Joseph Merrick (1862-1890), known throughout England as the Elephant Man, may have had the most severe case of neurofibromatosis (NF) documented in the annals of medical literature. In the 19th century, nothing was known about the genetic basis of NF, or of any other disease for that matter. In light of his disfiguring condition, the traveling show Merrick worked for dubbed him the Elephant Man, and the popular press quickly followed suit. In 1882, a German physician named Von Recklinghausen published a monograph describing the appearance and symptoms of patients with NF; hence, in the older literature NF is often called Von Recklinghausen disease.
NF is characterized by nerve sheath tumors called neurofibromas, which arise from the Schwann cells that myelinate peripheral nerve axons. These neurofibromas may arise anywhere on the skin surface or around internal nerve fibers throughout the body. Other signs of NF include patches of skin discoloration called cafe au lait spots; Lisch nodules in the iris of the eye; macrocephaly (enlarged head); scoliosis and other skeletal malformations, and a higher incidence of certain cancers, especially the adrenal medullary tumor pheochromocytoma.
NF is believed to affect 100,000 people in the U.S., making it among the most common hereditary neurological diseases. Estimates of its incidence are 1 in 3,000 to 4,000 newborns worldwide. Although NF is an autosomal dominant disease, nearly 50% of cases appear sporadically. Medical geneticists think that sporadic cases are caused by germline mutations in the NF-1 gene on chromosome 17 during meiosis. Occasionally, cases of NF may be relatively mild or even go undiagnosed due to a phenomenon called variable expressivity of the abnormal NF-1 gene. In other words, although the role of NF-1 in causing neurofibromatosis is solidly established, the factors underlying the highly variable manifestations of this disease remain unknown.
This leads to an obvious question: What does the NF-1 gene do normally? NF-1 is thought to act as a tumor suppressor gene. The protein it encodes, called neurofibromin, inhibits cell proliferation in certain cell types, especially glial cells – oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. As with other diseases arising from tumor suppressor gene mutations, such as Von Hippel Lindau and retinoblastoma, the tumors in NF arise from a specific cell type; other cell types tend to remain unaffected even though every cell in the person’s body contains at least one defective NF-1 gene.
Several other questions remain unanswered about Merrick’s condition. Why was Joseph Merrick’s case so severe? And did Merrick even have NF? No one knows for sure. Although Merrick died in 1890, some of his remains, including hair samples, were preserved and subjected to DNA analysis; unfortunately, a century had elapsed and the test results were inconclusive. Some have proposed that Merrick’s disease was actually a severe form of Proteus syndrome, an extremely rare disorder linked to a tumor suppressor gene on chromosome 10 called PTEN. Unlike NF-1, however, PTEN mutations are found in a wide variety of cancers (brain, lung, prostate), none of which Merrick had.