2. Hossein Moravej

4. Epidemiology The prevalence of congenital hypothyroidism is 1/4,000 infants worldwide. Twice as many girls as boys are affected.

5. Etiology Thyroid dysgenesis (aplasia, hypoplasia, or an ectopic gland) is the most common cause of congenital hypothyroidism, accounting for 85% of cases; Inborn error of thyroxine synthesis (10%) Transplacental maternal thyrotropin-receptor blocking antibody (5%).

6. Thyroid dysgenesis ⅓ of cases of thyroid dysgenesis are aplasia, however, In the other ⅔ of infants, rudiments of thyroid tissue are found in an ectopic location(hypoplasia).

7. Thyroid dysgenesis Most cases of hypoplasia are detected by newborn screening, but in some children ectopic thyroid tissue (lingual, sublingual, subhyoid) may provide adequate amounts of thyroid hormone for many years, or it may eventually fail in early childhood.

8. Defective Synthesis of Thyroxine (Dyshormonogenesis) Goiter is almost always present. When the defect is incomplete, compensation occurs, and onset of hypothyroidism may be delayed for years.

9. Dyshormonogenesis Defect of Iodide Transport Thyroid peroxidase defects of organification and coupling: After iodide is trapped by the thyroid, it is rapidly oxidized to reactive iodine, which is then incorporated into tyrosine units on thyroglobulin. This process requires generation of H 2 O 2, thyroid peroxidase, and hematin

10. Dyshormonogenesis Defects of Thyroglobulin Synthesis Defects in Deiodination: Monoiodotyrosine and diiodotyrosine released from thyroglobulin are normally deiodinated within the thyroid or in peripheral tissues by a deiodinase

11. Defects in Thyroid Hormone Transport: Passage of thyroid hormone into the cell is facilitated by plasma membrane transporters

12. Maternal thyrotropin receptor-blocking antibody An unusual cause of transitory congenital hypothyroidism. Transplacental passage of maternal TRBAb inhibits binding of TSH to its receptor in the neonate. It should be suspected whenever : history of maternal autoimmune thyroid disease, including Hashimoto thyroiditis or Graves disease, maternal hypothyroidism on replacement therapy, or recurrent congenital hypothyroidism of a transient nature in subsequent siblings.

13. Maternal thyrotropin receptor-blocking antibody The half-life of the antibody is 21 days, and remission of the hypothyroidism occurs in about 3-6 mo

14. Radioiodine administration Hypothyroidism can occur as a result of inadvertent administration of radioiodine during pregnancy for treatment of Graves disease or cancer of the thyroid.

15. Thyrotropin and Thyrotropin-Releasing Hormone Deficiency Deficiency of TSH can occur in developmental defects of the pituitary or hypothalamus. More often, the deficiency of TSH is secondary to a deficiency of TRH.

17. Most infants with congenital hypothyroidism are asymptomatic at birth, even if there is complete agenesis of the thyroid gland. It is due to the transplacental passage of moderate amounts of maternal T 4, which provides fetal levels that are approximately 33% of normal at birth.

18. The clinician depends on neonatal screening tests for the diagnosis of congenital hypothyroidism. Laboratory errors occur, and awareness of early symptoms and signs must be maintained.

19. Birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain. Prolongation of physiologic jaundice, may be the earliest sign. Feeding difficulties, especially sluggishness, somnolence, and choking spells during nursing, are often present during the 1st mo of life. Respiratory difficulties, due in part to the large tongue, include apneic episodes, noisy respirations, and nasal obstruction.

20. Cry little, sleep much, have poor appetites, and are generally sluggish. constipation that does not usually respond to treatment. Umbilical hernia Hypothermia <35°C Skin, particularly that of the extremities, may be cold and mottled. Edema of the genitals and extremities Bradycardia, heart murmurs, cardiomegaly, and asymptomatic pericardial effusion Macrocytic anemia refractory to treatment with hematinics

21. If congenital hypothyroidism goes undetected and untreated, these manifestations progress. By 3-6 mo of age the clinical picture is fully developed. When there is only partial deficiency of thyroid hormone, the symptoms may be milder, the syndrome incomplete, and the onset delayed.

23. The child's growth will be stunted, the extremities are short, and the head size is normal or even increased. The anterior and posterior fontanels are open widely; The palpebral fissures are narrow and the eyelids are swollen. The mouth is kept open, and the thick, broad tongue protrudes. Dentition will be delayed. The neck is short and thick

24. Myxedema is manifested, particularly in the skin of the eyelids, the back of the hands, and the external genitals

25. The hairline reaches far down on the forehead, which usually appears wrinkled, especially when the infant cries. Development is usually delayed, late in learning to sit and stand. The voice is hoarse, and they do not learn to talk. The degree of physical and mental retardation increases with age.

27. Some children with ectopic thyroid tissue (lingual, sublingual, subhyoid) produce adequate amounts of thyroid hormone for many years, or it eventually fails in early childhood.

29. newborn screening programs: Blood obtained by heel- prick between 2 and 5 days of life is placed on a filter paper card and sent to a central screening laboratory.

30. Measurement of T 4; identifies infants with primary hypothyroidism, hypothalamic or pituitary hypothyroidism, and infants with a delayed increase in TSH levels. Measurement of TSH; detects infants with primary hypothyroidism, and subclinical hypothyroidism (normal T 4, elevated TSH), but it misses infants with delayed TSH elevation and with hypothalamic or pituitary hypothyroidism

31. Regardless of the approach used for screening, some infants escape detection because of technical or human errors; clinicians must maintain their vigilance for clinical manifestations of hypothyroidism.

32. Serum levels of T 4 or free T 4 are low; serum levels of T 3 may be normal and are not helpful in the diagnosis. If the defect is primarily in the thyroid, levels of TSH are elevated

33. Special attention should be paid to identical twins; Transfusion of euthyroid blood from the unaffected twin normalized the serum level of T 4 and TSH in the affected twin at the initial screening. Perform a routine second test in same-sex twins.

34. Retardation of osseous development can be shown radiographically at birth in about 60% of congenitally hypothyroid infants The distal femoral epiphysis, normally present at birth, is often absent

36. Scintigraphy can help to pinpoint the underlying cause, but treatment should not be unduly delayed for this study. Ultrasonographic examination of the thyroid is helpful, but it can miss some ectopic glands.

37. The electrocardiogram: low-voltage P and T waves, diminished amplitude of QRS complexes.

38. Treatment Levothyroxine is the treatment of choice. Currently, in neonates, the recommended initial starting dose is 10-15 µg/kg/day (totaling 37.5- 50 µg/day).

39. Levels of serum T 4 or free T 4 and TSH should be monitored: Monthly in the first 6 mo of life, and then every 2-3 mo between 6 mo and 2 yr. The dose of levothyroxine on a weight basis gradually decreases with age. Children with hypothyroidism require about 4 µg/kg/24 hr, and adults require only 2 µg/kg/24 hr.

40. It is necessary for some infants to rule out the possibility of transient hypothyroidism. This is unnecessary in infants with proven thyroid ectopia or in those who manifest elevated levels of TSH after 6-12 mo of therapy because of poor compliance or an inadequate dose of T 4. Discontinuation of therapy at about 3 yr of age for 3-4 wk results in a marked increase in TSH levels in children with permanent hypothyroidism. The only untoward effects of sodium-l-thyroxine are related to its dosage. Overtreatment can risk craniosynostosis and temperament problems.

41. prognosis Early diagnosis and adequate treatment from the first weeks of life result in normal linear growth and intelligence.

42. Delay in diagnosis, failure to correct initial hypothyroxinemia rapidly, inadequate treatment, and poor compliance in the first 2-3 yr of life result in variable degrees of brain damage. Without treatment, affected infants are profoundly mentally deficient and growth retarded. When onset of hypothyroidism occurs after 2 yr of age, the outlook for normal development is much better even if diagnosis and treatment have been delayed,

44. Epidemiology Approximately 0.3% of school aged children, Subclinical hypothyroidism (TSH >4.5 mU/L, normal T 4 or free T 4 ) is more common, occurring in approximately 2% of adolescents.

45. Etiology The most common cause of acquired hypothyroidism is chronic lymphocytic thyroiditis. Autoimmune thyroid disease may be part of polyglandular syndromes; children with Down, Turner, and Klinefelter syndromes and celiac disease or diabetes are at higher risk for associated autoimmune thyroid disease In children with type 1 diabetes mellitus, approximately 20% develop anti-thyroid antibodies and 5% become hypothyroid.

46. ETIOLOGIC CLASSIFICATION OF ACQUIRED HYPOTHYROIDISM Autoimmune (Hashimoto thyroiditis) Polyglandular autoimmune syndrome, types I and II Iatrogenic : Propylthiouracil, methimazole, iodides, lithium, amiodarone Irradiation Radioiodine Thyroidectomy Systemic disease: Cystinosis Langerhans cell histiocytosis Hemangiomas (large) of the liver (type 3 iodothyronine deiodinase) Hypothalamic-pituitary disease

47. Clinical Manifestations Deceleration of growth is usually the first clinical manifestation, but this sign often goes unrecognized. Goiter, which may be a presenting feature, typically is nontender and firm, with a rubbery consistency and a pebbly surface. Weight gain is mostly fluid retention (myxedema), not true obesity. Constipation, cold intolerance, decreased energy, and an increased need for sleep develop insidiously. Surprisingly, schoolwork and grades usually do not suffer, even in severely hypothyroid children.

48. Clinical Manifestations Bradycardia muscle weakness or cramps Osseous maturation is delayed. Adolescents typically have delayed puberty; older adolescent girls manifest menometrorhhagia.

49. Abnormal laboratory studies include hyponatremia, macrocytic anemia, hypercholesterolemia, and elevated CPK.

50. Diagnostic Studies Measurement of serum T 4 and TSH. Measurement of antithyroglobulin and antiperoxidase antibodies can pinpoint autoimmune thyroiditis as the cause. Generally, there is no indication for thyroid imaging.

51. Treatment and Prognosis Levothyroxine is the treatment of choice. The dose on a weight basis gradually decreases with age. For children 1-3 yr, the average l-T 4 dosage is 4-6 µg/kg/day; for 3-10 y4, 3-5 µg/kg/day; and for 10-16 yr, 2-4 µg/kg/day. Treatment should be monitored by measuring serum T 4 and TSH every 4-6 mo as well as 6 wk after any change in dosage. In children with central hypothyroidism, where TSH levels are not helpful in monitoring treatment, the goal should be to maintain serum T4 in the upper half of the normal reference range for age.

52. During the 1st yr of treatment, deterioration of schoolwork, poor sleeping habits, restlessness, short attention span, and behavioral problems might ensue, but these are transient; forewarning families about these manifestations enhances appropriate management. These may be partially ameliorated by starting at sub-replacement T 4 doses and advancing slowly. An occasional older child (8-13 yr) with acquired hypothyroidism may experience pseudotumor cerebri within the first 4 mo of treatment.

53. In older children, after catch-up growth is complete, the growth rate provides a good index of the adequacy of therapy.