Congenital hypothyroidism

Congenital hypothyroidism (CH) is a thyroid hormone deficiency present at birth. If untreated soon after birth, severe congenital hypothyroidism can lead to growth failure and permanent intellectual disability. Infants born with congenital hypothyroidism may be asymptomatic, or may display mild symptoms that go unrecognized as a problem. Significant deficiency may cause excessive sleeping, reduced interest in nursing, poor muscle tone, low or hoarse cry, infrequent bowel movements, significant jaundice, and low body temperature.

In the era before newborn screenings, less than half of cases of severe hypothyroidism were recognized in the first month of life. As the months progressed, these babies would grow poorly and have significant neurologic and developmental delays. By several years of age, they would display the recognizable facial and body features of cretinism. Persistence of severe, untreated hypothyroidism resulted in severe mental impairment, with an IQ below 80 in the majority. Most of these children eventually ended up in institutional care. A hypoplastic gland may develop higher in the neck or even in the back of the tongue. A gland in the wrong place is referred to as ectopic, and an ectopic gland at the base or back of the tongue is a lingual thyroid. Some of these cases of developmentally abnormal glands result from genetic defects, and some are "sporadic," with no identifiable cause. One Japanese study found a statistical correlation between certain organochlorine insecticides and dioxin-like chemicals in the milk of mothers who had given birth to infants with congenital hypothyroidism. Neonatal hypothyroidism has been reported in cases of infants exposed to lithium, a mood stabilizer used to treat bipolar disorder, in utero. In another systematic review, topical iodine (i.e., iodine-containing disinfectant) was associated with transient hypo- or hyperthyroidism, particularly in preterm babies born before 32 weeks of gestation.

In some instances, hypothyroidism detected by screening may be transient. One common cause of this is the presence of maternal antibodies that temporarily impair thyroid function for several weeks. Preterm or ill neonates may also have a delayed rise in TSH, leading to false-positive newborn screenings and transiently low thyroid hormones.

The word "cretinism" is an old term for the state of mental and physical retardation resulting from untreated congenital hypothyroidism, usually due to iodine deficiency from birth because of low iodine levels in the soil and local food sources. The term, like many other 19th century medical terms, acquired pejorative connotations as it became used in lay speech. It is now deprecated; ICD-11 uses "congenital hypothyroidism due to iodine deficiency" with additional specifiers for the various types of endemic cretinism.

Genetics

Congenital hypothyroidism can also occur due to genetic defects of thyroxine or triiodothyronine synthesis within a structurally normal gland. Among specific defects are thyrotropin (TSH) resistance, iodine trapping defect, organification defect, thyroglobulin, and iodotyrosine deiodinase deficiency. In a small proportion of cases of congenital hypothyroidism, the defect is due to a deficiency of thyroid-stimulating hormone, either isolated or as part of congenital hypopituitarism.

Genetic types of nongoitrous congenital hypothyroidism include:

{| class="wikitable"

! OMIM

! Name

! Gene

| congenital hypothyroidism, nongoitrous 1 CHNG1

| TSHR

| CHNG2

| PAX8

| CHNG3

| ? at 15q25.3-q26.1

| CHNG4

| TSHB

| CHNG5

| NKX2-5

Nongoitrous congenital hypothyroidism has been described as the "most prevalent inborn endocrine disorder".

Diagnosis

Newborn screening for congenital hypothyroidism substantially reduces the risk of irreversible neurodevelopmental harm. In high-income settings, most cases are identified through heel-prick dried blood spot testing, in which thyroid-stimulating hormone (TSH) is measured on a filter-paper card. This timing accounts for the physiologic surge in TSH in the first 24 hours of life, after which levels decline and stabilize, allowing for more accurate screening results. Abnormal screening results are typically confirmed with serum TSH and fT4 before or shortly after starting treatment. In primary CH, the thyroid gland itself is defective and fails to secrete adequate thyroid hormones in response to stimulation by TSH. Levothyroxine is available as a small tablet and in several brands. The tablet is crushed and given to the baby with a small amount of water or milk. The most commonly recommended dose range is 10-15 μg/kg daily, typically 12.5 to 37.5 or 44 μg. Within a few weeks, the T<sub>4</sub> and TSH levels are rechecked to confirm that they are being normalized by treatment. Of note, in central CH, the treatment plan must address any associated pituitary hormone deficiencies, as some cases require replacement of other hormones prior to initiating thyroid hormone replacement therapy. If not urgently treated, neonates with CH typically have irreversible and significant growth and neurocognitive developmental delays.

Congenital hypothyroidism is the most common preventable cause of intellectual disability. Few treatments in the practice of medicine provide as large a benefit for as small an effort. The developmental quotient (from the Gesell Developmental Schedules) of children with hypothyroidism at age 24 months that have received treatment within the first 3 weeks of birth is summarized below:

{| class="wikitable"

! Severity !! Adaptive behavior !! Fine motor !! Gross motor !! Language !! Personal-social behavior

| Severe|| 92 || 89 || 90 || 89 || 90

| Moderate|| 97 || 97 || 98 || 96 || 96

| Mild|| 100 || 99 || 100 || 99 || 100

Epidemiology

The incidence of primary congenital hypothyroidism is 1 in every 2000 to 3000 births worldwide, while the incidence of central CH is 1 in every 16,000 to 30,000 births. The reported global prevalence of CH between 1969 and 2020 has ranged between 4.23 and 4.28 per 10,000 newborns, with significant differences noted across geographic regions and country income levels. Similarly, the increased prevalence may be attributed to preterm infants surviving for longer, a higher number of live births among older mothers, and greater exposure to environmental toxins. It is also found to be of increased association with female sex and gestational age >40 weeks.