NFKB2 – Deficiency in Anterior Pituitary Function-Variable Immunodeficiency Syndrome (DAVID Syndrome)

Heterozygous C-terminal mutations in the NF-κB2 gene (NFKB2) underlie deficiency in anterior pituitary function–variable immunodeficiency syndrome (DAVID syndrome) (Deficiency in Anterior Pituitary Function-Variable Immunodeficiency Syndrome). Clinical presentations combine adrenocorticotropic hormone deficiency with hypogammaglobulinemia, sometimes preceded or accompanied by neurological features such as pseudotumor cerebri and diplopia. The disease follows an autosomal dominant inheritance pattern with predominantly de novo truncating variants near the protein C-terminus.

Genetic studies identified four unrelated families harboring de novo or familial C-terminal NFKB2 mutations in six affected probands, with de novo origin confirmed in three families ([PMID:25524009]). A subsequent case report described a child presenting in Addisonian crisis with raised intracranial pressure carrying a truncating mutation c.2557C>T (p.Arg853Ter) ([PMID:36494638]). Segregation analysis revealed two additional affected relatives carrying the same C-terminal variants, manifesting primarily immunodeficiency. In total, five probands across four families support a strong gene–disease link.

The variant spectrum is dominated by truncating mutations affecting the ankyrin repeat domain and processing signals of p100, including c.2557C>T (p.Arg853Ter), c.2556_2563del (p.Arg853fsTer), and c.2596A>C (p.Ser866Arg). These variants disrupt proteolytic processing of p100 to p52, resulting in accumulation of unprocessed NF-κB2 in the nucleus and altered transcriptional regulation. Missense changes near processing motifs (e.g., p.Ser866Arg) have similarly been observed in isolated ACTH deficiency and common variable immunodeficiency cohorts.

Functional assessment in CRISPR/Cas9-engineered pituitary organoids harboring NFKB2D865G/D865G demonstrated impaired generation of corticotroph lineage cells and downregulation of POMC and TBX19, directly linking NFKB2 deficiency to ACTH deficiency ([PMID:39607428]). Animal models (Lym1 mice) recapitulate immune but not endocrine phenotypes, suggesting species-specific requirements for NF-κB2 in pituitary development. In vitro overexpression and reporter assays confirm that C-terminal truncations act as gain-of-function super-repressors, consistent with disrupted NF-κB signaling.

No studies have refuted the association for DAVID syndrome, although haploinsufficient NFKB2 alleles without endocrine manifestations imply incomplete penetrance for isolated hypopituitarism. The convergence of genetic, segregation, and organoid data supports a dominant gain-of-function mechanism in which unprocessed NF-κB2 impairs corticotroph differentiation and B-cell function. This robust evidence confirms a strong clinical validity.

Key Take-home: NFKB2 C-terminal truncating variants cause autosomal dominant DAVID syndrome by disrupting p100 processing, leading to combined ACTH deficiency and immunodeficiency—screening for NFKB2 mutations is indicated in children with idiopathic hypopituitarism and hypogammaglobulinemia.

References

• BMC Pediatrics • 2022 • The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome. PMID:36494638
• BMC Medical Genetics • 2014 • Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. PMID:25524009
• eLife • 2024 • Modeling corticotroph deficiency with pituitary organoids supports the functional role of NFKB2 in human pituitary differentiation. PMID:39607428

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