G protein-coupled receptors (GPCRs) are heterotrimeric protein complexes (composed of α, β, and γ subunits) that mediate cellular responses to a variety of environmental cues. Of the Gα subunits, the Gαi/o family contains inhibitory isoforms of the Gα subunit that have been shown to inhibit adenyl cyclase’s production of the secondary messenger cyclic adenosine monophosphate (cAMP). Our lab has recently shown that patients with activating mutations in Gαi2, encoded by GNAI2, suppress production of cAMP and develop MAGIS syndrome (defined by Midline malformations of the brain, Anterior hypopituitarism, Growth retardation, Immunodeficiency/immunodysregulation, and Skeletal abnormalities) [1]. Since phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce cAMP breakdown, we hypothesized that treatment to increase cAMP levels might improve disease. We explored this possibility in a 36-year-old woman with MAGIS syndrome whose disease manifests in recurrent infections, autoimmunity, and increased inflammation, as demonstrated by leukocytosis in the setting of enteropathic arthritis (characterized by tenosynovitis in multiple joints in the setting of chronic colitis). Additionally, she has type 1 diabetes mellitus, as well as severe mixed hyperlipidemia and hypertriglyceridemia, possibly related to her growth hormone deficiency. After starting roflumilast, weekly scoring using the Patient-Reported Outcomes Measurement Information System (PROMIS) showed increased physical function. This was consistent with the patient’s self-report of decreased joint pain and objective measures of improved joint and tendon disease as documented by sequential ultrasounds. Leukocytosis normalized and histological findings from sequential colonoscopies showed decreased active colitis. Additionally, her triglyceride, cholesterol, and hemoglobin A1C levels improved. These observations suggest that the suppressed cAMP might contribute to inflammatory disease in MAGIS, and if so, targeted therapy to normalize cAMP might be beneficial in some patients.

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2025
This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
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