Endocrine Abstracts

Introduction: Micronodular adrenocortical disease is a very rare cause of Cushing syndrome in children. This adrenocorticotropic hormone (ACTH)-independent form of Cushing syndrome is mostly a part of the Carney Complex, which is caused by mutations in the PRKAR1A gene (1). A young female with endogenous ACTH independent hypercorticism without the classical gene mutations in the pigmented and the non-pigmented form of micronodular adrenal disease is presented.

Case Report: An 11-year old girl presented with increasing adiposity despite a hypocaloric diet for several months. She was born after 38 weeks of an uneventful gestation with a birth weight of 3.23 kg (−0.25 SDS) and birth length 50 cm (0 SDS). Psychomotor development was normal. No previous health problems or use of medication were reported. Familial history was negative for endocrine and neoplastic problems and obesity. She had no other complaints, beside increasing acne. However, retrospective growth curve analysis showed a severely delayed linear growth (1.2 cm in the last 12 months). At physical examination, standing height was 136.7 cm (−1.9 SDS), BMI 20.28 kg/m² (+0.8 SDS), Tanner stage A1P2M1 and blood pressure 110/84 mmHg. No striae, lentigines or acanthosis nigricans were present, but slight facial acne and blushing cheeks were observed. Fasting glucose was 82 mg/dL, insulin 100 pmol/L, total cholesterol 267 mg/dL, HDL 79 mg/dL, LDL 177 mg/dL and triglycerides 52 mg/dL. Morning serum cortisol (187.2 μg/l) and DHEAS (0.44 mg/L), as well as IGF-1, FT4 and TSH were normal. Bone age was 9.48 years. Because of the clinical suspicion of Cushing syndrome, additional screening investigations were performed. Cortisoluria (586.7 μg/24h) and salivary night cortisol level (12.71 μg/L) were elevated. Repeated morning serum cortisol was slightly elevated (215.5 μg/L) with an undetectable ACTH concentration. The administration of a low dose of dexamethasone at 11 PM resulted in an overnight serum cortisol of 177.3 μg/L. An absent ACTH response to CRH was documented. Magnetic Resonance imaging, as well as additional Computed Tomography imaging of the adrenals were normal. The adrenal origin of the hypercorticism in combination with the absence of nodular findings on imaging raised suspicion for PPNAD. Ultrasound of the heart and thyroid was normal. Mutation analysis of the PRKAR1A, PDE11A and PDE8B gene were normal. Ketoconazole treatment resulted in a normal cortisoluria after 2 weeks. Diagnosis of isolated micronodular adrenal disease was made.

Discussion: Delayed growth and bone maturation, cutaneous changes (blushing cheeks and acne) raised the clinical suspicion of Cushing syndrome in the by a dietician referred young female, complaining of persisting weight gain despite an extreme hypocaloric diet. The finding of hypercortisoluria, non-suppressed adrenal androgens and a normal adrenal size at imaging supported the diagnosis of an endogenous cause of hypercorticism, since in children the hidden administration of glucocorticoids should always be suspected in case of un unexplained ACTH independent Cushing syndrome presenting with normal adrenal imaging (2). The diagnosis of micronodular adrenal disease is often a challenge due to a variable clinical presentation (often insidious) with variable lesions at different imaging techniques, especially when a family history or other clinical signs of Carney Complex are lacking (3). Genetic testing might therefore be helpful in the diagnosis of this difficult form of Cushing syndrome. The absence of PRKAR1A gene mutation however does not fit with the diagnosis of Carney Complex or the pigmented form in our case.

References: 1. Stratakis CA. Diagnosis and Clinical Genetics of Cushing Syndrome in Pediatrics. Endocrinol Metab Clin North Am. 2016;45(2):311–28.

2. Gunther DF, Bourdeau I, Matyakhina L, Cassarino D, Kleiner DE, Griffin K, et al. Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity? J Clin Endocrinol Metab. 2004;89(7):3173–82.

3. da Silva RM, Pinto E, Goldman SM, Andreoni C, Vieira TC, Abucham J. Children with Cushing's syndrome: Primary Pigmented Nodular Adrenocortical Disease should always be suspected. Pituitary. 2011;14(1):61–7.