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.

目的：ACTH非依赖性库欣综合征（Cushing’s syndrome, CS）是儿童CS的罕见病因。本研究旨在描述儿童ACTH非依赖性CS的临床特征，并按病因分组进行比较。

方法：我们对1992年至2022年间巴黎三家儿科医院确诊的0-18岁ACTH非依赖性CS患者开展回顾性观察研究。此外，比较了合并CS与未合并CS的McCune-Albright综合征（McCune-Albright syndrome, MCAS）患者的预后。

结果：15例CS患者中，7例为MCAS，7例为Carney复合征（Carney complex, CNC）相关的原发性色素结节性肾上腺皮质病（primary pigmented nodular adrenocortical disease, PPNAD），1例病因不明。MCAS组确诊年龄为0.3岁（范围0.17-1岁），PPNAD组为9岁（范围5-15岁）。MCAS组生长迟缓更显著（MCAS组-4.75 SDS vs CNC组-1 SDS，p=0.006），确诊时宫内生长迟缓（intrauterine growth retardation）（P=0.01）和肝功能异常（P=0.04）的患病率更高。7例MCAS患者均存在学习障碍，CNC组仅2例。15例患者中12例行双侧肾上腺切除术（bilateral adrenalectomy）。MCAS组无人接受生长激素治疗（growth hormone therapy），CNC组4例接受该治疗。随访终点时两组生长均有恢复，但MCAS组恢复程度较低（MCAS组-1.5 SDS vs CNC组-0.5 SDS），且肝功能异常常持续存在。

结论：ACTH非依赖性CS虽罕见，但对儿童造成的负担显著。早期诊断与管理至关重要，靶向肾上腺类固醇合成的新药研发值得期待。