ACTH-Independent Cushing Syndrome in an Adolescent Girl due to Micronodular Adrenal Hyperplasia

Case Report

J Pediatri Endocrinol. 2016; 1(1): 1004.

ACTH-Independent Cushing Syndrome in an Adolescent Girl due to Micronodular Adrenal Hyperplasia

Cebeci AN¹*, Guven A², Mutus M³ and Zemheri E4

¹Derince Training and Research Hospital, Clinic of Pediatric Endocrinology, Kocaeli, Turkey

²Amasya University Medical Faculty, Department of Pediatric Endocrinology & Goztepe Training and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Turkey

³Goztepe Training and Research Hospital, Clinic of Pediatric Surgery, Istanbul, Turkey

4Goztepe Training and Research Hospital, Clinic of Pathology, Istanbul, Turkey

*Corresponding author: Ayse Nurcan Cebeci, Derince Training and Research Hospital, Clinic of Pediatric Endocrinology, Kocaeli, Turkey

Received: June 09, 2016; Accepted: June 13, 2016; Published: August 16, 2016


Objective: Cushing Syndrome (CS) has a bimodal age distribution in children; preschool children mostly present with adrenocortical lesions, whereas the cause of hypercortisolism in older children is usually a corticotropin (ACTH) secreting pituitary adenoma. Bilateral Nodular Adrenal Hyperplasia (BNAH) may be a component of a genetic condition such as Carney complex and isolated BANH is very rare. We present an uncommon case of ACTH-independent CS in an adolescent girl.

Clinical Presentation: The patient was admitted with weight gain. She had truncal obesity, moon facies and mild hypertrichosis, but no hypertension, no striae and no skin pigmentation. Her height Standard Deviation Score (SDS) was below -2. Laboratory investigation revealed elevated plasma and urinary cortisol and normal ACTH levels. Overnight 1 mg dexamethasone and lowdose dexamethasone tests failed to supress cortisol. Imaging studies revealed nodular hyperplasia of the left adrenal gland. The patient underwent bilateral laparoscopic adrenalectomy and histological evaluation revealed diffuse proliferation of right adrenal gland and micronodular proliferation in addition to diffuse proliferative areas in left adrenal gland. The surgery was curative and the patient was put on glucocorticoid and mineralocorticoid replacement therapy.

Keywords: Cushing syndrome; Bilateral adrenal hyperplasia; Adrenal nodules; Adolescent; Laparoscopic adrenalectomy


ACTH: Corticotrophin; BNAH: Bilateral Nodular Adrenal Hyperplasia; CD: Cushing Disease; CS: Cushing Syndrome; CT: Computerized Tomography; MRI: Magnetic Resonance Imaging; PPNAD: Primary Pigmented Nodular Adrenocortical Disease; SDS: Standard Deviation Score; RR: Reference Range


Cushing Syndrome (CS) is a rare clinical entity in children which is characterized by glucocorticoid excess. The most common cause of CS is exogenous administration of glucocorticoids or corticotropin (ACTH). On the other hand, the term “Cushing Disease (CD)” describes hypercortisolism due to an ACTH-secreting pituitary adenoma and is the most common cause of endogenous CS. CD comprise 75-80% of pediatric cases in children over 5 years of age [1]. In younger children, CS may be caused by ACTH-independent cortisol producing adrenocortical lesions including adrenal adenoma, adrenal carcinoma or adrenal hyperplasia (diffuse or multinodular). These conditions are reported to be the cause of CS as many as half of CS cases in children younger than 7 years of age [2]. Ectopic production of ACTH is particularly rare in paediatric age group.

ACTH-independent multinodular adrenal hyperplasias may be divided in two groups based on the size of the nodules, with macronodular disorders associated with nodules larger than 1 cm and micronodular hyperplasias associated with nodules that are smaller than 1 cm [2]. Macronodular adrenal hyperplasias are usually related to McCune-Albright syndrome (OMIM 174800) in children. This condition occurs due to somatic mutations in the GNAS1 gene. Benign micronodular hyperplasias include Primary Pigmented Nodular Adrenocortical Disease (PPNAD- OMIM 610489) and isolated micronodular adrenal disease. PPNAD usually accompanies to the “Carney complex” (OMIM 160980), which is a rare multiple neoplasia syndrome depicted by pigmented lentigens, myxomas, schwannomas and various endocrine tumors [3]. Inactivating mutations of the PRKAR1A gene have been described in the majority of cases with Carney complex. Recently, in patients with Cushing syndrome caused by bilateral adrenocortical lesions who have neither GNAS nor PRKAR1A gene mutations, inactivating mutations in phosphodiesterase gene family have been identified [4]. In this report we describe an adolescent girl with Cushing syndrome caused by isolated bilateral micronodular adrenal disease who has been cured by bilateral laparoscopic adrenalectomy. We want to emphasize the importance of clinical suspicion in the diagnosis of this rare condition in this age group.

Case Presentation

12 years and 7 months old female patient was admitted with excess gain of weight. She was born 3200 grams to nonconsangenious parents at term, her developmental milestones were normal. Her weight has been always normal but she gained more than 15 kilograms for the last year although she had no significant changes in her eating habits and daily exercise. On physical examination, her systemic arterial blood pressure was 90/60 mmHg, height: 138.5 cm (-2.91 SDS), weight: 47 kg (-0.15 SDS), body mass index: 24.5 kg/m² (+1.49 SDS). She had truncal obesity, moon facies and mild hypertrichosis. Her pubic hair and breast development were stage 4 and stage 3 respectively, according to Tanner staging. No stretch marks were noticed. Physical examination of all other systems was normal. Laboratory measurements revealed mildly elevated morning cortisol levels (25.92 μg/dL, Reference range [RR]:3-10) with normal fasting glucose (71 mg/dl, RR:74-110) and insulin (13.53 μU/mL, RR: 0-17) and elevated serum lipids (Total Cholesterol: 267 mg/dL, RR: 0-200, Low Density Lipoprotein-Cholesterol: 167 mg/dL, RR: 0-130, High Density Lipoprotein: 66 mg/dL, RR: >40 and Triglyceride: 169 mg/dL, RR: 0-150). Other laboratory findings were within normal limits. The patient was further evaluated for hypercortisolism and hormonal investigation revealed loss of circadian rhythm (plasma morning cortisol 42.17 μg/dL (RR:3-10), midnight cortisol 16.44 μg/ dL (RR: <7.5) and morning ACTH 6.74 pg/ml (RR: 2-49), midnight ACTH: 7.97 pg/ml (RR 5-10, normally lower than morning level) and elevated Urinary Free Cortisol (UFC) level (573.3 mg/day [398 μg/ m²/day], RR: 10-100 μg/day). Overnight Dexamethasone (DXM) test showed no suppression (plasma cortisol after 1 mg DXM 24.96 μg / dL, RR: <1.8). Low dose DXM suppression test (0.5 mg every 6 hours for 8 doses) showed no suppression of cortisol levels (plasma cortisol 10.52 μg/dL, RR: <1.8, UFC 110 μg /day [76.38 μg /m²/day], normally < 10% of baseline, ACTH: <1.0 pg/ml after test).

The Computerized Tomography (CT) of the adrenals revealed diffuse thickening of the medial cruris of the left adrenal gland, whereas the right adrenal gland appeared normal in size. A Magnetic Resonance Imaging (MRI) with suppression of fat signal technique was obtained and it revealed nodular hyperplasia of the left adrenal gland with normal manifested right adrenal gland.

The hormonal and radiological findings confirmed the diagnosis of ACTH-independent CS and we decided to perform the adrenalectomy with laparoscopic approach. On surgery, both adrenals were enlarged. Macroscopically right adrenal was measured 15 grams and 5x4x3 cm, left adrenal was measured 23 grams and 7x3x2.5 cm. In cut section, both right and left adrenal gland revealed diffuse hyperplasia in focal areas of adrenal glands (Figure 1). There were neither macronodules nor pigmented areas. Histological assessment revealed diffuse proliferation of cells with uniform small round nuclei and clear cytoplasm cell showing alveolar and trabecular pattern in right adrenal gland (Figure 2A). In left adrenal gland, micronodular proliferation in addition to diffuse proliferative areas was detected (Figure 2B).