hes1-protein--human and Abnormalities--Multiple

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.

Topics: Abnormalities, Multiple; Basic Helix-Loop-Helix Transcription Factors; Congenital Hypothyroidism; DNA-Binding Proteins; Female; Forkhead Transcription Factors; Homeodomain Proteins; Humans; Hypothyroidism; Infant, Newborn; Male; Mutation; Nuclear Proteins; Paired Box Transcription Factors; PAX8 Transcription Factor; Radionuclide Imaging; Repressor Proteins; Sex Characteristics; Thyroid Gland; Thyroid Hormones; Trans-Activators; Transcription Factor HES-1

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

Topics: Abnormalities, Multiple; Alleles; Amino Acid Sequence; Animals; Basic Helix-Loop-Helix Transcription Factors; DNA; Embryonic and Fetal Development; Female; Genotype; Helix-Loop-Helix Motifs; Homeodomain Proteins; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mutation; Open Reading Frames; Optic Nerve; Pedigree; Pituitary Gland; Repressor Proteins; Septum Pellucidum; Transcription Factor HES-1