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：儿童及青少年罹患由大尺寸促肾上腺皮质激素腺瘤（macrocorticotropinoma, MC）引发的库欣病（Cushing’s disease, CD）是一种罕见病症，目前关于其临床特征的相关研究资料较为匮乏。本研究旨在阐明此类由MC引发CD的儿童及青少年患者的临床、生化、影像学、诊疗、预后及遗传学特征，并将其与微尺寸促肾上腺皮质激素腺瘤（microcorticotropinoma, mc）引发的CD患者进行对比分析。
方法：本研究为单中心三级医疗中心开展的回顾性研究。共纳入32例以大尺寸MC（影像学检查示肿瘤最大径≥10 mm）为病因的CD患者，以及65例由微尺寸mc（影像学检查示肿瘤最大径<10 mm）引发CD的患者，所有患者就诊时年龄均≤20岁。
结果：MC组共19例女性患者、13例男性患者，中位（四分位间距，IQR）发病年龄为14.5（12.0~17.9）岁。与mc组患者相比，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），神经眼科症状发生率（25% vs 9%，p=0.04）及身材矮小发生率（59% vs 34%，p=0.049）更高，但紫纹（livid striae）发生率（53% vs 77%，p=0.01）、低钾血症发生率（12% vs 36%，p=0.04）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）以及放疗（radiotherapy, RT）后的缓解率均无显著差异，但MC组患者放疗后达到缓解的时间更长（27 vs 13个月，p=0.05）。另有1例MC组患者检出CDH23基因致病性种系变异。
结论：在本项大型单中心儿科CD队列研究中，MC组患者的临床特征主要表现为常出现占位效应相关症状及身材矮小、体质量指数标准差评分更高、紫纹与低钾血症发生率更低，且皮质醇有效分泌水平更低。除放疗后缓解时间更长外，两组患者的手术及放疗预后均无显著差异。