Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1

  title={Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1},
  author={Helmut Grasberger and Martine Vaxillaire and Silvana Pannain and John C. Beck and Aviva Mimouni-Bloch and Vincent Vatin and Gilbert Vassart and Philippe Froguel and Samuel Refetoff},
  journal={Human Genetics},
Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe… 

Genetics and phenomics of hypothyroidism due to TSH resistance

Possible non-Mendelian mechanisms of thyroid dysgenesis.

Evidence that non-Mendelian mechanisms must be involved in the vast majority of cases of thyroid dysgenesis is reviewed, for which the percentage of sporadic cases and of discordance between monozygotic twins exceeds 95%.

Random variability in congenital hypothyroidism from thyroid dysgenesis over 16 years in Québec.

The incidence of CHTD did not vary over the observation period, and its monthly variation was random, suggesting that environmental factors do not appear to play a significant role in the etiology ofCHTD.

Screening for Pax8 Mutations in Patients with Congenital Hypothyroidism in South-West Germany

These findings confirm the contribution of mutations in the Pax8 gene to the etiology of thyroid dysgenesis with a variable penetrance, but also demonstrate the rare overall incidence in CH.

Severe skeletal dysplasia caused by undiagnosed hypothyroidism.

Congenital hypothyroidism

The prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls, but studies show that a lower neurocognitive outcome may occur in those infants started at a later age, on lower l-thyroxine doses than currently recommended, and in those babies with more severe hypothyroidism.

Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis.

Congenital Hypothyroidism

  • M. Al-Qahtani
  • Medicine
    The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
  • 2020
Congenital hypothyroidism is one of the rare serious diseases that should not be diagnosed clinically because late clinical features corresponds to advanced mental retardation, so neonatal screening detection is the best and preferable way of early diagnosis of this congenital disease.



Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.

A novel mutation of PAX8 is described causing autosomal dominant transmission of CH with thyroid hypoplasia, giving further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of Pax8 is a cause of CH in humans.

Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci.

These kindreds represent a distinct etiological entity of autosomal dominant RTSH, and according to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland.

By direct sequencing of the thyrotropin receptor gene, the substitution of threonine in place of a highly conserved alanine at position 553, in the fourth predicted transmembrane domain was identified, which resulted in extremely low expression at the cell surface as compared with the wild-type receptor.

PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis

Three point mutations in the coding region of PAX8 are reported in two sporadic patients and one familial case of TD, implicate PAX8 in the pathogenesis of TD and in normal thyroid development.

A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child.

Findings confirm the important role of PAX8 in the development of the thyroid, but they indicate that PAX8 gene mutations may have a variable penetrance or expressivity.

Genetics of specific phenotypes of congenital hypothyroidism: a population-based approach.

An entire population screened for CH over a long period of time, was studied, using a population-based approach, using the most likely candidate genes: thyroperoxidase in patients with CH goiter, Pax8 and thyrotropin receptor (TSHR) in the other group.

Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability.

Evidence is provided that the C-terminal region is essential for transcriptional activity in the PAX8 gene, associated with thyroid dysgenesis in the proband and both euthyroidism and compensated hypothyroidism in her family.

Low prevalence of thyrotropin receptor mutations in a large series of subjects with sporadic and familial nonautoimmune subclinical hypothyroidism.

In two of three families, but in none of 34 sporadic cases of isolated hyperthyrotropinemia, inactivating mutations of the TSHr were identified.

Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors.

Although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion than would be expected from chance alone, and strongly suggests that genetic factors could be involved in thyroid Dysgenesis with a common underlying mechanism for both etiological groups.

Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism.

Observations support the hypothesis of a common genetic component of the disorder with heterogeneous phenotypes, as thyroid developmental abnormalities are compatible with an autosomal dominant mode of inheritance.