Congenital and Acquired Hypothyroidism in Children

Thyroid Development and Function

• The thyroid gland arises as an outpouching of the foregut near the base of the tongue, also called the foramen caecum.
• Thyrotropin-releasing hormone(TRH) secreted from the hypothalamus and thyroid-stimulating hormone(TSH) secreted by the anterior pituitary begins at 10-12 weeks of gestation.
• Thyroglobulin synthesis begins at four weeks of life, and T4 and T3 synthesis begins at 12 weeks gestation.
• Special transcription factors like NKX2.1, FOXE1, and PAX8 mediate the development and migration of the thyroid gland to the normal site.
• The maturation of the hypothalamic-pituitary-thyroid axis occurs over the second half of gestation, but normal feedback relationships are not mature until one to two months of postnatal life.

Thyroid Hormone Synthesis

• Iodine in the form of an iodide ion is useful in forming thyroid hormones.
• It is the only role of iodine in the body.

• The thyroid follicle cell has a transport protein called NIS (sodium-iodine symporter) on the basolateral membrane. This protein transports iodine and sodium into the cell from the bloodstream.
• Another transport protein, pendrin, is present in the basolateral membrane, and it causes the release of iodide ions into the colloid.
• As the iodide ions are released into the colloid, a protein is formed inside the thyroid follicular cell, which is the precursor of thyroglobulin.
• This precursor molecule is then secreted into the colloid and combines with the iodide ions to form thyroglobulin.
• There are two types of precursors formed in thyroglobulin: DIT(Diiodotyrosine) and MIT (monoiodotyrosine)
• When two DIT molecules combine, they form the T4 molecules; when one DIT and one MIT molecule combine, they form the T3 molecules.
• Both T4 and T3 are stored inside the thyroglobulins. Endocytosis takes these thyroglobulins again and lies inside the thyroid follicle cell.
• The action of the TSH hormone causes the release of proteases from the thyroglobulin molecule; thus, T4 and T3 are released into the bloodstream for circulation.
• 70 % T4 and 50% T3 are bound to the thyroxine-binding globulin protein.
• 30% of T4 and 50% of T3 are bound to other transport proteins mainly albumin or pre-albumin(transthyretin).
• Only 0.03% of free T4 and 0.3% of free T3 are in the blood.
• Although it is present in the blood, only 1/50th the concentration of T4, T3 is the physiologically active thyroid hormone because it binds the thyroid hormone receptor with 10 to 15-fold greater affinity than T4.
• The thyroid gland secretes 20% of T3, and 80% is formed by the peripheral tissues from T4 using iodotyrosine deiodinase type 1 and 2.
• The brain is rich in type 2 deiodinase.
• Specific hormone transporters, especially the monocarboxylate transporter 8(MCT8), facilitate the entry of T4 and T3 cells.
• T3 and T4 thyroid hormones enter the target cells' cytoplasm and move into the nucleus.
• On entering the nucleus, they bind to specific receptors and affect gene transcription and translation to a certain degree.

Also Read: Nelson Syndrome – Causes, Symptoms And Treatment

Hypothyroidism in Children

• It is the deficiency of circulating thyroxine reaching the tissues.
• It can be 
• Primary Hypothyroidism
  • There is thyroid gland failure in primary hypothyroidism, and it cannot produce enough thyroxine due to any kind of disease.
  • It can occur due to thyroid dysgeneses like thyroid agenesis and thyroid hypogenesis or ectopic thyroid gland.
  • Thyroid dyshormogenesis is a group of conditions where the thyroid gland cannot produce its hormones due to enzyme or iodine deficiency.
  • It can happen due to TSH receptor-blocking antibodies.
  • It can also occur due to various genetic factors or antithyroid drugs.
• Secondary hypothyroidism
  • This is due to the lower secretion of TSH.
  • This TSH secretion deficiency can be isolated or due to generalized pituitary dysfunction.

Also Read: Autoimmune Polyglandular Syndromes And Ipex Syndrome

Congenital Hypothyroidism

Epidemiology of Congenital Hypothyroidism

• The most common preventable or treatable cause of children's mental retardation or intellectual dysfunction is congenital hypothyroidism.
• If thyroxine is unavailable in infancy, it can cause mental retardation, intellectual dysfunction, and delayed milestones in children.
• In India, it is seen in 1 in 1000 live births; in Western countries, it is found in 1 in 4000.
• Due to limited resources in India, conducting routine screening tests for the same is impossible.
• It is associated with conditions like Down’s syndrome, mothers with thyroid disease, low birth weight, and preterm babies.

Etiology of Congenital Hypothyroidism

• Thyroid dysgenesis
  • It is the most common cause of congenital hypothyroidism.
  • It is seen in 80-85% of the cases.
  • It has three types: agenesis, partial dysgenesis/hypogenesis, and ectopic thyroid gland.
  • It has a strong association with Down’s syndrome.
  • It is more common in females than males and is mostly sporadic.
  • No, there is no goitrous enlargement of the thyroid in these individuals.
  • Thyroid dysgenesis caused by transcription factor mutations is seen in 2-5 percent of the cases.
  • The transcription factors are implicated in the thyroid gland, and any mutation can cause thyroid dysgenesis. It was previously called TTF 1 transcription factor.
  • NKX2.1
    • Mutation in this factor produces thyroid dysgenesis, neurological problems(including chorea and ataxia), and respiratory distress.
    • A transcription factor is expressed in 3 organs: the lungs, the thyroid gland, and the central nervous system.
  • FOXE1
    • Previously, it was called TTF 2 transcription factor.
    • Mutations in this factor produce a syndrome known as Bamforth- Lazarus syndrome, which is characterized by thyroid dysgenesis, curly or spiky hair, cleft palate, choanal atresia, and bifid epiglottis.
  • PAX8
    • The mutations produce thyroid dysgenesis and renal or ureteric anomalies.
• Thyroid dyshormonogenesis
  • It comprises 15 percent of cases, and it shows autosomal recessive inheritance.
  • Goiter is frequently present.
  • It can be caused due to
    • Defects in iodine organification are mostly due to TPO gene defects, sometimes due to dual oxidase-2(DUOX-2)(the enzyme responsible for hydrogen peroxide generation) defects. This is the most common cause of dyshormonogenesis.
    • Defective iodide transporters like the NIS and pendrin mutations.
    • Defective thyroglobulin synthesis, defects in deiodination, iodine deficiency or endemic goiter, and defects in thyroid hormone transport inside the cell(MCT8 mutations).

Also Read: Maternal Diabetes And Neonatal outcomes

Clinical Features of Congenital Hypothyroidism

• Most infants are asymptomatic at birth and have normal weight and length.
• This is because thyroxine can pass the placenta, and the mother's thyroxine is enough for the baby's developed fetal development.
• The early signs of congenital hypothyroidism include wide and open posterior and anterior fontanelles.
• The posterior fontanelle is either closed at birth or closed soon after birth. It is usually less than 0.5cm, even if it is open after birth. 
• In these children, the posterior fontanelle is larger than 0.5cm, and the anterior fontanelle is wide at birth.
• The head size is slightly larger than usual.
• Myxedema of the brain tissue is also present.
• Prolongation of clinical jaundice is another sign of congenital hypothyroidism.
• These two signs appear in the first 15-20 days after birth.
• Other signs include Sluggish activity, poor feeding, lethargy, and choking spells.
• Constipation and hypothermia with skin mottling of the periphery are also seen in these children. 
• Macroglossia(large tongue) is seen in these children, which can produce apnea, noisy breathing, and nasal obstruction.
• Bradycardia, edema of the genitals, umbilical hernia( some may be associated with generalised hypotonia also), and macrocytic anemia are also observed.
• About 10% of the cases have congenital anomalies, and the cardiovascular system is the most commonly affected.
• A significant number of them have thyroglossal duct persistence.
• As age progresses and the disease is left untreated, other features like stunted growth, short limbs, persistence of open fontanelles, delayed dentition, hypotelorism with flat nasal bridge, and myxedema occur, particularly in the skin of the eyelids, the back of hands, and external genitalia.
• Coarse, brittle, and scanty hair with a low, posterior hairline is also seen in these patients with thickened scalp.
• Dry, scaly skin with short and broad hands and generalized pallor with carotenemia is seen.
• Developmental delay and hoarseness of voice are also prominent features in these children.

Also Read: Non-Immune Hydrops-Etiology, Investigations And Treatment

Investigations of Congenital Hypothyroidism

• If you are screening for hypothyroidism, three approaches are considered.
  • The primary TSH level test in the child is conducted, and a backup T4 level is done.
    • It is the most common approach in most places in India.
    • The disadvantage of this is that it misses central congenital hypothyroidism and also misses patients having a late rise in TSH.
  • The primary T4 test and backup TSH level test are done.
    • It tends to miss out on subclinical cases or cases where the maternal persisting T4 produces elevation and shows a slight rise in TSH levels but gradually falls off. So TSH rises, and T4 falls after the first week of life.
  • Both T4 and TSH levels are tested, which is considered ideal but costly.
• If there are signs and symptoms of hypothyroidism or suspicion of hypothyroidism due to maternal thyroid disease, down’s syndrome, or maternal antithyroid drug intake, both  T4 and TSH levels are tested.
• In most cases, TSH levels are elevated except in central hypothyroidism.
• T4 levels are found to be low in most individuals.
• The cut-offs are TSH greater than 20mIU/ml or 90th percentile and T4 less than 6.5micrograms/dl or 10th centile in age-based nomograms.
• When screening for TSH levels of capillary blood, if it is greater than 20mIU/ml, the patient is started on levothyroxine and repeat testing of both T4 and TSH levels using venous blood.
• When tested again, there are still elevated TSH levels and low T4 levels, and levothyroxine is continued. If normal levels are shown, levothyroxine can be stopped, but repeat the test in 2-4 weeks.
• X-ray
  • There is evidence of delayed ossification even at birth in 60% of the cases.
  • The distal femur and proximal tibial epiphyses normally present at birth are often absent.
  • As age advances, bone age is delayed as compared to chronological age.
  • Epiphyseal dysgenesis is seen, and multiple foci ossification is also observed.
  • Deformity/Beaking of T12, L1, and sometimes L2.
  • Wormian or interSutural bones will also be seen.
  • Enlarged and rounded sella turcica will be seen, and cardiomegaly will also be seen. The widely open anterior and posterior fontanelle are observed.
  • There is a delay in tooth eruption.
• Etiological workup
  • A radionuclide thyroid scan is done when there is a positive screening test.
  • Suppose there is increased uptake of the radioactive material. Thyroid dyshormogenesis is seen. The patients are also evaluated for iodine deficiency.
  • If there is ectopic uptake, then ectopic thyroid is suspected.
  • If there is no uptake, then an ultrasound is performed.
  • If the thyroid is absent, then it is thyroid agenesis.
  • If the thyroid is present, then look for receptor-blocking antibodies.
  • If there are receptor-blocking antibodies, it is due to maternal causes. If it is absent, then look for enzyme defects.
• Common Patterns of Investigations

Management Of Congenital Hypothyroidism

• The drug of choice is levothyroxine.
• The dosage is 10-15 micrograms/kg/day.
• After starting the drug, the T4 levels normalize in a week, and the TSH levels normalize in four weeks.
• These children must be monitored using the TFT every one to two months till six months of age and every two to three months between six and three years.
• In case of suspected transient hypothyroidism, levothyroxine is stopped for one month at about three years of age, and then T4 and TSH are repeated. In about 35% of patients, levothyroxine can be tapered or stopped. 
• If it is stopped, the T4 and TSH levels will be checked every six months throughout their life.
• The best sample for screening is from the heel pad prick for capillary blood.
• The best time to perform the screening test is between the 2nd to 4th day of life, beyond 48hrs of life, ideally at 72 hours of life.
• The screening test is TSH level(greater than 20mlU/ml) with backup T4 test(less than 6.5microgram/ml).

Thyroid Function in Preterm and LBW Infants

• The cord blood T4 concentration is decreased in proportion to gestational age and birth weight.
• T4 levels fall in the 1st week and then gradually rise to normal by the 6th week.
• It also shows delayed TSH elevation and apparent transient primary hypothyroidism. This is due to multifactorial reasons like compromised maternal transfer of T4 in the third trimester, immaturity of the hypothalamus-pituitary-thyroid axis, and the use of steroids or drugs.

Acquired Hypothyroidism

• It is mostly subclinical without any clinical manifestations.
• It is mostly seen in adolescence.
• It is seen more in females than males.

Etiology Of Acquired Hypothyroidism

• The single most common cause is chronic lymphocytic thyroiditis. It is also called Hashimoto’s thyroiditis or autoimmune thyroiditis.
• It occurs due to autoimmune causes(overall most common cause ) like chronic lymphocytic thyroiditis autoimmune polyglandular syndrome(APS-2 is more common than APS-1, with 70% of the cases showing hypothyroidism as compared to 10-15% cases in APS-1), celiac disease, type 1 diabetes mellitus, IPEX syndrome.
• Syndromes that show a high risk of autoimmune thyroid disease are Down’s(30%), Turner’s(40%), and Klinefelter syndrome.
•  Drug-induced causes include excess-iodide drugs like amiodarone, nutritional supplements, and expectorants. This induces the Wolff-Chaikoff effect, where the thyroid gland stops producing thyroxine as excess iodine is in the blood.
• Anticonvulsants like oxcarbazepine, phenytoin, phenobarbital, and valproate can also cause hypothyroidism. Oxcarbazepine produces central hypothyroidism and reduces the TSH levels, and the other three drugs affect the cytochrome P450 enzymes.
• Antithyroid drugs like methimazole, propylthiouracil and other drugs like lithium, rifampicin, tyrosine kinase inhibitors, IFN-alpha, Stavudine, Thalidomide, Aminoglutethimide, Dopamine, and tetracycline are drugs with can cause hypothyroidism.
• Post-ablative factors include radiation, I-131 radio ablation, and thyroidectomy.
• Systemic infiltrative diseases like cystinosis, LCH, brain tumors like craniopharyngiomas, meningoencephalitis, CNS radiation(Upto 10% develop hypothyroidism), and head trauma can cause hypothyroidism.
• Consumptive hypothyroidism is seen with large hepatic hemangiomas, which express an abnormal type of deiodinase called type 3 deiodinase.
• This deiodinase converts T3 and T4 into T2, RT3, and other inactive metabolites.
• The amount of thyroxine produced is insufficient compared to the amount used up.

Clinical Features Of  Acquired Hypothyroidism

• The first sign of this type of hypothyroidism is a slowdown of growth.
• Goiter often appears in these individuals.
• Weight gain due to fluid retention or myxedema occurs.
• Constipation, cold intolerance, decreased energy, and myxedema of the skin.
• There will be bradycardia, muscle weakness, nerve entrapment, and ataxia.
• School performance is not affected.
• There will be delayed bone age,  delayed puberty, and menstrual problems in females.
• Initially, high TRH levels will cause the secretion of prolactin from the pituitary gland, and this prolactin will produce galactorrhea.
• Continuous high TRH levels cause the enlargement of the pituitary gland, which can lead to brain tumors. Vision changes and pressure symptoms will appear in the brain.
• Pseudoprecocious puberty is seen in some children with acquired hypothyroidism due to very high TSH levels, which bind to and stimulate FSH receptors.

Investigations For Acquired Hypothyroidism

• Blood investigations show the presence of hyponatremia, macrocytic anemia, and hypercholesterolemia.
• CPK will be raised in many individuals.
• X-ray for bone age estimation needs to be done, and thyroid hormone levels are calculated.
• T4 levels will be low, and TSH levels will increase, high in primary causes and low in secondary/central causes.
• Anti-TPO is found to be positive in many autoimmune cases; if negative, then check for Anti-thyroglobulin Antibodies.
• Ultrasound of the thyroid will show goiter in autoimmune thyroiditis, and when the goiter is checked, it shows diffuse enlargement and heterogeneous echotexture.

Treatment Of Acquired Hypothyroidism

• Levothyroxine is the drug of choice.

• Monitor and measure the serum TSH every 4-6 months and 4-6 weeks after any change in dosage in primary hypothyroidism.
• In young children under three years of age, serum T4 should be measured and ideally maintained in the upper half of the age.

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