ESPE Abstracts

Background: Micronodular bilateral adrenal hyperplasia (MiBAH) is a rare cause of adrenal Cushing syndrome (CS) that may be subdivided in two main entities: primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). The most common presentation of MiBAH is familial PPNAD as part of Carney complex (CNC). The underlying genetic defect in most forms of PPNAD is inactivating germline mutations of the PRKAR1A gene encoding the regulatory subunit type I-alpha (RIalpha) of protein kinase A (PKA).

Case reports: Patient 1 presented at the age of 2 years and 4 months with rapid weight gain, centripetal obesity, moon facies, hypertension, decreased linear growth, muscle weakness and irritability. Biochemical evaluation confirmed hypercortisolemia with an elevated 24-h urinary free cortisol (UFC), and absent diurnal variation. He failed to suppress to 1 mg overnight dexamethasone. ACTH remained undetectable. The adrenal glands appeared as normal on computed tomography scan. The patient underwent bilateral adrenalectomy and pathological findings were micronodular cortical hyperplasia without pigmentation, consistent with i-MAD. Genetic testing showed a duplication on chromosome 19p that includes the PRKACA gene, which encodes the catalytic subunit alpha (Ca) of PKA. Testicular ultrasound showed tumors which were mixed Leydig cells primarily with a few abnormal Sertoli cells. Patient 2 presented at the age of 4 years with rapid weight gain, hirsutism, facial swelling, decreased energy. Hypercortisolemia was confirmed with elevated UFC, salivary free cortisol levels, undetectable ACTH. Adrenal imaging revealed an isolated nodule of 6 mm on the right adrenal gland. The patient was screened for manifestations of CNC. High values of IGF1 (429 µg/l) with pituitary MRI showing micronodules were observed. The patient underwent bilateral adrenalectomy with pigmented and nodular adrenals at laparoscopy and well delineated pigmented micronodules at pathological examination. No molecular defect has been identified so far.

Conclusion: To our knowledge, Patient#1 is the first case describing Leydig cell tumors in association with i-MAD due to defects of the PRKACA gene. The diagnosis of patients with MiBAH is challenging as the adrenal glands can be normal on imaging studies and the knowledge of any associated lesions is useful in making the diagnosis. PRKAR1A and PRKACA are among the genes that need to be tested in these situations. The exact biology of how the PRKACA duplications lead to tumor formation remains unknown but it is most likely linked to an increase in PKA signaling, just like PRKAR1A defects in CNC