Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Am J Med Genet A. 2013 May;161A(5):993-1001. doi: 10.1002/ajmg.a.35831. Epub 2013 Mar 26.
We report on a patient with early onset pediatric bilateral pheochromocytomas caused by mosaic chromosome 11p15 paternal uniparental isodisomy (UPD). Hemihyperplasia of the arm was diagnosed in a 4-month-old female and clinical methylation testing for 11p15 in the blood was normal, with a reported detection threshold for mosaicism of 20%. She was subsequently diagnosed at 18 months with bilateral pheochromocytomas. Single-nucleotide polymorphism (SNP) array analysis of pheochromocytoma tissue demonstrated mosaic deletions of 8p12pter, 21q21.1qter, 22q11.23qter; commonly seen in pheochromocytomas. In addition, mosaic 11p15.3pter homozygosity was noted. Molecular testing for other causes of pheochromocytomas was normal, suggesting that 11p15 homozygosity was the primary event. Subsequent SNP array analysis of skin fibroblasts from the hyperplastic side demonstrated 5% mosaic paternal UPD for 11p15. We have subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that was not detected by methylation analysis. Given the increased sensitivity of SNP array analysis to detect UPD along with the increased incidence of tumorigenesis in these UPD patients, we suggest that it has high utility in the clinical work-up of hemihyperplasia. The present case also suggests that 11p15 paternal UPD may be an under-detected mechanism of sporadic pheochromocytoma in the pediatric population. Furthermore, a review of the literature suggests that patients with 11p15 paternal UPD may present after 8 years of age with pheochromocytoma and raises the possibility that ultrasound screening could be considered beyond 8 years of age in this subset of hemihyperplasia and Beckwith-Wiedemann syndrome patients.
我们报告了一例由染色体 11p15 父源单亲二体性（UPD）嵌合体引起的早发性小儿双侧嗜铬细胞瘤病例。一名 4 月龄女性被诊断为臂部单侧性肥大，血液中 11p15 的临床甲基化检测正常，报道的嵌合体检测阈值为 20%。她随后在 18 个月时被诊断为双侧嗜铬细胞瘤。嗜铬细胞瘤组织的单核苷酸多态性（SNP）阵列分析显示，8p12pter、21q21.1qter、22q11.23qter 存在嵌合性缺失；这些缺失常见于嗜铬细胞瘤。此外，还观察到 11p15.3pter 纯合性缺失。其他嗜铬细胞瘤病因的分子检测正常，提示 11p15 纯合性缺失是主要事件。随后对肥大侧皮肤成纤维细胞进行 SNP 阵列分析，发现 11p15 存在 5%的父源 UPD 嵌合体。我们随后使用 SNP 阵列分析发现，有 4 例存在低水平嵌合性 UPD 的轻微单侧性肥大患者，甲基化分析未能检测到这种情况。鉴于 SNP 阵列分析在检测 UPD 方面的高灵敏度，以及这些 UPD 患者的肿瘤发生率增加，我们认为 SNP 阵列分析在单侧性肥大的临床检查中有很高的应用价值。本病例还表明，11p15 父源 UPD 可能是小儿散发性嗜铬细胞瘤中一种未被充分检测到的机制。此外，文献复习表明，11p15 父源 UPD 患者可能在 8 岁后出现嗜铬细胞瘤，并提出在这部分单侧性肥大和 Beckwith-Wiedemann 综合征患者中，超声筛查可以考虑在 8 岁以后进行。
