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At a glance

This Syndrome results from inadequate thyroid hormone (TH) levels during pregnancy or in the neonatal period and during infancy. Characterized in newborns by failure to thrive and physical and mental retardation.

Synonyms

Cretinism; for Congenital (Non-Goitrous) Hypothyroidism Type 1: Thyrotropin Resistance; Resistance to Thyroid-Stimulating Hormone; TSH Resistance; Congenital Hypothyroidism due to TSH Resistance. For Congenital (Non-Goitrous) Hypothyroidism Type 2: Thyroid Dysgenesis/Agenesis/Hypoplasia/Ectopy.

Incidence

1:3,000-4,000. Eighty-five percent of cases are sporadic, with wide ethnic variations (1:4,000 in Caucasians, 1:2,000 in Hispanics, 1:32,000 in Afro-Americans). Females are affected twice as often as men.

Genetic inheritance

Varying etiology. Congenital (Non-Goitrous) Hypothyroidism Type 1 is autosomal recessive inherited and caused by mutations in the TSHR (Thyroid-Stimulating Hormone Receptor) gene, which has been mapped to chromosome 14q31.1. Congenital (Non-Goitrous) Hypothyroidism Type 2 is autosomal dominant inherited and caused by mutations in the PAX8 (Paired Box 8) gene located on chromosome 2q13. Thyroid dysgenesis is occasionally autosomal recessive inherited, but most often it is nonhereditary/sporadic. Inborn errors of TH biosynthesis are typically autosomal recessive transmitted, except for defects in TH receptor actions that are autosomal dominant inherited. Several additional gene mutations can cause congenital hypothyroidism and some of these mutations are also associated with other disorders (eg, renal abnormalities with PAX8, interstitial lung disease and chorea with NKX2-1 [NK2 Homeobox 1; Thyroid Transcription Factor 1 on chromosome 14q13.3], cleft palate, bifid epiglottis, choanal atresia, and spiky hair with FOXE1 [Forkhead Box E1 on chromosome 9q22.33], and congenital hypothyroidism, neonatal diabetes mellitus, congenital glaucoma, mental retardation, hepatic fibrosis, and polycystic kidneys with GLIS3 [GLIS Family Zinc Finger Protein 3 on chromosome 9p24.2]). Thus, depending on the genetic cause, other anomalies might be present that may significantly influence the conduct of anesthesia.

Pathophysiology

The causes of primary congenital hypothyroidism can be categorized as failure of the thyroid to develop normally (dysgenesis) or failure of a structurally normal thyroid gland to produce normal amounts of TH (dyshormonogenesis). Congenital hypothyroidism can also be classified into two groups: endemic cretinism and sporadic cretinism. Endemic cretinism is caused by intrauterine and/or neonatal iodine deficiency frequently occurring in certain areas (eg, alpine regions of Europe), whereas sporadic cretinism may be the result of basically three different mechanisms:

  • Thyroid dysgenesis (85% of all cases): Thyroid dysgenesis includes thyroid (hemi-) agenesis, ectopic thyroid tissue, cysts of the thyroglossal duct, and thyroid hypoplasia. In the vast majority of cases, thyroid dysgenesis is sporadic, and familial in only about 2%. The pathogenesis is largely unknown, but suggested mechanisms include mutations in the genes coding for thyroid transcription factor 1 (TTF-1), thyroid transcription factor 2 (TTF-2, which is important for thyroid morphogenesis and differentiation), and PAX-8 (Paired Box 8; involved in the regulation of TH production), and mutations resulting in dysfunction of thyrotropin (TSH, thyroid stimulating hormone) receptor ...

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