甲状腺相关基因突变与先天性甲状腺功能低下症

先天性甲状腺功能低下症(CH)是引起儿童生长和神经发育障碍的常见内分泌疾病,主要由先天性甲状腺发育异常或甲状腺激素合成异常所致。近年来研究发现,部分CH患者存在甲状腺发育或甲状腺素合成相关基因的突变,文章就上述基因的生物学功能,基因突变患者的临床特征作一介绍。     

暂时性甲状腺功能减低伴甲状腺肿大患儿DUOX2基因突变的研究

目的 研究暂时性先天性甲状腺功能减退伴甲状腺肿大患者DUOX2基因突变情况.方法 对5例暂时性甲状腺功能减低伴甲状腺肿大患者DUOX2基因的全部外显子进行基因突变筛查,基因突变类型和特点.结果 在1例先天性甲状腺功能减低症( Congenital Hypothyroidism,CH)患儿中发现DUOX2基因一个等位基因的杂合性突变,为第10外显子cDNA的1329位点发生C＞T的突变(c.C1329T),导致第376密码子精氨酸突变为色氨酸(p.Arg376Trp).其他4例CH患儿均没有发现DUOX2基因突变.结论 在先天性甲状腺功能减退患儿中也发现了DUOX2基因的p.Arg376Trp突变,该突变的单个等位基因剂量的改变可能导致先天性甲状腺功能减退.     

先天性甲状腺功能减低症汉族儿童的促甲状腺素受体基因失活突变

目的探讨汉族儿童促甲状腺素受体（TSHR）基因失活突变与先天性甲状腺功能减低症（CH）的相关性。方法（1）选择79例CH汉族儿童（亚临床甲减14例,年龄1～5.5岁,男8例,女6例;甲减65例,年龄1.5～6岁,男27例,女38例）为研究对象;100名正常儿童（男40例,女60例,年龄1～8岁）作为对照组。（2）采用PCR和DNA测序技术检测TSHR基因失活突变。结果（1）79例CH患儿中有1例发生复合杂合子突变,其突变位点为（Pro52Thr／Val689Gly）。1例发生杂合子突变,其突变位点为（Gly245Ser）。30例患儿在第10外显子2181位核苷酸处发生C-G转换（GAC→GAG）,使727位密码子天冬氨酸被谷氨酸代替（Asp727Glu）。47例患儿在第7外显子561位核苷酸处发生T-c转换（AAT→AAc）,相应的187位氨基酸（Asn）不发生改变。（2）33例正常对照儿童在第10外显子2181位核苷酸处发生C-G转换;50例正常对照儿童在第7外显子561位核苷酸处发生T-c转换（AAT→AAc）。结论浙江汉族CH患儿TSHR基因有3个杂合子突变位点：（Pr052Thr）、（Gly245Ser）、（Val689Gly）,第10外显子2181位核苷酸处（GAc→GAG）及第7外显子561位核苷酸处（AAT→AAC）存在TSHR基因多态性。     

先天性甲状腺功能减低症患儿DUOXA2基因突变研究

目的 探讨广州地区先天性甲状腺功能减低症(CH)患儿DUOXA2基因突变特点及其基因型与表型的关系。方法 采用PCR及直接测序法,对2011年至2012年出生、广州市新生儿筛查中心诊断并排除DUOX2基因突变的20例疑似甲状腺激素合成障碍的CH患者进行DUOXA2基因突变分析。结果 20例CH患者中2例为p.Y246X/p.Y246X纯合突变;4例为单等位基因杂合突变:分别为已知致病突变c.413-414ins A携带者2例,p.Y246X携带者1例,新突变p.G79R携带者1例。2~3岁再评估时显示,2例p.Y246X/p.Y246X纯合突变者分别表现为暂时性CH及轻度永久性CH;4例单等位基因突变者,除1例p.Y246X携带者表现为典型永久性CH外,其余3例携带者均为暂时性CH。结论 DUOXA2基因突变是广州地区疑似甲状腺激素合成障碍性CH患儿较常见的分子发病基础,多数表现为暂时性CH,未发现DUOXA2基因型与表型的关系。新突变p.G79R为致病性突变的可能性大。     

Maternal thyrotoxicosis causing central hypothyroidism in infants

We describe three infants born to mothers with poorly controlled Graves' disease, who developed transient central hypothyroidism in the immediate postnatal period. Suppression of the fetal pituitary-thyroid axis may be due to placental transfer of thyroxine from the hyperthyroid mother. This may persist for months postnatally, necessitating treatment to optimise neurodevelopmental outcome.     

Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene.

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the betaTSH gene that was diagnosed in the early neonatal period. Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started. Because there was no indication for other pituitary hormone deficiencies, sequence analysis of the betaTSH gene was initiated. A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. This altered betaTSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result.     

Novel CRLF1 gene mutation in a newborn infant diagnosed with Crisponi syndrome

Crisponi syndrome is an infrequently described disorder with autosomal recessive trait. It is characterized by extensive muscular contractions in the face after even minimal stimuli or crying, hypertonia, opisthotonus, camptodactyly, and typical facial features. Muscle contractions attenuate during rest or when the infant calms down. As a recently described new disease, Crisponi syndrome may be confused with epileptic manifestations. Most of the patients die in the first months of life due to hyperthermia and feeding problems. Recently, it has been demonstrated that mutations of the CRLF1 gene ‘cytokine receptor‐like factor 1’ are associated with Crisponi syndrome. Here, we present a newborn diagnosed with Crisponi syndrome and report a novel homozygous CFRL1 gene mutation.     

甲状腺球蛋白低下的先天性甲状腺功能减退症一家系基因 突变分析

目的探讨甲状腺球蛋白(TG)低下的先天性甲状腺功能减退症(CH)家系TG基因突变特点,并分析基因型与临床表型的关系。方法回顾1个姐弟2人同患TG低下的CH家系,从外周血中提取基因组DNA,进行TG基因突变检测。结果患儿父亲TG基因发生c.274+2TG杂合变异,母亲为c.2512CT杂合变异。患儿姐弟二人TG基因均发现上述2个变异,为复合杂合变异,c.2512CT为新发现的突变位点,致病性尚未见文献报道。结论 TG基因突变引起蛋白质功能改变导致CH。该研究发现1个新的TG基因突变位点。     

Isolated central diabetes insipidus in a newborn with congenital toxoplasmosis

We present a 5 day-old male newborn with isolated central diabetes insipidus due to congenital toxoplasmosis. This patient was referred to us for hydrocephalus. As we investigated the aetiology of the hydrocephalus, the patient's serum and cerebrospinal fluid tested positive for toxoplasmosis via ELISA and polymerase chain reaction. Computed tomography showed obstructive hydrocephalus and disseminated cranial calcifications. Central diabetes insipidus developed on the 10th day, apparently as a result of the toxoplasmosis infection, and was treated successfully with oral desmopressin.     

Bilateral galactocele in a male infant with Down syndrome and congenital hypothyroidism

Galactocele is an uncommon benign breast lesion. Its cause is unknown. Here, we report a male infant with Down syndrome and congenital hypothyroidism during the newborn period. At follow up, when he was 6 months old, bilateral mammillary swelling was detected and diagnosed as galactocele. Although thyroid hormone levels were normal, serum prolactin levels were elevated. Cyst aspiration was performed on the left side and 6 months after the aspiration of the cyst on the left side, both cysts had clinically and sonographically regressed. No recurrence was observed at the end of the 4th year.     

Update of newborn screening and therapy for congenital hypothyroidism

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.     

Acquired central hypothyroidism in a male thalassaemic patient with severe iron overload

Acquired central hypothyroidism (CH) is a rare form of hypothyroidism that results from a variety of conditions affecting the hypothalamus and the pituitary gland. This pathology remains difficult to diagnose in patients with chronic disease. The Authors describe a 21-year-old patient with thalassaemia (TM) who was referred for the evaluation of short stature and hypogonadism, and was found to have CH.This case report stresses the importance of following thyroid function in TM patients and underlines the criteria for diagnosis and treatment.     

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??Abstract??Objective To identify thyroglobulin ?? TG?? gene mutation in patients with congenital hypothyroidism with goiter??in order to provide full evidence for gene diagnosis of congenital hypothyroidism. Methods Totally 11 patients with congenital hypothyroidism with goiter in Qingdao Women and Children hospital from Jan. 2012 to Aug. 2012 were enrolled in this study. The 7??14??22??33 and 38 exons of TG gene were amplified through PCR and the products were sequenced directly. The type and characteristic of TG gene mutation in patients with congenital hypothyroidism with goiter in this region were analyzed. Results Two single nucleotide polymorphism of TG gene were identified??but no gene mutation was observed. TG c.3218-81T??G ??rs 853324??homozygous??in 1 patient and c.3218-81T??G??rs 853324??heterozygosis??in 6 patients were found. Conclusion The incidence of TG gene mutation is very low in patients with congenital hypothyroidism with goiter from Qingdao City. It suggests that TG gene mutation may not serve as the mutation hotspot gene of congenital hypothyroidism with goiter in Qingdao City??     

Low TSH congenital hypothyroidism: identification of a novel mutation of the TSH beta-subunit gene in one sporadic case (C85R) and of mutation Q49stop in two siblings with congenital hypothyroidism

Isolated congenital hypothyroidism resulting from mutation of the TSH beta-subunit gene, has rarely been reported. In the present article, we report a new mutation (C85R) in exon 3 of the TSH beta-subunit gene in one sporadic case and the mutation Q49stop in two siblings with congenital hypothyroidism. The novel mutation is a T to C transition at codon 85, resulting in a change of cysteine to arginine (C85R) of the ss-subunit. Because the cysteine residues of all glycoproteins are highly conserved, this mutation is expected to result in conformational changes of the ss-subunit, rendering it incapable to form a functional heterodimer with the alpha-subunit. The second mutation described is a C to T transition resulting in a premature stop at codon 49 (Q49stop), leading to the formation of a truncated protein. Although the two siblings reported herein carried the same mutation, they had slightly modified clinical and biochemical phenotype. The mutation C85R and the previously described E11stop have, thus far, exclusively been detected in Greek patients. The Q49stop mutation initially detected in Greek patients was subsequently identified in an Egyptian girl and most recently in two Turkish siblings. These three reports possibly indicate the presence of a mutational hot spot on the TSH beta-subunit gene. Hence, with the novel mutation herein reported, a total of five mutations of the TSH beta-subunit gene are recognized as a cause of low-TSH congenital hypothyroidism worldwide.     

Goitrous congenital hypothyroidism in a twin pregnancy causing respiratory obstruction at birth: implications for management

We report a twin pregnancy complicated by fetal goitrous hypothyroidism secondary to dyshormonogenesis caused by thyroglobulin deficiency. Antenatal treatment with intra-amniotic thyroxine was considered but not performed, given the late gestational age at diagnosis and the multiple nature of the pregnancy. Both twins developed airway obstruction at delivery, requiring intubation and ventilation. We review the literature and describe the practical issues relating to the antenatal assessment and perinatal management of fetal goitre.     

Congenital hypothyroidism caused by a novel homozygous mutation in the thyroglobulin gene

Congenital hypothyroidism (CH) due to thyroglobulin (TG) deficit is an autosomal recessive disease (OMIM #274700) characterized by hypothyroidism, goiter, low serum TG, and a negative perchlorate discharge test. The aim of this study was to perform the genetic analysis of the TG gene in two sisters born from consanguineus parents and affected by CH and low serum TG levels. The index patient and her sister were identified at neonatal screening for CH and treated with L-thyroxine (L-T4). After discontinuation of L-T4 therapy, hypothyroidism was confirmed, serum TG was undetectable, and no organification defect after ¹²³I scintigraphy and perchlorate test was shown; thyroid ultrasound showed a eutopic gland of normal size. DNA was extracted from peripheral white blood cells of the two sisters and the father. All 48 exons of TG gene were amplified by polymerase chain reaction and subjected to direct sequencing. A novel homozygous point mutation in exon 10 of TG gene was identified in the patient and her sister. The mutation determined a stop codon at position 768 (R768X) resulting in an early truncated protein or in the complete absence of the protein. The father (euthyroid) was heterozygous carrier of the mutation. Conclusion: Genetic analysis of TG gene was performed in two sisters affected by CH. A novel point mutation of the TG gene determining a stop codon at position 768 of the protein was identified. The early truncated nonfunctioning protein or the absence of the protein due to the premature degradation of abnormal mRNA may be responsible of the observed phenotype.