Abstract Generalized glucocorticoid (GC) resistance (Chrousos syndrome) results from impaired GC receptor signaling due to variants in the NR3C1 gene. Severe neonatal presentations are extremely rare. We report an 8-week-old male infant born at 31-week gestation, with progressive respiratory failure, refractory hypotension, hypokalemic alkalosis, anasarca, jaundice, and multiorgan dysfunction. Laboratory evaluation demonstrated persistently elevated serum cortisol 60 µg/dL (SI: 1655 nmol/L) (reference range 2.5-9.1 µg/dL, SI: 69.0-251.0 nmol/L), adrenocorticotropic hormone 2400 pg/mL (SI: 528 pmol/L) (reference range 7.2-63.3 pg/mL, SI: 1.6-13.9 pmol/L), aldosterone 2036.0 ng/dL (SI: 56 nmol/L) (reference range 7.0-99.0 ng/dL, SI: 0.2-2.7 nmol/L), and androgens despite treatment with escalating doses of dexamethasone (up to 12 mg, 2000 mg/m2/day of hydrocortisone-equivalency). Whole-genome sequencing identified 2 NR3C1 variants: a maternally inherited variant of uncertain significance (c.2181+5 GC) and a de novo likely pathogenic ∼7.9 kb deletion encompassing exon 8. In silico analyses suggested both variants could disrupt the GC receptor ligand-binding domain, potentially resulting in complete loss of GC receptor function. Autopsy demonstrated adrenomegaly with marked proliferation of zona fasciculata, cholestasis with bile duct paucity, and chronic neonatal lung disease. This case represents a rare and fatal manifestation of complete generalized GC resistance. It highlights the broad physiological role of GC in neonatal homeostasis.
Segev et al. (Wed,) studied this question.