SAT343 Nicotinamide Nucleotide Transhydrogenase (NNT)-related Familial Glucocorticoid Deficiency: More Than Adrenal Insufficiency
Authors: Shanker Anita , Calero Humberto Luis , DeCarlo Kristen 
Published: October 2023

Disclosure: A. Shanker: None. H.L. Calero: None. K. DeCarlo: None.

Background: Familial glucocorticoid deficiency (FGD) is a rare cause of primary adrenal insufficiency, with an estimated prevalence of fewer than 5,000 cases in the United States. Patients often present as infants with signs including hypoglycemia, failure to thrive, seizures, and recurrent infections.

Clinical Case: A 25-year-old woman with a history of intellectual disability was admitted with MIS-A due to COVID-19. Her presenting symptoms were lethargy and fever for several days. Her vitals were significant for a heart rate of 122 with atrial flutter and blood pressure of 90/50. Her initial labs showed elevated TSH (24.07 mcIU/mL [0.35-4.00]), normal free T4 (0.7 ng/dL [0.6-1.7]), hyponatremia (133 mmol/L [135-145]), and low alkaline phosphatase (25 U/L [40-125). Her physical exam was notable for hyperpigmentation, macrognathia, and oral mucositis. Her parents report she has limited daily activities and recalls recurrent illnesses as a child. She has been amenorrheic for the past 5 years; menarche was at age 12. Further chart review revealed that ketotic hypoglycemic seizure was diagnosed during hospitalization at 11 months of age. . Pediatric Endocrinology diagnosed Addison’s disease, which was treated until age 12 when she was lost to follow-up. On this admission, ACTH was elevated (756.5 pg/mL [7.2 - 63.3]), 8 AM cortisol was 1.2 ug/dL, and peak cortisol obtained after high dose co-syntropin stimulation was abnormal at 1.1 ug/dL upon high dose. Primary adrenal insufficiency was confirmed, and stress-dose steroids were initiated; her clinical condition improved. She was discharged with prednisone and fludrocortisone maintenance therapy. As an outpatient, TSH was persistently elevated (17.9 mcIU/mL [0.35-4.00]) and weight-based levothyroxine was initiated. Secondary amenorrhea testing demonstrated normal FSH, LH, and estradiol levels and discussions began regarding progesterone withdrawal testing (pending given patient again lost to follow up). The nutritional screening revealed deficiencies in vitamins A, C, and D, and supplementation was initiated. A unifying diagnosis was reached with microarray and whole exome sequencing showing nicotinamide nucleotide transhydrogenase (NNT) -related FGD. Conclusions: In FGD, several causative genes have been identified. One of these, NNT is expressed in most tissues, including cardiac, renal, thyroid, gastrointestinal, and gonadal tissue. This may predispose patients to organ dysfunction outside of the prominent effect on the adrenal glands. Since NNT is widely expressed, routine screening can include nutritional, renal, and hepatic labs and patients should receive reproductive counseling due to the risk of gonadal dysfunction. Therefore, patients with NNT-related glucocorticoid FGD require significant care coordination to ensure that patients receive uninterrupted therapy and appropriate multispecialty follow-up.

Presentation: Saturday, June 17, 2023