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1. The disease:

Congenital hypothyroidism (CH) is defined as a thyroid hormone deficiency present from birth. Causes of primary CH include thyroid dysgenesis and inborn errors of thyroid hormone biosynthesis (dyshormonogenesis). Secondary or central CH results from thyroid-stimulating hormone (TSH) deficiency and is usually associated with congenital hypopituitarism. Peripheral CH results from defects in thyroid hormone transport, metabolism, or action. CH may also occur as part of a syndrome, for example in the Pendred and Genitopatellar syndrome.

2. The symptoms

The clinical manifestations are often subtle or not present at birth, probably because of trans-placental passage of some maternal thyroid hormone and the fact that many infants have some thyroid production of their own. More specific symptoms often do not develop until several months of age. Common clinical features include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment CH results in severe intellectual deficit and short stature. Lack of early signs or symptoms does not exclude the diagnosis.

  • Bamforth-Lazarus syndrome is characterized by cleft palate, spiky hair and thyroid dysgenesis (in most cases athyreosis) leading to congenital hypothyroidism.
  • In Brain-lung-thyroid syndrome is characterized by congenital hypothyroidism, infant respiratory distress syndrome and benign hereditary chorea.
  • Pendred syndrome is a syndromic genetic deafness clinically variable characterized by bilateral sensorineural hearing loss and euthyroid goiter. Hypothyroidism may develop if nutritional iodide intake is low.
  • Genitopatellar syndrome is characterized by patellar aplasia/hypoplasia associated with microcephaly, facial dysmorphism, arthrogryposis of the hips and knees, urogenital abnormalities, and intellectual deficiency. A minority of individuals have hypothyroidism – some of them having thyroid agenesis or hypoplasia.
  • Johanson-Blizzard syndrome (JBS) is a multiple congenital anomaly characterized by exocrine pancreatic insufficiency, hypoplasia/aplasia of the nasal alae, hypodontia, sensorineural hearing loss, growth retardation, anal and urogenital malformations, and variable intellectual disability. Some patients have hypothyroidism (30%-40%).
  • Pseudohypoparathyroidism type 1A is characterized by renal resistance to parathyroid hormone (PTH), resulting in hypocalcaemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thyroid stimulating hormone (TSH), gonadotropins and growth-hormone-releasing hormone (GHRH); and a constellation of clinical features known as Albright hereditary osteodystrophy (typical shortening of the 4th metacarpal, short stature, obesity and subcutaneous ossifications).
  • Abnormal thyroid hormone metabolism-1 (THMA1) is characterized by mild global developmental delay in childhood, short stature, delayed bone age, and abnormal thyroid and selenium levels in serum (high total and free T4 concentrations, low T3, high reverse T3, normal to high TSH, decreased selenium).
  • Macrothrombocytopaenia is characterized by congenital thrombocytopenia associated with the presence of large platelets. In three distinct families, TUBB1 mutations co-segregated with thyroid dysgenesis.
  • NDH syndrome is characterized by intrauterine growth retardation, permanent neonatal diabetes mellitus, and congenital hypothyroidism. Additional manifestations include congenital glaucoma, hepatic disease, polycystic kidneys, exocrine pancreatic dysfunction, sensorineural hearing impairment, developmental delay, and facial dysmorphism.

3. Actions to take in case of early diagnosis:

  • CH is a lifelong disease requiring lifetime management and regular follow-up with an Endocrinology Center Management is provided by multidisciplinary team.
  • Levothyroxine is the treatment of choice for Hypothyroidism.
  • Genetic counselling should be offered to at-risk family members.

4. For more information:

  • Orphanet:
  • Biblio:
    • Yamaguchi T, Nakamura A, Nakayama K, et al. Targeted Next-Generation Sequencing for Congenital Hypothyroidism with Positive Neonatal TSH Screening. J Clin Endocrinol Metab. 2020;105(8):dgaa308. PMID: 32459320.
    • Narumi S, Fox LA, Fukudome K, et al. Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity. Endocr J. 2017;64(11):1087-1097. PMID: 28867693.
    • Makretskaya N, Bezlepkina O, Kolodkina A, et al. High frequency of mutations in ‘dyshormonogenesis genes’ in severe congenital hypothyroidism. PLoS One. 2018;13(9):e0204323. PMID: 30240412.
    • Wang F, Liu C, Jia X, et al. Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis. Clin Chim Acta. 2017;470:36-41. PMID: 28455095.