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Deficient Anterior pituitary with common Variable Immune Deficiency (DAVID) syndrome results from NFKB2 heterozygous mutations, causing adrenocorticotropic hormone deficiency (ACTHD) and primary hypogammaglobulinemia. 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. Our results provide strong evidence for the direct role of NFKB2 mutations in the endocrine phenotype observed in patients leading to a new classification of a NFKB2 variant of previously unknown clinical significance as pathogenic in pituitary development., Competing Interests: TM, TF, NJ, PR, HE, AB, FC, TB No competing interests declared, (© 2023, Mac et al.)

Background: The noncanonical NF-κB2 (nuclear factor kappa B subunit 2) pathway is integral in regulating immunologic responses, supervising immune function, development, and homeostasis. NFKB2 encodes the cytoplasmic precursor p100, which undergoes processing of its inhibitory C-terminal half to generate p52. Impeding C-terminal defects are well established to cause primary immunodeficiency disorder. In contrast, the mechanism of truncating N-terminal defects remains obscure., Objective: We characterized clinical phenotypes associated with 3 distinct protein-defect types: (1) early truncations: typically occurring N-terminal relative to the nuclear localization sequence and affecting the Rel homology domain, predicting p100 expression to be halved and subsequent p52 generation by processing to be diminished; (2) central truncations: mainly affecting the ARD and predicting immediate expression of p52-like proteins and a 50% reduction of p100; and (3) C-terminal phosphorylation-/ubiquitination domain defects: causing expression of nonprocessable p100 with retained IκB-like activity and subsequently reducing generation of p52., Methods: We performed literature research on PubMed, Clinvar, and Human Gene Mutation Database collecting clinical and immunologic data on NFKB2 patients, focusing on comparing protein-defect-specific impacts., Results: The highest prevalence of early-onset primary immunodeficiency disorder and antibody deficiency occurred in the CTD-defect group. In addition, endocrinological abnormalities and T-cell-mediated autoimmunity were common and frequently required immunosuppression. An extensive immunologic workup revealed patients with C-terminal defects to have pan-hypogammaglobulinemia and reduced specific antibody responses and markedly impaired B-cell differentiation, but normal to elevated T-cell counts. In contrast, pathogenic NFKB2 variants causing central or early-truncating protein defects were only partially penetrant, with ameliorated symptoms and diminished T-cell-mediated autoimmunity., Conclusions: Our work defines a clear genotype-phenotype correlation for NFKB2 mutations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We report a novel presentation of deficit in anterior pituitary function with variable immune deficiency (DAVID) syndrome in a healthy young girl presenting in Addisonian crisis with raised intracranial pressure. Nearly all cases of DAVID syndrome described in the literature have presented with recurrent infections and variable immunodeficiency. Pseudotumour cerebri has not been reported in DAVID syndrome to date., Case Presentation: A four-year-old girl represented to hospital with vomiting, confusion and diplopia after ten days of tiredness, neck and abdominal pain, and headache. Her cranial nerve examination demonstrated a right abducens nerve palsy and papilloedema, and she was found to have ketotic hypoglycaemia and hypocortisolaemia secondary to adrenocorticotrophic hormone (ACTH) deficiency. Her neuroimaging was consistent with pseudotumour cerebri, and her lumbar puncture opening pressure confirmed raised intracranial pressure (30-40 cmH 2 O). Cerebrospinal fluid analysis was normal. The patient's symptoms improved with hydrocortisone replacement and acetazolamide, but the raised intracranial pressure recurred after acetazolamide was discontinued. She was subsequently found to have panhypogammaglobulinaemia, and DAVID syndrome was diagnosed. Genetic testing demonstrated a truncating mutation in the NFKB2 gene c.2557C > T, p.(Arg853*)., Conclusions: This case demonstrates pseudotumour cerebri as a novel neurological presentation of DAVID syndrome, highlights the rare association between adrenal insufficiency and intracranial hypertension, and shows the challenges in diagnosing isolated ACTH deficiency. We emphasise that cortisol should be checked in pre-pubertal children with pseudotumour cerebri and a diagnosis of DAVID syndrome considered in those presenting with low cortisol and neurological symptoms., (© 2022. The Author(s).)