The Case Report (also known as Case Study) is a poorly utilized resource. Every healthcare worker is familiar with case reports; medical journals sometimes contain a section devoted to them. Case reports typically begin with a comment regarding the extreme rarity of the featured disease. You can expect to see phrases such as "fewer than a dozen have been reported in the literature" or "the authors have encountered no other cases of this lesion," or such and such a finding makes this lesion particularly uncommon and difficult to diagnose; and so on. The point that the authors are trying to convey is that the case report is worthy of publication specifically because it is rare. After describing the clinical and pathologic features of the case, there is usually some obligatory paragraph explaining how the disease can be distinguished from more common diseases, with which it may have overlapping clinical or pathological features. Sometimes the case report will contain an end-paragraph that undermines the accuracy of the start-paragraph, suggesting that the lesion is more common than one might think; implying here that under-diagnosis is the root cause of the lesion's apparent rarity. Always, the case report serves as a cautionary exercise, intended to ward against misdiagnosis.
The "beware this lesion" approach to case reporting can easily miss the most important aspect of this type of publication. Science, and most aspects of human understanding, involve generalizing from the specific. When Isaac Newton saw an apple falling, he was not thinking that he could write a case report about how he once saw an apple drop, thus warning others not to stand under apple trees lest a rare apple might thump them upon the head. Newton generalized from the apple to all objects, and questioned the basic nature of gravity, to produce mathematically-described laws by which gravity interacts with matter.
Every case report of a rare disease or of a rare presentation of a common disease should serve as a special instance of a general phenomenon. In natural systems, there are no outliers. Every event, no matter how rare, is produced as the consequence of general laws of nature. The case report gives us an opportunity to clarify the general way things work, by isolating one specific and rarely observed factor.
Much of what we know about common tumors has come from studying familial cases, and then testing to see if the same gene that caused the familial cases is also present in the sporadic cases. Here are a few examples, taken from my recently published book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases.
- Germline mutations of the p53 tumor suppressor gene are present in the rare Li–Fraumeni syndrome. A somatic p53 mutation is present in about half of all human cancers .
- Families with germline mutations of the KIT gene develop gastrointestinal stromal tumors (GISTs). Somatic mutations of KIT occur in the majority of sporadic GIST tumors.
- Germline RET gene mutations occur in familial medullary carcinoma of thyroid, and in most cases of sporadic medullary carcinoma of thyroid [29,30].
- Germline RB1 gene mutations occur in familial retinoblastoma syndrome and in sporadic cases of retinoblastoma .
- Germline patched (ptc) gene mutations occur in basal cell nevus syndrome and in sporadically occurring basal cell carcinomas .
- Germline PTEN mutations occur in Cowden syndrome and Bannayan– Riley–Ruvalcaba syndrome, two inherited disorders associated with a high rate of endometrial carcinomas. PTEN mutations are found in 93% of sporadically occurring endometrial carcinomas .
In tumor after tumor, the genetic lesion present in sporadically occurring cancers would not have been found without prior knowledge of the syndromic gene (the gene responsible for the rare inherited condition). It would have been a terrible oversight if Li-Fraumeni syndrome, GISTs, medullary carcinoma of the thyroid, retinoblastoma, basal cell nevus syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome had merely served as rare case reports for the literature. Every rare disease should be accepted as an opportunity to find a cure for rare diseases and common diseases.
The process by which observations on rare diseases can be applied generally to all diseases, is discussed in detail in my recently published book, which builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.
- Jules J. Berman, Ph.D., M.D.
tags: case report, case study, rare diseases, orphan diseases, orphan drugs, case studies, Li-Fraumeni syndrome, GISTs, medullary carcinoma of the thyroid, retinoblastoma, basal cell nevussyndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome