ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab 2018;103:158-168

Defects at the GNAS locus give rise to various phenotypes, several of which are associated with subcutaneous ossifications (SCOs), which cause significant morbidity among the affected individuals. A subgroup of patients with paternally inherited GNAS mutations have progressive osseous heteroplasia (POH), characterized by severe heterotopic ossifications involving the deep connective tissue and skeletal muscle without the AHO phenotype or hormonal abnormalities. This study excluded patients with concomitant POH and rather aimed to explore the prevalence and risk factors of SCOs in other GNAS defects. The study is the largest to date and utilized prospectively collected data by a single examiner over a period of 16 years.

The study showed a high prevalence of SCOs in patients with mutations in GNAS; the prevalence was similar in PHP1A and PPHP, indicating that paternal imprinting, hormonal resistance, biochemical parameters and BMI are not involved in the pathogenesis of SCOs. The degree of SCO formation correlated with the severity of the GNAS mutation, and the SCOs were more frequent and extensive in males than in females. The severity increased with age. There are no successful drug therapies to date for the SCOs in AHO. Understanding the etiology for SCO formation – or preventing their invasion to deeper tissues - could lead to new treatment modalities.

The disorders related to GNAS locus are complicated and their diagnosis and treatment are challenging. The recently published international Consensus Statement (1) should prove useful in patient management.

1. Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018 Jun 29. doi: 10.1038/s41574-018-0042-0. [Epub ahead of print] Review.