Supplementary Material for: Pediatric Macrocorticotropinoma: Do They Differ from Microcorticotropinoma?

Introduction: Cushing’s disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). Methods: This retrospective study was conducted in a single tertiary care center. 32 patients of CD with MC (maximum tumor dimension ≥ 10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. Results: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0-17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70±2.60 vs 2.59±2.01, p=0.04), more frequent neuro-ophthalmic symptoms (25% vs 9% p=0.04) and short stature (59% vs 34%, p=0.049) but less frequent livid striae (53% vs 77%, p 0.01), and hypokalemia (12% vs 36%, p=0.04) and lower cortisol (nmol/l) to corticotropin (pmol/l) ratio (41.20 vs. 55.74, p=0.05) than those with mc. The remission (59% vs 64% p=1.0) and relapse (53% vs 37% p=0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts whereas time to remission after RT (27 vs 13 months, p=0.05) was longer in the MC group. A patient with MC had a pathogenic germ line variant in CDH23. Conclusion: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort.

引言：儿童及青少年大尺寸促肾上腺皮质激素腺瘤（macrocorticotropinoma, MC）相关库欣病（Cushing’s disease, CD）是一种罕见病症，目前针对其特征的相关研究资料较为有限。本研究旨在阐述儿童青少年MC相关CD患者的临床、生化、影像学、诊疗、预后及遗传学特征，并与微尺寸促肾上腺皮质激素腺瘤（microcorticotropinoma, mc）患者进行对比。
方法：本研究为单中心回顾性研究，在一家三级医疗中心开展。共纳入就诊时年龄≤20岁的32例MC相关CD患者（影像学检查显示肿瘤最大径≥10mm）及65例mc相关CD患者（影像学检查显示肿瘤最大径<10mm）。
结果：MC组共19例女性、13例男性，就诊中位年龄为14.5岁（四分位距12.0~17.9岁）。与mc组相比，MC组患者的体质量指数标准差评分（body mass index-standard deviation score, BMI-SDS）更高（3.70±2.60 vs 2.59±2.01，p=0.04），神经眼科症状（25% vs 9%，p=0.04）及身材矮小（59% vs 34%，p=0.049）的发生率更高，但紫纹（53% vs 77%，p=0.01）、低钾血症（12% vs 36%，p=0.04）的发生率更低，且皮质醇（nmol/L）与促肾上腺皮质激素（pmol/L）比值更低（41.20 vs 55.74，p=0.05）。两组患者的一线手术术后缓解率（59% vs 64%，p=1.0）、复发率（53% vs 37%，p=0.26）及放疗（radiotherapy, RT）后缓解率均无显著差异，但MC组放疗后达到缓解的时间更长（27个月 vs 13个月，p=0.05）。1例MC患者存在CDH23基因的致病性生殖系变异。
结论：在本项大型单中心儿童CD研究队列中，MC组患者的特征为常出现占位效应相关症状及身材矮小、BMI-SDS更高、紫纹与低钾血症发生率更低，且有效皮质醇分泌水平更低。两组患者的手术及放疗预后总体相似，仅MC组放疗后达到缓解的时间更长。