ESPE Abstracts

Our patient was a 19-year-old female who was referred for evaluation of secondary amenorrhea and underdeveloped secondary sexual characteristics, having undergone her first and only menstrual cycle at age 16. She had experienced four episodes of hypoglycemia during her childhood; two were associated with seizure activity. She was evaluated by endocrinology after her second episode of hypoglycemia at 3 years of age and no cause could be identified. She also had learning difficulties and delayed developmental milestones. Our exam showed diffuse hyperpigmentation over the entire body including her lips and tongue. She had no axillary hair; Tanner III breast development and Tanner II pubic hair distribution were evident. She had normal external female genitalia without clitoromegaly. Karyotype was reported as 46 XX. Current laboratory investigation revealed undetectable cortisol, ACTH level of 1493 pg/mL (normal 7.2-63.3 pg/mL), low circulating adrenal androgens (17-OHP, DHEA-S), pre-pubertal levels of estradiol and testosterone. However, she had a normal serum sodium, potassium, aldosterone levels and a normal plasma renin activity. Sixty minutes after a single 250 mg dose of cosyntropin, an unmeasurable cortisol was observed, along with an undetectable 17-Hydroxypregnenolone, 17-Hydroxyprogesterone, DHEA, pregnenolone, a very low progesterone and androstenedione levels. Leuprolide stimulation resulted in a prepubertal response of LH and FSH. Clonidine-arginine stimulation test revealed growth hormone deficiency (peak value = 4.8 ng/mL), however the patient has in fact exceeded her mid-parental height. Other remarkable findings included persistently elevated TSH (9.7-11.2 uIU/ml), low normal free T4, a very low IGF-1 level (33-46 ng/mL) and mild elevations in AST/ALT, of unclear etiology. Pelvic ultrasound revealed a normal uterus with 6 mm endometrial stripe and normal ovaries bilaterally. MRI pituitary was normal. The biochemical profile suggested ACTH resistance due to receptor loss of function, and a pathogenic homozygous variant in exon 2 of MC2R (melanocortin-2 receptor) gene was identified on extended gene analysis [c.C409T: p.R137W] and explains the loss of signal transduction at the ACTH receptor. Familial glucocorticoid deficiency type 1 is a rare autosomal recessive disorder, characterized by MC2R mutation leading to primary adrenal insufficiency with intact mineralocorticoid function. Treatment with physiologic doses of hydrocortisone was initiated. This case illustrates a unique phenotype of MC2R loss of function, presenting later in adolescence. Unusual features include growth hormone deficiency with normal growth, transaminitis, subclinical hypothyroidism and hypogonadism. These observations suggest a partial dependence upon ACTH for normal functioning of other endocrine axes.