P3C379: Novel GNAS Mutation Resulting in Pseudohypoparathyroidism with Phenotypic Features of Albright Osteodystrophy

Introduction: Albright’s hereditary osteodystrophy (AHO) is a rare disorder with a wide range of signs and symptoms to include short stature, obesity, round face, subcutaneous ossifications, and brachydactyly. The condition is inherited in an autosomal dominant manner and is the result of a heterozygous pathogenic variant the GNAS gene. Affected individuals may show hormone resistance. Most often, it is parathyroid hormone (PTH) with resulting pseudohypoparathyroidism. Additionally, resistance to other hormones (thyroid-stimulating hormone (TSH), gonadotropins, growth-hormone-releasing hormone, and calcitonin) can be observed. When speaking specifically of an elevated TSH shortly after birth, this can lead to a premature diagnosis of congenital hypothyroidism.

Case Description: This case pertains to a two-year-old female with a history of global developmental delays and congenital hypothyroidism who had a seizure on the day of her presentation to the emergency department. On arrival, patient was postictal with evidence of dysmorphic features, most noticeable of which was macrocephaly with frontal bossing. Patient had two additional seizures. A CMP revealed a calcium of 5.0. A follow up ionized calcium was 0.74. Patient was provided a loading dose of IV calcium gluconate followed by scheduled calcium carbonate. An EKG was ordered and demonstrated a mildly prolonged QTc (463). A head CT without contrast showed fairly symmetric, somewhat globular areas of hyperdensity concerning for intracranial calcifications. Patient was transported to the PICU for further management. Her hypocalcemia was not previously documented. Further laboratory testing revealed a low 25-hydroxy vitamin D, a normal phosphorus, an elevated PTH, and a normal 1,25 vitamin D. Her phenotypic features, in addition to her newfound laboratory and imaging abnormalities, were consistent with a diagnosis of AHO.

Discussion: The described patient had a previous genetic evaluation which included a normal chromosomal microarray. The next tier in testing was a comprehensive multigene autism/intellectual disability panel which revealed a heterozygous variant of uncertain significance in the GNAS gene (c.883G>T; p.(D295Y)). While this variant has not been published as disease causing in relation to AHO, it is currently classified as likely pathogenic in ClinVar. With consideration of discussed case and current variant evidence, we are suggesting this variant is pathogenic. Of note, with maternal inheritance, the features of AHO can have associated pseudohypoparathyroidism. On the contrary, if paternally inherited, patient can display the characteristic features of AHO but lack the additional hormonal issues.

Conclusion: A two-year-old female with diagnosed congenital hypothyroidism (now known to be TSH resistance) presented with hypocalcemia-induced seizures in the setting of an elevated PTH and phenotypic AHO. Previous genetic testing was significant for a variant of unknown significance in the GNAS gene, now suspected pathogenic. In young children with developmental delay and/or hormonal imbalances, a comprehensive laboratory work up and genetic testing should be strongly considered.