Supplementary Material for: Non malignant ACTH-Independent Cushing Syndrome in Pediatric Patients: A Retrospective Observational Cohort Study

Purpose: ACTH-independent Cushing’s syndrome (CS) is a rare cause of pediatric CS. Our objective was to describe the features of pediatric ACTH-independent CS and to compare groups defined by etiology. Methods: We conducted a retrospective observational study of patients aged 0–18 years at diagnosis between 1992–2022 for ACTH-independent CS in three Paris pediatric hospitals. Additionally, we compared the outcomes of McCune-Albright syndrome (MCAS) patients with CS and without CS. Results: Of the 15 patients with CS, seven had MCAS, seven primary pigmented nodular adrenocortical disease (PPNAD) as part of CNC (Carney complex), and one had CS with no etiology found. Age at CS diagnosis was 0,3 year old (0,17;1) in MCAS and 9 years old (5;15) in PPNAD. The MCAS group had more impaired growth retardation (-4,75 SDS in MCAS vs -1 SDS in CNC, p = 0,006) and higher prevalences of intrauterine growth retardation (P=0.01) and liver dysfunction at diagnosis (P=0.04). All seven MCAS patients had learning disabilities vs. only two CNC patients. 12 out of 15 had bilateral adrenalectomy. None of the MCAS patients received Growth hormone therapy, while 4 CNC patients benefited from growth hormon therapy. At end of follow up, growth recovered in both groups, albeit less in the MCAS group (-1,5 SDS in MCAS vs -0,5 SDS in CNC), in which liver dysfunction often persisted. Conclusions: ACTH-independent CS is rare but can lead to significant burden in children. Early diagnosis and management are essential. New drugs targeting adrenal steroid synthesis are awaited.研究目的：促肾上腺皮质激素非依赖性库欣综合征（ACTH-independent Cushing’s syndrome, CS）是儿童库欣综合征的罕见病因。本研究旨在描述儿童ACTH非依赖性库欣综合征的临床特征，并按病因分组进行对比分析。 研究方法：本研究在巴黎三家儿科医院开展回顾性观察研究，纳入1992年至2022年间确诊为ACTH非依赖性库欣综合征、诊断时年龄为0~18岁的患者。此外，本研究还对比了合并库欣综合征与未合并库欣综合征的McCune-Albright综合征（MCAS）患者的临床转归。 研究结果：本研究共纳入15例库欣综合征患者，其中7例为McCune-Albright综合征（MCAS）患者，7例为合并于Carney复合征（CNC）的原发性色素结节性肾上腺皮质病（PPNAD）患者，剩余1例库欣综合征患者未明确病因。MCAS组患者确诊库欣综合征时的中位年龄为0.3岁（四分位间距：0.17~1岁），PPNAD组为9岁（四分位间距：5~15岁）。MCAS组患者的生长迟缓程度更显著（MCAS组生长标准差评分为-4.75，CNC组为-1，P=0.006），且确诊时宫内生长迟缓发生率（P=0.01）与肝功能异常发生率（P=0.04）均更高。7例MCAS患者均存在学习障碍，而CNC组仅2例出现该情况。15例患者中12例接受了双侧肾上腺切除术。MCAS组无一例患者接受生长激素治疗，而CNC组有4例患者接受了生长激素治疗。随访结束时，两组患者的生长状况均有所恢复，但MCAS组的恢复程度更差（MCAS组生长标准差评分为-1.5，CNC组为-0.5），且MCAS组的肝功能异常通常持续存在。 研究结论：ACTH非依赖性库欣综合征虽为罕见病，但可对儿童造成显著健康负担。早期诊断与临床管理至关重要，亟待开发靶向肾上腺类固醇合成的新型治疗药物。