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The pituitary-gonadal axis was evaluated in a mother after two of her sons with familial male-limited pseudoprecocious puberty were found to have a constitutively activating mutation of the LH receptor (LHR). Genotyping demonstrated that all showed a mutation in one of the two alleles, a substitution of Gly for Asp578 in the sixth transmembrane segment of the LHR. Ovarian function was normal in the 36-yr-old mother as assessed by LH dynamics and FSH and androgen levels throughout the menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the boys upon presentation at 2.4 and 3.5 yr of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. Upon the inception of true puberty at 11 yr of age in the older brother, gonadotropin responses normalized for the state of development. The data show that this activating LHR mutation does not cause functional ovarian hyperandrogenism and causes only incomplete pubertal activation of Leydig cells. The results are compatible with relatively low constitutive activity associated with this structural abnormality of LHR.

Sequencing of the human thyrotropin receptor (hTSHR) gene using genomic DNA from peripheral blood leukocytes revealed a substitution of nucleotide 253 in the cDNA sequence. The replacement of the wild-type cytosine-253 to adenine results in the replacement of the wild-type Pro at codon 52 (CCC) with Thr (ACC) located in exon 1 of the TSHR. We screened genomic DNAs from 60 unrelated individuals for the presence of A253 by PCR amplification using a degenerate oligonucleotide primer that produces a Tth111 I restriction site only in the presence of A253. We found 12% having heterozygosity and all had normal free thyroxine index (FT4I) and TSH levels. We have no information concerning the functional significance of this amino acid substitution. However, in the heterozygous state, the variant allele does not result in thyroid function abnormalities.