It is essential for the clinical endocrinologist to have a good understanding of the genetics of endocrine disease. The first challenge is to recognize that the clinical scenario may be indicative of a genetic condition. This detection requires that the practitioner recognize clinical patterns, and take a good family history.
Salman Kirmani, MBBS, of the Department of Medical Genetics at Mayo Clinic in Rochester, Minn., says: "An accurate diagnosis not only directs current management, but also allows for a personalized road map for future surveillance of patients and presymptomatic family members. With the advent of prenatal and pre-implantation diagnosis of genetic disorders, couples who are at risk of having children with heritable endocrine disorders may want to use genetic information to make reproductive decisions, and they need appropriate counseling about the options available to them.
"Finally, with the flood of data coming in from genomewide association studies (GWASs) and with whole-genome sequencing just around the corner, endocrinologists have to be ready for the demands of practicing individualized medicine for all of their patients."
The ideal situation would be for the endocrinologist to partner with a medical geneticist in the care of such patients. Outside of the tertiary care setting, access to a medical geneticist or a genetic counselor continues to be limited, and the endocrinologist may have to navigate through the complex issues of genetic testing and its implications until the patient can be seen by a genetics provider.
What clinical situations demand consideration for a genetic syndrome?
Dr. Kirmani answers: "Pattern recognition may not be difficult for some well-known endocrine syndromes, but it is hard to expect even the best clinicians to recognize a rare genetic syndrome every time.
"Multiple endocrinopathies in the same patient are usually the first clue. A focused three-generation family history often reveals a syndromic diagnosis, even when the patient has only one clinical finding.
"For example, asking a patient with a norepinephrine-secreting pheochromocytoma questions about a family history of renal cell carcinoma or brain and retinal hemangioblastomas may uncover a diagnosis of von Hippel-Lindau (VHL) disease. Recognizing certain unusual clinical signs in association with an endocrine disorder also is essential to making a diagnosis.
"Use of the open-access Online Mendelian Inheritance in Man (OMIM) database is very helpful not only for looking up the cardinal features and inheritance pattern of a particular syndrome under consideration, but also for searching to see if a combination of clinical features is part of a recognized genetic syndrome.
"OMIM is also linked to another useful website called GeneTests, which not only provides an up-to-date review on a number of genetic syndromes, but also provides links to commercial and research laboratories performing genetic testing."
How would genetic testing be helpful in a particular situation?
Genetic testing can be used to confirm a clinical diagnosis. Dr. Kirmani explains: "Even when genetic testing is not essential for the diagnosis, if one is to identify presymptomatic individuals in the family who may benefit from screening, it is essential to confirm the presence of a pathogenic mutation in the proband, to ensure that accurate testing can be offered to family members at risk.
"In situations where the family history is not available, such as adoption, or the clinical scenario is not characteristic, genetic testing is essential in establishing a diagnosis," notes Dr. Kirmani.
"Results of genetic testing also direct management, even if a clinical diagnosis is well established. A classic example is in multiple endocrine neoplasia, type IIA, where the type of mutation in the RET proto-oncogene determines the age at onset of medullary thyroid cancer, directing the timing of prophylactic thyroidectomy in these individuals," says Dr. Kirmani.
How sensitive and specific is genetic testing for a particular disorder?
Dr. Kirmani highlights: "Using the example of VHL again, the testing methodology entails both sequencing and deletion or duplication analysis of the VHL gene. If both methodologies are used, testing is more than 99 percent sensitive, but if sequencing alone gives a negative result, the patient still may have a large deletion that could have been missed with sequencing alone. There also may be multiple genes responsible for a disorder, with some genes as yet undefined.
"Thus, limitations in both the testing methodologies and our understanding of the genetics of the disorder limit the sensitivity of most genetic tests to below 100 percent. Results may reveal variants of unclear significance, and a novel change in the nucleotide sequence may not necessarily be pathogenic, making interpretation of test results challenging."
What is the role of new genetic tests that give risk profiles to patients for common disorders, such as type 2 diabetes mellitus?
Type 2 diabetes mellitus is a multifactorial disorder, having both genetic and environmental components.
Dr. Kirmani says: "Even though the genetic contribution is notable, there most likely are multiple genes involved, each one contributing a small risk of disease. GWAS investigators are attempting to identify such genes, to better understand the pathophysiology of the disease. Data from such studies should be used to generate hypotheses and not to predict likelihood of disease.
"Unfortunately, some commercial entities are marketing these tests directly to consumers, giving them risk profiles based on the presence or absence of genetic variants. These data are not considered clinically relevant unless further prospective studies validate these concerns. Established clinical risk factors and the family history are better predictors of future onset of disease."
The endocrinologist should recognize clinical situations that warrant further consideration from a genetic standpoint. Decisions on whether genetic testing is needed should be made on a case-by-case basis, ideally with a geneticist involved from the outset, since interpretation of genetic test results can be challenging.