OBJECTIVE Molecular defects of hepatocyte nuclear factor 1B (HNF1B) are associated with a multiorgan disease, including diabetes (maturity-onset diabetes of the young 5) and kidney abnormalities. The HNF1B-syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B. Here, we described HNF1B-related diabetes and associated phenotypes and assessed genotype/phenotype correlations at diagnosis and in the long-term.

RESEARCH DESIGN AND METHODS This multicenter retrospective cohort study included 201 patients, aged 18 or older at follow-up, with HNF1B mutations (n = 101) or deletion (n = 100).

RESULTS Diabetes was present in 159 patients. At diagnosis, clinical symptoms of diabetes were present in 67 of 144 patients, and HNF1B-renal disease in 64 of 102. Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up. Diabetic retinopathy and/or neuropathy were present in 46 of 114 patients. Renal cysts were present in 122 of 166 patients, chronic kidney disease (CKD) stages 3–4 in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%). Compared with the patients with mutations, those with HNF1B deletion had less often CKD3–4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10⁻⁴) and in the long-term (40 of 78 vs. 71 of 91, P = 0.0003). They were leaner and more frequently treated with insulin.

CONCLUSIONS In patients with HNF1B-syndrome, diabetes complications, cardiovascular risk factors, CKD3–4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.

目的肝细胞核因子1B（HNF1B）的分子缺陷与多器官疾病有关，包括糖尿病（5岁以下的成熟期糖尿病）和肾脏异常。HNF1B综合征与HNF1B突变或跨越15个基因（包括HNF1B）的17q12缺失有关。在这里，我们描述了HNF1B相关的糖尿病和相关的表型，并评估了诊断和长期的基因型/表型相关性。

研究设计和方法这项多中心回顾性队列研究包括201例年龄在18岁或以上的随访患者，这些患者具有HNF1B突变（n = 101）或缺失（n = 100）。

结果159例患者中存在糖尿病。诊断时，144名患者中有67名出现了糖尿病的临床症状，102名患者中有64名出现了HNF1B肾病。尽管在51名测试者中有29名发现对磺酰脲类/瑞格列奈有反应，但140名患者中有111名（79％）得到治疗在随访中使用胰岛素。114名患者中有46名存在糖尿病性视网膜病变和/或神经病变。166例患者中有122例存在肾囊肿，169例中的75例中有3–4期慢性肾脏病（CKD）（44％），169例36例中有晚期肾病（ESRD）。与突变患者相比，具有HNF1B缺失的患者在诊断时（CK 3-4中的11比35中的27，P <10 ^-4）和长期（78中的40 vs. 71）中CKD3-4 / ESRD的发生率更低的91P = 0.0003）。他们更苗条，更经常用胰岛素治疗。

结论在患有HNF1B综合征的患者中，糖尿病并发症，心血管危险因素，CKD3-4和ESRD普遍存在。在糖尿病诊断中，形态和/或功能性肾脏疾病的存在可能有助于病因诊断。基因型/表型的相关性可能对这些患者的护理和预后有影响。