A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations

J Clin Endocrinol Metab. 1999 Jul;84(7):2502-6. doi: 10.1210/jcem.84.7.5831.


Permanent primary congenital hypothyroidism (CH) can be caused by abnormal thyroid differentiation (athyreosis), migration (ectopy), or function (leading to goiter). Goiters follow an autosomal recessive pattern of inheritance, whereas ectopy and athyreosis are considered as a single sporadic entity with a female preponderance. On the other hand, a high prevalence of extrathyroidal malformations has been reported in CH, but without linking specific defects to specific types of CH. On the basis of TSH screening, 273 newborns were referred to an academic pediatric endocrinology clinic in the province of Quebec between 1988 and 1997. Of 230 patients with permanent primary CH who had scintigraphy at diagnosis, 141 had ectopy (104 girls), 36 had athyreosis (21 girls), 42 had goiter (18 girls), 10 (3 girls) had a normal scan, and 1 girl had hemiagenesis. Only in the ectopies was the proportion of girls significantly higher than 0.5 (P<0.001). Isolated cardiac malformations were observed in 7 patients (3.0%), a prevalence 5-fold higher than that in the general population; this was largely due to atrial and ventricular septal defects, which were only observed in ectopy and athyreosis. Our data suggest that the molecular mechanisms that lead to complete absence of thyroid differentiation or defective thyroid migration 1) may be similar, but are modulated by the genetic makeup of the embryo and/or the hormonal milieu of the fetus; and 2) may also be involved in septation of the embryonic heart.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Basic Helix-Loop-Helix Transcription Factors
  • Congenital Hypothyroidism*
  • DNA-Binding Proteins / genetics
  • Female
  • Forkhead Transcription Factors
  • Homeodomain Proteins / genetics
  • Humans
  • Hypothyroidism / etiology
  • Hypothyroidism / genetics*
  • Infant, Newborn
  • Male
  • Mutation
  • Nuclear Proteins*
  • PAX8 Transcription Factor
  • Paired Box Transcription Factors
  • Radionuclide Imaging
  • Repressor Proteins / genetics
  • Sex Characteristics*
  • Thyroid Gland / abnormalities*
  • Thyroid Gland / diagnostic imaging
  • Thyroid Hormones / blood
  • Trans-Activators / genetics
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • FOXE1 protein, human
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Nuclear Proteins
  • PAX8 Transcription Factor
  • PAX8 protein, human
  • Paired Box Transcription Factors
  • Repressor Proteins
  • Thyroid Hormones
  • Trans-Activators
  • Transcription Factor HES-1
  • HES1 protein, human