Endocrine Abstracts

Founded 3 decades ago, the Genhypopit network, an international consortium to identify genetic causes of hypopituitarism (such as mutations in pituitary transcription factor genes like POU1F1, PROP1 or LHX3/4), allowed to decipher several phenotype-genotype correlations in various presentations of congenital pituitary hormone deficiencies. These include congenital isolated corticotroph deficiency (ACTHD), the focus of this presentation. In collaboration with the group of Jacques Drouin (Canada), which discovered Tpit as the main regulator of mouse corticotroph development, we identified in patients referred to this network the first two families with ACTHD caused by mutations of TPIT, currently known as TBX19, demonstrating its major role in corticotroph function in humans also (Cell 2001). When further characterizing ACTHD patients with or without TBX19 mutations, we recognized in the latter group 3 families with both ACTHD and variable immunodeficiency, an association that we first described as DAVID syndrome (JCEM 2012) and found to be due to NFKB2 gene mutations (JCEM 2014). Using a model of in vitro differentiation of mature human pituitary cell types from human induced pluripotent stem cells (3D culture of hypothalamo-pituitary organoids with or without pathogenic variations of NFKB2), we recently demonstrated the role of this gene in corticotroph differentiation (eLife 2024). Bridging from ACTHD to Cushing’s disease, we were the first to show that TPIT/TBX19 immunostaining could be used to characterize adenomatous corticotroph cells (JCEM 2003), currently one of the main criteria for defining corticotroph tumors in the WHO classification of pituitary tumors. In terms of pathophysiology of this disease, further collaborative works with the group of J. Drouin led to the involvement of CABLES1 inactivation or Brg1 loss of function, and the roles of cyclin E or Pax7. Recently, in collaboration with Guido Kroemer in Paris, we found that plasma ACBP/DBI - Acyl coenzyme A binding protein that stimulates food intake and lipo-anabolic reactions - was elevated in both patients and mice with Cushing’s syndrome. In mice, ACBP/DBI inhibition abolished manifestations of Cushing’s syndrome such as weight gain or type 2 diabetes, which opens promising therapeutic avenues (Nature Metab 2024). These studies highlight the role of rare diseases in the identification of important physiological mechanisms and the added value of collaborative work between adult or pediatric specialists and experimental researchers. Hypothalamo-pituitary organoids represent a unique model for several genetically determined pituitary diseases affecting pituitary development and/or proliferation and for the study of developing or mature human pituitary cells.