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Congenital Hypothyrodism
- 2. Congenital hypothyroidism: Overview Thyroid hormone deficiency at birth1 Most common neonatal metabolic disorder2 Most common preventable cause of mental retardation3 Untreated congenital hypothyroidism resulting in development of cretinism4 1. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. 2. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005;42:379-389. 3. Rose RR, Brown RS. Update of newborn screening and therapy for congenital hypothyroidism. American Academy of Paediatric. 2006, 117 (6) 2290- 2303. 4. Roberts CGP, Ladenson PW. Hypothyroidism. Lancet. 2004;363:793-803.
- 4. Congenital hypothyroidism: Epidemiology 1:2630 Indian new borns1 Incidence lower in whites and blacks, somewhat higher in Hispanics, and highest in the Asian population1 Higher incidence in twin/multiple births, older mothers and preterm infants2 Female to male ratio 2:11 Higher incidence in patients with Down’s syndrome2 1. IAEA. Screening of Newborns for Congenital Hypothyroidism. International Atomic Energy Agency. Available from: http://www- pub.iaea.org/MTCD/publications/PDF/Pub1234_web.pdf 2. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 5. Maternal and pregnancy history Maternal and pregnancy history: In 20% of cases, gestation extends beyond 42 weeks Maternal autoimmune thyroid disease Radioactive iodine treatment during pregnancy (rare) Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 6. Clinical manifestations Most patients being asymptomatic Symptoms: Decreased activity, increased sleep, feeding difficulty, constipation, hoarse cry and prolonged jaundice Signs: Myxoedematous facies, large fontanels, macroglossia, cold or mottled skin, distended abdomen with umbilical hernia, bradycardia, hypotonia and decreased reflexes. One-third of patients birth weight >90th percentile Radiographs: Absent distal femoral epiphysis Formation and maturation of bone: Delayed Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 7. Congenital malformations Congenital hypothyroidism is associated with increased risk of congenital malformations such as: Cardiac malformations Spiky hair Cleft palate Neurologic abnormalities Genitourinary malformations Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 8. Classification and aetiology of congenital hypothyroidism Primary hypothyroidism Thyroid dysgenesis: Hypothyroidism due to a developmental anomaly (thyroid ectopia, athyreosis, hypoplasia, hemiagenesis) Associated mutations: (Account for only 2% of thyroid dysgenesis cases; 98% unknown) TTF-2, NKX2.1 NKX2.5 PAX-9 Thyroid dyshormonogenesis: Hypothyroidism due to impaired hormone production Resistance to TSH binding or signalling Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 9. Classification and aetiology of congenital hypothyroidism Central hypothyroidism (secondary hypothyroidism) Isolated TSH deficiency (TSH b subunit gene mutation) Thyrotropin-releasing hormone resistance Hypothyroidism due to deficient transcription factors involved in pituitary development or function2 Peripheral hypothyroidism Resistance to thyroid hormone Abnormalities of thyroid hormone transport Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 10. Classification and aetiology of congenital hypothyroidism Syndromic hypothyroidism1 (Pendred syndrome) Transient congenital hypothyroidism1 Maternal autoimmune thyroiditis Maternal medication for Graves’ disease 1. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. 2. NIDCD. Pendred syndrome. National Institute on Deafness and Other Communication Disorders. Available from: https://www.nidcd.nih.gov/sites/default/files/Documents/health/hearing/NIDCD-Pendred-Syndrome.pdf Diagram of normal inner ear and enlarged vestibular aqueduct in Pendred syndrome.2
- 11. Newborn thyroid screening tests Primary congenital hypothyroidism (CH) screening has been shown to be effective for the testing of cord blood or blood collected after the age of 24 hours, although the best “window” for testing is 48 to 72 hours of age. Blood is spotted onto filter paper, allowed to dry, and eluted into a buffer for TSH analysis. This method detects primary CH more effectively than primary T4 screening. Primary T4 screening with confirmatory TSH testing entails a risk of missing some cases of mild forms of primary CH but can detect some cases of central CH. 1. Léger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism. The Journal of Clinical Endocrinology and Metabolism. 2014;99(2):363-384.
- 12. Newborn thyroid screening tests Screening strategies: Initial T4 assay <10th percentile, follow-up TSH test To detect infants with secondary or central (hypopituitary) hypothyroidism and infants with delayed TSH rise Initial blood TSH assay >30 mU/L serum (>15 mU/L whole blood) To detect infants with mild or ‘subclinical’ hypothyroidism Simultaneous T4 assay and TSH assay To detect infants with defects of thyroid transport, metabolism or action Thyroid radionuclide uptake and scan Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 13. Serum tests of thyroid function Reference ranges for thyroid function tests at ages 1 to 4 days and 2 to 4 weeks Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. Age Free T4 (pmol/L) Total T4 (nmol/L) TSH (mU/L) 1–4 days 25–64 129–283 <39 2–4 weeks 10–26 90–206 <10
- 14. Management of congenital hypothyroidism Oral L-Thyroxine (L-T4), 10 to 15 µg/kg/d is the treatment of choice Serum T4 concentration should become normal within 1 to 2 weeks, and serum TSH should be normal in most infants after 1 month of treatment.1 Treatment goals given by the American Academy of Pediatrics are:2 Serum free T4 or total T4 should be kept in the upper range of normal during the first year of life Target values during the first year are 130 to 206 nmol/L (10–16 μg/dL) for the serum T4 and 18 to 30 pmol/L (1.4–2.3 ng/dL) for free T4 Serum TSH should be kept below 5 mU 1. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27(3):315-389. 2. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- 15. Management of Congenital Hypothyroidism Goal: To normalize T4 within 2 weeks and TSH within 1 month Assess permanence of congenital hypothyroidism If initial thyroid scan shows ectopic/absent gland, congenital hypothyroidism is permanent If initial TSH is <50 mIU/L and there is no increase in TSH after newborn period, off- therapy period is recommended at 3 years of age If TSH increases during the off-therapy period, consider the condition as permanent congenital hypothyroidism Medications: LT4: 10-15 g/kg by mouth once-daily Monitoring: Recheck T4 and TSH At 2-4 weeks after initiation of LT4 treatment Every 1-2 months in the first 6 months Every 3-4 months between 6 months and 3 years of age Every 6-12 months from 3 years of age to end of growth
Editor's Notes
- Congenital hypothyroidism is due to thyroid hormone deficiency at birth. It is the most common neonatal metabolic disorder and the most common preventable cause of mental retardation. Untreated congenital hypothyroidism results in development of cretinism. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005;42:379-389. Rose RR, Brown RS. Update of newborn screening and therapy for congenital hypothyroidism. American Academy of Paediatric. 2006, 117(6):2290-2303. Roberts CGP, Ladenson PW. Hypothyroidism. Lancet. 2004;363:793-803.
- Congenital hypothyroidism (CH) occurs in approximately 1:2630 Indian newborns. Incidence was lower in whites and blacks, somewhat higher in Hispanics, and highest in the Asian population. Higher incidence was also noticed in twin/multiple births, newborns of older mothers and preterm infants. Female to male ratio is 2:1. Patients with Down’s syndrome have a higher incidence. References: IAEA. Screening of Newborns for Congenital Hypothyroidism. International Atomic Energy Agency. Available from: http://www-pub.iaea.org/MTCD/publications/PDF/Pub1234_web.pdf Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- Owing to the slow development of obvious clinical features of congenital hypothyroidism, many new born infants at birth often remain undiagnosed; however, maternal and pregnancy history may provide some clues. In 20% cases, gestation extends beyond 42 weeks. There may be a history of maternal autoimmune thyroid disease, iodine deficient diet and rarely radioactive iodine treatment during pregnancy. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- Most of the patients are asymptomatic. The symptoms of CH include decreased activity, increased sleep, feeding difficulty, constipation, hoarse cry and prolonged jaundice. The signs may include myxedematous facies, large fontanels, macroglossia, cold or mottled skin, a distended abdomen with umbilical hernia, bradycardia, hypotonia and decreased reflexes. One-third of patients have a birth weight greater than 90th percentile. Radiographs may reveal absent distal femoral epiphysis. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- Congenital hypothyroidism is associated with increased risk of congenital malformations such as cardiac malformations, spiky hair, cleft palate, neurologic abnormalities and genitourinary malformations. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- Types of congenital hypothyroidism are primary hypothyroidism, central hypothyroidism (secondary hypothyroidism), peripheral hypothyroidism, syndromic hypothyroidism and transient congenital hypothyroidism. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17.
- Classification and aetiology of congenital hypothyroidism are given in the slide. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010.
- Congenital hypothyroidism can also be syndromic hypothyroidism as seen in Pendred syndrome or transient congenital hypothyroidism that occurs due to maternal autoimmune thyroiditis or maternal medication for Graves’ disease.
- Three major screening strategies are used. Initial T4 assay is carried out followed by TSH test if T4 is <10th percentile. This is used to detect infants with secondary or central (hypopituitary) hypothyroidism and infants with delayed TSH rise. Initial blood TSH assay is helpful in detecting infants with mild or ‘subclinical’ hypothyroidism. Simultaneous T4 assay and TSH assay are used to detect infants with defects of thyroid transport, metabolism or action. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010.
- Reference ranges for thyroid function tests at ages 1 to 4 days and 2 to 4 weeks are mentioned in the table. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010.
- Oral L-Thyroxine (L-T4), 10 to 15 μg/kg/d is the treatment of choice for CH. The treatment goals given by the American Academy of Paediatrics (AAP) are as follows: Serum free T4 or total T4 should be kept in the upper range of normal during the first year of life. Target values during the first year are 130 to 206 nmol/L (10–16 μg/dL) for the serum T4 and 18 to 30 pmol/L (1.4–2.3 ng/dL) for free T4. Serum TSH should be kept under 5 mU. References: Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010.