ESPE Abstracts

Pseudohypoparathyroidism, or syndromes associated with PTH resistance, share a common defect in the PTH1R/Gsalpha/cAMP signaling pathway. Therefore, this entity is now labeled as “inactivating PTH/PTHrP disorder” or iPPSD. IPPSD is a genetic disorder characterized by target-organ unresponsiveness to PTH and/or PThrP. it mimics hypoparathyroidism, as patients present with hypocalcemia and hyperphosphatemia; however, due to an abnormal signaling pathway downstream of the PTH/PTHrP receptor, PTH cannot activate properly its receptor; PTH levels are therefore found elevated in affected patients, defining PTH resistance. iPPSDs are rare, highly heterogeneous, and deeply impairing disorders with proven genetic component; their prevalence is estimated to be approximately 0.79 per 100.000. Albright hereditary osteodystrophy (AHO) is a group of symptoms often associated with PTH resistance, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. Affected patients were formerly classified according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro. However, this historical classification fails to differentiate patients presenting with different clinical and molecular findings. As for today, iPPSD is considered as a group of rare disorders sharing major clinical features such as PTH resistance, ectopic cutaneous ossifications and/or brachydactyly; the different iPPSD forms can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (former PHP1A, PHP1C and PPHP) as iPPSD2, loss of methylation at the GNAS DMRs (PHP1B) as iPPSD3, PRKAR1A mutations as iPPSD4, PDE4D mutations as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. In recent years, phenotypic features such as severe constipation, asthma, craniosynostosis or sleep apnea have been associated with iPPSD, thus expanding the understanding of the role of the signaling pathway in various biological processes.