Thyroid Diseases: Kendall-Taylor P

Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. · Department of Clinical Medicine, University of Insubria, Varese, Italy. · Thyroid. · Pubmed #18341379 No free full text.

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Kendall-Taylor P. · No affiliation provided · BMJ. · Pubmed #11976226 links to  free full text

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Kendall-Taylor P. · No affiliation provided · Clin Endocrinol (Oxf). · Pubmed #11422102 No free full text.

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Mallick UK, Lucraft H, Proud G, Perros P, Fenwick J, Kendall-Taylor P, Johnson S, Lennard T, Ball S, James RA, Douglas F, Weightman DR. · No affiliation provided · Clin Oncol (R Coll Radiol). · Pubmed #11202089 No free full text.

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Anonymous00251, Wiersinga WM, Perros P, Kahaly GJ, Mourits MP, Baldeschi L, Boboridis K, Boschi A, Dickinson AJ, Kendall-Taylor P, Krassas GE, Lane CM, Lazarus JH, Marcocci C, Marino M, Nardi M, Neoh C, Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Sartini MS, Stahl M, von Arx G. · Department of Endocrinology, Academic Medical Centre, Amsterdam, The Netherlands. · Eur J Endocrinol. · Pubmed #16914591 links to  free full text

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Vaidya B, Kendall-Taylor P, Pearce SH. · School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #12466323 links to  free full text

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Perros P, Kendall-Taylor P. · Department of Endocrinology, University of Newcastle upon Tyne, United Kingdom. · Thyroid. · Pubmed #11952047 No free full text.

Abstract: The medical management of thyroid-associated ophthalmopathy has been, and remains a clinical challenge. Several drugs have been used. Systemic steroids seem to be beneficial in patients with active disease. The evidence for the remaining drugs reported to be potentially useful, is unconvincing.

Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. · Endocrine Unit, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #15985483 links to  free full text

Abstract: CONTEXT: Radioiodine is an effective and safe treatment for hyperthyroidism but has been implicated as a risk factor for deterioration or new presentation of Graves' ophthalmopathy (GO). Prophylactic glucocorticoids appear to prevent this effect. OBJECTIVE: The objective of this study was to document the course of GO after radioiodine therapy. DESIGN: This was a prospective observational study. Patients were assessed at baseline and 2, 4, 6, and 12 months after radioiodine therapy. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Seventy-two GO patients with minimally active eye disease participated in the study. Intervention: A fixed dose of radioiodine was administered. T(4) was commenced 2 wk later to prevent hypothyroidism. MAIN OUTCOME MEASURES: Change in activity and severity of GO were analyzed. RESULTS: Exophthalmometer readings, the width of the palpebral aperture, diplopia scores, and the clinical activity score improved significantly. By clinically significant criteria, the eye disease improved in four patients (transiently in three of the four cases), most likely attributable to the natural course of the disease. No patient's eyes deteriorated. CONCLUSIONS: Radioiodine is not associated with deterioration of GO in patients with minimally active eye disease when postradioiodine hypothyroidism is prevented.

Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E, Andrews CD, Hesse L, Heverhagen JT, Heufelder AE, Kendall-Taylor P. · Department of Ophthalmology, Royal Victoria Infirmary, Newcastle on Tyne NE1 4LP, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #15579735 links to  free full text

Abstract: Several uncontrolled studies suggest octreotide is beneficial in thyroid-associated ophthalmopathy (TAO); however, the natural tendency of TAO to improve mandates randomized, controlled trials. We report results of a double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR). Fifty euthyroid patients (11 males, 39 females; age 22-74 yr, median 50 yr) with active TAO [clinical activity score (CAS) > or =3, NOSPECS (no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction) 2a-5a] of median duration 0.9 yr received either 30 mg LAR or placebo every 4 wk for 16 wk; both groups then received 30 mg LAR for wk 16-32 and were followed up without treatment for a further 24 wk. Objective assessments included all individual parameters of TAO, CAS, and derived scores for soft tissue inflammation (STI) and ophthalmopathy index (OI). During wk 0-16 there was significant reduction in STI, subjective diplopia, and CAS in LAR-treated patients; STI and CAS were also reduced with placebo. The OI reduced by -1.12 in LAR (P = 0.0017) vs. -0.23 in placebo (P = 0.33), giving a barely significant treatment effect by Wilcoxon (P = 0.043), but analysis of covariance failed to confirm this (P = 0.16). During wk 16-32 there was no significant change in OI in either group. The overall results (wk 0-32) showed reduction in STI and CAS in both groups. In this double-blind, placebo-controlled trial, no significant therapeutic effect of octreotide LAR was seen in patients with moderately severe TAO. The improvements in both treated and placebo groups emphasize that the results of open studies must be viewed with caution.

Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, Anonymous00022. · Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy. · Eur J Endocrinol. · Pubmed #18299459 links to  free full text

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Anonymous00698, Perros P, Baldeschi L, Boboridis K, Dickinson AJ, Hullo A, Kahaly GJ, Kendall-Taylor P, Krassas GE, Lane CM, Lazarus JH, Marcocci C, Marino M, Mourits MP, Nardi M, Orgiazzi J, Pinchera A, Pitz S, Prummel MF, Wiersinga WM. · Department of Endocrinology, Freeman Hospital, Newcastle upon Tyne, UK, and Department of Ophthalmology, Orbital Center, Academic Medical Center, Amsterdam, The Netherlands. · Eur J Endocrinol. · Pubmed #16868132 links to  free full text

Abstract: OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

Vaidya B, Shenton BK, Stamp S, Miller M, Baister E, Andrews CD, Dickinson AJ, Perros P, Kendall-Taylor P. · Department of Endocrinology, Newcastle University, Newcastle upon Tyne, United Kingdom. · Thyroid. · Pubmed #16187917 No free full text.

Abstract: Thyroid-associated ophthalmopathy (TAO) is thought to be a T-cell-mediated autoimmune disorder. We sought to characterize abnormalities in the peripheral blood T-cell subsets in patients with TAO, and examine whether the long-acting somatostatin analogue, octreotide-LAR, treatment affects these cells. We analyzed peripheral blood T-cell subsets by flow cytometry in 26 euthyroid patients with moderately severe active TAO and 24 controls. Twenty-five of the patients with TAO were enrolled in a randomized trial to receive either 30 mg of octreotide-LAR (n = 11) or placebo (n = 14) every 4 weeks for 16 weeks; all 25 patients subsequently received octreotide-LAR 30 mg every 4 weeks from week 16 to 32. T-cell subsets were analysed at baseline, week 16, and week 32. At baseline, the relative percentage of CD4+ helper T-cells (p = 0.0003) and the CD4+/CD8+ ratio (p = 0.008) were significantly higher in patients with TAO compared to controls. Patients with TAO had higher naïve active T cells (CD45RA+, CD45RA+ CD4+) and lower memory T cells (CD45RO+, CD45RO+ CD4+) than controls. At weeks 16 and 32, there were no significant differences in any T-cell subsets between the octreotide-LAR-treated and placebo groups. These results support a role of T cell in the pathogenesis of TAO, and show that octreotide-LAR has no effect on T-cell subsets during 32-weeks of treatment.

Hart RH, Kendall-Taylor P, Crombie A, Perros P. · Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom. · J Ocul Pharmacol Ther. · Pubmed #16117697 No free full text.

Abstract: BACKGROUND/AIMS: The results for 18 consecutive patients with severe thyroid-associated ophthalmopathy (TAO) treated with high-dose, pulsed intravenous methylprednisolone (MP) are presented in this paper. METHODS: Eighteen (18) patients with severe TAO, defined as either optic neuropathy, progressive diplopia, or severe soft-tissue swelling accompanied by evidence of NOSPECS class 2b or more severe eye disease, were studied in a prospective, noncontrolled case series. Patients were treated with 1.5 g of intravenous MP, divided over 3 days, followed by a tapering course of oral prednisolone. All patients were examined before treatment, 1 week and 1 month after commencement of treatment and at 2-3 monthly intervals thereafter. Assessment of visual acuity, differential intraocular pressure (IOP), soft-tissue inflammation, diplopia, and exophthalmometry were used to calculate a modified ophthalmopathy index (OI) for each patient at each visit. Median duration of follow-up was 14 months. RESULTS: A statistically significant reduction in OI following treatment with high-dose MP was observed after 1 week of treatment from 10.8 +/- 3.9 standard deviation (SD) to 8.3 +/- 3.4 (SD) (P < 0.001) and between 1 week and the end of the treatment period (OI, 7.2 +/- 3.4 (SD); P < 0.05). A response occurred in 83% of patients within a week but only 66% maintained this response. There was a significant negative correlation between response to treatment (OI before treatment-OI after treatment) and duration of eye disease (P = 0.034, Spearman correlation). CONCLUSIONS: High-dose, pulsed intravenous MP is an effective medical treatment for severe TAO. Responders can be identified within the 1st week. Treatment response is inversely related to disease duration.

Vaidya B, Oakes EJ, Imrie H, Dickinson AJ, Perros P, Kendall-Taylor P, Pearce SH. · Department of Endocrinology, University of Newcastle, Newcastle upon Tyne, UK. · Clin Endocrinol (Oxf). · Pubmed #12780750 No free full text.

Abstract: OBJECTIVE: Recent studies have shown that Graves' disease (GD) is linked to and associated with alleles of the cytotoxic T lymphocyte antigen-4 (CTLA4) locus. However, the true pathogenic polymorphism(s) at this locus remains uncertain. Moreover, the association studies of the promoter CTLA4(-318)C/T polymorphism in white GD populations have produced conflicting results. Therefore, we have analysed three CTLA4 single nucleotide polymorphisms, including promoter CTLA4(-318)C/T, exon 1 CTLA4(49)A/G and intron 1 CTLA4(1822)C/T in our GD cohort from the UK. PATIENTS AND METHODS: We studied 301 white patients with GD and 349 healthy ethnically matched local controls. Amongst GD probands, 129 had significant thyroid-associated orbitopathy (TAO; NOSPECS class III or worse). The CTLA4(-318)C/T, CTLA4(49)A/G and CTLA4(1822)C/T polymorphisms were genotyped by using the restriction enzymes MseI, Bst71I and HaeIII, respectively. RESULTS: We found no association between GD and alleles of CTLA4(-318)C/T. GD was found to be associated with the G allele of CTLA4(49)A/G[P = 5.9 x 10(-6), odds ratio (OR) 1.65] and the T allele of CTLA4(1822)C/T (P = 7.7 x 10(-6), OR 1.64). The frequencies of these alleles were significantly higher in GD probands with significant TAO than in those without TAO (G allele: P = 0.001, OR 1.68; T allele: P = 0.001, OR 1.70). CONCLUSIONS: The promoter CTLA4(-318)C/T polymorphism is not in linkage disequilibrium with the pathogenic polymorphism(s) at the CTLA4 locus. The alleles of both the exon 1 CTLA4(49)A/G and the intron 1 CTLA4(1822)C/T polymorphisms are associated with GD, which is stronger in patients with TAO.

Prummel MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, Perros P, Neoh C, Dickinson AJ, Lazarus JH, Lane CM, Heufelder AE, Kahaly GJ, Pitz S, Orgiazzi J, Hullo A, Pinchera A, Marcocci C, Sartini MS, Rocchi R, Nardi M, Krassas GE, Halkias A. · Department of Endocrinology and Metabolism, F5-171 Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands. · Eur J Endocrinol. · Pubmed #12720530 links to  free full text

Abstract: To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. AIM: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. METHODS: Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. RESULTS: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. CONCLUSIONS: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.

Kendall-Taylor P, Anonymous00215. · Department of Medicine, Leech Bldg, Floor 4, Medical School, University of Newcastle, Newcastle on Tyne, NE2 4HH, UK. · Clin Endocrinol (Oxf). · Pubmed #12641620 No free full text.

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Vaidya B, Pearce SH, Charlton S, Marshall N, Rowan AD, Griffiths ID, Kendall-Taylor P, Cawston TE, Young-Min S. · Department of Endocrinology, School of Clinical Medical Sciences, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, UK. · Rheumatology (Oxford). · Pubmed #11886967 links to  free full text

Abstract: OBJECTIVE: To examine the allelic association of the single nucleotide polymorphism (CTLA4A/G) in exon 1 of the cytotoxic T lymphocyte antigen-4 (CTLA4) gene with early rheumatoid arthritis (RA). METHODS: One hundred and twenty-three unrelated white probands with early RA from the north-east of England and 349 local ethnically matched controls were studied. The CTLA4A/G polymorphism was genotyped with a polymerase chain reaction (PCR) method and digestion with the restriction enzyme Bst71I. Probands were also screened by allele-specific PCR for alleles HLA DRB1*01 and DRB1*04. RESULTS: The frequency of the G allele at CTLA4A/G was significantly increased in probands with early RA compared with controls [43 vs 36%; P=0.028, odds ratio (OR) 1.35, 95% confidence interval (CI) 1.01-1.82]. Most of this increased frequency was attributable to RA individuals with coexisting autoimmune thyroid disease or type 1 diabetes (58 vs 36% in controls; P=0.005, OR 2.50, CI 1.29-4.84). The frequency of the G allele in RA patients without autoimmune endocrinopathy was 40%, which was not significantly different from that in controls (P=0.140). CONCLUSION: The association between the CTLA4 G allele and early RA is largely explained by individuals with RA who have coexisting autoimmune endocrinopathies.

Davison S, Lennard TW, Davison J, Kendall-Taylor P, Perros P. · Endocrine Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK. · Clin Endocrinol (Oxf). · Pubmed #11318795 No free full text.

Abstract: A 31-year-old woman presented with neutropenia due to thionamide drug therapy for Graves' disease. She also reported 8 weeks of amenorrhoea and had a positive pregnancy test. Her drug therapy was discontinued and her neutropenia resolved uneventfully. The hyperthyroidism recurred a week later. After consideration of all treatment options, it was decided to observe until 14 weeks when an elective thyroidectomy was planned. Mother and fetus were monitored closely and both tolerated moderate hyperthyroidism well. At 14 weeks the patient underwent a total thyroidectomy after rendering her euthyroid with a short course of sodium ipodate. Labour was induced at 41 weeks. Delivery was complicated by fetal distress and precipitated a forceps delivery. A 3250 g male infant was born with poor Apgar score and required 2 h of ventilation. At 1 year, the child had reached all developmental milestones at appropriate times. Both mother and fetus may tolerate moderate thyrotoxicosis well in early pregnancy, an alternative that should be considered when thionamide drug therapy is contraindicated.

Imrie H, Vaidya B, Perros P, Kelly WF, Toft AD, Young ET, Kendall-Taylor P, Pearce SH. · Endocrine Group, Department of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HH. · J Clin Endocrinol Metab. · Pubmed #11158020 links to  free full text

Abstract: Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P = 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (lambda(s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population.

Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D, Large DM, Toft AD, Kendall-Taylor P, Pearce SH. · Department of Endocrinology, School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom. · Am J Hum Genet. · Pubmed #10762555 links to  free full text

Abstract: Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.

Gleeson H, Kelly W, Toft A, Dickinson J, Kendall-Taylor P, Fleck B, Perros P. · Metabolic Unit, Western General Hospital, Edinburgh, United Kingdom. · Thyroid. · Pubmed #10595461 No free full text.

Abstract: Four unusual cases of patients are described with severe thyroid eye disease (TED) who presented with primary hypothyroidism and thyroid-associated dermopathy (TAD). All four patients had moderate or severe TED and elevated circulating thyrotropin (TSH) receptor antibodies.

Esapa CT, Duprez L, Ludgate M, Mustafa MS, Kendall-Taylor P, Vassart G, Harris PE. · Department of Diabetes, Endocrinology and Internal Medicine, King's Guy's and St Thomas' School of Medicine, London, United Kingdom. · Thyroid. · Pubmed #10560955 No free full text.

Abstract: An infant girl was born at 37 weeks gestation and found to be clinically thyrotoxic at 9 months of age. Thyroid autoantibodies were negative, and thyroid function failed to normalize with medical treatment. The patient underwent a total thyroidectomy. DNA obtained from her thyroid gland and leukocytes was analyzed for thyrotropin receptor (TSHR) mutations using single strand conformation polymorphism and direct sequencing. A mobility shift of polymerase chain reaction (PCR)-amplified DNA was detected on single strand conformation polymorphism gel. Direct sequencing identified a novel point mutation in the fifth transmembrane domain of the TSH receptor at codon 597 (GTC to CTC), resulting in the amino acid substitution of leucine for valine. The mutation was heterozygous and germline, and was not identified in DNA from either of her parents. Expression of the V597L mutant is transiently transfected COS 7 cells displayed increased constitutive cyclic adenosine monophosphate (cAMP) production compared with the wild-type receptor. The mutant is expressed at very low levels on the surface of COS cells, and its response to TSH is marginal.

Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. · Department of Diabetes, Endocrinology and Internal Medicine, Guys', King's and St Thomas' School of Medicine, London, UK. · Clin Endocrinol (Oxf). · Pubmed #10468914 No free full text.

Abstract: OBJECTIVE: Mutations at codons 12, 13 or 61 of ras which result in constitutive activation occur frequently in human malignancies. There have been varied reports on their prevalence and hence their likely significance in the pathogenesis of primary thyroid neoplasia. To address this, we have examined a large series of benign and malignant thyroid tumours for ras mutations. DESIGN: Genomic DNA was analysed for the presence of mutations at codons 12, 13 and 61 of H-ras, K-ras and N-ras by allele-specific oligonucleotide hybridization. Direct DNA sequencing was used to confirm the mutations. PATIENTS: A total of 90 samples with benign (66) and malignant (24) thyroid disease were investigated. RESULTS: A total of 14/90 (15.5%) samples had a ras mutation. All mutations were at codon 61 of either N-ras or K-ras. The positive cases were 1/25 (4%) nodular goitre, 7/38 (18%) follicular adenoma, 4/9 (44%) follicular carcinoma, 1/1 anaplastic carcinoma, 1/1 follicular variant of papillary carcinoma, and 1 metastatic follicular carcinoma in which the primary tumour had the same mutation. CONCLUSIONS: Our data demonstrate a relatively low overall prevalence of ras mutations in thyroid neoplasia, with a predominance in follicular neoplasms. Their presence in follicular adenomas suggests that they may have an early aetiological role in the development of thyroid neoplasia.

Reardon W, Coffey R, Chowdhury T, Grossman A, Jan H, Britton K, Kendall-Taylor P, Trembath R. · Department of Clinical Genetics and Fetal Medicine, Institute of Child Health, London, UK. · J Med Genet. · Pubmed #10465108 links to  free full text

Abstract: BACKGROUND: We have sought to establish the prevalence of goitre within a Pendred syndrome (PS) cohort and to document the course of thyroid disease in this patient group. As part of a genetic study of PS we have assessed 57 subjects by perchlorate discharge test and in 52 (M 21, F 31, age range 9-54 years) a discharge of radioiodide of >10% was observed. RESULTS: Goitre was present in 43 (83%) of the cohort (28 F, 15 M), generally developing after the age of 10 years, 56% remained euthyroid (age range 9-37 years), and 19 patients (44%) had objective evidence of hypothyroidism, all of whom had goitre. CONCLUSIONS: In summary, thyroid dysfunction in PS is variable and inclusion of goitre as a diagnostic requirement will maintain significant underascertainment. The recent identification of the genetic defect underlying PS is likely to provide an important diagnostic aid in the identification of this disorder and this communication should assist clinicians in identifying deaf patients who ought to be considered for this investigation.

Vaidya B, Coffey R, Coyle B, Trembath R, San Lazaro C, Reardon W, Kendall-Taylor P. · Department of Medicine (Endocrinology), University of Newcastle upon Tyne, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #10443670 links to  free full text

Abstract: Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness. There is no specific biochemical marker of this disease, and the diagnosis depends upon the demonstration of the triad of congenital sensorineural hearing loss, goiter, and abnormal perchlorate discharge test. Pendred syndrome is caused by mutations within the putative ion transporter gene (PDS gene), located on chromosome 7q. A wide variation in the clinical presentation of this condition, and its well documented phenotypic overlap with other thyroid disorders (such as Hashimoto's thyroiditis), can lead to diagnostic difficulties. The potential for misdiagnosis increases when these disorders occur coincidentally in the same family. We describe a kindred in which Pendred syndrome, autoimmune thyroiditis, and simple goiter coexisted, to highlight these diagnostic pitfalls and to illustrate the use of mutational analysis in resolving diagnostic confusion.