Inheritable isolated central hypothyroidism (ICH) due to mutations of TSH beta gene has been reported in few patients. For this reason the diagnostic criteria are vague. The disorder is usually characterized by undetectable TSH levels, although low/normal serum TSH, depending on TSH measurement methods, has been documented in some patients. Here we report an Egyptian girl with ICH due to a novel nonsense mutation of the TSH beta gene (Q49X). She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T(4) and free T(3) levels, impaired TSH response to TRH, absence of (99)Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. All other pituitary hormones, including PRL, were normally secreted. A diagnosis of idiopathic ICH was made, and substitutive L-T(4) treatment was started at 81 days of age. At the age of 7 yr the patient had normal thyroid hormone levels, but was severely mentally retarded. Interestingly, the sella computed tomography scan had completely normalized. At 8 yr of age the patient was reinvestigated after 6-week L-T(4) withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant TSH beta lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. In conclusion, high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and, possibly, hyperplastic pituitary gland are the hallmark of ICH due to mutations of the TSH beta gene.
