Transl Pediatr. 2026 Feb 28;15(2):60. doi: 10.21037/tp-2025-630. Epub 2026 Feb 12.
ABSTRACT
BACKGROUND: Familial glucocorticoid deficiency type 4 (GCCD4), caused by nicotinamide nucleotide transhydrogenase (NNT) gene mutations, represents a rare multisystem disorder with poorly characterized cardiac manifestations.
CASE DESCRIPTION: A 12-year-old female presented with recurrent fatigue, syncope, and severe arrhythmias. After multiple misdiagnoses [including dilated cardiomyopathy, fulminant myocarditis, and long QT syndrome (LQTS)], comprehensive evaluation revealed hypocortisolism (<1.0 µg/dL), markedly elevated adrenocorticotropic hormone (ACTH) (>1,250 pg/mL), and hypothyroidism. Genetic testing identified compound heterozygous NNT mutations (c.639_640insC/p.Val214Argfs*32 and c.2764C>T/p.Arg922*). Comprehensive whole-exome sequencing (WES) ruled out pathogenic variants in genes associated with isolated cardiomyopathy or congenital hypothyroidism. Cardiac assessment showed left ventricular dilation [left ventricular end-diastolic diameter (LVEDD) 5.14 cm], reduced left ventricular ejection fraction (LVEF) 53%, and corrected QT interval (QTc) prolongation (559 ms) with torsades de pointes. The patient was managed with hormone replacement (hydrocortisone 8.8→16.1 mg/m2/day; levothyroxine 16.7 µg/day) and cardioprotective therapy (propranolol, captopril, coenzyme Q10), resulting in significant improvement at 3-year follow-up: ejection fraction (EF) normalized to 68%, thyroid function recovered permitting levothyroxine discontinuation, hyperpigmentation resolved completely, and no arrhythmias recurred.
CONCLUSIONS: This case underscores GCCD4 as a differential diagnosis in pediatric cardiomyopathy with arrhythmias. Multidisciplinary collaboration and early genetic testing are critical for diagnosis. Individualized glucocorticoid dosing combined with cardiac support enables favorable outcomes.
PMID:41810200 | PMC:PMC12969219 | DOI:10.21037/tp-2025-630