Hepatocyte nuclear factor 4α gene mutation associated with familial neonatal hyperinsulinism and maturity-onset diabetes of the young

Neonatal macrosomia and hyperinsulinemic hypoglycemia with strong family history of diabetes may indicate monogenic diabetes. Here we report a family in which 4 individuals in 3 generations were found to have a mutation (Arg80Gln) in hepatocyte nuclear factor 4α. Genetic testing was a factor in choosing sulfonylurea therapy for diabetes.     

Triple diabetes: coexistence of type 1 diabetes mellitus and a novel mutation in the gene responsible for MODY3 in an overweight adolescent

Abstract:  We report an interesting and unique case of an overweight adolescent with a novel mutation of the maturity-onset diabetes of the young (MODY)3 gene [hepatocyte nuclear factor-1 alpha (HNF-1α)] and positive islet cell autoantibodies. The patient is a 17-yr-old Caucasian female, who was diagnosed with type 2 diabetes mellitus, treated with metformin and glipizide, with poor control for 18 months prior to being referred to the Endocrinology clinic. Family history was strongly positive for type 2 diabetes (father, paternal aunts, uncles, and grandmother). All were diagnosed at age 40–50 and treated with oral hypoglycemic agents. The patient's body mass index was 36.4 kg/m². She had no acanthosis nigricans. Initial hemoglobin A1c was 11.9%, with fasting glucose of 234 mg/dL and fasting insulin 10.7 μU/mL. She was started on insulin therapy (0.6 units/kg/d), resulting in good glycemic control. Oral hypoglycemic agents were discontinued. Immunologic studies showed positive islet cell (29 U/mL, normal <1.0) and glutamic acid decarboxylase-65 (0.9 U/mL, normal <0.5) antibodies. Sequencing for HNF-1α gene revealed a nucleotide A to G substitution (ACC to GCC), resulting in a missense mutation, T196A. To our knowledge, T196A has not been previously reported. The coexistence of type 1 diabetes autoimmunity and a mutation in the gene responsible for MODY3 in this overweight patient is intriguing and might explain the early onset of progressive insulinopenia compared with the later age of diabetes onset of the earlier generation in the family.     

B淋巴细胞激酶基因突变致青少年发病的成人糖尿病11型一家系

对2018年8月南京医科大学附属儿童医院诊治的1例B淋巴细胞激酶( BLK)基因突变致青少年发病的成人糖尿病11型( MODY11)患儿的临床资料进行回顾性分析,对其家系进行糖尿病调查。先证者,男,13岁,因"发现高血糖0.5年"入院,病初当地医院诊断为1型糖尿病。查体：身高169.2 cm,体质量65.5 ...     

Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1

Background:  The aim of the study was to search for mutations in the NEUROD1 and IPF-1 genes in patients with clinical characteristics of maturity-onset diabetes of the young (MODY) but with no mutations in the HNF-4A (MODY1), GCK (MODY2) and TCF1 (MODY3) genes.
Methods:  We studied 30 unrelated Czech probands with a clinical diagnosis of MODY (median age at testing, 18 yr; median age at the recognition of hyperglycaemia, 16 yr). The promoter, exons and exon/intron boundaries of the NEUROD1 and IPF-1 genes were examined by polymerase chain reaction–denaturing high performance liquid chromatography and direct sequencing.
Results:  While no mutations were found in the IPF-1 gene, a novel H241Q substitution of NEUROD1 gene was identified in two unrelated families. In the first proband, the H241Q mutation led to early diagnosed (20 yr) hyperglycaemia followed by development of diabetic microvascular complications by the age of 32 yr. The second proband suffered from slowly progressing hyperglycaemia detected at the age of 30 yr. Affected members of both families were obese. The overall prevalence of the variant among the general population was 4 of 13 568 chromosomes.
Conclusions:  We report a novel disease-associated variant in NEUROD1 identified among a set of MODYX families. The variant seems to precipitate type-2-like diabetes in excessively obese individuals.     

胰岛素样生长因子-1(IGF-1)对缺氧缺血脑损伤新生鼠内源性IGF-1和IGF-1受体基因表达的影响

目的　胰岛素样生长因子 1(IGF 1)对损伤的神经组织有修复作用 ,但外源性IGF 1是否会抑制内源性IGF 1、IGF 1受体的生成 ,从而减弱IGF 1的神经保护作用尚不明确。本文通过观察IGF 1治疗新生大鼠缺血缺氧脑损伤 (HIBD)后脑IGF 1和IGF 1受体mRNA水平的变化 ,研究IGF 1对HIBD新生大鼠内源性IGF 1、IGF 1受体的影响。方法　制作新生大鼠HIBD模型 ,用原位杂交方法观察HIBD后各时间点海马和大脑皮层IGF 1和IGF 1受体基因表达的动态变化 ,并比较IGF 1治疗组与未治疗组HIBD后 12h、72hIGF 1、IGF 1受体mRNA的表达水平。结果　HIBD后 4 8h海马IGF 1和IGF 1受体mRNA开始升高 ,72h达高峰。损伤后 12 0h ,IGF 1mRNA降至正常水平 ,而IGF 1受体mRNA仍处于较高水平。在皮层 ,IGF 1和IGF 1受体mRNA开始升高时间稍早于海马 ,2 4h上升 ,96h降至正常 ,但是上升幅度相对较小。与未治疗组比较 ,IGF 1治疗后内源性IGF 1表达无明显变化。IGF 1受体的表达在治疗后 12h无明显差别 ,但在 72h时显著增加。结论　HIBD后皮层、海马等脑损伤区的IGF 1和IGF 1受体表达均升高。给予外源性IGF 1后并不降低内源性IGF 1的表达 ,还能刺激IGF 1受体表达增加。     

地塞米松对新生鼠高氧肺损伤肺组织甲状腺转录因子-1和表面活性蛋白C表达的影响

目的探讨甲状腺转录因子-1（TTF-1）和表面活性蛋白C（SPC）在地塞米松干预新生鼠高氧肺损伤中的作用。方法将3日龄新生SD大鼠随机分为高氧组（95％氧7d）、高氧＋地塞米松组（地塞米松组）和空气组。HE染色观察肺组织形态结构变化，并做辐射状肺泡计数（RAC）。采用免疫组化法检测肺组织TTF-1和SPC表达。结果（1）高氧组可见肺泡壁较薄、结构简单化、肺泡大小不均，有些肺泡融合、体积增大；地塞米松组除具有上述高氧组特征外，肺组织结构明显紊乱，部分肺泡壁及间隔破坏；高氧组和地塞米松组RAC值分别为（9．50±1．05）、（10．03±3．26），较空气组（13．00±1．79）减少，差异均有显著性（P〈0．05）。（2）空气组TTF-1阳性显色细胞分布在肺间隔和肺泡壁II型肺泡上皮细胞（AECII），无扩张肺组织处也有阳性细胞，各级支气管及小血管部位未见阳性显色。高氧组较空气组表达减少，散在分布于肺泡壁、肺间隔增厚部位及脱落于肺泡腔的AECII；地塞米松组较空气组明显增强，变薄及扩张的肺泡壁也有阳性显色。空气组、高氧组、地塞米松组TTF-1表达积分分别为（1．32±0．55）、（0．96±0．67）、（1．76±0．69），高氧组较地塞米松组和空气组明显减少，差异有显著性（P均〈0．05）；而地塞米松组较空气组明显增高，差异有显著性（P〈0．05）。（3）SPC阳性显色主要在肺间隔和肺泡壁AECII，支气管黏膜上皮细胞也可见弱阳性表达，但存在个体差异，有些标本整个切片未见表达。高氧组、地塞米松组和空气组SPC表达积分差异无显著性，分别为（1．58±0．49）、（1．52±0．50）、（1．66±0．48）．P〉O．05。结论（1）SPC不仅在AECII表达，也表达在支气管黏膜上皮细胞；在高氧肺损伤及地塞米松干预肺组织SPC表达变化不大，有可能是AECII增殖、分化不足的反映。（2）高氧肺损伤组织TTF-1表达减少，地塞米松可使TTF-1表达增强，加重肺部病理改变。[第一段]     

46, XY 性发育障碍儿童 NR5A1 基因突变 1 例报告及文献复习

目的探讨NR5A1基因突变导致的46,XY性发育障碍(DSD)的临床表现和分子诊断。方法回顾分析1例社会性别为女性的46,XY DSD患儿的临床资料,并复习相关文献。结果社会性别为女性的11.5岁患儿,因偶然发现阴蒂肥大半个月就诊;初步系列实验室检查诊断考虑支持46,XY DSD,高促性腺激素性发育不良。全基因组外显子组DNA测序提示NR5A1基因,c.937 CT,p.Arg313Cys杂合突变;母亲为杂合突变携带者,父亲无异常。结论临床表现为46,XY DSD,性腺发育不良、外生殖器女性化合并肾上腺功能不足;提示存在SF1基因突变的可能性,全基因组外显子基因测序可帮助明确诊断。     

Insulin-like growth factor-1 receptor expression in the placentae of diabetic and normal pregnancies

BACKGROUND: Septal hypertrophic cardiomyopathy (sHCM) is a characteristic anomaly of the infant of diabetic mother (IDM). Insulin-like growth factor-1 (IGF-1) has been identified as a mediator of tissue overgrowth and we have previously shown that maternal IGF-1 levels were significantly elevated among neonates with asymmetrical sHCM. IGF-1 does not cross the placenta; it exerts physiologic action through binding to the IGF-1 receptor (IGF-1R). Localisation and expression of IGF-1R in term diabetic pregnancies are largely unclear. We have studied IGF-1R in the placentae of diabetic and normal pregnancies and this receptor expression in association with neonates with sHCM. METHODS: IGF-1R localization and expression in the placentae of six diabetic pregnancies associated with neonatal sHCM were compared with six each of randomly selected diabetic and normal pregnancies without neonatal sHCM by immunohistochemistry. The staining for IGF-1R in the deciduas, cytotrophoblasts, syncytiotrophoblasts and villous endothelium for these 18 samples were assessed and scored by two pathologists who were blinded to the respective diagnoses. RESULTS: Placental IGF-1R staining was negative in the villous endothelium for all three groups. IGF-1R staining was present in deciduas, cytotrophoblasts and syncytiotrophoblasts but the staining was weaker in the entire group of infants with sHCM compared to those without sHCM. CONCLUSIONS: IGF-1R is localized in all cell types of the placenta except in villous endothelium. Weaker placental IGF-1R staining in the placentae of diabetic pregnancies associated with sHCM suggests reduced expression of IGF-1R. This may be a down-regulatory response to elevated maternal IGF with neonatal sHCM outcome.     

An 8-year-old boy with autoimmune hepatitis and Candida onychosis as the first symptoms of autoimmune polyglandular syndrome (APS1): identification of a new homozygous mutation in the autoimmune regulator gene (aire)

An 8-year-old boy presented in 1995 with a 2-year history of hypertransaminasemia and hypergammaglobulinemia. Afterwards the patient displayed onychosis with a positive culture test for Candida albicans (CA). Because of the persistence of hypertransaminasemia, a percutaneous liver biopsy was performed showing ‘low grade chronic active autoimmune hepatitis’ (AIH), positive for liver-kidney microsomal autoantibodies and antibodies to the hepatic autoantigen cytochrome P450-1A2. Immunosuppressive treatment was initiated. In 2003 he developed Addison’s disease resulting in the diagnosis of autoimmune polyendocrinopathy candidiasis-ectodermal dysplasia (APECED) syndrome, also known as autoimmune polyendocrine syndrome type 1 (APS1). Anti-17OH hydroxylase antibodies tested negative, anti-21-OH hydroxylase autoantibodies were positive. Among the other relevant organ- and non organ- specific autoantibodies, aromatic L-amino acid decarboxylase (ADDC) autoantibodies and anti-tryptophan hydroxylase autoantibodies were positive. The patient also presented polyuria and polydypsia with diabetes insipidus. Because of the presence of two diagnostic criteria of APS1, mutations in the autoimmune regulator gene (AIRE) were performed, which revealed the presence of a novel mutation (c1314- 1326 del 13/insGT) in exon 11. In conclusion, the diagnosis of APECED should be suspected in any child with minimal hypertransaminasemia, anti-microsomal autoantibodies and Candida albicans onychosis.     

Mutations of retinoblastoma gene (Rb-1) as a prognostic factor in children with acute leukemia and neuroblastoma

Rb-1 is a tumor suppressor gene encoding for a nuclear phosphoprotein acting as a cell cycle regulator, normally expressed in hematopoietic cells and more often inactivated by point mutations with predominance for exons 20-24. The aim of this study is to correlate the retinoblastoma-1 (Rb-1) gene mutations with the prognosis and progression of childhood acute leukemia and neuroblastoma. Bone marrow slides from 26 children with leukemia (18 acute lymphoblastic leukemia [ALL] and 8 acute myeloid leukemia [AML]) and 4 children with neuroblastoma were studied. Exons 20, 21, and 22 were amplified using the polymerase chain reaction technique. Single strand conformational polymorphism (SSCP) and heterodoublex analysis were performed to detect mutations. In ALL cases, two samples in exon 20 (11.11%), one in exon 21 (5.56%), and four in exon 22 (22.22%) had altered conformation. All but one of these cases were classified as high-risk leukemia patients who either relapsed or never achieved remission. Two of the AML cases who did not achieve remission and one of the neuroblastoma cases with concomitant bone marrow infiltration had altered conformation as well. The SSCP and heterodoublex analysis showed that all but one who did not belong to the high-risk group had the same altered conformation. These data suggest that Rb-1 gene could possibly be used as an independent prognostic factor for the acute leukemia of childhood and result in the intensification of chemotherapy. In solid tumors with bone marrow involvement it could play a role as a marker of aggressive disease.     

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT): initial aims and impact of the family history of type 1 diabetes mellitus in Japanese children

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) was established in July 1994 with the chief aim to improve the quality of therapy for type 1 diabetes in children, an entity far less common in Japan than in Europe. We proposed four initial research topics: (i) to determine the current status of medical care and glycemic control in Japanese children with type 1 diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii) to establish a registry of a large cohort of patients in order to enable prospective studies to improve the quality of therapy for children with type 1 diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a workshop twice annually. We registered a total of 736 patients from 45 hospitals throughout Japan. Intervention via insulin treatment was instituted after 2 yr for those patients whose hemoglobin A1c level was more than 8.1%. The proportion of patients receiving multiple insulin injections increased after intervention; however, average hemoglobin A1c in females remained significantly higher than in males. We identified two forms of diabetes in Japanese children: a rapidly progressive form and a more slowly progressive form. There was a significantly higher prevalence of a family history of diabetes in first-degree relatives in the slowly progressive form. These preliminary findings are the result of the first collaborative study of childhood diabetes in Japan.     

Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis

We report on a family with familial male-limited precocious puberty (FMPP) due to a D564G mutation of the LHCGR gene. Family members show a varied phenotypic expression from severe precocity unresponsive to therapy with compromise of the predicted final height in some members, to attainment of tall final stature in other members who never received medical treatment. DNA amplification and sequencing of exon 11 of the LHCGR gene was done for the three affected male members and their mother. DNA analysis revealed a D564G mutation in the third cytoplasmic loop of the LHCGR receptor. All three males had precocious puberty with elevated testosterone levels. The index case developed central precocious puberty and evidence of compromised final height while on therapy. In contrast, the untreated older siblings attained a tall final height. This report underscores the possibility that the effects of the mutant luteinizing hormone/choriogonadotropin receptor on phenotypic expression of FMPP, such as adult final height, are modified by other factors.     

Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected

We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.     

Inaccurate hemoglobin A(1C) levels in patients with type 1 diabetes and hereditary persistence of hemoglobin F

We report 2 African-American boys with type 1 diabetes and hereditary persistence of hemoglobin F. The diagnosis came to light after both patients exhibited inconsistent hemoglobin A(1C) (HbA(1C)) levels with respect to serum glucose measurements. This demonstrates the importance of frequent glucose monitoring and interpreting the HbA(1C) level in light of serum glucose measurements.