Bakker Boudewijn, Sonneveld Laura J H, Woltering M Claire, Bikker Hennie, Kant Sarina G
Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
J Clin Endocrinol Metab. 2015 Nov;100(11):3963-6. doi: 10.1210/jc.2015-2260. Epub 2015 Sep 14.
Several patients with Beckwith-Wiedemann Syndrome (BWS) with multiple imprinting defects found by genetic analysis have been described. However, only two cases have been described with both genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects.
The girl in this case presented at the age of 6 months with morbid obesity (body mass index, +7.5 SDS) and a large umbilical hernia. Genetic analysis showed BWS (hypomethylation of the KCNQ1OT1 gene). Calcium homeostasis was normal, and she had no signs of Albright hereditary osteodystrophy. At the age of 10 years, she presented with fatigue, and laboratory analyses showed marked hypocalcemia with signs of PTH resistance, but without evidence for Albright hereditary osteodystrophy, thus suggesting pseudohypoparathyroidism type 1B. Consistent with this diagnosis, methylation analysis of the GNAS complex revealed hypomethylation (about 20%) of the GNAS exon 1A, NESPAS, and GNASXL loci and hypermethylation (100% methylation) of the NESP locus.
Imprinting defects at several different loci can occur in some patients, thus causing multiple different diseases. Symptoms of pseudohypoparathyroidism type 1B may be absent at diagnosis of BWS, yet prolonged subclinical hypocalcemia and/or hyperphosphatemia can have negative consequences (eg, intracerebral calcifications, myocardial dysfunction). We therefore suggest that patients with an imprinting disorder should be monitored for elevations in PTH, and epigenetic analysis of the GNAS complex locus should be considered.
已有文献报道了数例经基因分析发现存在多种印记缺陷的贝克威思-维德曼综合征（BWS）患者。然而，仅有两例同时具有由印记缺陷导致的多种疾病的基因和临床体征及症状。
该病例中的女孩6个月大时出现病态肥胖（体重指数，+7.5标准差评分）和巨大脐疝。基因分析显示为BWS（KCNQ1OT1基因低甲基化）。钙稳态正常，且无奥尔布赖特遗传性骨营养不良的体征。10岁时，她出现疲劳，实验室分析显示明显低钙血症并有甲状旁腺激素抵抗的迹象，但无奥尔布赖特遗传性骨营养不良的证据，因此提示为1B型假性甲状旁腺功能减退症。与该诊断一致，GNAS复合体的甲基化分析显示GNAS外显子1A、NESPAS和GNASXL位点低甲基化（约20%），而NESP位点高甲基化（100%甲基化）。
一些患者可能在几个不同位点出现印记缺陷，从而导致多种不同疾病。在诊断BWS时可能不存在1B型假性甲状旁腺功能减退症的症状，但长期的亚临床低钙血症和/或高磷血症可能会产生负面后果（如脑内钙化、心肌功能障碍）。因此，我们建议对印记障碍患者监测甲状旁腺激素水平升高情况，并考虑对GNAS复合体位点进行表观遗传学分析。
