Isolated central hypothyroidism (ICH) is a rare disease whose pathogenesis is so far linked to germinal mutations of TSHβ (several cases) or TRH receptor (TRHR) genes (only two cases). Here, we report the studies performed to elucidate the pathogenesis of idiopathic ICH in five cases (two men, three women) with low/normal TSH levels and low freeT4 levels (38 pmol/l). One male, negative at neonatal TSH screening, showed signs of severe hypothyroidism at 44 days, while the other patients were diagnosed during childhood or adulthood (age range: 342 years). All, but one with a partial empty sella, had a normal pituitary MRI, and negative history of traumatic or ischemic brain injuries. Thyroid ultrasound showed hypoplasia in two and normal glands in the others. Thyroid autoantibodies were negative in all cases. Absent/impaired TSH responses to TRH stimulation accompanied by normal PRL increases were registered in the three female patients and in the neonate. In this latter case, a homozygous intronic mutation (IVS2+5 G>A) known to alter the splicing of TSHβ gene was detected. No genetic alterations were detected in the 3 female patients with acquired ICH. The remaining patient presented at 3 years of age with severe obesity (48% excess of the ideal weight) and type 2 diabetes. He had a conserved TSH response to TRH, but TSHβ, Leptin receptor and TRH genes were normal. In all four negative cases, the possible autoimmune origin of ICH was then tested by evaluating anti-pituitary antibodies (APA). Interestingly, APA were positive in the three ICH women (two highly and one weakly positive) but not in controls. In conclusion, idiopathic isolated CH can have a heterogeneous pathogenesis involving genetic defects but, surprisingly, also autoimmunity. Autoimmune origin should be suspected when ICH appears to be acquired beyond infancy and the genetic origin has been excluded.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology