Endocrine Abstracts

Deficient Anterior pituitary with common Variable Immune Deficiency (DAVID) syndrome results from heterozygous mutations of the nuclear factor kappa-B subunit 2 (NFKB2) gene, causing adrenocorticotropic hormone deficiency (ACTHD) and primary hypogammaglobulinemia. Only a few cases of DAVID syndrome have been reported since its first description by our team through the international multicenter GENHYPOPIT network (Quentien MH et al. JCEM 2012). We analyzed 28 cases with ACTH deficiency published from 2012 to 2022 (Mac TT et al. J Neuroendocrinol. 2023). ACTH deficiency was the only hormone deficiency in 79% of patients, but some patients harbored growth hormone (GH) and thyroid stimulating hormone (TSH) deficiencies. The first presenting symptoms were sinus/pulmonary infections (82%, mean age of 3 years) and alopecia (mean age of 4.7 years). ACTH deficiency was the third presenting condition (mean age at diagnosis: 8.6 years). All patients had hypogammaglobulinemia (decreased IgA and IgM levels), and 57% of patients had at least one autoimmune manifestation. Heterozygous mutations at the 3’ end of the NFKB2 gene, coding for the C-terminal domain of the protein, were identified in all cases. While NFKB signaling plays a crucial role in the immune system, its connection to endocrine symptoms is unclear. We established a human disease model to investigate the role of NFKB2 in pituitary development by creating pituitary organoids from CRISPR/Cas9-edited human induced pluripotent stem cells (hiPSCs). Introducing homozygous TBX19^K146R/K146R missense pathogenic variant in hiPSC, an allele found in congenital isolated ACTHD, led to a strong reduction of corticotrophs number in pituitary organoids. Then, we characterized the development of organoids harboring NFKB2^D865G/D865G mutations found in DAVID patients. NFKB2^D865G/D865G mutation acted at different levels of development with mutant organoids displaying changes in the expression of genes involved on pituitary progenitor generation (HESX1, PITX1, LHX3), hypothalamic secreted factors (BMP4, FGF8, FGF10), epithelial-to- mesenchymal transition, lineage precursors development (TBX19, POU1F1) and corticotrophs terminal differentiation (PCSK1, POMC), and showed drastic reduction in the number of corticotrophs (Mac TT et al. Elife. 2024). Our results provide strong evidence for the direct role of NFKB2 mutations in the endocrine phenotype observed in DAVID syndrome patients and demonstrate the role – to be further analyzed - of NFKB2 in pituitary differentiation, especially for the corticotroph lineage.