Introduction: Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine disorders characterized by target-organ resistance to the action of PTH, manifesting with hypocalcemia, hyperphosphatemia, and increased serum concentrations of PTH. PTH receptor couples with the stimulatory G protein (Gsα), leading to cAMP formation. Most cases of PHP are caused by heterozygous inactivating mutations in the GNAS gene, encoding Gs〈 (PHP type 1A) or methylation defects within the imprinted GNAS locus (PHP type 1B). Resistance to other hormones signaling through G proteincoupled receptors, particularly TSH, is typical in type 1A PHP and can also occur in type 1B PHP.
Case report: In 2014, a 30-year-old woman sought medical attention because of fatigue. Laboratory tests showed: serum calcium 7.4 mg/dl, serum phosphate 5.2 mg/dl, PTH 916 pg/ml, 25OHD 19.8 ng/ml, TSH 5.78 mU/l and free T4 0.8 ng/dl. After 2 years without follow-up, the patient was referred to our hospital because of similar laboratory test results. Except for thigh muscle pains, she was asymptomatic. Clinical examination ruled out Albright hereditary osteodysthrophy, obesity or cognitive impairment. Laboratory examination included: serum calcium 7.2 mg/dl, albumin 3.9 g/dl, serum phosphate 5 mg/dl, magnesium 1.9 mg/dl, urine calcium 40.3 mg/24 h, urine phosphate 475.8 mg/24 h, PTH 948.3 pg/ml, 25OHD 20.8 ng/ml, 1.25(OH)2D3 66 pg/ml, TSH 6.2 mU/l, free T4 0.57 ng/dl, TPOAb 2 U/ml. Hands x-ray showed no brachydactyly. Thyroid ultrasonography was normal. The patients genetic study revealed a methylation defect at GNAS exons XL, AS and A/B, and a gain of methylation at NESP55. DNA analyses from both parents showed normal methylation pattern at all differentially methylated regions, confirming the diagnosis of sporadic PHP type 1B. The patient was treated with oral calcium supplements, calcitriol and levothyroxine. Ten months later she begun with symptoms of severe hyperthyrodism and goiter. A new biochemical assessment showed normalization of serum calcium and phosphate, PTH 304.2 pg/ml, TSH <0.001 mU/l, free T4 3.77 ng/dl, free T3 17.93 pg/ml, TSI 11.2 mU/ml and TPOAb 10.4 U/ml. Since then, she is being treated with antithyroid drugs.
Conclusions: This case demonstrates that, although TSH and stimulating TSH receptor antibodies share signal transduction pathways for cell activation and growth, Graves disease is possible even upon defective Gsα signalling and resistance to TSH, suggesting alternative effector mechanisms for TSH receptor antibodies.
18 - 21 May 2019
European Society of Endocrinology