肝细胞核因子1β基因突变S148L导致中国青少年的成年起病型糖尿病5型表型分析并文献复习

Phenotype of a Chinese patient with maturity-onset diabetes of the young type 5 caused by S148L mutation in hepatocyte nuclear factor 1β and literature review

目的分析一例中国青少年的成人起病型糖尿病5型(MODY5)的基因型和表型特征并做文献复习。方法先证者为23岁男性,10岁起病,随机血糖38 mmol/L,糖化血红蛋白17.6%;胰岛β细胞功能评估示胰岛素分泌不足;胰岛细胞抗体阴性;伴先天性肾发育不良、肾囊肿和肾功能不全,否认糖尿病家族史,诊断为"1型糖尿病(T1DM)",予胰岛素治疗。随访中发现无精症、肾盂积水、精囊腺囊肿。对该患者及其父亲进行外周血MODY基因测序。同时检索MEDLINE文献数据库,对同一突变致MODY5病例表型进行汇总分析。结果先证者HNF-1β基因第2外显子区域发生错义突变c.443C>T(p.S148L)。文献复习已知该位点存在2种突变类型S148L和S148W,其中S148L突变发生频率最高,已报道患者7例,均有肾脏结构病变(肾发育不良、肾囊肿等)和早发糖尿病,部分患者存在低出生体重或胰腺畸形,其中6位患者缺乏家族史。结论原发肾脏病变,发病年龄<25岁和T1DM相关自身抗体阴性可能是重要MODY5的诊断线索。对于伴肾脏、胰腺及生殖系统异常并且T1DM抗体阴性的青少年糖尿病患者,无论有无家族史都需要警惕MODY5。

Objective To characterize the clinical and molecular features of a patient with maturity onset diabetes of the young (MODY)5 caused by S148L mutation in hepatocyte nuclear factor 1β(HNF-1β). Methods The proband was a 23-year-old male with diabetes onset at ten. At that time, a random blood glucose level of 38 mmol/L and hemoglobin A1c level of 17.6% were detected. Renal insufficiency and renal dysplasia were present at the same time. There′s no family history of diabetes or renal disease in the pedigree. Although the islet cell antibody was negative, he was diagnosed as type 1 diabetes mellitus (T1DM) on account of low C-peptide level. During the follow up, azoospermia, cysts of seminal vesicle and bilateral acute hydronephrosis occurred. MODY-related genes of the proband and his father as well were sequenced using next-generation sequencing. Literature review was conducted for previously reported cases with the same mutation in HNF-1β. Results A mutation in the HNF-1β gene S148L (c.443>T) in exon 2 was identified in the proband, but not in his father. Literature review revealed that there were two mutations S148L and S148W reported in eight cases. Seven of the eight probands had S148L mutation. Renal involvement and early-onset diabetes are typical characteristics of most subjects affected by S148L mutation. Some of them had low birthweight or pancreatic malformation and six cases were the first patients in the family. Conclusions Congenital renal abnormality, early-onset of diabetes before age of 25 years and with negative T1DM antibodies probably are important clues for diagnosis of MODY5. Therefore, T1DM antibodies negative juvenile diabetes patients accompanied by abnormalities in kidney, pancreas and genital organs should be suspected for MODY5, even those without family history.