Thyroid for Dummies (37 page)

The expression of a gene is sometimes controlled at the level of the gene itself, while at other times the gene happily transcribes itself to make messenger RNA, but for some reason the cell ignores that type of mRNA and the protein it codes for is never made. In these and in many other ways still undiscovered, cells use only the genes they need to function within their environment.

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The Origins of Genetic Thyroid Diseases

This understanding of genetics helps to explain how some thyroid diseases are transmitted through inheritance. A child inherits a thyroid disease in one of three ways:

ߜ A single gene from a parent may transmit a dominant or recessive trait to the child. This is the method Mendel recognised with his peas.

ߜ Often, many genes are involved in the inheritance of a disease so the child has to inherit all of them to get the disease.

ߜ An abnormality affecting an entire chromosome may result in disease.

For example, if a female ends up with only one X chromosome, instead of two, that lack produces a condition known as Turner’s syndrome, which often includes a thyroid disorder.

Inheriting a disease through a single gene

Many diseases are inherited through a single gene, often as a result of a gene mutation. If the disease is inherited as a recessive gene, both parents must supply the same gene in order for the disease to appear. If it is inherited as a dominant gene, only one parent supplies the gene necessary to cause the disease. Alternatively, if a disease is inherited with the X chromosome in a recessive form, then only a male can get the disease, as he has just one X

chromosome (paired with a Y chromosome), while a female is spared unless both her X chromosomes carry the gene.

The entire list of diseases transmitted by single-gene inheritance may be found at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=

OMIM, the homepage of Online Mendelian Inheritance in Man (OMIM), a huge database compiled by Dr. Victor McKusick at Johns Hopkins University. If you search the term ‘thyroid’ from the homepage, 559 different thyroid diseases are listed at the time of writing. Each one is fully described, with citations for all the research that has helped to define the defect and a complete bibliogra-phy at the end of each description.

Recessive inheritance

Many conditions in which thyroid hormone isn’t made properly fall into the category of recessive inheritance. It takes two ‘bad’ genes to develop one of these conditions. If you have just one bad gene, you’re a carrier of the disease, but you don’t experience it yourself. The phenotype (the way this genetic pattern makes itself known) is usually a large thyroid that doesn’t produce 24_031727 ch17.qxp 9/6/06 10:44 PM Page 215

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sufficient thyroid hormone. Although several conditions appear similar, in that the final result is absence of thyroid hormone, each condition involves a defect at a different step in thyroid hormone production. Among the conditions inherited this way are:

ߜ
A defect in the production of thyroid hormone
(see Chapter 3): People with this condition are hypothyroid (see Chapter 5) and have goitres.

This condition stems from an abnormality in the creation of the enzyme that produces thyroid hormone.

ߜ
Thyroid hormone unresponsiveness:
If you inherit a bad gene instead of the gene that makes the receptor protein for thyroid hormone, your cells are not responsive to the thyroid hormone your body produces.

People with this condition are deaf and have goitres. With this condition, the T3, T4, and TSH levels are all elevated (see Chapter 4).

ߜ
Pendred Syndrome:
People with this disease are deaf and have goitres, but their thyroid function is normal. The disease also causes mental impairment and an increased tendency to develop thyroid cancer. The defect is in the production of thyroid hormone, but at some point it improves so that hypothyroidism isn’t present later on.

ߜ
Thyroid transcription factor defect:
People affected have a goitre and decreased levels of thyroglobulin.
Transcription
is the term for the production of messenger RNA from DNA, which is where this defect arises.

ߜ
Defect in thyroid production:
This is different from
thyroid
transcription factor defect. Someone with this condition is hypothyroid, has a goitre, and experiences mental impairment. Lab tests show a defect in the formation of thyroid hormone. Normally, two molecules of tyrosine with iodine attached couple together to form thyroid hormone, but this process fails in this particular inherited condition.

Dominant inheritance

Many inherited thyroid conditions are passed from parents to children this way: Only one ‘bad’ gene is needed to produce this disease. These diseases are more common than those inherited by recessive genes, and examples include: ߜ
A thyroid hormone receptor defect:
If you have this condition, your body is resistant to the action of thyroid hormones. At the same time, you experience mild hyperthyroidism. People with this condition have short stature, learning disabilities, deafness, and a goitre. Lab tests show high levels of T3, T4, and TSH.

ߜ
Papillary thyroid carcinoma
(see Chapter 8): This type of cancer usually occurs at an earlier age than thyroid cancer that isn’t inherited.

ߜ
A different defect in thyroid hormone receptor:
This produces a child with severe cretinism of the neurologic form (see Chapter 12).

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ߜ
Thyroid hormone resistance
(also found in a recessive form): Someone with this condition has a goitre and as a child begins to speak at a later than expected age, but thyroid function is normal. Lab tests show that T3 and T4 levels are high, but the TSH level is normal.

ߜ
Multiple Endocrine Neoplasia, Type II:
This condition causes tumours in multiple organs, including medullary carcinoma of the thyroid (see Chapter 8), a tumour of the adrenal glands, and tumours of the parathyroid glands. Lab tests show increased levels of epinephrine (adrenaline) and calcitonin in the blood.

ߜ
Medullary Carcinoma of the Thyroid, Familial:
People with this condition have medullary cancer (see Chapter 8).

X-linked inheritance

X-linked inheritance presents fewer examples because men have only one X

chromosome and women have two, compared to 44 other chromosomes that can produce a disease by recessive or dominant inheritance. If a disease passed on with the X chromosome is recessive, both parents must give the gene to a daughter in order for the disease to appear, but a son gets the disease if only one parent passes along the gene (as he only has one X chromosome, paired against a Y). These conditions are therefore much more common in males. Some examples of diseases inherited this way include: ߜ
Immunodeficiency and Polyendocrinopathy:
A baby with this condition has unmanageable diarrhoea, diabetes, and thyroid autoimmune disease. Sadly, a child born with this condition often dies very young.

ߜ
Thyroid-binding globulin abnormality:
This condition produces mental disability. Lab tests show that someone with this disease has decreased thyroid-binding globulin (see Chapter 3).

ߜ
Multinodular goitre:
The thyroid is larger and multinodular (see Chapter 9).

Inherited thyroid diseases can affect every step in thyroid hormone production, transportation, and action. The ones listed here are only 14 of the 559

currently listed in the OMIM database, and new conditions are discovered all the time.

Inheriting a disease through

multiple genes

Autoimmune thyroiditis is the major thyroid disease that is inherited as a result of abnormalities of multiple genes. This disease is much more common in women than men, so it seems likely that the inheritance is linked to the 24_031727 ch17.qxp 9/6/06 10:44 PM Page 217

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X chromosome. If this is the case, the method in which the X chromosome passes the disease along isn’t yet known. Another idea is that the female sex hormone, oestrogen, influences the occurrence of this disease, but just how this may happen isn’t understood.

Autoimmune thyroiditis is easy to diagnose because lab tests show that a person has autoantibodies (see Chapter 5) that damage the thyroid. Many genes are involved in the production of autoantibodies. The substance (such as thyroid tissue) that provokes antibodies is called an antigen. The antigen is first broken into small pieces that are bound to special proteins on cell membranes called major histocompatibility molecules. These molecules are involved in recognising self antigens from non-self antigens, so the immune system doesn’t normally attack the body’s own components. When a non-self antigen combines with these proteins, it leads to the activation of another cell called the T cell. The T cell helps yet another cell, the B cell, recognize the foreign antigens and produce antibodies against it. Multiple genes are involved in all these steps.

The major histocompatibility region of the chromosomes is on the short arm of chromosome 6. It determines which self antigens are found on white blood cells. These self antigens are the human leukocyte antigens (HLA). Using chemicals to identify these self antigens, scientists have found that in Caucasians, HLA-B8 and HLA-DR3 are the antigens most associated with Graves’ disease (see Chapter 6), while in Koreans, the DR5 and DR8 are most common. In Japanese, the antigen most associated with Graves’ disease is DR5, and in Chinese, it’s DR9. All of this is important because doctors can test for these antigens in relatives of affected individuals. If the antigens are present, they are more likely to get the disease.

Another disease that is found more often in people with certain human leukocyte antigens is postpartum thyroiditis (see Chapter 11). In Caucasians, the antigens involved are HLA DR3, DR4, or DR5, while in Chinese, it is DR9.

Inheriting a chromosome abnormality

As new cells are formed during the creation of a zygote (fertilised egg), it’s possible for a mistake to occur when chromosomes are divided between two new cells so that one cell ends up with an extra chromosome and the other ends up with one less chromosome. The most well-known conditions associated with this kind of chromosome mistake are Turner’s syndrome and Down’s syndrome. Down’s syndrome results when new cells contain three copies of the 21st chromosome instead of two, while Turner’s syndrome results when an X

chromosome is left behind, so that cells contain one female sex chromosome instead of two. Both conditions are associated with hypothyroidism, but Down’s syndrome is also associated with hyperthyroidism on occasion.

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The Future of Managing Hereditary

Thyroid Disease

Up until now, scientists have not had much success in their attempts to remove a ‘bad’ gene from a human and replace it with a healthy gene – a process known as genetic engineering. The main problem is in delivering the new gene successfully. As soon as scientists determine how to do this, the door is open to an exciting future world in which diseases that are inherited through a single gene are readily prevented.

Genetic engineering

If a disease is due to a recessive gene, replacing that gene with its dominant form in sufficient amounts should cure the condition. Usually in a recessive gene disorder, the disease occurs because that particular gene isn’t functioning at all, so providing even a small level of function may cure the condition.

Blood system disorders are expected to most easily respond to genetic engineering as blood is easily removed and replaced with a new gene spliced into the cells. The first trial of gene therapy, performed in 1990, was for a disorder that resulted in severe loss of immunity so the patient was susceptible to infections, as well as a cancer. Scientists tried connecting the necessary gene to a virus, which infected the blood cells of the patient and added the gene to their DNA. The cells were then cultured to increase their number and rein-serted. Unfortunately, the trial didn’t work, probably because the efficiency of splicing the gene into the cells was low.

Trials of gene therapy have also taken place for other genetic disorders, including familial hypercholesterolemia (where excessive production of cholesterol leads to heart attack); cystic fibrosis (where lack of a certain gene leads to excessive production of a thick mucus in the lungs); and Duchenne muscular dystrophy (where there is severe muscle deterioration).Unfortunately, gene replacement therapy in all three of these conditions is so far unsuccessful.

Another novel way of managing diseases caused by defective genes is to find a gene that is active during fetal life, but which becomes dormant later on.

If isolated, and encouraged to express itself, such a gene might replace the activity of the defective gene. A prime candidate for this treatment is sickle cell disease in which red blood cells carry abnormal haemoglobin (the pigment that carries oxygen). As a result, they are sickle or crescent-shaped in appearance, and block blood flow to tissues, causing great pain. A gene 24_031727 ch17.qxp 9/6/06 10:44 PM Page 219

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active during fetal life produces fetal haemoglobin, which doesn’t sickle. If scientists can find a way to turn on this gene during adult life, it can replace the defective haemoglobin.

Cancer treatment has seen a lot of activity in the area of gene therapy. One approach is to insert a gene that increases the sensitivity of cancer cells to a drug, or to insert a poison into cells that are then injected directly into a tumour. Another approach is to insert a gene that increases the activity of the patient’s immune system. Finally, some tumours arise when the activity of tumour suppressors (chemicals in the body that suppress the growth of tumours) declines. Treatment aims to restore tumour suppressor activity with a new gene that is inserted into blood cells. All these treatments have seen some success, but no one has yet cured cancer with gene therapy. And, so far, none of the cancer therapy trials have targeted thyroid cancer.