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BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P

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.

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.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.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) (P0.001) and between 1 week and the end of the treatment period (OI, 7.2 +/- 3.4 (SD); P0.05). 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).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.

Objective: To review clinical presentation, management and outcomes following different therapies in patients with pituitary apoplexy. Methods: Retrospective analysis of case-records of patients with classical pituitary apoplexy treated in our hospitals between 1983–2004. Results: Forty-five patients (28 men; mean age 49 years, range 16–72 years) were identified. Only 8 (18%) were known to have pituitary adenomas at presentation. Thirty-four (81%) patients had hypopituitarism at presentation. CT and MRI identified pituitary apoplexy in 28% and 91% cases, respectively. Twenty-seven (60%) patients underwent surgical decompression, whilst 18 (40%) were managed conservatively. Median time from presentation to surgery was 6 days (range 1–121 days). Patients with visual field defects were more likely than those without these signs to be managed surgically (p = 0.01). Complete or near-complete resolution occurred in 93% (13/14), 94% (15/16) and 93% (13/14) of the surgically treated patients with reduced visual acuity, visual field deficit and ocular palsy, respectively. All patients with reduced visual acuity (4/4), visual field deficit (4/4) and ocular palsy (8/8) in the conservative group had complete or near-complete recovery. Only 5 (19%) patients in the surgical group and 2 (11%) in the conservative group had normal pituitary function at follow up. One (4%) patient in the surgical group and 4 (22%) in the conservative group had a recurrence of pituitary adenoma. Conclusions: This large series suggests that the patients with classical pituitary apoplexy, who are without neuro-ophthalmic signs or exhibit mild and non-progressive signs, can be managed conservatively in the acute stage.

Summary 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 × 10−6, odds ratio (OR) 1·65] and the T allele of CTLA4(1822)C/T (P = 7·7 × 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.

Hyperprolactinaemia frequently causes secondary hypogonadism through central suppression of gonadotropin secretion. Macroprolactinomas (>1 cm diameter) are more common in males and may additionally cause more generalised hypopituitarism. Recovery of the thyrotropic and/or corticotropic axes is well described following selective adenomectomy, but remains poorly defined in relation to medical (dopamine-agonist) therapy of macroprolactinomas. We therefore performed a retrospective examination of case records of male patients who had received medical therapy alone for macroprolactinoma between 1980–2001 (n = 35) and in whom tumor shrinkage was documented by interval pituitary imaging (reported throughout by a single neuroradiologist). Mean prolactin level at baseline was 59,932 mU/L (median 31,400; range 3,215–332,000); mean period of follow up was 4.2 years (median 2.6; range: 1.0–15). Defects of the following axes were evident at diagnosis: LH/FSH-testosterone (n = 27; 77%), TSH-T4 (n = 14; 41%-not including one case with pre-existing 1° hypothyroidism), ACTH-cortisol (n = 8; 23%). Overall, 14 men (40%) were deficient in 1 axis, seven (20%) in 2 axes and seven (20%) in 3 axes. Growth hormone secretory status was not systematically evaluated. In all but 6 patients, prolactin levels fell to normal or near-normal levels (mean 764 mU/L; median 260; range

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 ...

The initial presentation of macroprolactinoma with visual field impairment, especially in males, is well recognized. Successful treatment with dopamine agonist therapy is characterized by a reduction in hyperprolactinaemia and often rapid and progressive resolution of the visual impairment. A small proportion of patients may subsequently develop a secondary deterioration in both their visual fields and visual acuities despite normalization of prolactin levels and tumour shrinkage. When pituitary apoplexy can be excluded this may result from traction on the optic chiasm which is pulled down into the now partially empty sella. We report a series of seven patients in whom chiasmal traction is believed to be the cause of their secondary deterioration in visual acuity occurring after dopamine agonist therapy for macroprolactinoma. The clinical history of two patients both of whom had rapid resolution of field defect with bromocriptine therapy but subsequently developed a recurrence of their bitemporal hemianopia is detailed. In both patients MRI scanning showed not only tumour involution but also marked optic chiasm herniation into the pituitary fossa. Surgical treatment was considered too risky; but on reduction of bromocriptine dosage the field defect improved in both cases; there was a modest elevation of prolactin and a degree of tumour re-expansion. The latter is believed to have released tethering of the optic chiasm and/or its vascular supply and thus obviated the need for surgery. Regular monitoring of visual fields in patients with macroprolactinoma receiving medical treatment is therefore important. Early recognition of secondary field loss due to chiasmal herniation enables correction of the visual field loss by manipulation of the medical therapy.

IntroductionIn recent years there have been many advances in ourunderstanding of the molecular pathogenesis of both congenitaland acquired adrenocortical failure (autoimmune or otherwise).As well as providing some fascinating insights into adrenalgland development and steroid hormone biosynthesis, therecognition of these various distinct disorders, either at aclinical or molecular genetic level, often has implications forthe management of the patient and their immediate family. In thispaper, we review the salient clinical and molecular features of thevarious causes of primary adrenocortical failure (Table 1).Genetics of autoimmune Addison’s diseaseAutoimmune Addison’s disease (AAD) is a chronic disorder ofthe adrenal gland, characterized by insufficiency of adrenocor-tical hormones due to autoimmune destruction of steroidogenicadrenocortical cells (Oelkers, 1996). The cytochrome P450enzymes involved in steroidogenesis, including 21-hydroxylase(Baumann-Antczak et al., 1992; Winqvist et al., 1992), 17-hydroxylase (Krohn et al., 1992) and side chain cleavageenzyme (Winqvist et al., 1993) have been identified as primaryautoantigens in AAD. With the overall decrease in theprevalence of tuberculosis, AAD has emerged as the mostcommon cause of primary adrenal failure in developedcountries (Nerup, 1974; Kong & Jeffcoate, 1994). Nevertheless,AAD is a relatively rare endocrinopathy; recent epidemiologi-cal studies showing an estimated prevalence in the generalEuropean population of about 100 per million (Kong J Laureti et al., 1999).The results of human leucocyte antigen (HLA) typing, takentogether with the clinical heterogeneity of presentation anddifferent modes of inheritance, have suggested distinctpathogenic bases for different forms of AAD. Thus, AADmay occur in isolation, as a manifestation of the autoimmunepolyendocrinopathy type 1 syndrome (APS1), or as part of theautoimmune polyendocrinopathy type 2 (APS2) syndrome(Table 1) (Spinner et al., 1968; Neufeld et al., 1981; Maclaren& Riley, 1986).Autoimmune polyendocrinopathy type 1 syndrome: amonogenic autoimmune disorderIn the autoimmune polyendocrinopathy type 1 (APS1)syndrome, which is also known as the autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy(APECED) syndrome, AAD occurs in association withautoimmune hypoparathyroidism, chronic mucocutaneous can-didiasis and other organ-specific autoimmune disorders. Theseinclude type 1 diabetes, primary gonadal failure, perniciousanaemia, chronic active hepatitis and hypothyroidism (Neufeldet al., 1981; Ahonen et al., 1990). The age of onset of AAD inAPS1 is typically between 11 and 15years, although othermanifestations of APS1 (e.g. hypoparathyroidism and candi-diasis) are likely to present at an earlier age. APS1 is amonogenic disorder with autosomal recessive inheritance,affecting both sexes with equal prevalence (Ahonen, 1985),and is rare in most populations. However, because of foundereffects, it is relatively common in the Finnish population andIranian Jews with estimated prevalences of 1/25000 and 1/9000, respectively (Ahonen, 1985; Zlotogora & Shapiro, 1992).Initial genetic studies of APS1 focused on HLA, and noassociation of this disorder with any specific HLA haplotypehas been found (Neufeld et al., 1981; Maclaren & Riley, 1986;Aaltonen et al., 1993; Huang et al., 1996). The gene underlyingAPS1 was subsequently localized on chromosome 21q22 bylinkage analysis (Aaltonen et al., 1994) and identified bypositional cloning (Finnish-German APECED consortium,1997; Nagamine et al., 1997). This gene, designated auto-immune regulator-1 (AIRE-1), encodes a 545 amino acidprotein that has two plant homeodomain (PHD)-type zinc-finger motifs, suggesting a role as a transcription factor(Finnish-German APECED consortium, 1997; Nagamine etal., 1997). AIRE-1 mRNA is expressed in lymphoid tissuesincluding thymus, lymph node and spleen, and possibly also inother tissues including the adrenal cortex (Finnish-GermanAPECED consortium, 1997; Nagamine et al., 1997), whichsuggests that it may have an important role in the developmentof a normal immune response.

Although autoimmune Addison's disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964de113) in United Kingdom subjects with APS1, by using the restriction enzymes Bst7II and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.

The use of somatostatin analogues for the treatment of acromegaly is now well established. Recently long-acting preparations of octreotide and lanreotide have been introduced. In this study we have assessed the efficacy and tolerability of the long acting somatostatin analogue octreotide LAR in patients with acromegaly, and compared it with lanreotide SR.

OBJECTIVE The normal decline in physiological function with ageing is associated with a decrease in bioavailable growth hormone. Growth hormone has been shown to alter body composition and increase fat-free mass in older men. Increased physical fitness is accompanied by an increase in 24-h growth hormone release. The purpose of this study was to examine the effect of exercise on declining growth hormone concentrations with increasing age. DESIGN AND PATIENTS The growth hormone production of 10 male subjects running over 40 miles per week was compared to 10 healthy age-matched sedentary males (controls 57.7 ± 2.8 vs. runners 60.5 ± 3.4 years). All subjects underwent a basal assessment including a two-hour serum growth hormone profile followed by estimation of maximal exercise capacity on a cycle ergometer with growth hormone estimations at peak exercise activity and every five minutes whilst cycling at 40% of maximal exercise capacity. RESULTS Maximal exercise capacity confirmed the lifestyles of the two groups (VO2 max controls 22.36 ±6.05 vs. runners 34.91 ± 13.13 l/min/kg, P = 0.01). The runners had lower body-mass indices than controls (BMI 22.3 ± 1.5 vs. 25.5 ± 2.0 kg/m2, P = 0.002). Peak growth hormone level during a two-hour resting profile was higher in the runners (median (range) controls 2.10 (0.20–12.20) vs. runners 5.25 (0.80–21.00) mU/l, P = 0.03) as was the average growth hormone level during the two hour profile (mean growth hormone per 2 h median (range): controls 0.54 (0.03–4.88) vs. runners 2.17 (0.25–7.45) mU/l, P = 0.04). Growth hormone production at maximal exercise capacity was similar. Sex hormone binding globulin and testosterone were significantly higher in the runners. CONCLUSIONS The results suggest that regular intensive exercise in older male subjects is associated with higher growth hormone and testosterone levels and that exercise may have a role in counteracting the normal decline in growth hormone with ageing.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.

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.

OBJECTIVE Few data exist on the prevalence of hyperprolactinaemia in the community. This study was intended to determine the prevalence of hyperprolactinaemia in a sample closely matched to the current British population aged 38 years and over. DESIGN AND PATIENTS The 1877 survivors at the 20-year follow-up of the Whickham Survey were a cross-sectional sample of the community aged 38 years and over. Serum was frozen and stored at −30°C from 90% of the survivors (751 men, 924 women, median age 58 years (range 38 to 93 years)) who participated in the follow-up survey. MEASUREMENTS Two years after the follow-up survey, serum prolactin concentrations were measured by ELISA/1 step sandwich assay (reference range ≤ 600 mU/l in men and women). A repeat prolactin measurement was made in those subjects who had prolactin levels within the top 2.5% of men and women in this sample. RESULTS At screening, 0.7% of the men and 2.5% of the women had serum prolactin levels greater than 600 mU/l. For men, 2.5% were above 400 mU/l. The prevalence of hyperprolactinaemia, if defined as greater than 400 mU/l in men and greater than 600 mU/l in women on repeat testing, was 1.4% in the men and 1.2% in the women. The aetiology in men was prolactin-raising drugs (n = 3), renal failure (n = 1), microprolactinoma (n = 1), and unknown (n = 2), and in women it was prolactin-raising drugs (n = 7), microprolactinoma (n = 1), and unknown (n = 1). Logarithmic transformation of serum prolactin concentrations produced Gaussian distributions with 95% reference ranges of 60–430 mU/l in men and 40–560 mU/l in women. No significant relationship was found in either sex between hyperprolactinaemia and age or evidence of autoimmune thyroid disease at either survey. In women, there was no association with age, distance beyond the menopause or duration of reproductive years but prolactin levels were slightly higher in those on oestrogen therapy (geometric mean prolactin 226 mU/l compared to 178 mU/l; t-test on log prolactin t = 3.79; P

The characterization of a spontaneous animal model equivalent to a human form of thyrotoxicosis would provide a useful resource for the investigation of the human disorder. Feline thyrotoxicosis is the only common form of hyperthyroidism found in domestic or laboratory animals, but its etiopathogenesis remains poorly defined. We have used the polymerase chain reaction (PCR) to amplify codons 480-640 of the previously uncharacterized feline thyrotropin receptor (TSHR) gene, and have determined the DNA sequence in this transmembrane domain region. We have analyzed single stranded conformational polymorphisms in thyroid DNA from 11 sporadic cases of feline thyrotoxicosis and leukocyte DNA from two cases of familial feline thyrotoxicosis. We have also determined the DNA sequence of this region of the TSHR in five of the cases of sporadic feline thyrotoxicosis and the two familial thyrotoxic cats. The normal feline TSHR sequence between codons 480-640 is highly homologous to that of other mammalian TSHRs, with 95%, 92%, and 90% amino acid identity between the feline receptor and canine, human, and bovine TSHRs, respectively. Thyroid gland DNA from 11 cats with sporadic thyrotoxicosis did not have mutations in this region of the TSHR gene. Leukocyte DNA from two littermates with familial feline thyrotoxicosis did not harbor mutations of this region of the TSHR gene. These studies suggest that TSHR gene mutations are not a common cause of feline thyrotoxicosis.

Pendred syndrome is an autosomal recessive condition classically characterized by deafness and goitre. Since both cochlear and thyroid pathology are required to secure the diagnosis, it is unclear whether the condition might present without the classical features. The perchlorate discharge test, the gold-standard investigation for Pendred syndrome, is non-specific, and in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown. We used the recent mapping of the gene to chromosome 7q to identify pedigrees with a likely diagnosis of Pendred syndrome, and assessed the prevalence of clinical parameters of disease in affected patients. Thirty-six familial cases showed co-segregation between disease and the Pendred syndrome locus on chromosome 7q. Clinical and investigative findings were compared in index cases (n = 18) vs. affected siblings (n = 18). The overall prevalence of goitre was 73%, higher in index cases (94%) than in siblings (56%), many of whom had not previously been considered to have the condition. One perchlorate discharge test was false-negative (2.9%). Radiological malformations of the cochlea were identified in 86% of cases. Securing a diagnosis of Pendred syndrome may be difficult, especially in the single case. The perchlorate discharge test, although valuable, is difficult to undertake in the younger patient, and radiology may assist in diagnosing such patients.

The cAMP pathway plays a central role in thyroid follicular cell growth and function. Mutations of the TSH receptor (TSHR) or G proteins (gsp) that activate adenylyl cyclase have been identified in autonomously functioning thyroid nodules. Gsp mutations have been identified also in other forms of thyroid neoplasia, but their reported prevalence has been extremely variable. We have studied the prevalence of gsp mutations and activating mutations of Gi2α (gip) in a series of 66 benign and 34 malignant thyroid tumors. Thirty-six tumors were from Boston and 64 from the UK. In addition, we examined the 64 UK tumors for mutations of the TSHR gene. DNA extracted from fresh-frozen or paraffin-embedded tissue was amplified by PCR and examined for mutations using oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis. No G protein gene mutations were identified in the Boston tumors. One gsp mutation, R201C, in a Hürthle cell adenoma and 1 gip mutation, R179C, in a follicular adenoma were demonstrated in tumors from the UK. Oligonucleotide-specific hybridization and single-strand conformation polymorphism analysis of the UK tumors did not demonstrate any mutations of the TSHR gene. Eleven normal thyroid tissue samples were wild-type for Gsα, Gi2α, and the TSHR gene.

OBJECTIVE Previous studies have shown that somatostatin analogues such as octreotide and lanreotide are effective in suppressing GH and IGF-I levels in acromegaly, but the mode of administration and the frequency of injections were inconvenient for the patients. We have evaluated the effects of a new slow-release (SR), long-acting formulation of lanreotide, a somatostatin analogue, on clinical, biochemical and safety responses in acromegaly. DESIGN We studied the effects of SR-lanreotide 30mg administered intramuscularly twice or three times monthly for 6 months. Ten patients were studied, in whom acromegaly was confirmed by clinical features,mean GH>5 mU/l, and failure to suppress GH to

Summary BACKGROUND AND OBJECTIVE Activating mutations of Gsα (gsp) and Gi2α (gip) have been described in various endocrine neoplastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in clinically non-functioning pituitary tumours (NFTs) and to compare the clinical phenotypic characteristics of tumours bearing G protein gene mutations with wild-type tumours. DESIGN Twenty-two NFTs and 20 normal anterior pituitary glands screened for G protein gene mutations. PATIENTS Twenty-two patients; 14 female (median age 59 years, range 19–76) and 8 males (median age 66·5 years, range 50–77). MEASUREMENTS Site-directed hybridization or direct sequencing of polymerase chain reaction amplified Gsα and Gi2α DNA. RESULTS G protein gene mutations were identified in 3/22 (13%) of NFTs. Two tumours demonstrated gsp mutations, one at codon 201 arginine to cysteine, and the second at codon 227 giutamine to arginine. Three tumours demonstrated gip mutations at codon 205 giutamine to arginine. Two tumours with gsp mutations also harboured gip mutations. All tumours with G protein gene mutations demonstrated local bone infiltration into the surrounding structures. CONCLUSIONS G protein gene mutations have been demonstrated in a proportion of non-functioning pituitary tumours. The presence of dual gsp and gip mutations in two tumours suggests the possibility of multiple hits in a stepwise pathogenesis of pituitary neoplasia.

The thyrotropin (TSH) receptor is implicated in the pathogenesis of thyroid-associated ophthalmopathy, but its presence has not been demonstrated in orbital tissues. Binding of 125I-TSH to porcine orbital connective tissue and thyroid membranes was studied. At pH 7.4 125I-TSH bound to thyroid membranes with high affinity, but not to orbital connective tissue membranes. At pH 5.2, binding of 125I-TSH was evident on thyroid and orbital connective tissue membranes, although of low affinity. Low affinity binding at pH 5.2, could also be demonstrated on orbital fibroblasts; binding to membranes prepared from extraocular muscle, or from abdominal adipose tissue was not detected. Immunoglobulin G from healthy subjects (n = 17) and patients with ophthalmopathy (n = 19) were tested for inhibition of 125I-TSH binding to membranes. As anticipated patients' IgG exhibited greater inhibition than normal controls with thyroid membranes at pH 7.4 (p0.001). Similar results were obtained with thyroid membranes (p0.05), and orbital connective tissue membranes at pH 5.2 (p0.001). Significant correlations were found when percentage inhibition by IgG was compared between: thyroid membranes at pH 7.4 and thyroid membranes at pH 5.2, orbital connective tissue membranes at pH 5.2 and thyroid membranes at pH 7.4, and orbital connective tissue membranes at pH 5.2 and thyroid membranes at pH 5.2. A low affinity TSH-binding site is present in orbital connective tissue, and is recognized by IgG's from patients with ophthalmopathy which suggests that TSH receptor antibodies may target the orbit.

Activin A is a homodimer of inhibin βA subunits, and was first isolated from gonadal fluids on the basis of its ability to stimulate FSH secretion by rat pituitary cells in vitro. The βA subunits of activin and their mRNAs have been found in many cell types, in several species and at different stages of development, suggesting that activin A has a wide range of diverse biological roles. Apart from the modulation of gonadotroph function, in-vitro studies have demonstrated inhibitory effects of activin A on GH synthesis, GH secretion and possibly somatotroph proliferation. We have therefore investigated the potential role of activin A in the pathophysiological regulation of GH secretion by human somatotrophinoma cells using in-vitro techniques. Cell cultures were established by enzyme dispersion of adenoma tissue obtained from six patients with acromegaly, and treated for 72 h with 0·01–10 nmol recombinant human activin A/1 followed by a 2-h stimulation test with 10 nmol GH-releasing factor (GRF)/l. Medium was collected at 24, 48 and 72 h, as well as after GRF treatment, and GH concentrations were measured by immunoradiometric assay. Basal GH secretion from the cells of two tumours was significantly stimulated 12–63% above control values during treatment with 0·01–10 nmol activin A/1, whereas the peptide had no effect on GH release from cells of the remainder of the tumours. GRF significantly stimulated GH release from the cells of two different adenomas, and pretreatment with 0·01–1 nmol activin A/1 partially but significantly blocked GRF-stimulated GH release from the cells of one of these. These data demonstrate that activin A stimulates basal GH secretion from the cells of some, but not all, human somatotrophinomas in vitro. Pretreatment with the peptide may also partially block GRF-stimulated GH release from GRF-responsive somatotrophinoma cells. The importance of these actions in the pathophysiological regulation of human somatotrophinomas remains to be determined. Journal of Endocrinology (1993) 137, 329–334

Summary BACKGROUND The pathogenesis of thyroid-associated ophthalmopathy is thought to be autoimmune, although environmental and genetic factors are also considered to be important. As the morbidity of thyroid-associated ophthalmopathy is considerable and treatment often unsatisfactory, there a need to identify possible predisposing factors. OBJECTIVE The study was undertaken in order to ascertain the relationship between age, gender and severity of thyroid-associated ophthalmopathy. PATIENTS One hundred and one consecutive patients with thyroid-associated ophthalmopathy who presented over a period of 5 years to a combined thyroid-eye clinic. METHODS Patients were assessed by grading their inflammatory signs and degree of diplopia, and by measurement of exophthalmos, palpebral aperture, differential intraocular pressure, and visual acuity. On the basis of the above an ophthalmopathy index was devised to grade the overall severity of eye disease. RESULTS The mean age was 49.2 years (SD 13.4), the female-to-male ratio was 405, and mean ophthalmopathy index 6.49 (SD 3.3). Optic nerve compression was present in 9–9% of patients. There was a positive relationship between age and ophthalmopathy index (P

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.

FAMILIAL hypoparathyroidism is an unusual condition that can present at any time from early infancy until well into adulthood.1 2 3 4 It can be inherited in an autosomal dominant,3 , 4 autosomal recessive,5 or X-linked recessive6 , 7 pattern. Its presence has been associated with other congenital abnormalities, such as absence of the thymus (DiGeorge's syndrome).8 We recently encountered a patient with long-standing sensorineural deafness who presented with symptoms of thirst and polyuria and was found to have diabetes mellitus. He also had hypocalcemia, subsequently proved to be due to hypoparathyroidism, and a high serum creatinine concentration; further studies revealed small kidneys with a large right-sided . . .

Thyroid-associated ophthalmopathy is thought to be an autoimmune disease affecting the orbit. The precise pathogenetic mechanisms are not known, but extraocular muscle and/or orbital fibroblasts are the likely targets of the autoimmune attack. Sera from 41 normal controls, 79 patients with thyroid-associated ophthalmopathy and 72 patients with other autoimmune diseases were examined for antibodies to cultured orbital fibroblasts and extraocular muscle by enzyme-linked immunosorbent assay. Orbital fibroblast antibody levels varied widely in all subject groups studied, and failed to distinguish patients with thyroid-associated ophthalmopathy from patients with other autoimmune diseases or controls. Eye-muscle binding antibody levels were higher amongst patients with ophthalmopathy compared to normal controls and patients with Graves' hyperthyroidism without clinical evidence of ophthalmopathy. Furthermore, eye-muscle binding antibody levels were found to be particularly high in patients with ophthalmopathy and concurrent dermopathy, and in patients with ophthalmic (euthyroid) Graves' disease.

Thec-erbB-2 proto-oncogene encodes a 190-kD putative membrane receptor that shows considerable homology to the epidermal growth factor (EGF) receptor.c-erbB-2 is overexpressed in many human tumors but has not previously been studied in pituitary tumors. In the normal pituitary gland, EGF is believed to play a regulatory role, but EGF receptors were found to be absent in a study of 22 pituitary adenomas. In the present study, 32 human pituitary adenomas and 7 samples of normal human pituitary were stained for thec-erbB-2 oncoprotein. All were negative for membrane staining, which suggests that amplification of thec-erbB-2 oncogene is not important in the etiology and progression of human pituitary adenomas.

Epidermal growth factor (EGF) was measured in the saliva of 36 patients with chronic renal failure (CRF) and 29 matched control subjects. Salivary EGF in controls was 0.65 +/- 0.009 nmol/L compared with 0.99 +/- 0.24 nmol/L in nondialyzed CRF patients, 1.15 +/- 0.23 in hemodialyzed patients and 1.96 +/- 0.25 (p less than 0.01, Wilcoxon Rank Sum Test) in CAPD-treated patients. On Sephadex chromatography, the major peak of immunoreactive EGF from patient and control saliva samples coeluted with purified human EGF. We conclude that salivary concentrations of human EGF are significantly elevated in end-stage renal failure, particularly in patients treated by CAPD.

L-363,586 is a cyclic, hexapeptide analogue of somatostatin-14 with potent inhibitory actions on rat growth hormone (GH) release in vitro. The studies reported here investigate the direct effects of L-363,586 on basal and growth hormone-releasing factor (GRF)-stimulated GH secretion from 3 human somatotrophinomas in dispersed cell culture. 1nM and 10nM L-363,586 inhibited both basal and GRF-stimulated GH release from cells of all 3 somatotrophinomas during a 2h treatment period, whilst 100nM L-363,586 had a prolonged inhibitory action on basal GH secretion from cells of 2 of the tumours throughout treatment and recovery periods. Rebound release of GH was observed with cells of 1 tumour following treatment with L-363,586 plus GRF. The actions of L-363,586 were similar to those of somatostatin-14. These data suggest that L-363,586 may have a role in the treatment of acromegaly.

Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Serum concentrations of LH and FSH and their response to the separate administration of GnRH (100 micrograms i.v.) and TRH (200 micrograms i.v.) have been studied preoperatively in 12 patients with a clinically functionless pituitary adenoma, of whom nine (3F: 6M) were found to secrete gonadotrophins in vitro. In three patients with a gonadotrophin-secreting adenoma (GSA) the pulsatile release of LH and FSH was also assessed preoperatively. An elevated serum FSH was recorded in six of nine patients with a GSA, and was subnormal in one, whilst an elevated LH was recorded in only two and was subnormal in six. A doubling of LH occurred in only four of the nine patients after GnRH and in three of six after TRH. None of the three patients with a non-GSA was shown to have an aberrant response to GnRH or TRH. In patients with a GSA, pulsatile release of LH and FSH was usually asynchronous and neither hormone demonstrated any regular harmonic pattern. These data show that in patients with a GSA the serum FSH level is usually elevated but this is not invariable, and the LH may well be low. Pathological responses of LH are frequently found following the administration of either GnRH or TRH and these stimulation tests should be performed separately in patients presenting with a clinically 'non-functioning' pituitary tumour to assist in the preoperative diagnosis. The absence of normal LH and FSH pulsing also appears to be a feature of GS adenomas, and suggests that tumorous gonadotrophin secretion is not under physiological control by hypothalamic GnRH.

Summary Autoimmune polyendocrinopathy syndrome type 1 (APS1) is characterized by autoimmune destruction of endocrine tissues and chronic mucocutaneous candidiasis. Type 1 diabetes (T1D) affects 12–25% of patients with APS1, and the prediction of whether this complication will affect an individual is not currently possible. However, alleles of a variable number tandem repeat (VNTR) 5′ of the insulin gene are known to influence the development of T1D in the general, non-APS1 population. Therefore, we investigated the prevalence of these IDDM2 alleles in British Caucasian patients with APS1. The study employed genotyping of 33 patients with APS1 for the HphI polymorphism that is in tight linkage disequilibrium with the insulin gene VNTR alleles. Thirty-three patients with APS1 were studied, the mean age was 23.5 years and 24% have T1D. Six of eight (75%) APS1 patients with T1D were homozygous for the class I INS VNTR (susceptibility) allele, compared with eight of 25 (32%) of APS1 patients without T1D (P = 0.042). Our data suggest an association between the development of T1D and homozygosity for the T1D susceptibility class IINS VNTR allele in patients with APS1.

This chapter has reviewed the UK guidelines for the management of thyroid cancer and made reference to other available guidelines. The objective for clinicians involved in treating thyroid cancer must be to achieve lower recurrence rate and lower mortality rate. This will require early diagnosis and treatment, specialist management of patients by an MDT, adherence to guidelines, better detection of recurrence, and more effective treatment for progressive disease. In addition, clinicians should aim for improved wellbeing of the patient, and to that end consideration must be given to improving communication as well as the avoidance of hypothyroidism.

Summary We report a case of Riedel's thyroiditis presenting with a systemic illness, life-threatening stridor and a stony hard goitre. Diagnosis was confirmed by open thyroid biopsy. Treatment with corticosteroid resulted in a dramatic improvement. A possible autoimmune mechanism in the pathogenesis of Riedel's thyroiditis is discussed.

Background: Craniopharyngioma is a parasellar tumour that, although benign, tends to behave aggressively. It can occur at any age but most commonly presents in childhood or adolescence. Objectives: To investigate the frequency and severity of problems associated with craniopharyngioma, using the large international database (KIMS) for adult patients with GH deficiency (GHD), and to assess the differences between the adult onset (AO, aged 18 or above) disease and adults with childhood onset (CO) craniopharyngioma. Design: Inclusion criteria were: an established diagnosis of craniopharyngioma, severe GHD and no recent GH treatment. These criteria were fulfilled by 393 (184 female, 209 male) patients; 241 had AO (mean age 28.7±8.7 years) and 152 had CO disease (age 42.0±12.3 years). Disease history, clinical features and anthropometric data were recorded at the time of enrolment in the database, and body composition, serum IGF-I, serum lipids and quality of life (QoL) were assessed. Results: Peak age at onset of craniopharyngioma was 15–20 years. Ninety percent of patients had been treated surgically. CO patients were shorter than AO patients and had much lower IGF-I standard deviation scores (SDS). The majority had hypopituitarism and over 60% had diabetes insipidus. Body mass index (BMI) was higher in AO males (30.2±5.5) than in CO males (28.5±7.5); waist circumference was also greater. Obesity was more common in AO patients (51.8% vs 39.1%). Body composition did not differ between groups. Cholesterol and triglycerides were higher in AO than in CO patients, but high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol did not differ. Quality of life, assessed by Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Nottingham Health Profile, was markedly reduced in all groups with no significant differences between them; the QoL-AGHDA score correlated with age at onset of both craniopharyngioma and GHD, and also with BMI in AO patients. Conclusions: These data emphasise the generally poor state of health of patients treated for craniopharyngioma, with respect to endocrine and metabolic function, and also the markedly reduced quality of life. In addition to GHD, most patients have evidence of hypothalamic damage with associated obesity, diabetes insipidus and hypopituitarism. Adults with CO craniopharyngioma were shorter, had lower IGF-I, lower BMI, less obesity and slightly lower blood lipid levels than patients with AO craniopharyngioma.

In epidemiological studies, hypopituitary adults show increased mortality compared with population controls. Patients with hypopituitarism caused by a craniopharyngioma (CP) and/or its treatment have a higher mortality than patients with other etiologies, such as a nonfunctioning pituitary adenoma (NFPA). To analyze this difference, we used the KIMS database (Pfizer International Metabolic Database) comparing CP and NFPA patients in terms of baseline characteristics and responses to GH replacement.Baseline characteristics were studied in 351 CP patients (189 men and 162 women; mean age, 42.5 yr) and compared with 370 NFPA patients, matched for age and sex (185 men and 185 women; mean age, 42.5 yr). The effects of 2 yr of GH replacement were analyzed in a subgroup of 183 CP and 209 NFPA patients.At baseline, both CP and NFPA patients had characteristic features of GH deficiency, with low serum IGF-I, increased body fat, dyslipidemia, and reduced quality of life. Male CP patients were significantly more obese (30.0 vs. 28.2 kg/m2; P = 0.0003) compared with NFPA patients, had a higher waist/hip ratio (P = 0.004), higher triglycerides (P = 0.003), and lower high-density lipoprotein cholesterol (P = 0.03). Similar, but much smaller, differences were seen in female CP compared with NFPA patients, only reaching significance for waist/hip ratio (P = 0.05) and triglycerides (P = 0.0004). CP patients had more often undergone surgery by the transcranial route (68.8% vs. 30.9%; P0.0001), and panhypopituitarism was more prevalent in CP than in NFPA patients (58.7% vs. 19.8%; P0.0001). The incidence of previous fractures, hypertension, coronary heart disease, claudication, and diabetes mellitus was high, but not different, between CP and NFPA patients. After 2 yr of GH replacement therapy, similar significant improvements were evident in both groups in fat-free mass, total and low-density lipoprotein cholesterol, and Quality-of-Life-Assessment in GH Deficient Adults score compared with baseline. In contrast to NFPA patients, CP patients had no significant decrease in body fat with GH therapy.In the KIMS database, patients with CP have more often undergone surgery by the transcranial route than patients with NFPA, have a higher prevalence of pituitary deficiencies, are more obese (predominantly males), and have more dyslipidemia. This could provide an explanation, at least in part, for the higher mortality rate in CP patients observed in epidemiological studies. CP patients respond equally well to GH therapy in fat-free mass, lipids, and quality of life, but are less likely to lose body fat. We assume that this difference in response merely reflects the stronger tendency of CP patients to accumulate fat over time.

Hyperprolactinaemia frequently causes secondary hypogonadism through central suppression of gonadotropin secretion. Macroprolactinomas (1 cm diameter) are more common in males and may additionally cause more generalised hypopituitarism. Recovery of the thyrotropic and/or corticotropic axes is well described following selective adenomectomy, but remains poorly defined in relation to medical (dopamine-agonist) therapy of macroprolactinomas. We therefore performed a retrospective examination of case records of male patients who had received medical therapy alone for macroprolactinoma between 1980-2001 (n = 35) and in whom tumor shrinkage was documented by interval pituitary imaging (reported throughout by a single neuroradiologist). Mean prolactin level at baseline was 59,932 mU/L (median 31,400; range 3,215-332,000); mean period of follow up was 4.2 years (median 2.6; range: 1.0-15). Defects of the following axes were evident at diagnosis: LH/FSH-testosterone (n = 27; 77%), TSH-T4 (n = 14; 41%-not including one case with pre-existing 1 degress hypothyroidism), ACTH-cortisol (n = 8; 23%). Overall, 14 men (40%) were deficient in 1 axis, seven (20%) in 2 axes and seven (20%) in 3 axes. Growth hormone secretory status was not systematically evaluated. In all but 6 patients, prolactin levels fell to normal or near-normal levels (mean 764 mU/L; median 260; range:10-4,833). Of the patients in whom adequate reassessment had been performed, thyrotroph function recovered in 4/9, corticotroph function in 4/6 and gonadotroph function in 16/26 cases. In four cases (11%) previously described, development of visual impairment as a result of the chiasmal traction syndrome necessitated a dose reduction in medical therapy to allow a degree of controlled tumor re-expansion. The prevalence at diagnosis of TSH and ACTH deficiency in men with macroprolactinomas was 41% and 23%, respectively. Among eight patients with insufficiency of TSH and/or ACTH secretion who underwent complete interval reassessment over several years of treatment, recovery of at least one axis occurred in six cases (75%). This study highlights the importance of screening ACTH- and/or TSH-deficient men during dopamine agonist therapy in order to identify cases where hypopituitarism has resolved.

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 $ 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. European Journal of Endocrinology 148 491–495

Autoimmune thyroid disease (AITD) comprises a series of interrelated conditions including hyperthyroid Graves’ disease (GD), Hashimoto’s (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis (PPT), and thyroid-associated orbitopathy (TAO). These different manifestations of AITD may occur synchronously, most frequently as the combination of GD and TAO. Different AITD phenotypes may also occur sequentially in the same individual, for instance, spontaneous hypothyroidism following an episode of GD or PPT. This clustering of different AITD phenotypes within an individual suggests that these conditions have a common pathophysiological basis. Together, AITDs are the commonest autoimmune disorders in the population, affecting between 2% and 4% of women and up to 1% of men (1–3). Furthermore, AITD prevalence increases with advancing age, with more than 10% of subjects over 75 yr of age having biochemical evidence of mild (subclinical) hypothyroidism, the majority of which is due to autoimmune disease (2, 3). A widely accepted model for the pathogenesis of AITD suggests that each subject has a background inherited predisposition to autoimmunity, with additional environmental and hormonal factors that trigger or contribute to the development of disease. In support of this model, there is good evidence that both cigarette smoking and adverse psychosocial events are associated with the development of GD (4– 6). Similarly, the female preponderance of human AITDs (1), the modulation of animal models of AITD with gonadal steroids (7), the amelioration of GD during pregnancy, and the occurrence of PPT all support the important role of sex steroids in these disorders. In contrast, there is little convincing evidence that infective agents, which are thought of as classical environmental precipitants for autoimmunity, trigger AITDs (8). A recent statistical model, based on data from a large twin study, found that 79% of the predisposition to GD is due to genetic factors, with only 21% due to nongenetic (environmental and hormonal) influences (9). This study has profound implications for the study of AITD and suggests that if we are to make progress in understanding the molecular basis for AITDs, the elucidation of the genetic factors is most likely to hold the key. Recent years have seen a flurry of activity in this research field, and in this article we will review these advances in understanding about the genetic basis of AITDs.

Objective. To examine the allelic association of the single nucleotide polymorphism (CTLA4A/G) in exon I 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, Cl 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.

Defining the susceptibility loci for complex multigenic disorders, such as Graves’ disease (GD), remains difficult. We have screened diverse chromosome regions of the human genome in 68 multiplex white GD families (75 GD affected sib-pairs) from the U.K. in an attempt to identify susceptibility loci for GD. This genome screening has, to date, shown evidence to support linkage of GD at four chromosome regions: 2q33 (CTLA-4), 18q21 (IDDM6), 6p21 (MHC), and Xp11 (IDDMX). There was weak evidence to suggest linkage to chromosome 20q13 (GD2), but only in a sub-set of 12 families with an apparent dominant pattern of inheritance. Our results show that (a) loci at different chromosome regions confer susceptibility to GD, (b) some of these GD loci coincide with the susceptibility loci for type 1 diabetes and other autoimmune disorders, (c) there is genetic heterogenecity between the U.K. and other populations with GD, and (d) the family ascertainment criteria may affect the ability to detect linkage to some susceptibility loci.

Graves’ ophthalmopathy (GO) is clinically apparent in about 35% patients with Graves’ disease, but is subclinically present in most patients (8). The presentation of GO is highly variable. None of the clinical signs of GO are pathognomonic, yet this condition is rarely a diagnostic challenge to the experienced clinician. However delays in making the diagnosis by nonspecialists is common. Clinicians managing patients with GO have to decide which aspects of a patient’s presentation warrant referral to a specialist centre. The clinical course of GO through time is multiphasic and spontaneous regression occurs in most patients. The “natural history” of this disease is a concept of critical importance in prognosis, and timing of therapeutic interventions.

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.

To the Editor: The susceptibility loci for Graves disease (GD [MIM 275000]), which is a common complex trait (Brix et al. 1998), have been difficult to define (Roman et al. 1992; McLachlan 1993; Davies 1998; Farid 1998; Vaidya et al. 1999). Tomer et al. (1998) recently found evidence for linkage of GD to markers on the long arm of chromosome 20 (MIM 603388), with a peak multipoint LOD score of 3.5 at the marker D20S195. Their linkage analysis was performed by both parametric and nonparametric methods, and their cohort of 53 families with at least two first-degree relatives affected with autoimmune thyroid disease (AITD) was derived from the North American, Italian, Israeli, and British populations (Tomer et al. 1998). We have examined this chromosomal region in a homogeneous cohort of 71 affected GD sib pairs derived from 64 multiplex British GD kindreds (146 subjects with GD, 20 with autoimmune hypothyroidism [MIM 140300], and 72 unaffected). In six families, an additional sibling had autoimmune hypothyroidism, resulting in a total of 77 affected sib pairs with AITD (i.e., either GD or autoimmune hypothyroidism) (table 1). Parents (n=49) and unaffected sibs (n=36) were studied wherever available. All subjects were white, and >95% of the grandparents were from the mainland United Kingdom or were of Irish origin. The clinical definitions of GD and autoimmune hypothyroidism were identical to those described elsewhere (Tomer et al. 1998). Fifty-four (37%) of the patients with GD had significant thyroid-associated orbitopathy (class 3 or worse) (Werner 1977). Background allele frequencies were derived from typing of DNA obtained from local subjects without evidence of autoimmune disease. Nonparametric, parametric, and exclusion-mapping analyses were performed with the use of the GENEHUNTER package, version 2.0 (Kruglyak et al. 1996). For parametric analyses, a population frequency of 1% for GD was assumed, with a nonsusceptibility-genotype penetrance of .005, and allele frequencies were varied, according to Hardy-Weinberg equilibrium, for each susceptibility-genotype penetrance studied. Table 1 Phenotypes of Affected Sib Pairs with AITD Multipoint nonparametric analysis with the use of five microsatellite markers spanning a 21-cM area of 20q13.11 showed no evidence to support linkage in the 71 GD sib pairs, with a peak NPL (nonparametric linkage) score of 0.1 occurring at the marker D20S884 (fig. 1). We were able to formally exclude (LOD score 2.5 from this entire region (fig. 1). Parametric analysis was performed both with and without the assumption of heterogeneity, with both recessive and dominant models. There was no evidence for linkage of GD to this region at disease penetrances of 30%, 60%, or 90%, with either model of inheritance, in the 71 sib pairs (table 2). Figure 1 Linkage analysis in all 64 affected GD kindreds. A, Percentage information content shown at each of the map positions. B, Multipoint nonparametric linkage analysis of kindreds with GD for chromosome 20q13.11 markers. Genotyping was performed by PCR with ... Table 2 Peak Multipoint Parametric LOD Scores for the Chromosome 20q13.11 Markers in the 64 Families with GD and in the Subset of 12 Kindreds with Dominant Transmission of GD The ascertainment strategy (at least two affected sibs with GD) used to recruit families for our study was different from that (at least two affected first-degree relatives with AITD) used by Tomer et al., such that their cohort of families was likely to contain many more affected parent-offspring kindreds (Tomer et al. 1998). We speculated that such affected parent-offspring kindreds might have enriched their cohort for families segregating dominant loci and that this difference in ascertainment might explain the apparent discrepancy between our findings, if the susceptibility locus segregated as a dominant (McCarthy et al. 1998). Therefore, we investigated linkage both in a subgroup of 12 families (38 subjects with GD) who had apparent dominant transmission of GD from parent to offspring and in a subgroup of 28 families with dominant transmission of AITD from parent to offspring (75 subjects with GD and 17 with autoimmune hypothyroid). Multipoint nonparametric analysis in the 12 families with dominant transmission of GD showed a 4-cM plateau suggestive of linkage, with a peak NPL score of 2.02 (P=.023) occurring at the marker D20S106 (fig. 2). This was not observed in the larger subgroup of 28 families with parent-to-offspring transmission of AITD (fig. 2). Parametric analysis in the subgroup with dominant transmission of GD, with the assumption of heterogeneity, showed a peak LOD score of 1.06 occurring at the marker D20S884 with a dominant model (table 2). Figure 2 Linkage analysis of the subset of 12 GD kindreds with dominant transmission of GD, and other groups. A, Percentage information content for the 12 families with dominant transmission of GD is shown at each of the map positions. B, Multipoint nonparametric ... Our study provides some evidence to support the presence of a GD-susceptibility locus in this region of 20q13.11 (Tomer et al. 1998), and we show that this locus appears to be important only in families with dominant inheritance of GD. The small number of such kindreds that we have studied precludes a reliable estimate of the strength of effect of this locus, but our ability to detect the effect using only 12 families with this structure, coupled with the 1:0 allele-sharing ratio of 69% between the sib pairs with GD, suggests that it may have a strong effect. In contrast, our families with affected subjects with GD in only one generation and our families with dominant transmission of AITD do not show evidence of linkage to this locus (figs. 1 and ​and2).2). Analysis of a larger cohort of kindreds with dominant transmission of GD is necessary to confirm the presence of this susceptibility locus for GD. However, the recent mapping of a susceptibility locus for systemic lupus erythematosus (MIM 152700) to this region of chromosome 20 in two different mixed American cohorts (Gaffney et al. 1998; Moser et al. 1998) suggests that this region may harbor a polymorphism(s) that is important in other autoimmune disorders. In addition, our study illustrates that the ascertainment strategies employed in the collection of cohorts of kindreds with complex disorders may have a marked effect on the ability to detect a given susceptibility locus (McCarthy et al. 1998).

Smoking and demographic variables are known to be risk factors for the development of thyroid-associated orbitopathy (TAO) among patients with Graves' hyperthyroidism, but a firm genetic basis for TAO has not been established. We show that the presence and severity of TAO are associated with an allele of the cytotoxic T lymphocyte antigen-4-gene.

PREMESSE: La terapia dell’ipertiroidismo con radioiodio e efficace e sicura, ma e stata indicata come potenziale fattore di rischio per il peggioramento o la comparsa ex novo della oftalmopatia basedowiana (OB). SCOPO: Lo scopo di questo studio era di determinare l’andamento della OB dopo terapia con radioiodio. DISEGNO: Studio prospettico osservazionale. I pazienti venivano valutati prima della terapia e 2, 4, 6, e 12 mesi dopo il radioiodio. SETTING: Lo studio veniva condotto in un Centro di riferimento terziario. PAZIENTI: 72 pazienti con OB minimamente attiva partecipavano allo studio. A tutti veniva somministrata una dose prefissata di radioiodio e dopo due settimane veniva iniziata la terapia con L-tiroxina per prevenire l’ipotiroidismo. PRINCIPALI OBIETTIVI:Valutazione delle variazioni della attivita e della gravita della OB. RISULTATI: La misurazione della proptosi, l’apertura palpebrale, la diplopia e il Clinical Activity Score miglioravano significativamente. Utilizzando un criterio di rilevanza clinica, si verificava un miglioramento sostanziale della OB in 4 pazienti (solo transitorio in 3 casi), verosimilmente attribuibile alla storia naturale della malattia. In nessun caso la OB peggiorava. CONCLUSIONI: la terapia con radioiodio non e associata ad un peggioramento della OB se l’ipotiroidismo post-radioiodio viene prevenuto.