National Neurofibromatosis Foundation). I found the lecture to be particularly interesting because during graduate school I had become interested in the phenomenon of transposable genetic elements – bits of DNA that can move from place to place in the genome. The original study of the phenomenon (long before transposable elements were known) was done by the plant geneticist Dr. Barbara McClintock, who studied spotted kernels in corn, which were later shown to be due to the action of transposable elements. I had wondered if there might be a human counterpart and thought NF might be a candidate.  

Hence, with these few bits of exposure I met with Dr. Murray (who, incidentally, was awarded the Nobel Prize several years later for his pioneering work in renal transplantation, a history of which I was unaware when we met) and announced the formation of the clinic. It was originally intended to meet monthly, on Mondays, but it quickly became clear that the demand was sufficient for it to meet weekly, which it continued to do through the time I left Boston Children’s Hospital in 1999. The clinic continues to this day, and it is not rare for me to hear from people whom I had seen in the clinic as children, who are now grown up, asking questions about the condition.

It turned out that the spottiness of NF manifestations was not due to transposable genetic elements (though these elements sometimes can be the source of an NF1 mutation if they integrate into the gene and disrupt it – one of the first NF1 mutations to be discovered was of this type), but rather to the “two-hit” mechanism of formation of lesions such as tumors or café-au-lait spots. (The mutation a person is born with is the “first hit,” but to develop a lesion such as a neurofibroma, the remaining intact copy of the gene needs to be damaged by mutation – the “second hit.” The random nature of the second hits is what causes the spottiness.) Nevertheless, as I saw more and more people with NF, I began to develop some experience with the condition and saw the need for someone to be looking after the big picture of medical care for affected individuals. 

Much has changed since I began seeing NF patients in 1983. We saw individuals with both NF1 and NF2, though those names were not officially coined until the NIH Consensus Conference on Neurofibromatosis in 1987. Schwannomatosis (using the older nomenclature) was not then known to exist, though I believe we did see some individuals who, in retrospect, probably had this disorder.  Genetic testing did not become available until after the NF1 and NF2 genes were identified, so diagnosis was strictly clinical. Along the way, we were able to contribute one large family to a genetic linkage study that helped identify the genetic location of the NF1 gene, a prelude to its eventual discovery in 1990 by groups at the University of Michigan and the University of Utah.  The clinic started before magnetic resonance imaging was routinely available, though computerized tomography (CT) scanning was available. 

Treatment options were also very limited – surgery, of course, but little else.  It was common early on for individuals with NF1 optic gliomas to have radiation treatments, a practice that was abandoned as the side effects became clear and alternatives were introduced (including watchful waiting, since not all optic gliomas are progressive). 

This brief blog is nowhere near long enough to enumerate all that I learned in the 40 years since starting the clinic, so I’ll highlight only a few things. One is the value of focusing on a specific condition and becoming intimately familiar with it.  Genetics is a challenging discipline, with over 7,000 recognized genetic conditions, many of which are vanishingly rare.

Working with just one of these has made it clear how many questions patients and family members have, and gathering experience has made a huge difference in being able to answer these questions. It is often said that “there is no substitute for experience.” I hope that is not true, as the rarity of many conditions makes it hard for any one specialist to gain significant experience. Maybe tools such as artificial intelligence will help to bridge this gap for those rare conditions and even to make expertise about NF more widely available.

Another lesson is the amazing resilience displayed by individuals who live with the various forms of neurofibromatosis. We have finally entered an era where treatments are becoming available, though there is much more to be accomplished in this area for all forms of the condition. Meanwhile, people with NF1 and the various forms of schwannomatosis must adapt to the many challenges imposed by these conditions every day, hoping for a time where treatments will help to relieve the burden – or even prevent manifestations from ever becoming a burden. 

After these 40 years we are just now seeing major progress, but a final lesson I’ll highlight is the sense of urgency that clinicians and investigators must share with affected individuals to ensure that progress is as rapid as humanly possible.