Absence of mutation in the follicle-stimulating hormone receptor gene in severe primary hypothyroidism associated with gonadal hyperstimulation

Severe hypothyroidism can cause a distinct form of precocious puberty in children, characterized by delayed skeletal maturation, predominance of FSH-mediated effects over LH-mediated function, and reversal of sexual precocity upon thyroid hormone replacement. The etiology of this unusual form of precocious puberty in children remains poorly understood. Recently, three mutations of the FSH receptor gene have been identified in women with spontaneous ovarian hyperstimulation during pregnancy. All three mutated receptors displayed abnormally high sensitivity to hCG which caused gonadal stimulation. Two of these mutations displayed concomitant increase in sensitivity of the mutated receptor to TSH. In this report, we describe four children with primary hypothyroidism and gonadal hyperstimulation. The aim of this study was to determine whether these patients' gonadal hyperstimulation is due to a mutation in their FSH receptor gene.

DNA was extracted from all four patients with primary hypothyroidism and gonadal stimulation. The entire FSH receptor gene was sequenced and analyzed.

Direct sequencing of these patients' FSH receptor gene did not demonstrate any mutation, proving that the cause of gonadal stimulation in these patients is not due to the increased sensitivity or constitutive activation of a mutated FSH receptor.

The elevated TSH in these patients and prior demonstration of the in vitro ability of TSH to bind to the FSH receptor lead us to hypothesize that the gonadal stimulation in these patients is TSH-mediated. The fact that gonadal stimulation is not seen in all patients with severe hypothyroidism raises the question as to whether polymorphisms of the FSH receptor gene and/or possible changes in the TSH molecular structure may contribute to the TSH-mediated activation of the FSH receptor.