Hedi Claahsen (48) is a pediatric endocrinologist at the UMC St Radboud in Nijmegen.

What exactly is being tested with the heel prick screening for CH-T?

Screening for CH-T (congenital hypothyroidism) has been included in the heel prick since 1981. Since 1995, we also test for the regulatory hormone TSH as well as the thyroid hormone T4. We not only measure TSH, which they do in other countries, but also T4. This way we also detect thyroid gland disorders of a central (coming from the pituitary) origin.

Does the test always produce clear-cut results?

Not always. It mostly happens that results are false positives. Of course, this causes a lot of stress for people, but it can't be avoided. You do the screening so you won't miss anyone. That means that we also see a lot of children for whom we ultimately could not make a diagnosis. It is our job to make the correct diagnosis, but we must also be vigilant about overdiagnosing.

And the other way around? Can CH-T turn up later after a negative screening result?

Occasionally we see a child whose thyroid gland levels become abnormal later on. We then ask ourselves whether this is related to a false negative screening or whether this child actually had a normal value right after birth, which set us off down the wrong path. In the medical world, we call this confounding.

In cases like that, do you go ahead with the treatment for CH-T?

Sometimes it is difficult to be sure, for example, if there are very vague symptoms. In those cases, we go ahead and start the treatment. Then, we expressly discuss with the parents the fact that we don't want to take any risks, because there is a chance of a thyroid problem. It we don't treat it now, there is the risk that the thyroid levels will drop. This would result in the chance that the brain may be damaged and that developmental problems may arise. In that case, we treat the child for a period of three years. After that, it is safe to stop the treatment temporarily and to perform the diagnostics again. Such cases do happen. Unfortunately, measuring is not always knowing. As a doctor, you have to keep that in the back of your mind.

And what about the screening in premature children?

Premature children are a separate group. For them, we do not have any good values against which to compare. And, we cannot take unlimited blood samples to confirm the diagnosis. Furthermore, these children are often sick and on respirators and have many other problems. Euthyroid sick syndrome also plays a role with these children. Here, the production of TSH is suppressed during a phase of severe illness. This results in the development of hypothyroidism; at least that is what the blood levels show. Whether or not this happens as a result of the body's adaptation mechanism, we are not sure.
We often see newborns with a positive CH-T in our NICU (Neonatal Intensive Care Unit). These children are on respirators and are experiencing severe problems. If the thyroid gland results are low but acceptable, we consider this an adaptation mechanism that the body goes through, and we will not immediately start treatment with Thyrax®. The idea behind this is that if you stimulate the metabolism with a Thyrax treatment, it may have the exact opposite effect. If the thyroid hormone levels really are too low, then we administer a very small amount of Thyrax® to keep them within the normal range. In short, euthyroid sick syndrome is the reason that the CH-T screening for premature babies and neonates may be positive.

When do abnormal thyroid levels indicate congenital pituitary insufficiency?

If the screening turns up a low concentration of thyroid hormone (T4) in addition to a low or normal concentration of the regulating hormone from the pituitary (TSH), then that indicates a problem with the pituitary gland. Because if the problem were only in the thyroid gland itself, then the levels of this regulating hormone from the pituitary gland would be increased. This is then called congenital pituitary insufficiency. Often, in addition to the insufficient production of thyroid hormone, there is also insufficient production of the stress hormone (cortisol), among others. The child can become severely ill from this condition.

What do you see when you physically examine these children?

The symptoms of congenital pituitary insufficiency are often non-specific. If you examine these children, you see that they are not thriving. They are jaundiced for a longer time, their temperature fluctuates, they are more lethargic, they do not gain weight as they should, they show developmental delays and they do not drink as well as other babies. If you see this, then you must be alert. But you always need a biochemical diagnosis as confirmation. And you must not base your diagnosis on just one abnormal value. Just as one bad value in an otherwise healthy child does not reveal a great deal, one good value in a child with a poor clinical condition also doesn't tell you much. The puzzle of physical examination and biochemical values must make sense before you can make the diagnosis.

What happens to the child in a case like this?

When we suspect congenital pituitary insufficiency, we admit the children to the hospital, regularly measure their blood sugar levels and their cortisol levels, and also test the adrenal glands. We do this by means of an ACTH stimulation test in which we give the children a substance via an IV that stimulates the adrenal glands. If the cortisol levels increase, we know whether the adrenal glands function sufficiently.

Do you ever see cases of central pituitary insufficiency in which only the thyroid gland does not function?

Congenital hypothyroidism of central origin (only the hypothalamus-pituitary-thyroid axis does not function) almost never occurs. Congenital pituitary insufficiency is usually a matter of the total failure of the pituitary. So, if we have a positive screening that indicates central hypothyroidism, we first look at whether that is correct. But we also always check the adrenal glands, because if that organ fails, the patient can end up in an acute, life-threatening situation. Children will not suddenly die if the thyroid gland does not function due to a congenital pituitary problem. But the central failure of the adrenal glands does immediately cause very serious problems.

So, with congenital pituitary insufficiency, several hormones are affected. Is this obvious immediately after delivery?

As I mentioned before, an isolated thyroid hormone insufficiency due to a central failure occurs only very rarely. Therefore, we remain alert to the disruption of other hormones. Sometimes this disruption of several hormones is present immediately after the baby is born. Sometimes it develops over time. This is related to the development of the pituitary gland, which involves a number of transcription factors (certain types of proteins that play a role in gene expression) which cause the pituitary to fail over time. This may take years. The infamous example in this case is the disruption of growth hormone, which affects the overall health of these children and sometimes results in low blood sugar levels (hypoglycemia) in combination with the failure of the adrenal glands.

How do you handle disruptions in the adrenal gland?

By administering hydrocortisone. Normally, a healthy body produces a certain maintenance dosage of stress hormones (cortisol is naturally produced in the body; hydrocortisone is a drug). This can be given in tablet or capsule form. In stressful situations, our body self-regulates to produce more stress hormones, which makes the body more resilient. But if a child's body cannot do this, the parents must take over. We teach them to increase the hydrocortisone in stress situations or when the child is sick. If they do not do this, then the child may develop an Addisonian crisis. This may lead to nausea, vomiting, grogginess, low blood sugar and muscle weakness and, in some cases, to life-threatening situations. Of course, that is something we want to avoid. That is why we train the parents and the child, if he or she is old enough, to remain alert to these types of signals and to give extra medication ahead of time, when necessary. This takes the form of a stress framework.

And when do you start administering growth hormone?

During his or her first year of life, a child grows on food alone. The growth that occurs due to the stimulus of hormones begins only after the first year. So, these children grow just fine during their first year. After that, the curve starts to drop. In children with pituitary failure who also suffer from hypothyroidism and adrenal insufficiency with low blood sugar levels (hypoglycemia), we see low growth hormone levels. Therefore, these children receive treatment with growth hormone earlier.

Can girls and boys with congenital pituitary insufficiency become fertile?

Theoretically, they can. Although the internal reproductive organs of these children are normal, these children are unable to synthesize sex hormones during puberty because the girls' ovaries and the boys' testes are not being controlled by the pituitary. If the hypothalamus fails to secrete GnRH (gonadotropin-releasing hormone), then LH and FSH are not produced. On the other hand, it is possible that the GnRH functions just fine but that the LH and the FSH do not work as they should. Truly isolated disruption of the pituitary sex hormones in combination with a reduced sense of smell is called Kallmann syndrome.

How can girls be treated for this?

We initiate puberty in these children by giving them sex hormones or gonadotropins.
Since the source of the problem is in the pituitary, the structure of these girls' reproductive organs is normal. They have normal genitalia, uteruses and ovaries. Theoretically, there is a chance of fertility, but they will not be fertile spontaneously, since these girls do not have a spontaneous menstrual cycle. But, with targeted gynecological support, fertility may be achieved.

And what about the boys' fertility?

The same goes for the boys. In principle, the testes and the reproductive organs in these boys are not affected, although we do not know whether the testes develop fully in the absence of LH and FSH. All you need to initiate puberty is testosterone. Under the influence of LH, the Leydig cells will produce testosterone, which will initiate puberty. In order to be fertile, you also need FSH and the maturation of the Sertoli cells, which support the production of sperm. So, with a combination of LH and FSH, you can try to initiate sperm production so that spontaneous fertilization can be achieved. Boys therefore have a chance of being fertile in principle, certainly with the latest techniques.

Do parents who have a child with congenital pituitary insufficiency also receive genetic advice?

Very often, congenital pituitary failure is related to a genetic abnormality which we cannot always adequately trace at first. Genetic testing is not always available, because the complete clinical picture is not always clear. Ultimately, this involves children with a very rare illness. We know of patients where it shows up in other family members, but that occurs only extremely rarely. If the parents want to have other children, they are guided by our clinical geneticist. This work focuses primarily on estimating the risk of having a second child with the same illness. The chance of having a child with a pituitary problem is already small, and that also applies to the chance of a repeat occurrence. All in all, it remains difficult to predict.

Is it possible to make a diagnosis of congenital pituitary insufficiency by other means?

Yes. We can also perform genetic testing to see what is going on. We look at the transcription factors that are responsible for the development of the pituitary. The genetic analysis is reliable, but because there are several possible genes that may be affected, oftentimes a variety of genes must be tested before you find the affected gene. And frequently, you don't find it at all. You can also perform an MRI. But performing an MRI on a newborn is quite a feat. You must consider whether it is useful to do so. So, we prefer not to. Later, when the child is older, we always perform an MRI.

All in all, the caution used to arrive at a thyroid diagnosis is for good reason, isn't it?

We commit ourselves to making the correct diagnosis and to adequately treating the children at risk. But we also have a duty to prevent overdiagnosis and overtreatment. Therefore, children who have a single instance of low or abnormal thyroid values are not directly considered to be children with a hormonal problem. You must look not only at the blood values but also at the symptoms and, if necessary, you take all the measurements again. It can be good to repeat the clinical examination and the tests to see whether the problem is actually endocrine in nature. Because once you have started the treatment, it is very difficult to stop and see what happens. Once you have started, the child grows accustomed to a particular medicine. And then it becomes really difficult to reduce the medication again. Then they are stuck with it for the rest of their lives, with all of its consequences: doctor's visits, blood tests and taking medicines. As a doctor, that is also something you want to avoid.