Congenital Hypothyroidism: Horses and Zebras

In my last entry, I discussed a bit about the diagnostic process and the importance of first thinking of common disorders and then the rare ones. Here, I will discuss why it is important not to totally ignore the zebras.

Congenital Hypothyroidism: The Basics

Congenital hypothyroidism (CH) is a very important pediatric endocrinology diagnosis. About 1/3000-4000 children are born with this condition; the prevalence is higher in females (about 2:1), much lower in blacks (about 1/20,00) and higher in Hispanics (about 1/2000 ). The condition is most commonly caused by abnormal development of the thyroid gland, called thyroid dysgenesis, which in most cases means that the gland is missing or only a remnant. The specific cause of this form of CH is unknown but is only rarely on a genetic basis (I have cared for 2 sets of identical twins where only one of each of the twin pairs had CH). It must be some intrauterine insult quite early on since the thyroid gland is fully formed and “in place” (the gland migrates from the base of the tongue to the anterior neck) by day 50 in utero.

There are other causes of CH which include disorders of thyroid hormone syntheses and disorders of the pituitary or hypothalamus (called secondary and tertiary hypothyroidism, respectively). The disorders of thyroid hormone synthesis are called “dyshormonogenesis” and are mostly on well described genetic bases (all are autosomal recessive disorders). The dyshormonogenesis causes of CH can be differentiated from “classic” CH because most are associated with enlargement of the thyroid gland at birth.

What is such a big deal about CH?

CH is important to diagnose as soon as possible after birth because thyroid hormone is critical for postnatal brain development as well as growth and various metabolic processes. CH will result in permanent brain damage if not treated within a few months after birth. Unfortunately, many patients with CH do not show any signs or symptoms of CH until it is too late to prevent developmental disorders. That is why, throughout the U.S. and most of the rest of the world, newborn screening programs test for CH from dried blood spots, easily obtained from heel stick blood samples. Once diagnosed, the condition (whatever the specific cause) can be easily treated with thyroid hormone replacement. Mental retardation from CH is now quite unc0mmon, a true triumph for modern medicine.

Enter the zebra

A recent article in the New England Journal of Medicine (Moreno, J.C., and Associates- 358:1811-18, 2008) reported 4 cases of a dyshormonogenesis cause for CH, a mutation in a gene responsible for recycling iodine within the thyroid gland; iodine, in the form of iodide, is necessary for thyroid hormone syntheses (each molecule of thyroid hormone has 4 molecules of iodine). In effect, if the gland cannot recycle iodine from thyroid hormone precursor molecules, the iodine is lost in the urine and stool and causes iodine deficiency which results in enlargement of the thyroid gland- a “goiter,” and hypothyroidism. The article was actually mostly about the sophisticated studies defining the specific genetic disorder in the 4 cases but the authors also discussed the clinical implications of their findings.

As it turns out, most cases of CH due to dyshormonogenesis are detected by the newborn screens or by an astute clinician finding a goiter. But, the authors documented that at least 1 of the cases had a normal newborn screen. When finally diagnosed, all cases had goiters. The authors concluded that clinicians should not rely on newborn screening tests to detect all cases of CH.

In an accompanying editorial, P.A. Kopp (pages 1856-59) emphasized the importance of careful clinical observation of infants and children to avoid making a diagnosis of CH after permanent brain damage has occurred. It isn’t so hard- infants and children with clinically significant hypothyroidism (i.e., where the blood level of thyroid hormone is abnormally low) will demonstrate slowed linear growth and maybe other signs and symptoms too. These days with our medical care system in disarray, some parents do not seek medical care for their children unless there are acute problems. Routine medical care for infants and children following some routine is the best way to prevent preventable catastrophes.  Without a first class medical care system we will miss both zebras and horses.

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