Advances in genetic testing have been crucial to discovering the underlying causes of many endocrine disorders. These tests not only act as a guide to treatment, but also as a precaution for family members.
As genome sequencing continues to reveal the functions — and dysfunctions — of particular genes, genetic tests are gaining currency, particularly when hormone tests give ambiguous results.
From common conditions like thyroid disease to rare adrenal tumors, these tests can reveal the inheritable component of a patient’s condition and can change the approach to treatment. The patient’s family can also benefit from this knowledge — or in some cases provide important information about a mutation’s actual effects.
“Generally speaking in endocrine diseases, we find abnormalities in a particular hormone level, and then we make a diagnosis and recommend a treatment,” says Roy E. Weiss, MD, PhD, chair of the department of medicine at the University of Miami Miller School of Medicine and coeditor of the text, “Genetic Diagnosis of Endocrine Disorders.” “Certain times, however, based on the history and physical examination, you can measure the hormone levels, and there may be ambiguity about what the diagnosis is. Therefore, you need to understand at a deeper level what the genetic cause is for the abnormal hormone level. Once you understand better the mechanism for the abnormality, you can provide specific treatment.”
Weiss says that there are several thyroid conditions caused by mutations that can be pinned down by genetic testing, citing the examples of syndromes of impaired sensitivity to thyroid hormone. These patients’ test results can be confusing. A patient might present with hyperactivity and a goiter but discordant blood tests: Although the patient’s thyroid hormone levels are elevated, the thyroid-stimulating hormone (TSH) level is normal, rather than being suppressed. There are several potential diagnoses in this case — calling for different treatments — but no single clinical test will nail down the diagnosis.
The problem could be a pituitary gland tumor that is making TSH, and the treatment would be removal of the tumor. The problem could be that the patient has an antibody interfering with the test making his TSH appear normal when it is really low. That patient may need to be treated for hyperthyroidism.
Resistance to Thyroid Hormone Syndrome
Or the problem could be the syndrome of resistance to thyroid hormone, an inherited condition caused by mutations in the thyroid receptor beta gene that is characterized by reduced responsiveness of target tissues to thyroid hormone. “If you send a blood sample and the laboratory reports a mutation in the thyroid hormone receptor that aff ects function of the receptor, you have made the diagnosis,” Weiss says. And that knowledge puts the clinician on track for the correct treatment.
Of course, no treatment can correct the mutation, but in many patients the thyroid compensates for the lack of sensitivity of tissues to thyroid hormone by increasing its secretion of thyroxine (T4) and generation of triiodothyronine (T3), and treatment may not be needed. “Recognizing that no treatment is needed is very valuable because reduction of thyroid hormone levels would be incorrect in such a patient,” Weiss says.
A family history can help in deciding whether treatment is necessary. “Perhaps there is a sibling or parent who also has this mutation and is living perfectly well without any treatment whatsoever and still has the abnormal blood test. That would tell the clinician,” that treatment is not needed because the thyroid is compensating for the defect, Weiss says. “In other instances, when the patient is very symptomatic, knowing that the symptoms are due to decreased sensitivity to thyroid hormone, there are specific treatments that can be given. One example would be administration of thyroid hormone analogues or high doses of thyroid hormone at diff erent intervals to reduce the goiter.”
Other conditions involving impaired sensitivity to thyroid hormone that can be detected by genetic tests include a syndrome of impaired conversion of T3 from T4 (deiodinase defects) and defects that impair the transport of thyroid hormone into cells.
Rare Adrenal Tumors
Thyroid cases are among the most common conditions that endocrinologists see, but genetic testing can be helpful in the rare adrenal tumors — pheochromocytomas and paragangliomas. Th ese tumors produce large amounts of the catecholamines — epinephrine and norepinephrine — and lead to symptoms including high blood pressure, episodic severe headaches, excess sweating, racing heart, feelings of anxiety, and trembling. Some 0.1% to 0.6% of hypertensive patients have pheochromocytomas, but the condition is notoriously slow to be diagnosed because of its rarity and the nonspecifi c and paroxysmal nature of symptoms like headaches.
“The average delay in diagnosis is still about three years,” says Jacques W.M. Lenders, MD, PhD, of Radboud University Nijmegen Medical Center, Nijmegen, Th e Netherlands. Lenders chaired the committee that wrote “Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline.”
The diagnosis is important because “in addition to the strain these tumors put on the cardiovascular system, between 10% and 17% of the tumors can become malignant,” Lenders says. “This is one of the rare instances when a pathologist cannot tell us definitely with 100% certainty in an individual patient that this is malignant or benign disease.”
More Definitive Information
Blood and urine tests for the catecholamine metabolites (metanephrines) in conjunction with functional imaging techniques are reliable for identifying and locating tumors, but genetic testing can provide information about an underlying hereditary condition. “About 30% to 40% of these patients have an underlying mutation in some of the genes that are involved in the development of the pheochromocytoma and paraganglioma. Some of these genetic mutations are associated with a very high risk of malignancy,” Lenders says.
“If you have a young patient and you know that the patient has a mutation that is associated with a very high risk of developing malignant disease, you can monitor the patient much more closely,” Lenders says. But there are also mutations that are not related to an increased risk of malignancy. “If you know the mutation, you can check the relatives to see if they have the mutation, and if they have an occult or hidden tumor. Early detection can benefit family members who may be at risk.”
The genetic testing can lead to other avenues as well. For example, a patient who presents with a pheochromocytoma could turn out to have the mutation for Von Hippel-Lindau syndrome. “Then you will look for other manifestations of the syndrome like cerebral hemengioblastomas and renal cell carcinoma. The clinical follow up of such patients is completely diff erent,” Lenders says.
Genetic tests generally involve the classic questions about what to do with the information. The Endocrine Society guideline recommends counseling pheochromocytoma patients about the value of genetic testing — for example, a mutation does not guarantee that the patient will have cancer but raises the risk considerably.
Tests of the Future?
Most of these tests are performed at specialized centers, but the spread of “next generation sequencing” technology will make these tests more widely available, Lenders says.
“Measuring the hormones alone may not be sufficient to give the clinician a clue as to what is really going on,” Weiss concludes. The genetic diagnoses are becoming more definitive and useful for more conditions, “whether it’s gene abnormalities in aspirates of thyroid nodules to aid in the diagnosis of thyroid cancer, or genetic analysis to determine the cause and best treatment of diabetes, or analysis of the genes responsible for thyroid hormone function abnormalities, such genetic tests will direct the physician to a more specific treatment.”