J Clin Res Pediatr Endocrinol. Ahead of Print: JCRPE-01488 | DOI: 10.4274/jcrpe.galenos.2023.2023-9-15

Atypical Presentation and Course of ACTH-independent Cushing’s Syndrome in Two Families

Kübra Yüksek Acinikli¹, Sezer Acar², Ahu Paketçi³, Özgür Kýrbýyýk⁴, Mert Erbaþ⁵, Özge Besci¹, Gözde Akýn Kaðýzmanlý¹, Deniz Kýzmazoðlu⁶, Oktay Ulusoy⁷, Erdener Özer⁸, Kutsal Yörükoðlu⁸, Ayhan Abacý¹, Handan Güleryüz⁹, Ece Böber¹, Korcan Demir^1
1Pediatric Endocrinology, Dokuz Eylül University, Faculty of Medicine, Ýzmir, Turkey
²Pediatric Endocrinology, Manisa City Hospital,Manisa, Turkey
³Pediatric Endocrinology, Medipol University Hospital,Ýstanbul, Turkey
⁴Genetic Diagnosis Center, Tepecik Training and Research Hospital, Ýzmir, Turkey
⁵Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Ýzmir, Turkey
⁶Pediatric Oncology, Dokuz Eylul University Institute of Oncology, Izmir, Türkiye
⁷Pediatric Surgery, Dokuz Eylül University, Faculty of Medicine, Ýzmir, Turkey
⁸Department of Pathology, Dokuz Eylül University, Faculty of Medicine, Ýzmir, Turkey
⁹Department of Radiology, Division of Pediatric Radiology, Dokuz Eylül University, Faculty of Medicine, Ýzmir, Turkey

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type 1A (RIα) of the cAMP-dependent protein kinase (PRKAR1A) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing's disease in one case. All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in PRKAR1A (case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provide important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.

Keywords: Cushing's disease, cancer, myxoma, lentigo, PEG precipitation, macronodule

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