Endocrine Abstracts

Introduction: TSH-secreting pituitary adenomas (TSHomas) are a rare cause of central hyperthyroidism, accounting for less than 1% of all pituitary adenomas, with a prevalence in the general population of 1-2 cases per million.

Case Presentation: A 45-year-old female patient presented in 2009 with hypertension and tachycardia: blood tests revealed an inappropriately normal TSH with high fT3/fT4 levels and primary hyperaldosteronism. She declined further investigations and was started on nebivolol and hydrochlorothiazide by her GP. In November 2021, aged 58 years, she came to our observation for a compressive multinodular goiter with intrathoracic extension requiring surgery. In spite of a persistent biochemical picture of central hyperthyroidism, she did not complain symptoms of thyrotoxicosis. We ruled out possible interferences in the thyroid function tests and started the appropriate workup.

Diagnostic Investigations: We found an absent TSH response to exogenous TRH stimulation, suggestive for a TSHoma with a MRI showing a 12 mm pituitary macroadenoma. The remaining pituitary function was normal. Moreover, a primary hyperaldosteronism and a mild normocalcemic hyperparathyroidism despite cholecalciferol supplementation were found. No hyperplastic parathyroid glands were found at US scan, while the abdomen CT scan showed a slightly enlarged left adrenal gland. Due to the co-occurrence of a TSH-secreting pituitary adenoma, hyperparathyroidism and adrenal hyperplasia, suggestive of MEN1-4, we performed molecular analysis, by a targeted-NGS sequencing custom panel. We did not find variants in the CDNK1B or MEN1 gene, while a heterozygous variant in the glial-cell-line-derived neurotrophic factor (GDNF) gene, previously reported in Hirschsprung disease, substituting an Isoleucine with a Methionine (p.I211 M) was found.

Discussion and Conclusion: GDNF is a plausible candidate gene for multiple endocrine syndromes, as GDNF family members bind to the GDNF-family-receptor alphas (GFRαs), leading to RET dimerization. In addition, it is expressed in normal pituitary and parathyroid glands and in pituitary/parathyroid adenomas. Furthermore, somatic mutations have been reported in parathyroid adenomas/hyperplasia. Nevertheless, the impact of p.I211 M variant in the pathogenesis of this case remains unclear. Previous studies showed that this GDNF variant retained its ability to induce RET tyrosine phosphorylation. These results suggest that the p.I211 M variant might act as a disease modifier in conjunction with other genetic lesions (Eketjall, 2002) still not identified in our patient. The curious association of central hyperthyroidism with primary hyperaldosteronism and hyperparathyroidism is suggestive of a novel MEN syndrome variant.