ESPE Abstracts (2016) 86 P-P2-151

Progressive Development of PTH Resistance in Patients with Maternal GNAS Inactivating Mutations

Alessia Usardia, Asmaa Mamounea, Elodie Nattesb, Anya Rothenbuhlera & Agnès Linglarta,b


aAPHP, Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d’Expertise Paris Sud Maladies Rares, Le Kremlin Bicêtre, France; bINSERM U1169, Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, Le Kremlin Bicêtre, France


Background: Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A is caused by mutations in GNAS exon 1 through 13 with multihormone resistance (PTH, TSH and gonadotropins), Albright’s hereditary osteodystrophy, and obesity. However, patients often do not present with elevated levels of PTH until after the first years of life.

Objective and hypotheses: Assessment of the development of PTH and TSH resistance over time in 20 patients affected by PHP1a, diagnosed because of familial history, ectopic ossification or short stature and carrying a maternal GNAS mutation.

Method: Data for serum calcium, phosphate, TSH and PTH levels were collected from the date of PHP1a diagnosis until calcidiol treatment. PTH infusion test was performed in one patient.

Results: Patients were diagnosed around 5 years of age and had a mean duration of follow-up of 2 years. PTH levels significantly increased over time (184–338 pg/ml; P<0.05), while TSH resistance was already observed at diagnosis in all patients. Calcium levels decreased from 2.31 to 2.19 mmol/l (P<0.05), while phosphate levels did not change with age. One patient born with ectopic ossification and familial history showed an increase in cAMP and phosphaturia upon PTH infusion, similar to controls, at 7 months old, but an impaired response at 4 years old, therefore establishing PTH resistance.

Conclusion: This work suggests that, an early diagnosis of PHP1A patients could be achieved by screening for maternal GNAS mutation in the presence of varying degrees of AHO, resistance to TSH even in the absence of PTH resistance at diagnosis. An early diagnosis of PHP1A will permit to start calcidiol treatment at early stages of the disease in order to improve the care of PHP1A patients.

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