Hypothyroidism, Congenital, Nongoitrous, 3

For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see 275200.

Clinical Features

Mimouni et al. (1996) described a Jewish Ashkenazi family in which 11 members in 3 generations had clinical and subclinical hypothyroidism caused by unresponsiveness to TSH (see 188540). Goiter was notably absent. This was said to be the first instance of autosomal dominant transmission of TSH unresponsiveness.

Grasberger et al. (2005) reported 4 additional families with congenital nongoitrous hypothyroidism manifesting as resistance to thyrotropin and segregating in an autosomal dominant pattern with variable expressivity. Affected individuals had elevated TSH and normal to low free T3 and free T4 levels discovered at neonatal screening or later in life. There were no aplastic or ectopic thyroid glands identified; some affected members of 1 family had benign nodules and 1 gland was described as 'small.' Grasberger et al. (2005) stated that the thyroid phenotype was indistinguishable from that observed with mutations in the PAX8 (167415) and TSHR (603372) genes.

Mapping

In 5 large pedigrees, 1 previously reported by Mimouni et al. (1996), segregating resistance to thyrotropin in an autosomal dominant pattern of inheritance, Grasberger et al. (2005) excluded linkage to the TSHR and PAX8 genes. In the 3 largest families, they also excluded linkage to the TITF1 (600635), FOXE1 (602617), and GNAS (139320) genes, which are known to be associated with syndromic forms of congenital hypothyroidism. Grasberger et al. (2005) performed genomewide scans in 2 of the families and found independently significant linkage to chromosome 15q25.3-q26.1, with maximum multipoint lod scores of 8.51 and 4.31 at D15S655 and D15S979, respectively. Linkage to this locus was replicated in the 3 remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3-cM/2.9-Mb interval.