两例严重胰岛素抵抗综合征的临床及遗传学研究

Clinical and genetic research on two patients with severe insulin resistance syndrome

目的研究我院收治的两例严重IR综合征的临床及遗传学特征。方法两例均进行弥散加权显像（DWI）脂肪定量、高分子量脂联素测定及胰岛素受体基因测序。结果两例严重IR的患者共同临床特征为高胰岛素血症、黑棘皮征、糖代谢异常及BMI正常。例1有脂肪性肝病和TG升高,全身脂肪含量为6.7%,高分子量脂联素水平为0.2（2.0-20.0）mg/L,胰岛素受体基因正常;例2齿列不齐和生长发育障碍,全身脂肪含量为34.8%,高分子量脂联素水平为17.9mg/L,胰岛素受体基因检测发现c.275G〉A及c.2495delT的复合杂合突变,均为新发突变。结论两例均为罕见的遗传性严重IR综合征,例1符合先天性全身性脂肪萎缩的诊断,目前尚未发现有意义的突变基因;例2符合RabsonMendenhall综合征的诊断,由胰岛素受体基因编码区的复合杂合突变所致。

Objective To explore the clinical,biochemical,genetic and imaging features of two cases with genetic severe insulin resistance（IR）from PUMCH.Case 1,male,21 years old,was admitted because of skin hyperpigmentation and liver dysfunction for 11 years.Case 2,female,9years old,was admitted because of dark skin and linear growth retardation for 8years.They both had clinical features of normal BMI,extreme hyperinsulinemia,acanthosis nigricans,impaired glucose tolerance or elevated HbA1 c. Hyperglyceridemia,fatty liver and hepatic dysfunction were identified in case 1. The characteristic features of case 2were abnormal dentition,protuberant abdomen,pineal gland hypertrophy and linear growth retardation. Methods Adipose tissue quantification was determined by diffusion weighted imaging（DWI）.High molecular weight（HMW）adiponectin was determined by ELISA.Insulin receptor（INSR）gene including all the exons,was amplified by PCR. Results The body fat percentage of case 1and case 2was 6.7% and 34.8%.The HMW-adiponectin level of case 1was 0.2（2.0-20.0）mg/L,while 17.9mg/L in case 2.Two mutant alleles of the insulin receptor gene were identified in case 2who was a compound heterozygote for a missense mutation of exon 2[c.275G 〉A（p.R92Q）]and a deletion mutation in exon 12[c.2495delT（p.Pro818Profs）].These two previously undescribed mutations were inherited separately from her parents who both had normal glucose tolerance.The results of INSR gene in case 1 were normal. Conclusion The characteristics of case 1are in accordance with the diagnosis of congenital generalized lipodystrophy,however,the pathogenic gene has not been identified.Case 2is diagnosed as Rabson-Mendenhall syndrome caused by compound heterozygous mutation of INSR gene.