(10.10) A Newly Described Variant of GNAS (p.Ile56Phe) Results in Multiple Endocrine Manifestations of Disease

The gene encoding the alpha-subunit of the stimulatory G protein (Gsα or GNAS) is a key component to G-protein coupled receptor (GPCR) signaling in response to a hormone binding to its cognate receptor. The receptors for ACTH, TSH, LH/FSH, PTH, vasopressin and GHRH are GPCRs dependent on GNAS. Genetic variants in GNAS can manifest as endocrine disorders or syndromes. We describe the clinical and biochemical findings of a 17-year-old female with a heterozygous missense variant of GNAS p.Ile56Phe in exon 2. This mutation has only been described for one other individual to our knowledge and we have noted overlapping and also unique phenotypic findings.

Case(s) Description :

Our patient presented at birth with failure to thrive and low body weight and was found to have hyponatremia attributed to disturbances in aldosterone signaling. Sodium levels were maintained with sodium citrate, fludrocortisone, and the addition of table salt. Delayed milestones became apparent, with the patient progressing from sitting to walking at approximately 3 years of age. Precocious puberty occurred with menarche at 6 years, at which time thelarche and adrenarche were already apparent. Skeletal abnormalities included genu varum for which she underwent epiphyseal stapling, with height surpassing that of mid-parental height, and she had a right arm fracture during sibling play.  The physical examination was notable for mild facial plethora, small vitiligo patch, mildly enlarged thyroid, and possible brachydactyly of 5^th fingers but was otherwise unremarkable.  Imaging of her hands revealed acroosteolysis and remodeling of the volar distal aspects of the proximal phalanges. Most recent lab work was suggestive of subclinical hyperthyroidism (suppressed TSH), along with elevated PTH and hypovitaminosis D. The patient's mother carries the same variant of uncertain significance (VUS) and has a history of skeletal issues with genu valgum, elevated height (5’10”), despite history of epiphyseal stapling in grade 5, but none of the other hormonal findings. The patient's two siblings appear unaffected.

Discussion :

This is only the second report of a patient with the GNAS variant p.Ile56Phe and the clinical presentation expands the phenotype described with the first patient. This variant has been determined to cause a 50% reduction in Gsα activity but is  associated endocrine findings suggestive of both loss and gain of function. This unique case contributes additional insights into the role of GNAS in the endocrine system and also the impact of imprinting on the clinical manifestations of GNAS variants that affect endocrine hormone signaling.