PSEUDOHYPOPARATHYROIDISM

Pseudohypoparathyroidism describes a condition that mimics hypofunction of the parathyroid glands. Despite sufficient production of parathyroid hormone, the organs show decreased sensitivity to PTH. Inactivations of the GNAS gene are associated with pseudohypoparathyroidism Ia, Ib, and Ic, pseudopseudohypoparathyroidism, progressive osseous heteroplasia, and cutaneous osteomas. These conditions may be caused by inactivating variants in the GNAS gene or by methylation or deletions of regulatory regions of GNAS, leading to a loss of expression of the maternal allele. These alterations can be inherited from the parents or acquired de novo.

In contrast, activating somatic variants in the GNAS gene cause McCune-Albright syndrome (MAS), characterized by fibrous bone dysplasia, café-au-lait spots, and endocrine dysfunction. These activating alterations occur during embryonic development, leading to excessive proliferation and migration of the affected cells. The severity of MAS depends on the timing of the genetic alteration during embryonic development and the tissues affected. The likelihood of detecting a mosaic variant in peripheral blood is also dependent on these factors.

References
Baumgartner et al. 2020, J. Klin. Endokrinol. Stoffw. 13:77 / Elli et al. 2016, J Clin Endocrinol Metab 101:3657 / Lemos et Thakker 2015, Hum Mutat 36, 11 / Narumi et al. 2013, PLoS One 8:e60525 / Haldeman-Englert et al. Disorders of GNAS Inactivation. 2017. In: Adam et al. GeneReviews® / Boyce et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2019. In: Adam et al. GeneReviews®