台灣羅素-西弗氏症及擬羅素-西弗氏症個案之分子診斷與臨床分析

Abstract

目的: 羅素-西弗氏症是一罕見的先天疾病，其臨床表現極為多樣亦具有多種分子變異曾在文獻中被提及。羅素-西弗氏症的臨床表現特色為子宮內生長遲滯、身材矮小及典型的臉部特徵等。目前關於羅素-西弗氏症診斷標準尚無定論，第七對染色體母源單親二體症(maternal uniparental disomy of chromosome 7)及第十一對染色體短臂印記中心甲基化低下(hypomethylation of the imprinting in 11p15)是目前羅素-西弗氏症最常被提及的分子變異類型。但台灣目前尚無關於羅素-西弗氏症個案之分子診斷與臨床分析的相關研究。 方法: 我們收集由臨床醫師診斷為羅素-西弗氏症個案轉介至本研究中心之個案，針對第七對染色體母源單親二體症(maternal uniparental disomy of chromosome 7)及第十一對染色體短臂印記中心甲基化異常進行分析，並回溯收集其臨床表現以進行分子診斷與表現型相關分析。此研究中，我們設計一個羅素-西弗氏症臨床表現評分表來量化個案之表現型。 結果: 在我們研究發現第七對染色體母源單親二體症及第十一對染色體短臂印記中心甲基化低下分別在羅素-西弗氏症個案占了3.6%和 26.8%的比例。這些具有突變之個案其臨床表現以羅素-西弗氏症臨床表現評分表評估均大於或等於六分, 而此評分方式顯示: 相較於第十一對染色體短臂印記中心甲基化低下, 第七對染色體母源單親二體症的病患症狀均較輕微。在羅素-西弗氏症與疑似羅素-西弗氏症兩組個案中，子宮內生長遲緩、出生後生長遲緩、典型臉部特徵、頭部/軀幹或肢體不對稱性與第五手指彎斜的比率，均有明顯差異。 結論: 在本研究中，針對具有羅素-西弗氏症表現型的個案，分析其分子診斷結果，有分子診斷異常佔30.4 % ，其中第七對染色體母源單親二體症及第十一對染色體短臂印記中心甲基化低下分別在羅素-西弗氏症個案占了3.6%和 26.8%的比例。運用我们提出的羅素-西弗氏症臨床表現評分表，我們可以針對疑似羅素-西弗氏症之個案臨床表現進行評分予以量化。在本研究中，羅素-西弗氏症臨床表現評分大於或等於六分是評估可否找到羅素-西弗氏症分子診斷異常的分岐點。

Objective: Silver-Russell syndrome (SRS) is a clinical and genetically heterogenous disorder characterized by severe intrauterine growth restriction, postnatal growth retardation, and specific dysmorphisms. But no consensus on clinical diagnostic criteria was made. Maternal uniparental disomy of chromosome 7 and hypomethylation of the imprinting in 11p15 are the major epigenetic disturbance in patients of Silver-Russell syndrome. The incidence of epigenetic disturbance in Taiwanese patients of Silver-Russell syndrome and the epigenetic-phenotype analysis have never been surveyed. Materials and methods: We report on our experience of molecular testing in 107 Taiwanese patients referred for routine diagnostics of Silver-Russell syndrome. We also retrospectively investigated the clinical manifestations of those probands with suspected Silver-Russell syndrome phenotypes. We designed a clinical SRS scoring system to help the pediatrians in clinical setting . Results: The molecular results in our study cohort showed that maternal uniparental disomy of chromosome 7 and hypomethylation of the H19 imprinted region in 11p15 accounts for the epigenetic disturbance in 3.6% and 26.8% of patients with clinically scored as SRS group (n=56). respectively. All cases with epimutation were scored >= 6 by the clinical SRS scoring system. Maternal uniparental disomy of chromosome 7 carriers showed relatively mild Silver-Russell syndrome phenotype as compared with 11p15 epimutation carrier. The percentage of small for gestational age, postnatal growth retardation, typical facies, aymmetry and clinodactyly of 5th fingers was significantly different between SRS group and SRS-like group. Conclusions:The detection rate of epigenetic anomalies in our study cohort of 56 Taiwanese individuals with SRS phenotypes was around 30.4 %; epimutations at the PEG1/MEST locus and the H19/IGF2 locus occurred in about 3.6% and 26.8% of patients with SRS respectively. By our new clinical SRS scoring system, we can quantify the phenotype severity, and it showed that “clinical SRS score 6” was a good discrimination point to distinguish the cases with or without epimutation for SRS inour study.