Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene

Germline mutations of thyrotropin receptor (TSHR) gene determining a constitutive activation of the receptor were identified as a molecular cause of familial or sporadic congenital nonautoimmune hyperthyroidism (OMIM: 609152) (Nat Genet 7:396-401, 1994; N Engl J Med 332:150-154, 1995; Acta Endocrinol (Copenh) 100:512-518, 1982). We report the case of an Italian child subjected to the first clinical investigation at 24?months for an increased growth velocity; biochemical investigation showed high FT4 and FT3 serum values and undetectable thyrotropin in the absence of anti-thyroid antibodies; the thyroid gland was normal at ultrasound examination. Treatment with methimazole was started at the age of 30?months when her growth velocity was high and the bone age was advanced. DNA was extracted from her parents', brother's, and the patient's blood. Exons 9 and 10 of the TSHR gene were amplified by polymerase chain reaction and subjected to direct sequencing. In proband, a heterozygous substitution of cytosine to thymine determining a proline to serine change at position 639 (P639S) of the TSHR was detected while the parents and brothers of the propositus, all euthyroid, showed only the wild-type sequence of the TSHR gene. This mutation was previously described as somatic in patients affected by hyperfunctioning thyroid nodules and as germline in a single Chinese family affected by thyrotoxicosis and mitral valve prolapse. This constitutively activating mutation is able to activate both the cyclic AMP and the inositol phosphate metabolic pathways when expressed in a heterologous system. In conclusion, we describe the first case of sporadic congenital nonautoimmune hyperthyroidism caused by de novo germinal P639S mutation of TSHR.     

非自身免疫性甲状腺功能亢进症1例临床和基因变异分析

目的 分析非自身免疫性甲状腺功能亢进症的临床及遗传学特征.方法 回顾分析1例非自身免疫性甲状腺功能亢进症患儿的临床资料和基因检测结果.结果 患儿,男,9月龄,以心率增快为主要表现,合并全面性发育迟缓、先天性心脏病等.实验室检测提示促甲状腺激素降低,游离三碘甲状腺原氨酸及游离甲状腺素均升高,相关抗体检查全部阴性.基因检测...     

A family with a novel TSH receptor activating germline mutation (p.Ala485Val)

Autosomal dominant nonautoimmune hyperthyroidism (ADNAH) is caused by gain of function mutations in the TSH receptor (TSHr) gene and characterized by toxic thyroid hyperplasia with a variable age of onset in the absence of thyroid antibodies and clinical symptoms of autoimmune thyroid disease in at least two generations. We report here a Turkish family with a novel TSHr gene mutation with distinct features all consistent with ADNAH. Thyroid function tests of the proband were as follows: free T3: 13.1 pg/ml (N: 1.8–4.6); free T4: 5.1 ng/dl (N: 0.9–1.7); TSH: 0.01 μIU/ml (N: 0.2–4.2); and TSH receptor antibody: 2 IU/ml (N: 0–10). A heterozygous missense mutation in exon 10 of the TSHr gene (c.1454C>T) resulting in the substitution of valine for alanine at codon 485 (p.Ala485Val) was found in the father and his son and daughter. This mutation had arisen de novo in the father. Functional studies of the novel TSHr germline mutation demonstrated a higher constitutive activation of adenyl cyclase than wild type without any effect on phospholipase C activity. In conclusion, our data indicate that gain of function germline mutations in the TSHr gene should be investigated in families with members suffering from thyrotoxicosis and progressive growth of goiter, but without clinical and biochemical evidence of autoimmune thyroid disease. In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.     

Prolonged suppressed thyroid-stimulating hormone levels in hyperthyroidism in a neonate born to a mother with Graves' disease

Abstract We report here a case of neonatal hyperthyroidism born to a mother, whose pregnancy was complicated by poorly controlled Graves' disease. The patient demonstrated exophthalmos and marked goiter at birth, indicating the existence of thyrotoxicosis in utero. The mother's Graves' disease was well controlled in the third trimester, resulting in a slightly lower level of free thyroxine (FT₄) in the umbilical cord blood serum; however, thyroid-stimulating hormone (TSH) was undetectable. Thyroid-stimulating hormone remained undetectable for 2 months, while FT₄ levels varied in the course. This case suggests that severe and prolonged thyrotoxicosis in utero, due to poor control of pregnancy with Graves' disease, might induce unresponsiveness of the hypothalamo-pituitary system in the newborn.     

Characterization of AQP‐2 gene mutation (R254Q) in a family with dominant nephrogenic DI

We identified the AQP‐2 gene mutation (R254Q) in a family with dominant NDI. The patient studied here has NDI with partial response to the anti‐diuretic effect of AVP and dDAVP. Hereditary NDI seems to have the uniform clinical manifestations, but this might only reflect the information on screened patients with clear clinical presentations. It may be that a milder form of NDI has been overlooked due to a lack of genetic identification. Gene mutation analysis should be considered even in patients with mild NDI symptoms. Fortunately, both V2R and AQP2 genes are small and can be easily analyzed.     

A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) causes non-syndromic craniosynostosis

A unique Pro250Arg mutation in fibroblast growth factor receptor 3 (FGFR3) was recently found in patients with non-syndromic craniosynostosis. We studied 18 Taiwan Chinese patients with various types of craniosynostosis to evaluate if this mutation is also prevalent in the Chinese population. Genomic DNA was analysed by polymerase chain reaction based restriction analysis and direct sequencing to identify the Pro250Arg mutation in FGFR3. Five (28%) of 18 probands were heterozygous for the Pro250Arg mutation. Only those patients with coronal synostosis carried this mutation.­­Conclusion: Our findings suggest that all patients with coronal synostosis should be examined for this unique mutation.     

NBAS基因突变致婴儿肝功能衰竭综合征2型1例报告

<正>婴儿肝功能衰竭综合征2型(infantile liver failure syndrome 2,ILFS2)为常染色体隐性遗传性疾病,主要表现为在婴儿期或儿童早期发热性疾病期间发生反复的急性肝功能衰竭。NBAS基因变异可导致一组复杂的疾病,临床表现范围广泛,SOPH综合征(身材矮小、Pelger-Huёt细胞畸形、视神经萎缩,无明显肝衰竭)和婴儿肝功能衰竭综合征2型最为常见。本文回顾性分析1例反复发热、肝功能异常患儿,经基因检测存在NBAS突变,最终诊断为婴儿肝功能衰竭综合征2型,以加深对本病认识。1病历资料     

Laron综合征家系患者生长激素受体基因突变分析

目的研究Laron综合征患者的临床特点及生长激素受体（GHR）的基因突变。方法对一家系中2例表现为身材明显落后的患儿进行研究，分别进行体格测量和GH-IGF—I轴功能测定。提取外周血白细胞基因组DNA，运用聚合酶链式反应（PCR）扩增GHR基因第2～9外显子及其两侧的侧翼序列，直接进行测序，将所测结果与正常人GHR基因序列进行对比，确定突变位点和突变类型。对突变基因均经2次测定证实。结果2例患儿自出生后身长明显落后于同龄儿童，呈现Laron综合征的独特面貌，空腹血清GH值均明显高于正常儿童。空腹血清IGF-I明显低于同年龄同性别正常儿童。血浆IGFBP-3和GHBP低于检测线。GHR基因序列测定结果显示2例患儿均存在外显子4上第65为氨基酸的纯合突变S65H，为新发现突变。结论Laron综合征患者存在典型的面貌特征，结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是该Laron综合征患者的致病原因。     

A simple and rapid polymerase chain reaction-based method for detecting a prevalent mutation (R413P) in Japanese phenylketonuria patients

A convenient molecular method for the detection of R413P (¹²³⁸G←C) mutation in exon 12 of the phenylalanine hydroxylase gene, one of the prevalent mutations among Japanese patients with classical phenylketonuria (PKU) is described. The mutation was previously detected by polymerase chain reaction (PCR)-direct sequencing or allele specific oligonucleotide hybridization. However, these methods were cumbersome and only a few laboratories could provide such a diagnostic service. An improved version of the method has been developed here, involving 30 cycles of PCR following restriction enzyme digestion. In the upstream primer encompassing G-1207 to C-1237, two substitutions are artificially introduced, so that a Bam-HI site involving C-1238 is introduced in the copies of the mutant allele. With the use of this method, R413P-homozygote and -heterozygote can be readily and unequivocally distinguished from normal using genomic DNA extracted from peripheral blood leukocytes. Among 10 Japanese PKU patients investigated, three were homozygous and three were heterozygous for the R413P allele, whereas four did not carry this mutant allele, indicating that the prevalence of the mutant allele is 45%. The result suggests that it is technically feasible to develop a program for carrier detection of the mutation in the Japanese population.     

线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症1例并文献复习

目的探讨线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症的临床表现及基因突变特点。方法回顾分析1例确诊为可逆性婴幼儿呼吸链缺乏症患儿的临床资料,并复习相关文献。结果男性患儿,2个月23天,入院时消瘦,呼吸急促,双肺可闻及痰鸣音及喘鸣音;肌力IV级,肌张力减弱。有一胞姐生后不久因重症肺炎去世。入院时肌酸激酶同工酶123 U/L,肌酸激酶890 U/L;血乳酸8.9 mmol/L;病原学检查均为阴性。头颅MRI无异常。入院后患儿持续高乳酸血症、肌酶异常升高,伴呼吸困难,放弃治疗后死亡。基因检查示线粒体MT-TE基因存在14674TC突变,来源于母亲。国外文献报道线粒体MT-TE 14674TC突变患儿早期临床表现与进展型线粒体病类似,呼吸肌无力、喂养困难,运动发育里程碑延迟,肌酶及乳酸升高。予补充能量,维持内环境稳定等治疗,约1岁左右逐渐好转。结论线粒体MT-TE基因突变致可逆性婴幼儿呼吸链缺乏症早期表现与进展型线粒体病类似,积极治疗预后良好。早期进行基因检测可明确预后,增强治疗的信心。     

A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond‐Blackfan anemia

Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by pure red cell aplasia, various congenital anomalies, and cancer predisposition. We report a novel mutation in the RPS17 gene in a Korean patient with DBA. The mutation occurred in the translation initiation codon, changing Atg to Gtg (c.1A>G), thus disrupting the natural start of the RPS17 protein biosynthesis. This is the third case of DBA from a RPS17 mutation in the literature and is the second case of a RPS17 mutation in the translation initiation codon, following c.2T>G. Pediatr Blood Cancer 2010;54:629–631. © 2009 Wiley‐Liss, Inc.     

Critical Diamond–Blackfan anemia due to ribosomal protein S19 missense mutation

Diamond–Blackfan anemia (DBA) is a rare congenital disorder characterized by pure erythrocyte aplasia, and approximately 70% of patients carry mutations in the genes encoding ribosomal proteins (RP). Here, we report the case of a male infant with DBA who presented with anemic crisis (hemoglobin [Hb] concentration 1.5 g/dL) at 58 days after birth. On admission, the infant was pale and had tachypnea, but recovered with intensive care, including red blood cell transfusions, and prednisolone. Based on the clinical diagnosis of DBA, the father of the infant had cyclosporine‐A‐dependent anemia. On analysis of RP genes when the infant was 6 months old, both the infant and the father, but not the mother, were found to harbor a mutation of RPS19 (c.167G > C, p. R56P). Therefore, genetic background search and early neonatal health check‐ups are recommended for families with a history of inherited bone marrow failure syndromes.     

Diagnostic and management challenges from childhood,puberty through to transition in severe insulin resistance due to insulin receptor mutations

Two Caucasian girls, both of normal weight and body mass indices, were diagnosed with type A insulin resistance (IR) in childhood. Case 1 presented with premature adrenarche aged 7 years, then by age 12 years had hirsutism, acne, acanthosis nigricans, and asymptomatic diabetes. Subsequent investigation revealed raised adiponectin (15.3 mg/L) and heterozygous p.Pro1205Leu mutation in the INSR gene encoding the insulin receptor. She experienced postprandial hypoglycaemia on metformin; acarbose was trialled and discontinued aged 16 years, as she became normoglycaemic. Hirsutism was treated with topical eflornithine, oral spironolactone and flutamide, and laser therapy. Unfortunately, diabetes reemerged in young adulthood with obesity. Case 2: during an emergency admission for acute abdominal pain aged 11 years, hyperglycaemia was noted which led to further investigation. An oral glucose tolerance test showed diabetes and ultrasound showed polycystic ovaries. Further investigations revealed raised adiponectin (18 mg/L) and compound heterozygous mutations in the INSR gene: p.Pro1263Ala and p.Ser748Leu (latter probable normal variant). She was treated with metformin and experienced postprandial hypoglycaemia. Symptoms of hyperandrogenism were controlled by flutamide. She maintained a healthy weight and reassessment at young adulthood showed resolution of diabetes. Type A IR may present in childhood with overlapping features of common endocrine entities such as premature adrenarche and polycystic ovarian syndrome. Patients with abnormal glucose tolerance yet normal weight merit screening with adiponectin; raised adiponectin levels prompt insulin receptor mutational analysis. Postprandial hypoglycaemia is characteristic. Management includes optimization of glycaemic control with oral hypoglycaemic agents and maintenance of healthy weight, and controlling the effects of hyperandrogenism.     

Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

Pyruvate dehydrogenase (PDH) deficiency is one of the most common causes of congenital lactic acidosis. Correlations between the genetic defect and neuroimaging findings are lacking. We present conventional and diffusion-weighted MRI findings in a 7-day-old male neonate with PDH deficiency due to a mosaicism for the R302H mutation in the PDHA1 gene. Corpus callosum dysgenesis, widespread increased diffusion in the white matter, and bilateral subependymal cysts were the main features. Although confirmation of PDH deficiency depends on specialized biochemical analyses, neonatal MRI plays a role in evaluating the pattern and extent of brain damage, and potentially in early diagnosis and clinical decision making.     

Permanent neonatal diabetes due to a novel insulin signal peptide mutation

We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51‐month‐old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non‐conservative change substitutes the highly conserved L¹³ residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non‐mutant counterpart progression and processing within the β‐cells, and this resulted to a permanent form of congenital diabetes.     

COA6基因新发变异致婴儿细胞色素c氧化酶缺陷致心脑肌病4型1例报告并文献复习

目的 提高对婴儿细胞色素c氧化酶缺陷致心脑肌病4型(CEMCOX 4)临床表型及基因型的认识.方法 回顾分析1例婴儿CEMCOX 4患儿的临床资料并复习相关文献.结果 女性患儿,5日龄,出生后即出现呼吸困难;多次血气分析示乳酸增高;心脏彩超示肥厚型心肌病,双侧心室流出道梗阻.全外显子测序发现患儿COA 6基因存在c.4...