Here is an excerpt from Chapter 12:
It is easy to find cases wherein a rare disease accounts for a somewhat uncommon clinical presentation of a common disease.
12.1.2 Rule—Uncommon presentations of common diseases are sometimes rare diseases, camouflaged by a common clinical phenotype.Rare diseases may produce a disease that approximates the common disease; the differences being subtle findings revealed to the most astute observers. Here is some pithy wisdom that senior physicians love to impart to junior colleagues: “When you see hoof prints, look for horses, not zebras.” The message warns young doctors that most clinical findings can be accounted for by common diseases. Nonetheless, physicians must understand that zebras, unlike unicorns and griffins, actually exist. Occasionally, a rare disease will present with the clinical phenotype of a common disease.
Brief Rationale—Common diseases tend to occur with a characteristic clinical phenotype and a characteristic history (e.g., risk factors, underlying causes). Deviations from the normal phenotype and history are occasionally significant.
For example, mutations of the JAK2 gene are involved in several myeloproliferative conditions, including myelofibrosis, polycythemia vera (see Glossary item, Polycythemia), and at least one form of hereditary thrombocythemia (i.e., increased blood platelets) [9–11]. Surprisingly, somatic blood cells with JAK2 mutations are found in 10% of apparently healthy individuals . The high incidence of JAK2 mutations in the general population, and the known propensity for JAK2 mutations to cause thrombocythemia and thrombosis, should alert physicians to the possibility that some cases of idiopathic thrombosis may be caused by a platelet disorder caused by undiagnosed JAK2 mutation of blood cells. As it happens, it has been shown that a JAK2 mutation can be found in 41% of patients who present with idiopathic chronic portal, splenic and mesenteric venous thrombosis . Such thrombotic events are uncommon in otherwise healthy patients. The search for a zebra, in this case a cryptic myeloproliferative disorder caused by a JAK2 mutation, pays off (see Glossary item, Myeloproliferative disorder).
Zebras can hide among the horses. Consider lung cancer, the number one cause of cancer deaths in the U.S. When lung cancer occurs in a young person, you might wonder if this is a rare disease cloaked as a common disease. Midline carcinoma of children and young adults is an extremely rare type of lung cancer. It is characterized by a NUT gene mutation, not typically found in commonly occurring lung cancers of adults . Hence, midline carcinoma of children and young adults is an example of a rare disease hidden in a common disease. Secretory carcinoma, formerly known as juvenile breast cancer, is a rare form of breast cancer. It has a less aggressive clinical course than commonly occurring breast cancer, and occurs at a younger median age (i.e., about 25 years) than the median age of occurrence of common breast cancer (i.e., 61 years). In 2002, it was discovered that the expression of the ETV6-NTRK3 gene fusion is a primary event in the carcinogenesis of secretory breast carcinoma . Once again, an uncommon presentation of a common tumor was found to hide a rare disease with its own characteristic genetic mutation.
Myelodysplastic syndrome, formerly known as preleukemia, is a rare blood disorder occurring almost exclusively in older individuals. The specific gene causing myelodysplastic syndrome is unknown, but recurrent cytogenetic alterations have been found in bone marrow cells, particularly losses of the long arm of chromosome 5 (i.e., 5q-) and of chromosome 7 (i.e., monosomy 7). Myelodysplastic syndrome occurs in very young children, with extreme rarity. Virtually all such childhood cases involve monosomy 7. An inherited predisposition to lose one copy of chromosome 7 in somatic cells has been reported in kindreds whose children have a high likelihood of developing myelodysplastic syndrome, or of acute leukemia. Hence, it seems that a somatic chromosomal abnormality associated with a rare disease occurring in adults is also associated with an even more rare childhood form of the disease. The childhood disease may occur when an inherited mutation predisposes children to the equivalent somatic chromosomal abnormality observed in the adult form of the disease [16,17].
As a final example, there are two recognized types of acute myelogenous leukemia (AML): AML following myelodysplasia, a preleukemia, and de novo AML, which develops in the absence of an observed preleukemic condition . De novo AML can occur in children or in adults. The de novo AML cases in children have a different set of cytogenetic markers than those observed in adult de novo AML .
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- Jules J. Berman, Ph.D., M.D. tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, cryptic disease