What tests are required for a diagnosis to be confirmed ?
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Kallmann's syndrome is extremely rare and requires specialist diagnosis. A teenager failing to go through puberty and who is not seen by a specialist may be told that he or she is only an example of "delayed" puberty ; i.e. a "late developer". If a girl has not begun puberty by her mid-teens, then this could indeed be a case of delayed puberty and it is unusual that an hormonal disorder such as hypogonadism or even Kallmann's syndrome is suspected instead at this time. Similarly, if a teenage boy has not entered puberty by a certain age, he could also be a case of delayed puberty. The main difference between delayed puberty and Kallmann's syndrome is that in the former case puberty, although delayed, is reached eventually. In Kallmann's syndrome however, puberty can only occur with the help of hormonal therapy.
Usually, a GP will refer his or her patient to an endocrinologist if delayed puberty or an hormonal disorder is suspected. It is the endocrinologist who is able to establish exactly why puberty has failed to occur. If delayed puberty is eliminated as a possible cause, the next step is to look at any hormonal causes. It is relatively easy to establish an initial diagnosis of Kallmann's syndrome by performing a smell test to test the extent of anosmia, if any. There are two main types of smell tests: the first involves attempting to smell and identify the contents of small bottles and the second type of test uses "scratch & sniff" cards. If there is an absent or exceptionally weak sense of smell, then this is a strong indication that the problem is indeed Kallmann's syndrome. If it turns out the patient has a normal sense of smell, he or she may be suffering from a different form of hypogonadism.
Other characteristics of hypogonadism help the endocrinologist to eliminate delayed puberty as being the cause of the lack of sexual development. These could include the previously discussed characteristics of eunuchoidism, cryptorchidism, small genitalia and sometimes osteoporosis, especially in older untreated patients. A family history of Kallmann's syndrome and the possible existence of bimanual synkinesis and unilateral renal agenesis may lead the endocrinologist to conclude that the disease has been inherited (see answer to Question 16).
Once these initial tests have been carried out, more tests may be required if an initial diagnosis of Kallmann's syndrome is to be confirmed and treatment begun. One of the most common of these is a blood test used to measure the levels (if any) of LH and FSH as well as testosterone or oestrogen (see answer to Question 6). Very low levels of these hormones mean that there is a problem with either the hypothalamus or pituitary gland, the former normally releasing the hormone GnRH which in turn releases LH and FSH from the latter.
Abnormalities of the hypothalamus and pituitary gland may also be detected using the insulin tolerance and glucagon tests. A typical insulin tolerance test procedure is to inject a small amount of the hormone insulin into the bloodstream which then lowers blood glucose (sugar) levels. Glucose is an important "fuel" of the human body and at these reduced levels, the body should respond by sweating mildly and by releasing a number of hormones from the pituitary and adrenal glands. The sweating normally lasts only a few minutes, but blood samples are collected every 15 minutes for the 90 minute duration of the test. At the end of the test, blood sugar levels can be easily restored by drinking a glass of Lucozade which contains high levels of glucose. Hormone levels in the blood samples are then measured and these will help the doctor to identify a defective hypothalamus or pituitary gland as being the most likely cause of the patient's hypogonadism. The glucagon test is an alternative to the insulin tolerance test and even though glucagon has exactly the opposite effect to insulin (i.e. it increases blood glucose levels), the test conclusions are the same.
Other tests are available to test for the presence or absence of GnRH from the hypothalamus. If these show that no GnRH is being released, then the cause of absent puberty must lie within the hypothalamus. This could lead to a diagnosis of Kallmann's syndrome.
Now that the problem has been identified as resulting from a hypothalamic deficiency of GnRH, other features of the disease may be examined. You remember from the answers to Questions 10 & 11 that somebody with Kallmann's syndrome is anosmic because of his or her absent olfactory bulbs. It is possible to establish whether or not the patient's anosmia is due to the absence of these structures by having an MRI scan. MRI stands for "Magnetic Resonance Imaging". MRI uses modern technology to "see through" bone. It is much like an X-ray but far more effective and yet much less harmful. Every part of the body has magnetic properties which respond in different ways to an electro-magnetic field. MRI technology exploits this. An MRI scanner is basically a large magnet linked to a computer, producing an image on a computer screen which can then be processed and printed as a photograph. If the head is scanned, the skull is "transparent" and the image on the screen clearly shows the brain. An MRI scan taken of the brain and skull of a man with Kallmann's syndrome (Figure 17) shows that the patient has one partially formed and one absent olfactory bulb and he therefore has no sense of smell.
Figure 17 - MRI scan of somebody with Kallmann's syndrome
Until quite recently, MRI technology was not widely available. Many hospitals now have MRI scanners, but they are extremely expensive machines and waiting lists can be several months or more. Before MRI, a different type of scan was used, the CT scan. CT stands for "Computed Tomography" and a CT scanner uses X-rays, rather than a magnetic field to "see through" the skull to the brain. CT technology is not as effective as MRI technology in determining the presence or absence of the olfactory bulbs, but it can be used to identify any tumours which may be causing the hypothalamus to malfunction and exclude this as a possible cause of the symptoms.
Sometimes an X-ray is taken of a patient's wrist or hand in order to estimate bone "age". You remember from the answer to Question 12 that the bones of untreated hypogonadal patients fail to grow and strengthen normally due to the absence of sex hormones in their bodies. If hormone replacement therapy is not given until after the normal age of puberty (i.e. after 16-18 years of age), bones will continue growing. They stop growing when the epiphyseal plates eventually fuse, sometimes not until well into adulthood. By measuring how far advanced epiphyseal plate fusion has become in the bones of the wrist or hand, it is possible to estimate bone age. This information is useful in that it helps the doctor to estimate the full extent of the patient's hypogonadism.
Since several forms of hypogonadism exist, it is important to locate the actual cause or causes of absent puberty (be they a defective hypothalamus, the pituitary gland, the gonads or even a combination of these) in order for any hormone treatment to be fully effective. Not all of the above tests and examinations are necessary in all cases but a hypogonadal patient who, having taken a smell test, is shown to be anosmic or hyposmic and who has perhaps had an MRI scan showing absent or defective olfactory bulbs is almost certainly going to be diagnosed as having Kallmann's syndrome rather than a different form of hypogonadism.
