Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations

Abstract

The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.

Metyrapone Versus Osilodrostat in the Short-Term Therapy of Endogenous Cushing’s Syndrome: Results From a Single Center Cohort Study

“…As previously performed ( 20 , 21 ), commercially available analytical procedures were used for measurement of serum and salivary cortisol (the Immulite 2000 Xpi from Siemens), and for the analysis of UFC (a manual radioimmunoassay from Immuntech).…”

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

“…For ACAs, the endocrine workup was conducted according to the adrenal incidentalomas guidelines issued by the European Society of Endocrinology/European Network for the Study of Adrenal Tumors 5 and the Endocrine Society guidelines for the diagnosis of Cushing’s syndrome 82 . Hormone levels were measured using commercially available analytical procedures (details in Supplementary Material), as previously reported 83 . CPA derived from patients with overt Cushing’s syndrome and unequivocal laboratory results (for details see Supplementary Material).…”

Genetics of Cushing's disease

“…[67][68][69][70][71][72][73][74][75][76][77] A somatic USP8 mutation was found in the corticotroph tumour of a patient that presented with both adrenal Cushing's syndrome and central Cushing's disease and additionally carried somatic mutation in NR3C1 in the corticotroph tumour and CTNNB1 in the adrenal tumour. 78 A somatic USP8 mutation was found in an adult patient with Cushing's disease, who also suffered from growth hormone deficiency due to GH1 mutation. 79 USP8 mutations were also detected in 13/45 paediatric patients with Cushing's disease, but not in a single centre study of 18 paediatric patients.…”

“…Subsequent sequencing efforts in Caucasian and Asiatic populations identified USP8 mutations in 35%–60% of cases as well as in ~50% of cases of progressive corticotroph tumour growth after bilateral adrenalectomy (Nelson's syndrome) 67–77 . A somatic USP8 mutation was found in the corticotroph tumour of a patient that presented with both adrenal Cushing's syndrome and central Cushing's disease and additionally carried somatic mutation in NR3C1 in the corticotroph tumour and CTNNB1 in the adrenal tumour 78 . A somatic USP8 mutation was found in an adult patient with Cushing's disease, who also suffered from growth hormone deficiency due to GH1 mutation 79 …”