RESUMO
The GNAS gene (OMIM#139320), located on chromosome 20q13.2, encodes for the alpha-subunit of the stimulatory signaling protein, Gsα protein. GNAS variants with inactivating properties are associated with Albright's hereditary osteodystrophy (AHO) and when maternally inherited, pseudohypoparathyroidism 1a (OMIM#103580), which includes multiple hormone resistance. In this clinical report we describe a novel GNAS variant, c.159A>G, p.K53N, in an individual with features consistent with AHO and pseudohypoparathyroidism 1a and its segregation through multiple maternal relatives, including two genotype positive maternal first cousins who also display features classic for AHO. The proband developed unique features including cardiomyopathy which required a heart transplant at 5 years old and immune dysregulation resulting in multisystem organ failure and ultimately, death at the age of 18 years. Additional investigations exploring alternative explanations for the proband's presentation were pursued including whole genome sequencing which was negative. We postulate that the atypical features seen in the proband may have resulted from dysregulated Gsα signaling in cardiac tissue. Future studies are needed to explore the properties of the K53N GNAS variant and this proposed mechanism.