Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan and its different etiologies in comparison with other countries, the high rate of parental consanguinity, and the role of NIS gene in permanent CH due to dyshormonogenesis, the aim of this study was to investigate the G395R mutation of the NIS gene in patients with permanent CH due to dyshormonogenesis
In this case–control study, patients diagnosed with permanent CH due to dyshormonogenesis during CH screening program were selected. Venous blood sample was obtained to determine the G395R mutations of NIS gene using polymerase chain reaction (PCR) sequencing method.
In this study, 35 CH patients with permanent CH due to dyshormonogenesis and 35 neonates with normal screening results as a control group were studied. We did not find any changes of the mentioned mutation of NIS gene in the patients’ group.
Considering the findings of the current study, it seems that further studies with larger sample size and with consideration of other gene mutations such as pendrin and thyroglobulin are needed for more accurate conclusion.
Congenital hypothyroidism; dyshormonogenesis; G395R; mutation; sodium/iodide symporter (NIS) gene
Purpose of Review
Overview of congenital hypothyroidism (CH) caused by thyroid hormone synthesis defects, the current understanding of their pathophysiology, and clinical implications of molecular diagnoses.
Genetic defects in all known thyroid-specific factors required for thyroid hormone synthesis have been described. These include defects in iodide trapping (NIS), in the facilitated iodide efflux across the apical membrane (PDS), the organification of iodide within the follicular lumen (TPO, DUOX2, DUOXA2), the substrate for thyroid hormone synthesis (TG) and the ability to recover and retain intrathyroidal iodine (IYD). Clinical and biochemical evaluation aids in selecting the most appropriate candidate gene(s).
A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counselling, and has prognostic value in differentiating transient from permanent CH and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement.
CH due to thyroid dyshormonogenesis is a heterogenic disorder that may be caused by mutations in any of the known steps in the thyroid hormone biosynthesis pathway. An exact molecular diagnosis allows genetic counselling, the identification of asymptomatic mutation carriers at risk of recurrent hypothyroidism, and provides a rationale for adjunct iodide supplementation.
congenital hypothyroidism; genetics; thyroglobulin; thyroid peroxidase; dual oxidase
Thyroid peroxidase (TPO) is the key enzyme in the synthesis of thyroid hormones, and the TPO defects are believed to be the most prevalent causes of the inborn errors of thyroid metabolism. We investigated an adopted boy with iodide organification defect, who presented with florid hypothyroidism at the age of 4 mo, poorly complied with thyroxine treatment, and developed a compressive goiter necessitating partial resection at the age of 12 yr. Biochemical studies revealed the absence of TPO activity in the resected tissue. Genomic DNA studies identified a 4 base-pair insertion in the eighth exon of the TPO gene, and showed that the patient was homozygous for this frameshift mutation. The direct genetic diagnosis of this mutation can be made by digestion of polymerase chain reaction products with NaeI restriction enzyme. This will help assessing its prevalence among the heterogenous genetic group of TPO defects.
Congenital hypothyroidism (CH) with multinodular goiter (MNG) is uncommonly seen in children. However, CH associated with goiter is often caused by defective Thyroid peroxidase (TPO) gene. In this study, we screened for mutation(s) in the TPO gene in two siblings with CH and MNG and their healthy family members. The two sisters, born to consanguineous parents, were diagnosed with CH during infancy and received treatment since then. They developed MNG during childhood despite adequate L-thyroxine replacement and negative thyroid antibody screening. PCR-amplification of all exons using flanking primers followed by DNA sequencing revealed that the two sisters were homozygous for a novel c.1502T>G mutation. The mutation is predicted to substitute valine for glycine at a highly conserved amino acid residue 501 (p.Val501Gly). Other healthy family members were either heterozygotes or mutation-free. The mutation was not detected in 50 healthy unrelated individuals. In silico analyses using PolyPhen-2 and SIFT predicted that the p.Val501Gly mutation is functionally “damaging.” Tertiary modeling showed structural alterations in the active site of the mutant TPO. In conclusion, a novel mutation, p.Val501Gly, in the TPO gene was detected expanding the mutation spectrum of TPO associated with CH and MNG.
Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). It has been reported that the serum of patients with RTH is free of auto-antibodies against thyroglobulin (Tg) and thyroid peroxidase (TPO), except in rare cases where coincidental autoimmune thyroiditis is also present. We describe a 13-year-old girl with chronic thyroiditis and RTH. This patient had increased plasma free T3, free T4 at the upper limits with unsuppressed TSH. She had peripheral manifestations of thyroid hormone excess, hypertension and growth acceleration. Anti-TPO antibodies were positive. Sequence analysis of the TRβ gene was performed and revealed a novel mutation I54V in exon 4. The same mutation was also found in the mother and two asymptomatic sisters. The clinical presentation of our patient is not habitual in RTH because growth retardation is frequently reported in this syndrome. The association between RTH and thyroiditis complicate the management of the hypothyroidism.
Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited. The candidate genes associated with this genetically heterogeneous disorder form two main groups: those causing thyroid gland dysgenesis and those causing dyshormonogenesis. Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsα and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. There is also early evidence for a third group of congenital hypothyroid conditions associated with iodothyronine transporter defects associated with severe neurological sequelae. This review focuses on the genetic aspects of primary congenital hypothyroidism.
To study pregnancy outcomes in relation to thyroid peroxidase antibody (TPOAb) status with optimum thyroxine replacement for subclinical hypothyroidism.
Materials and Methods:
Ninety-eight women with subclinical hypothyroidism were followed up until the end of their pregnancy. TPO antibody status was performed for 59 women (positive 20, negative 39). Levothyroxine was supplemented to maintain TSH between 0.3-3 mIU/l in all patients, irrespective of TPOAb status. Pregnancy outcomes were noted as pregnancy-induced hypertension (PIH), antepartum or postpartum hemorrhage, preterm delivery, and spontaneous abortion. Outcomes were compared between 3 groups as per TPO antibody status (positive, negative, and undetermined), which were matched for age and gestational period.
Thyroid autoimmunity was noted in 34% of women screened for TPO antibody. A total of 11 adverse pregnancy outcomes were recorded (4 spontaneous abortions, 4 preterm deliveries, 3 PIH) with no significant difference between the groups.
Adverse pregnancy outcomes were not different in the 3 groups with adequate thyroxine replacement for pregnant women with subclinical hypothyroidism targeting TSH in euthyroid range, irrespective of thyroid autoimmunity status.
Pregnancy; subclinical hypothyroidism; thyroid autoimmunity
Sixty-three Arabic patients (16 males and 47 females) with thyroid toxic and nontoxic goiter who attended the endocrinologist in Nuclear Medicine Hospital and Al Yarmok Nuclear Medicine Department in Baghdad, Iraq were examined for thyroid peroxidase (TPO) gene mutations. A total of ten heterozygous mutations have been identified in the human TPO gene associated with thyroid toxic and nontoxic goiter. These mutations involved transition or transversion of cysteine either by thymine or guanine at the position 1708 of the exon 10 (c.1708C>T) and the position 1978 of the exon 11 (c.1978C>G). From a total of ten detected mutations, two c.1978C>G mutations were detected in nontoxic goiter patients and eight (two c.1708C>T and six c.1978C>G mutations) were detected in toxic goiter. In conclusion, this study identified ten TPO mutations associated with toxic and nontoxic goiter that have not been yet reported in Iraq, and most of them are detected among females (90 %) and adults age between 30 and 50 years old (80 %).
Thyroid disorders; TPO; c.1708C>T; c.1978C>G; Mutation
The most common organ-specific autoimmune disease in humans involves the thyroid. Autoantibodies against thyroid peroxidase (TPO) are present in the sera of virtually all patients with active disease. We report the molecular cloning of the genes for 30 high-affinity, IgG-class human autoantibodies to TPO from thyroid-infiltrating B cells. Analysis of the putative germline genes used for the TPO human autoantibodies suggests the use of only five different H and L chain combinations involving four H chains and three L chains. In addition, the same combination of H and L chains was found in multiple patients. The F(ab) proteins expressed by these genes define two major, closely associated domains (A and B) in an immunodominant region on TPO. These A and B domains contain the binding sites of approximately 80% of IgG-class TPO autoantibodies in the sera of patients with autoimmune thyroid disease. The present information permits analysis, not previously possible, of the relationship between autoantibody H and L chain genes and the antigenic domains on an autoantigen. Our data, obtained using target organ-derived autoantibodies, indicate that there is restriction in H and L chain usage in relation to the interaction with specific antigenic domains in human, organ-specific autoimmune disease.
The aim of this study is to delineate laboratory diagnostic strategies for subclinical hypothyroidism in patients who are clinically symptomatic but may have a normal thyroid profile. Tri — iodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) and anti thyroid peroxidase antibodies (anti-TPO) were estimated on fasting blood samples from 99 patients using electrochemiluminescence methods on ELECSYS 1010 (Roche). 74% of study subjects had elevated anti-TPO levels.61% patients had subclinical hypothyroidism. 45 of the 61 subclinical hypothyroid patients had elevated anti-TPO levels (73%). This is an important finding suggesting an autoimmune etiology for subclinical thyroid dysfunction with a higher risk of developing overt hypothyroidism.
Hypothyroidism; Thyroid Profile; T3; T4; TSH; Anti TPO
A 420-bp fragment from the 5' end of the rat thyroperoxidase (TPO) gene was fused to a luciferase reporter and shown to direct cell-type-specific expression when transfected into rat thyroid FRTL-5 cells. Analysis of this DNA fragment revealed four regions of the promoter which interact with DNA-binding proteins present in FRTL-5 cells. Mutation of the DNA sequence within any of these regions reduced TPO promoter activity. The trans-acting factors binding to these sequences were compared with thyroid transcription factor 1 (TTF-1) and TTF-2, previously identified as transcriptional activators of another thyroid-specific gene, the thyroglobulin (Tg) gene. Purified TTF-1 binds to three regions of TPO which are protected by FRTL-5 proteins. Two of the binding sites overlap with recognition sites for other DNA-binding proteins. One TTF-1 site can also bind a protein (UFB) present in the nuclei of both expressing and nonexpressing cells. TTF-1 binding to the proximal region overlaps with that for a novel protein present in FRTL-5 cells which can also recognize the promoter-proximal region of Tg. Using a combination of techniques, the factor binding to the fourth TPO promoter site was shown to be TTF-2. We conclude, therefore, that the FRTL-5-specific expression of two thyroid restricted genes, encoding TPO and Tg, relies on a combination of the same trans-acting factors present in thyroid cells.
Dyshormonogenesis is an uncommon cause of congenital hypothyroidism. The most common abnormality is absent or insufficient thyroid peroxidase enzyme. Maternal intake of antithyroid drug can also lead to elevated thyroid stimulating hormone (TSH) in a neonate, albeit the scenario is temporary. We report one such interesting case where a clinically euthyroid neonate borne to a mother on antithyroid drug presents on 12th day of life with reports of elevated TSH and increased tracer uptake in 99mTc thyroid scan. Disproportionately high TSH in comparison to low maternal antithyroid drug dosage and further elevation of TSH after stopping mother's antithyroid drugs ruled out maternal antithyroid drug-induced congenital hypothyroidism in the baby. Early institution of therapy in these patients can prevent mental retardation and other features of hypothyroidism.
Antithyroid drug; congenital hypothyroidism; dyshormonogenesis
Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12–13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl); TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl); TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl); TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl); TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.
About 30% of children with elevated TSH levels during neonatal screening have a transient form of disorder.
On the other hand, it has been reported that subclinical hypothyroidism persists in late childhood in about
30% of children found to be false-positive during neonatal screening. The aim of this study was to determine
whether transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening are
influenced by genetic background. The TSH receptor (TSHR), thyroid peroxidase (TPO) and dual oxidase 2 (DUOX2)
genes, for which it has been reported that heterozygous defects cause neonatal transient thyroid dysfunction,
were analyzed. Nine children with transient thyroid dysfunction or subclinical hypothyroidism detected during
neonatal screening were studied. One child was heterozygous for a TSHR gene mutation (R450H), and another
child was heterozygous for a TPO gene mutation (P883S). No children with mutation of the DUOX2 gene were
identified. Genetic background may contribute to development of transient thyroid dysfunction and subclinical
hypothyroidism detected during neonatal screening.
neonatal screening; transient hyperthyrotropinemia; subclinical hypothyroidism; TSH receptor; thyroid peroxidase
Objective: To investigate if L-thyroxine (T4) treatment may influence the clinical course of autoimmune thyroiditis (AIT) or prevent progression to subclinical or overt hypothyroidism in euthyroid nongoitrous pediatric patients with type 1 diabetes mellitus (T1DM) and AIT.
Methods: The study was performed in four Polish pediatric diabetes centers. Of 330 children with T1DM and AIT followed between 2008 and 2012, 101 received L-T4 and 160 underwent clinical observation for 24 months. Thyroid stimulating hormone (TSH), free T4 (fT4), anti thyroid peroxidase antibody (anti-TPO), anti thyroglobulin antibody (anti-TG), glycosylated hemoglobin (HbA1c) levels, and lipid profile were assessed in all patients. Ultrasonographic evaluation was also performed in all children at each examination.
Results: Patients treated with thyroid hormones had higher TSH levels (3.99; interquantile 3.5 to 4.52 vs. 2.09 mIU/L; interquantile 1.55 to 3.06; p<0.0001). A fall in TSH level (0.87 mIU/L 95% CI 0.43-1.30; p<0.0001) was documented after the first year of treatment. FT4 level did not differ between the groups at baseline (p=0.7434), but rose in the treatment group and fell in the control group [mean difference 0.78 95% CI
-0.22-1.53 pmol/L (p=0.02) after 12 months and 0.98 95% CI 0.04-1.76 (p=0.005) after 24 months]. Higher levels of anti-TPO were initially found in the treated patients (p<0.0001) and significantly decreased over the 24-month period (p<0.0001). Children in the treatment group had higher anti-TG levels (p<0.0001), which showed a borderline decrease (p=0.08) in time. In the control group, anti-TG levels rose marginally (p=0.06) during the study.
Conclusions: The data demonstrate that treatment with L-T4 in euthyroid pediatric patients with T1DM and AIT stabilizes autoimmune inflammation in the thyroid gland and is to be recommended as soon as the diagnosis is established.
Conflict of interest:None declared.
autoimmune thyroiditis; type 1 diabetes mellitus; L-thyroxine treatment; lipid profile; glycemic control; thyroid volume SDS
Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Presence of inner ear malformations is essential for the clinical diagnosis. Most individuals with PDS are clinically and biochemically euthyroid. Mutations in the PDS gene encoding pendrin protein have been shown to be associated with PDS. It has been recently demonstrated that some families with features of PDS do not have the inner ear malformations and mutations in the PDS gene. This condition has been named as “pseudo−Pendred syndrome” (pseudo−PDS), and has been hypothesized to be of autoimmune origin. Here we report four siblings who have goiter, severe hypothyroidism, a positive perchlorate discharge test and sensorineural deafness, but not the inner ear abnormality which is diagnostic for PDS. We suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo−PDS patients with congenital goitrous hypothyroidism and deafness.
Conflict of interest:None declared.
Pendred syndrome; pseudo−Pendred syndrome; congenital hypothyroidism; thyroid peroxidase defect
Background: The causes of neonatal transient hypothyroidism (NTH) remain incompletely understood. Whether it is influenced by genetic background is rarely discussed and remains unproven. A defect in thyroid peroxidase is a common cause of dyshormonogenesis of the thyroid gland in Taiwanese, with a novel mutation (2268insT) present in nearly 90% of alleles studied.
Objective: To determine if the presence of this common mutation is associated with NTH in Taiwan.
Methods: A mismatched primer was designed and used for this specific 2268insT mutation to screen 1000 normal babies and 260 babies with confirmed NTH.
Results: The carrier rate for 2268insT in normal babies (1/200) was significantly lower than in babies with NTH (1/13; p<0.0001).
Conclusions: The results strongly suggest that the presence of this thyroid peroxidase mutation contributes to the development of NTH. Likely pathogenetic explanations include the effect of the stress of extrauterine adaptation during labour on an immature pituitary-thyroid axis in genetically predisposed individuals, combined with environmental triggers such as iodine deficiency, perinatal iodine exposure, and/or goitrogen contamination.
To develop a model for endogenous thyroid autoantigen presentation, we transfected EBV-transformed B lymphoblastoid cell lines (EBV-LCL), established from patients with autoimmune thyroid disease and normal controls, with cDNA for the human thyroid autoantigen thyroid peroxidase (hTPO). hTPO-antigen presentation to patient peripheral blood T cells was demonstrated after stimulation in vitro for 7 d with irradiated hTPO-transfected or untransfected autologous EBV-LCL. Anti-hTPO-reactive T cells were subsequently cloned in the presence of irradiated, autologous hTPO-transfected EBV-LCL and IL-2.10 T cell-cloned lines exhibited specific hTPO-induced proliferation (stimulation indices of 2.1-7.9) towards autologous hTPO-transfected EBV-LCL, and were subjected to human T cell receptor (hTCR) V gene analysis, using the PCR for the detection of V alpha and V beta hTcR gene families. The results indicated a preferential use of hTCR V alpha 1 and/or V alpha 3 in 9 of the 10 lines. In contrast, hTCR V beta gene family use was more variable. These data demonstrate a model for the endogenous presentation of human thyroid peroxidase in the absence of other thyroid specific antigens. The high frequency of antigen-specific T cells obtained from PBMC using this technique will facilitate further studies at both the functional and hTCR V gene level.
We aimed to investigate the relation-ships among various mutations of the p53 gene and their protein products, histological characteristics, and disease prognosis of primary colorectal cancer in Isfahan, central Iran.
Sixty-one patients with colorectal adenocarcinoma were enrolled in the study. Mutations of the p53 gene were detected by single-stranded conformation polymorphism and DNA sequencing. The protein stability was evaluated by immunohistochemistry. Patients were followed up to 48 months.
Twenty-one point mutations in exons 5 and 6 were detected in the tumor specimens of 14 patients (23%). Of those, 81% and 9.5% were missense and nonsense mutations, respectively. There were also two novel mutations in the intronic region between exons 5 and 6. In 11 mutated specimens, protein stability and protein accumulation were identified. There was a relationship between the type of mutation and protein accumulation in exons 5 and 6 of the p53 gene. The presence of the mutation was associated with an advanced stage of cancer (trend, p<0.009). Patients with mutated p53 genes had significantly lower survival rates than those with wild type p53 genes (p<0.01).
Mutations in exons 5 and 6 of the p53 gene are common genetic alterations in colorectal adenocarcinoma in central Iran and are associated with a poor prognosis of the disease.
Colorectal neoplasms; p53 gene mutation; Missense; Nonsense
Studies in different populations have shown great variation in the prevalence of thyroid diseases in patients with type 1 diabetes mellitus (T1DM). Our aim was to study the prevalence of thyroid disorders such as autoimmunity of thyroid (AIT), thyroid dysfunction, and goiter in children and adolescents with T1DM, compared with age- and sex-matched healthy controls in Isfahan.
One hundred patients with T1DM who were referred to Isfahan Endocrine and Metabolism Research Center and 184 healthy schoolchildren matched for age and sex were included. They were examined for goiter by two endocrinologists. Thyroid function test and serum thyroid antibodies (anti-TPO Ab and anti-Tg Ab) were measured.
The prevalence of subclinical hypothyroidism was high in both groups (18%). T1DM patients had lower frequency of goiter (21% vs. 38%, P=0.001), and higher prevalence of positive AIT (22% vs. 8%, P=0.001), anti-TPO Ab positivity (19.3% vs. 5.3%, P=0.000), and anti-Tg Ab (11.1% vs. 6.4%, P=0.1) in comparison with the control group. Being positive for AIT in diabetic patients meant an odds ratio of 5 (CI 95%: 1.5-15.6) for thyroid dysfunction. There was no association between age, sex, duration of diabetes and HbA1C with serum anti-TPO Ab and anti-Tg Ab concentrations in this group.
Our results demonstrated the high prevalence of AIT and thyroid dysfunction in patients with T1DM. We suggest regular thyroid function and antibody testing in these patients.
Type 1 diabetes mellitus; Autoimmune thyroid disease; Thyroid dysfunction disease; Goiter; Thyroid antibody
The scant data on ethnic differences in the prevalence of congenital hypothyroidism (CH) have generally not taken etiology of CH into account. Our hypothesis is that the prevalence of CH due to thyroid dysgenesis (TD) varies by ethnicity.
This case–control study included all patients with CH due to TD (a condition of unknown origin) or to dyshormonogenesis (DH, of known autosomal recessive transmission) between 1987 and 2009. Etiology was established by 99mTc scintigraphy. The parents self-assessed their ethnicity, which we grouped in Caucasian, Hispanic, black, Asian, and Maghreb/Middle East. We compared ethnicity between the 190 patients with TD (147 ectopies, 40 athyreoses, and 3 orthotopic hypoplasias) and the 44 patients with DH. Ethnicity was also compared to the reference population of the city of Montreal. Prevalence odds ratios (POR) were calculated and compared by the bilateral Fisher's exact test.
The ethnic composition of the DH group was similar to that of the reference population. In blacks, TD prevalence of 1 in 190 (0.5%) was low compared to that of DH (4 in 44; 9.1%; POR 0.06; 95% confidence interval: 0.001–0.56; p = 0.005). In contrast, Caucasians showed an increased TD prevalence of 166 in 190 (87.3%) compared to that of DH (30 in 44; 68.2%; POR 3.21; 95% confidence interval: 1.37–7.34; p = 0.0052). No statistically significant differences were observed between other ethnic groups.
TD is less prevalent in blacks and more prevalent in Caucasians. Blacks being more genetically diverse, this is an argument for an oligogenic inheritance of susceptibility to TD.
There is disagreement concerning the expression of thyroid peroxidase (TPO) in thyroid cancer, some studies finding qualitative as well as quantitative differences compared to normal tissue. To investigate TPO protein expression and its antigenic properties, TPO was captured from a solubilizate of thyroid microsomes by a panel of murine anti-TPO monoclonal antibodies and detected with a panel of anti-human TPO IgGκ Fab. TPO protein expression in 30 samples of malignant thyroid tissue was compared with TPO from adjacent normal tissues. Virtual absence of TPO expression was observed in 8 cases. In the remaining 22 malignant thyroid tumours the TPO protein level varied considerably from normal to nearly absent when compared to normal thyroid tissue or tissues from patients with Graves' disease (range less than 0.5 to more than 12.5 μg mg−1 of protein). When expressed TPO displayed similar epitopes, to that of TPO from Graves' disease tissue. The results obtained by the TPO capturing method were confirmed by SDS-PAGE and Western blot analysis with both microsomes and their solubilizates. The present results show that in about two-thirds of differentiated thyroid carcinomas, TPO protein is expressed, albeit to a more variable extent than normal; when present, TPO in malignant tissues is immunologically normal. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
differentiated thyroid cancer; TPO; mAb; IgGκ; Fab; epitope
In 67 patients with congenital hypothyroidism radioiodide tests, including thyroid scintigraphy, were used to study the aetiology. Athyrosis was found in 5 boys and 16 girls (31%), maldevelopment of thyroid gland in 1 boy and 2 girls (5%), ectopic gland in 4 boys and 20 girls (36%), and dyshormonogenesis in 7 boys and 12 girls (28%). In the last-mentioned group, organic binding of iodide was defective in 13; in the 9 families studied there was evidence of autosomal recessive inheritance. Duration of pregnancy had exceeded 42 weeks in 20 (32%) out of 63 pregnancies. Birthweights in 22 out of 64 patients and birth lengths in 21 out of 61 were over the 90th centile for the duration of gestation.
At the time of diagnosis a goitre was observed in only 3, and some thyroid tissue in 2 of the 19 patients with dyshormonogenesis, but a goitre frequently appeared later, particularly at puberty.
Neurological defects were found in 33%, and mental retardation in 44% of the patients. The prognosis was best in the children with a persisting ectopic thyroid gland and poorest in those with defective organic binding of iodide. The importance of early diagnosis of hypothyroidism is again emphasized.
Background. Vitiligo is a common skin disorder characterized by macular depigmentation of the skin. The etiopathogenesis of the disease is still unclear,
but there is evidence that autoimmunity and endocrine disfunction may be involved. Objective. The aim of this study was to determine whether vitiligo is statistically associated with thyroid autoimmunity. Method. In a prospective case-control study, we compared the frequency of thyroid autoantibodies (thyroglobulin antibody, anti-Tg and thyroid peroxidase antibody, and anti-TPO) in 33 patients with vitiligo and in 33 healthy volunteers. Thyroid autoantibodies and thyroid hormones (thyroxine (T4), triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured in all subjects. Results. Thyroid functional abnormalities were found in 6 (18.18%) patients. Anti-Tg and anti-TPO were positive in 9 (27.27%) and 8 (24.24%) patients, respectively. In control group, only one subject (3.03%) had abnormalities in thyroid hormonal status, and two subjects had positive thyroid autoantibodies. Compared with the control group, the frequency of both anti-Tg and anti-TPO was significantly higher in those with vitiligo (P < .05). Conclusion. This study shows a significant association between vitiligo and thyroid autoimmunity, and that tests to detect thyroid autoantibodies are relevant in patients with vitiligo.
To characterize the nature of thyroid peroxidase (TPO) autoantibodies present in the sera of patients with autoimmune thyroid disease, we cloned three IgG1/kappa Fab fragments which bind 125I-TPO. This was accomplished by the molecular cloning and expression in bacteria of IgG gene fragments from B cells infiltrating the thyroid of a patient with Graves' disease. The three Fab fragments (SP2, SP4, and SP5) are coded for by a common heavy chain (VH1, D, JH3) and three related, but different, light chains (VK1, JK2). The SP Fab fragments bind specifically to TPO with high affinities (6 x 10(-11)-2 x 10(-10) M) comparable to those of serum TPO autoantibodies. TPO autoantibodies represented by the SP Fab fragments are present in all 11 patients studied, constitute a high proportion (36-72%) of serum TPO autoantibodies in individual patients and interact with a conformational epitope on TPO.