GNAI2 activating variants and MAGIS syndrome: long-term endocrine and growth outcome

Germline activating variants in the GNAI2 gene have recently been associated with MAGIS syndrome, characterized by midline malformations of the brain, anterior pituitary gland dysfunction, growth retardation, immunodysregulation, and skeletal defects. However, the full phenotypic spectrum, particularly regarding endocrine dysfunction, remains incompletely defined.

We report on a 9.5-year-old male presenting with MAGIS syndrome due to a de novo GNAI2 (NM_002070.4):c.544A>C, p.(Thr182Pro) variant. He initially presented at 17 months with short stature and hypopituitarism. Pituitary MRI confirmed anterior pituitary hypoplasia with thin stalk and normal posterior pituitary. Long-term follow-up revealed suboptimal response to recombinant growth hormone therapy with persistent low IGF-1, profound prolactin deficiency, and evolving gonadotropin deficiency. He also had delayed developmental milestones, recurrent infections, chronic diarrhea, subclinical hypothyroidism, and skeletal abnormalities. Immunological evaluation showed low T-cell counts, inadequate antibody responses and no overt autoimmune features apart from infantile atopic dermatitis.

This report details the longitudinal clinical, endocrine, and growth data in a patient with MAGIS syndrome harboring a GNAI2 p.Thr182Pro variant. It highlights the suboptimal growth response to GH with fluctuating height velocity and the development of additional endocrine abnormalities such as prolactin, thyroid dysfunction and suspected gonadotropin deficiency. Detailed phenotypic characterization in such cases is crucial for understanding this complex genetic disorder.