Pseudohypoparathyroidism (PHP) refers to a group of heterogeneous genetic diseases, characterized by resistance to PTH and frequently other hormones activating cAMP-dependent events down-stream of different G protein-coupled receptors. PHP-Ia and Ib, the most frequent forms, are caused by mutations within the GNAS locus that encodes Gαs and several splice variants thereof. We describe a 36-year-old man with sporadic PHP-Ib with renal PTH-resistance, yet severe hyperparathyroid bone disease. The patient presented at age 8 years with limping due to bone deformities, who was treated with multiple osteotomies. Biochemical evaluation showed hypocalcemia (7.5 mg/dl) with high PTH (504 pg/ml) and increased ALP (487 IU/l). After restoring serum calcium to the low-normal range by oral calcium (1 g/day) and calcitriol (0.51 μg/day), PTH and ALP progressively increased (2100 pg/ml and 980 IU/l, respectively). Cortical bone mineral density (BMD) was markedly reduced (distal radius T-score: −7.7). Subperiosteal bone resorption with acroosteolysis, salt-and-pepper appearance of the skull, bone cysts and long bone deformities were observed radiographically. Parathyroid ultrasound showed four-gland hyperplasia. Epigenetic analyses of GNAS locus documented loss of methylation at all four DMRs without evidence for patUPD20q; the 3-kb STX16 deletion was excluded. No features of PHP-Ib were present in first-degree relatives. After increasing calcitriol to 4 μg/day, a progressive fall of PTH and ALP occurred over the course of 8 months (130 pg/ml and 97 U/L, respectively), while serum calcium remained within normal limits without evidence for hypercalciuria. Cortical BMD markedly increased (+6.5%) and bone pain vanished. Nine months later hypercalcemia developed, likely because of completion of the remineralization process. Calcitriol was reduced to 1.5 μg/day and normocalcemia was restored. This is an unusual case of sporadic PHP-Ib with marked bone involvement, in whom the standard dose of calcitriol was insufficient. Despite long-standing disease, PTH levels declined dramatically and approached the normal range.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
05 - 09 May 2012
European Society of Endocrinology