Lack of mutations in the gene coding for the hGR ( NR3C1) in a pediatric patient with an ACTH-secreting pituitary adenoma, absence of stigmata of Cushing syndrome, and unusual histologic features

Abstract

Loss of heterozygosity at the human glucocorticoid receptor (hGRα) gene ( NR3C1) locus has been found in pituitary adenomas of patients with Cushing disease (CD); rare cases of NR3C1 mutations have also been described in the gemline or somatic state in CD. We describe a pediatric patient with CD with clinical evidence of partial glucocorticoid resistance (GR) because of relative absence of stigmata of Cushing syndrome (CS), who did not have any mutations in the hGRα gene ( NR3C1). A 14-year-old boy with slow growth and hypertension but no other signs of CS (i.e. no weight gain, no striae, no facial plethora) was admitted for evaluation of CD. Pituitary MRI revealed a 3 x 4 millmeter hypoenhancing lesion in the right side of the pituitary gland anteriorly (microadenoma). Urinary free cortisol levels (UFC) were consistently 2–3-fold the upper normal range (100–129 mcg/24 hours. A graded dexamethasone suppression test indicated that the patient had partial GR. Histology confirmed an ACTH-producing pituitary adenoma, characterized by proliferation of anterior lobe cells of similar morphology with reticulin breakdown and strong diffuse ACTH staining. However, in contrast to a series of 5 ACTH producing pituitary adenomas characterized by hGRα patchy positive staining in both cytoplasm and nuclei of tumor cells, no GR staining was detected in our patient’s microadenoma. We hypothesized that a NR3C1 mutation was present in the patient’s peripheral DNA but sequencing studies of the entire coding region of the gene produced normal results. We present the case of a pediatric patient with little evidence of CS, despite the unequivocal presence of an aggressive ACTH-producing tumor and high UFCs. This patient did not have peripheral DNA NR3C1 coding sequence mutations; possible explanations for this phenotype include somatic mosaicism for NR3C1 mutations or a mutation in another molecule that participated in hGRα-signaling.