G Barbesino

Boston Children's Hospital, Boston, MA, United States

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Publications (52)238.09 Total impact

  • Giuseppe Barbesino, Yaron Tomer
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    ABSTRACT: CONTEXT:TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of TRAb measurement in the differential diagnosis of hyperthyroidism, the prediction of remission of GD hyperthyroidism, the prediction of fetal/neonatal thyrotoxicosis and the clinical assessment of Graves' ophthalmopathy (GO) is controversialEVIDENCE ACQUISITION:We reviewed and analyzed the literature reporting primary data on the clinical use of TRAb. We focused our analyses on clinical studies analyzing third generation TRAb assays.EVIDENCE SYNTHESIS:The performance of TRAb in the differential diagnosis of overt hyperthyroidism is excellent, with sensitivity and specificity in the upper 90%. TRAb can accurately predict short-term relapses of hyperthyroidism after a course of antithyroid drugs, but are less effective in predicting long-term relapses or remissions. Pregnancies in GD women with negative TRAb are highly unlikely to result in fetal hyperthyroidism, while high titers of TRAb in pregnancy require careful fetal monitoring. GD patients with GO frequently have high TRAb levels. However there is insufficient data to use the test to predict the clinical course of GO and response to treatment.CONCLUSIONS:Third generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies.
    The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
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    ABSTRACT: BACKGROUND: Fine-needle aspiration biopsy (FNAB) of the thyroid categorized as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a newly defined category according to the recent Bethesda guidelines. We sought to assess the characteristics and treatment of patients with an AUS/FLUS FNAB at our institution. Additionally, we evaluated the utility of the recommended 3-month timing of repeat FNAB. METHODS: A retrospective study of all patients with an FNAB categorized as AUS/FLUS at an academic tertiary-care center. Clinical, cytological, and ultrasound variables were compared among management groups. Differences in patients receiving repeat FNAB before or after a 3-month interval were compared. RESULTS: A total of 203 patients of the 5,391 FNABs performed at our institution met the Bethesda criteria for AUS/FLUS; 62 % were sent directly to surgery, 25 % had a repeat FNAB, and 13 % were observed. Younger (p = 0.006) and male patients (p = 0.04) were more likely to go directly to surgery. Microcalcifications, irregular margins, and marked hypoechogenicity on ultrasound did not appear to influence the decision to repeat the FNAB, observe the patient, or refer the patient for surgery. Timing of repeat FNAB (<3 months or ≥3 months) did not alter the diagnostic results of the second FNAB (p = 0.73). The overall rate of malignancy in patients undergoing surgery was 15.7 %. CONCLUSIONS: Gender and age, not ultrasound characteristics, appear to influence the decision for surgery in AUS/FLUS patients. Timing of repeat biopsy did not alter management, repeat FNAB diagnosis, or rate of malignancy in our cohort.
    Annals of Surgical Oncology 09/2012; · 4.12 Impact Factor
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    ABSTRACT: Guidelines from the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference recommend a repeat fine-needle aspiration biopsy (FNAB) after 3 months for thyroid nodules with a nondiagnostic (ND) result. Our aims were to assess which factors influenced their clinical management and to determine if the timing of the repeat FNAB affects the diagnostic yield. A retrospective institutional review of 298 patients from 1/2006 to 12/2007 with an ND FNAB was performed. The factors influencing the next step in management, including age, gender, history of radiation, presence of Hashimoto's thyroiditis, thyroid-stimulating hormone levels, and ultrasound characteristics, were evaluated. The effect of the time of the repeat FNABs on their diagnostic yield was assessed. Of the 298 patients in our cohort, 9% were referred directly for surgery, 76% had a repeat FNAB, and 15% were observed. Tumor size was the only independent variable correlated with treatment strategy after a ND FNAB. There was not a significant difference in diagnostic yields between repeat FNABs performed earlier than 3 months compared to those preformed later (p=0.58). The timing of repeat FNAB for an initial ND FNAB does not affect diagnostic yield of the repeat FNAB.
    Thyroid: official journal of the American Thyroid Association 06/2012; 22(6):590-4. · 2.60 Impact Factor
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    ABSTRACT: Abstract Background: Guidelines from the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference recommend repeat fine needle aspiration biopsy (FNAB) after three months for thyroid nodules with a non-diagnostic (ND) result. Our aims were to assess which factors influenced clinical management and to determine if the timing of repeat FNAB affects the diagnostic yield. Methods: A retrospective institutional review of 298 patients from 1/2006 - 12/2007 with a ND FNAB was performed. The factors influencing the next step in management, including age, gender, history of radiation, presence of Hashimoto's thyroiditis, TSH levels, and ultrasound characteristics. The affect of timing of repeat FNAB on diagnostic yield of repeat biopsy was assessed. Results: Of the 298 patients in our cohort, 9% percent were referred directly for surgery, 76% had repeat sampling and 15% were observed. Tumor size was the only independent variable correlated with treatment strategy following ND FNAB. There was no statistically significant difference in diagnostic yield between repeat FNAB's performed earlier or later than three months (p = 0.58). Conclusion: Timing of repeat sampling for ND FNAB does not affect diagnostic yield of repeat FNAB.
    Thyroid: official journal of the American Thyroid Association 04/2012; · 2.60 Impact Factor
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    ABSTRACT: Radioactive iodine lobe ablation (RAI-L-ABL) is a possible alternative to completion thyroidectomy (C-Tx) for follicular thyroid carcinoma (FTC), but no long-term outcome data are available after lobe ablation. We analyzed the long-term outcome of lobe ablation in a series of patients with FTC. This was a retrospective study of patients who were treated with lobe ablation between 1983 and 2008. Of 134 patients with FTC, 37 (27.6%) had lobe ablation with (131)I (30-32 mCi) (RAI-L-ABL), 68 (50.7%) had C-Tx, and 29 (21.6%) had initial total thyroidectomy (T-Tx). The main outcomes analyzed were (131)I uptake after lobe ablation, C-Tx or T-Tx, serum thyroglobulin (Tg), serum thyroid-stimulating hormone (TSH), long-term disease-specific mortality, and disease-free survival. After lobe ablation, radioiodine uptake was significantly lower for the RAI-L-ABL group (0.6%) than for the C-Tx group (2.0%, p<0.005) or T-Tx group (1.3%, p=0.054). Subsequent remnant ablation was performed in 12 of 37 (32%) patients in the RAI-L-ABL group, in 58 of 68 (85.3%) patients in the C-Tx group, and in 25 of 29 (86.2%) patients in the T-Tx group (p<0.01). With median follow-up of 95 months for the RAI-L-ABL group, 47 months for the C-Tx group, and 53 months for the T-Tx group, there was one death in the RAI-L-ABL group and one death in the T-Tx group. No other RAI-L-ABL patients had detectable disease, whereas patients in the C-Tx group and two patients in the T-Tx group had detectable disease (p=0.18). Long-term stimulated or suppressed Tg of <1 ng/mL were found in 87.5% of the RAI-L-ABL group (n=28), 86.3% of the C-Tx group (n=57), and 77.8% of the T-Tx group (n=21). Tg was detectable in 40.6% of the RAI-L-ABL group compared to 13.8% of C-Tx and 28.6% of T-Tx groups (p<0.05, between groups). RAI-L-ABL, C-Tx, and T-Tx are equally effective in achieving serum TSH concentrations of >25 mIU/L and preparing patients for conventional (131)I treatment and whole body scanning with similar long-term outcomes. However, persistent measurable Tg (range 0.2-2.2 ng/mL) is more common after RAI-L-ABL.
    Thyroid: official journal of the American Thyroid Association 03/2012; 22(4):369-76. · 2.60 Impact Factor
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    ABSTRACT: Background: Radioactive iodine (RAI) lobe ablation is a possible alternative to completion thyroidectomy for follicular thyroid carcinoma (FTC), but no long-term outcome data are available after lobe ablation. We analyzed the long-term outcome of lobe ablation in a series of FTC patients. Methods: This was a retrospective study of FTC patients treated with lobe ablation between 1983 and 2008. Of 134 patients with FTC, 37 (27.6%) had lobe ablation with 131 I (30-32 mCi) (RAI-L-ABL), 68 (50.7%) had completion thyroidectomy C-Tx and 29 (21.6%) had initial total thyroidectomyT-Tx. The main outcomes analyzed were 131-I uptake after lobe ablation, completion thyroidectomy, or total thyroidectomy, serum thyroglobulin, serum TSH, long-term disease-specific mortality and disease-free survival. Results. After lobe ablation, RAI uptake was significantly lower for the RAI-L-ABL group (0.6%) compared to the C-Tx group (2.0%, p<0.005) or TT group (1.3%, p=0.054). Subsequent remnant ablation was performed in 12 of 37 (32%) patients in the RAI-L-ABL group, in 58 of 68 (85.3%) patients in the C-Tx group, and in 25 of 29 (86.2%) patients in the T-Tx group (p<0.01). With median follow-ups of 95 months for the RAI-L-ABL group, 47 months for the C-Tx group, and 53 months for the T-Tx group, there was one death in the RAI-L-ABL group and one death in the T-Tx group. No other RAI-L-ABL patients had detectable disease whereas patients in the C-Tx group and two patients in the T-Tx group had detectable disease (p=0.18). Long-term stimulated or suppressed Tg of < 1 ng/mL were found in 87.5 % of the RAI-L-ABL group (n=28), 86.3 % of the C-Tx group (n = 57), and 77.8 % of the T-Tx group (n=21). Tg was detectable in 40.6 % of the RAI-L-ABL group compared to 13.8 % of C-Tx and 28.6 % of T-Tx groups (p<0.05, between groups). Conclusions. RAI lobe ablation, completion thyroidectomy and total thyroidectomy are equally effective in achieving TSH greater than 25 and preparing patients for conventional 131-I remnant treatment and whole body scanning with similar long-term outcomes. However, persistent measurable Tg (range 0.2-2.2 ng/mL) is more common after RAI-L-ABL.
    Thyroid: official journal of the American Thyroid Association 12/2011; · 2.60 Impact Factor
  • Giuseppe Barbesino, Patrick M Sluss, Patrizio Caturegli
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    ABSTRACT: Acquired central hypothyroidism is rare, especially when isolated, and is typically associated with detectable, although biologically inactive, serum TSH. We describe a 56-yr-old woman with profound central hypothyroidism and partial central hypoadrenalism, in the absence of other endocrine abnormalities. In contrast to most cases of central hypothyroidism, serum TSH remained undetectable for 9 months before the initiation of thyroid hormone and hydrocortisone treatment. A test for pituitary autoantibody was moderately positive. Serum free T(4), serum T(3), and neck radioiodine uptake were low but detectable. The thyroid and pituitary glands appeared morphologically normal on neck ultrasound and head magnetic resonance imaging, respectively. The study was conducted in a tertiary academic medical center. This case illustrates the variable clinical presentation of pituitary autoimmunity. The persistence of low but detectable thyroid hormone levels and radioiodine neck uptake in the absence of TSH suggests that significant TSH-independent thyroid hormone synthesis may occur in the normal thyroid.
    The Journal of clinical endocrinology and metabolism 11/2011; 97(2):345-50. · 6.50 Impact Factor
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    ABSTRACT: Paragangliomas in the region of the thyroid gland are rare tumors that can present a diagnostic challenge by mimicking follicular and c-cell derived thyroid tumors. Thyroid-associated paragangliomas are likely a subset of laryngeal paragangliomas and, although quite rare, should be considered in the differential diagnosis of a hypervascular thyroid nodule. The preoperative diagnosis of thyroid-associated paragangliomas can be challenging since the cytologic and histologic features overlap with more common primary thyroid neoplasms, in particular medullary carcinoma. Differential expression of a panel of immunohistochemical markers, including neuro-specific enolase, chromogranin A, synaptophysin, keratin, and S100, can be used to distinguish thyroid-associated paragangliomas from primary thyroid tumors. Intraoperatively, thyroid-associated paragangliomas may be associated with significant intraoperative bleeding and are often densely adherent to surrounding tissues, including the recurrent laryngeal nerve. Interestingly, the aggressive local behavior of these tumors does not correspond to potential for malignancy, as there are no patients with malignant thyroid-associated paragangliomas reported in the medical literature. Therefore, these tumors may be treated with limited resection. Postoperatively, patients with paragangliomas should receive hormonal evaluation for functional disease, imaging evaluation for multicentric and metastatic disease, and genetic counseling. Thyroid-associated paragangliomas are an important part of the differential diagnosis of a hypervascular thyroid nodule, especially in a patient with a fine-needle aspiration biopsy suggestive of medullary thyroid carcinoma, but with unremarkable serum calcitonin levels. Consideration of a thyroid-associated paraganglioma also has important operative and postoperative implications for determining the extent of thyroid resection as well as follow-up testing.
    Thyroid: official journal of the American Thyroid Association 05/2011; 21(7):725-33. · 2.60 Impact Factor
  • Journal of Surgical Research - J SURG RES. 01/2011; 165(2):273-274.
  • Giuseppe Barbesino
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    ABSTRACT: Over the years, several drugs used in the treatment of nonthyroidal conditions have been shown to affect thyroid function. As novel drugs are introduced, novel interactions are described. The aim of this review is to summarize clinically relevant thyroidal side effects of drugs used for nonthyroidal conditions. Special focus is given to recent developments and to drugs with the largest clinical relevance. Thyrosine kinase inhibitors are novel drugs used in the treatment of several neoplasias, including thyroid cancer. Thyroidal side effects are being increasingly detected with these drugs. Some drugs in this category affect thyroid hormone metabolism and therefore only affect patients on thyroid replacement. Others affect the thyroid directly profoundly, causing primary hypothyroidism. Immune modulators used in infectious, inflammatory, and neoplastic conditions also cause hyper- and hypothyroidism, through poorly understood immune or nonimmune mechanisms. The effects of amiodarone on the thyroid have been long recognized. However, given the complexity of these effects, several areas in this field remain problematic, such as the identification of subtypes of hyperthyroidism and the best treatment strategies. Lithium also has important antithyroid effects and it is a commonly prescribed medication. Its antithyroid effects may have clinical utility in selected clinical situations. Other drugs known to affect thyroid hormone absorption, metabolism, and transport are also briefly reviewed. Several drugs are known to alter thyroid function as a side effect of their primary pharmacological action. Some of these effects have been recognized for decades, but novel thyroid-drug interactions are being recognized as new drugs are developed. It is important for the clinician to be familiar with thyroid-drug interactions, as enhanced surveillance may be necessary in patients undergoing therapies known to affect thyroid function.
    Thyroid: official journal of the American Thyroid Association 07/2010; 20(7):763-70. · 2.60 Impact Factor
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    ABSTRACT: Thyroid carcinoma is an extraintestinal manifestation of familial adenomatous polyposis (FAP) syndrome, but the precise risk is unknown. The optimal approach for thyroid cancer screening has not been established. We sought to define the prevalence of thyroid cancer and the role of screening ultrasound in FAP patients. We performed a retrospective chart review of 51 patients with a proven diagnosis of FAP at a single tertiary institution. Clinical records, genetic test results, ultrasound examinations, and histopathology were reviewed. Papillary thyroid cancer was diagnosed in 6 female patients (12%). The mean age of thyroid cancer diagnosis was 33 years, and mean tumor size was 12 mm. However, all patients had additional malignant foci that were small (1-9 mm), and none had suspicious features of malignancy on ultrasound. Of 28 patients who had at least one screening ultrasound, 22 (79%) had thyroid nodules, and 2 (7%) had papillary thyroid carcinoma. Of those with nodules, 68% had multinodular disease. A follow-up ultrasound in 12 patients after a mean of 15 months revealed no changes in either the number or size of nodules. The 12% prevalence of thyroid cancer in this series of FAP patients is significantly higher than in previous reports. Among patients undergoing screening ultrasound, 7% had thyroid cancer. Nodular thyroid disease is very common in FAP. Because small nodules (<9 mm) might also be malignant, close follow-up with ultrasound and fine-needle aspiration might be warranted.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 03/2007; 5(3):367-73. · 5.64 Impact Factor
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    ABSTRACT: Abundant epidemiological data point to a strong genetic susceptibility to the development of autoimmune thyroid diseases (AITD), Graves' disease (GD) and Hashimoto's thyroiditis (HT). However, identifying the AITD susceptibility genes has been confounded by significant genetic heterogeneity that exists in AITD. The goals of the present study were to dissect the genetic heterogeneity in AITD in order to identify novel AITD genes. We studied a dataset of 102 multiplex Caucasian AITD families (540 individuals) and divided them into three subsets: (1) families with young age of onset (AO< or =30), (2) families with females-only affected, and (3) Italian families. These subsets were analyzed separately for linkage with AITD in a whole genome screen. Four subset-specific loci were mapped: analyzing the families with AO< or =30, we identified a locus on 10q (linked with AITD) and a locus on Xp containing the FOXP3 gene (linked with GD); analysis of markers flanking the FOXP3 gene demonstrated association of one of the FOXP3 markers with juvenile GD in females (p=0.02); in the subset of families with females-only affected the thyroglobulin (Tg) gene locus was linked with AITD; and in the Italian subset, a novel locus on 3q was linked with GD. Finally, applying the predivided-sample test confirmed that all four loci were specific to the subsets. We conclude that distinct genes predispose to AITD in different subsets of patients. We have identified four subset-specific AITD loci, and two putative subset-specific AITD susceptibility genes; the FOXP3 gene in juvenile GD and the thyroglobulin gene in females with AITD. In view of the significant genetic heterogeneity observed in AITD, analyzing subsets is an efficient way to resolve heterogeneity and identify novel genes.
    Journal of Autoimmunity 01/2007; 29(2-3):69-77. · 8.15 Impact Factor
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    ABSTRACT: The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.
    Genes and Immunity 01/2004; 4(8):586-93. · 3.68 Impact Factor
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    ABSTRACT: The autoimmune thyroid diseases (AITDs), comprising Graves disease (GD) and Hashimoto thyroiditis (HT), develop as a result of a complex interaction between predisposing genes and environmental triggers. Previously, we identified six loci that showed evidence for linkage with AITD in a data set of 56 multiplex families. The goals of the present study were to replicate/reject the previously identified loci before fine mapping and sequencing the candidate genes in these regions. We performed a whole-genome linkage study in an expanded data set of 102 multiplex families with AITD (540 individuals), through use of 400 microsatellite markers. Seven loci showed evidence for linkage to AITD. Three loci, on chromosomes 6p, 8q, and 10q, showed evidence for linkage with both GD and HT (maximum multipoint heterogeneity LOD scores [HLOD] 2.0, 3.5, and 4.1, respectively). Three loci showed evidence for linkage with GD: on 7q (HLOD 2.3), 14q (HLOD 2.1), and 20q (LOD 3.3, in a subset of the families). One locus on 12q showed evidence of linkage with HT, giving an HLOD of 3.4. Comparison with the results obtained in the original data set showed that the 20q (GD-2) and 12q (HT-2) loci continued to show evidence for linkage in the expanded data set; the 6p and 14q loci were located within the same region as the previously identified 6p and 14q loci (AITD-1 and GD-1, respectively), but the Xq (GD-3) and 13q (HT-1) loci were not replicated in the expanded data set. These results demonstrated that multiple genes may predispose to GD and HT and that some may be common to both diseases and some are unique. The loci that continue to show evidence for linkage in the expanded data set represent serious candidate regions for gene identification.
    The American Journal of Human Genetics 11/2003; 73(4):736-47. · 11.20 Impact Factor
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    ABSTRACT: Orbital radiotherapy is a well-established method of treatment for severe Graves' ophthalmopathy, because of its anti-inflammatory and locally immunosuppressive effects. It has been used for 60 years. Conventional external x-ray and cobalt therapy have been abandoned, and most groups now use supervoltage linear accelerators (4-6 MeV). Cumulative doses may vary, but in most studies a cumulative dose of 20 Gy delivered over 2 weeks was utilized. Successful outcome depends on the selection of patients, because recent onset, active ophthalmopathy is much more favorably affected than longstanding, inactive disease. Inflammatory signs, recent onset eye muscle dysfunction, and optic neuropathy respond well to orbital radiotherapy, while proptosis and longstanding eye muscle restriction respond poorly. Overall, favorable responses have been reported, with few exceptions, in approximately 60% of cases. Combination of irradiation with high-dose systemic glucocorticoids provides better results than either treatment alone. Orbital radiotherapy is well tolerated and safe. Preexisting retinopathy (e.g., in patients with diabetes) is a contraindication to this treatment for the risk of further retinal damage. No case of radiation-induced tumors has so far been described after orbital radiotherapy for Graves' ophthalmopathy.
    Thyroid 04/2002; 12(3):245-50. · 3.54 Impact Factor
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    ABSTRACT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is caused by mutations of the autoimmune regulator gene. We identified an Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and a pattern of inheritance suggestive of a dominant mechanism. Serological and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classical autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Direct sequencing of the entire coding region of the autoimmune regulator gene revealed the presence in the proband of a novel missense (G228W) mutation in exon 6 in a heterozygous state. The same heterozygous mutation was identified in all family members with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and/or hypothyroid autoimmune thyroiditis. None of the unaffected family members and 50 unrelated Italian controls carried the mutation. In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in our family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the hypothyroid autoimmune thyroiditis/polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype to the offspring in each generation in the absence of consanguinity, further supporting a dominant inheritance. The G228W closely cosegregated with hypothyroid autoimmune thyroiditis in our family, whereas a low penetrance of the full autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype was observed. In conclusion, we report a novel mutation of the autoimmune regulator gene in a family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, closely cosegregating with hypothyroid autoimmune thyroiditis. The G228W mutation acts in a dominant fashion and may shed light on the structure-function relationship of the autoimmune regulator protein.
    Journal of Clinical Endocrinology &amp Metabolism 11/2001; 86(10):4747-52. · 6.43 Impact Factor
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    ABSTRACT: Eighty-two consecutive patients with moderate-to-severe and active Graves' ophthalmopathy were randomly treated with orbital radiotherapy combined with either oral (prednisone; starting dose, 100 mg/d; withdrawal after 5 months) or iv (methylprednisolone; 15 mg/kg for four cycles and then 7.5 mg/kg for four cycles; each cycle consisted of two infusions on alternate days at 2-wk intervals) glucocorticoids. The two groups did not differ for age, gender, duration of hyperthyroidism and ophthalmopathy, prevalence of smokers, thyroid volume, and pretreatment ocular conditions. Both groups of patients received radioiodine therapy shortly before treatment for Graves' ophthalmopathy. Follow-up lasted for 12 months. A significant reduction in proptosis (from 23.2 +/- 3.0 to 21.6 +/- 1.2 mm in the iv glucocorticoid group, P < 0.0001; and from 23 +/- 1.8 to 21.7 +/- 1.8 mm in oral glucocorticoid group, P < 0.0001) and in lid width (from 13.3 +/- 2.5 to 11.8 +/- 2.2 mm, and from 13.6 +/- 2.0 to 11.5 +/- 1.9 mm, respectively; P < 0.001 in both cases) occurred, with no difference between the two groups. Diplopia significantly improved in both groups: it disappeared in 13 of 27 (48.1%) iv glucocorticoid patients (P < 0.005) and in 12 of 33 (36.4%) oral glucocorticoid patients (P < 0.03). The degree of amelioration of diplopia did not significantly differ between the two groups (P = 0.82). Optic neuropathy improved in 11 of 14 iv glucocorticoid (P < 0.01) and only in 3 of 9 oral glucocorticoid (P = 0.57) patients, with no significant difference in these outcomes. The Clinical Activity Score decreased from 4.5 +/- 1.2 to 1.7 +/- 1.0 (P < 0.0001) in the iv glucocorticoid group and from 4.2 +/- 1.1 to 2.2 +/- 1.2 (P < 0.0001) in the oral glucocorticoid group; final Clinical Activity Score was significantly lower in iv glucocorticoid than in oral glucocorticoid patients (P < 0.01). By self-assessment evaluation, 35 (85.3%) iv glucocorticoid and 30 (73.2%) oral glucocorticoid patients reported an improvement of ocular conditions (P = 0.27). Overall, both treatments produced favorable effects in most patients, but responders in the iv glucocorticoid group (36 of 41, 87.8%) were more than in the oral glucocorticoid group (26 of 41, 63.4%) (P < 0.02). Moreover, iv glucocorticoid treatment was better tolerated than oral glucocorticoid treatment. Side effects occurred in 23 (56.1%) iv glucocorticoid and 35 (85.4%) oral glucocorticoid patients (P < 0.01); in particular, cushingoid features developed in 5 of the former and 35 of the latter patients. One iv glucocorticoid patient had severe hepatitis of undetermined origin at the end of glucocorticoid treatment, followed by spontaneous recovery. In conclusion, high-dose iv glucocorticoid and oral glucocorticoid (associated with orbital radiotherapy) are effective in the management of severe Graves' ophthalmopathy, but the iv route seems to be more effective and better tolerated than the oral route and associated with a lower rate of side effects.
    Journal of Clinical Endocrinology &amp Metabolism 08/2001; 86(8):3562-7. · 6.43 Impact Factor
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    ABSTRACT: One of the hallmarks of the human autoimmune thyroid diseases (AITDs) is the production of high titers of autoantibodies against thyroglobulin and thyroid peroxidase that often precedes the development of clinical disease. A high percentage of family members of patients with AITDs have significant titers of thyroid antibodies (TAbs), suggesting a genetic predisposition for their development, and segregation analyses have favored a dominant mode of inheritance. The aim of the present study was to identify the susceptibility genes for TAb production. We completed a genome-wide scan in 56 multiplex families (323 individuals) in which all family members with AITDs and/or detectable TAbs were considered affected. The highest 2-point logarithm of odds (LOD) score of 3.6 was obtained for marker D2S325 on chromosome 2q33 at 210.9 centimorgans. This locus showed no evidence for linkage to Graves' disease or Hashimoto's thyroiditis (2-point LOD scores, 0.42 for Graves' disease and -0.60 for Hashimoto's thyroiditis), demonstrating that the gene in this region conferred susceptibility to TAbs, but that clinical disease development required additional genetic and/or environmental factors. We then fine-mapped the region linked with TAbs using 11 densely spaced microsatellite markers. Multipoint linkage analysis using these markers showed a maximum LOD score of 4.2 obtained for marker D2S155 at 209.8 centimorgans (with heterogeneity, alpha = 0.41). As the linked region contained the CTLA-4 and CD28 genes, we then tested whether they were the susceptibility genes for TAbs on chromosome 2q33. The CD28 gene was sequenced in 15 individuals, and a new C/T single nucleotide polymorphism (SNP) was identified in intron 3. Analysis of this SNP revealed no association with TAbs in the probands of the linked families (families that were linked with D2S155) compared with controls. The CTLA-4 gene was analyzed using the known A/G(49) SNP, and the results showed a significantly increased frequency of the G allele in the probands of the linked families compared with the probands of the unlinked families or with controls (P = 0.02). We concluded that 1) a major gene for thyroid autoantibody production was located on chromosome 2q33; 2) the TAb gene on chromosome 2q33 was most likely the CTLA-4 gene and not the CD28 gene; and 3) CTLA-4 contributed to the genetic susceptibility to TAb production, but there was no evidence that it contributed specifically to Graves' or Hashimoto's diseases.
    Journal of Clinical Endocrinology &amp Metabolism 05/2001; 86(4):1687-93. · 6.43 Impact Factor
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    ABSTRACT: We previously showed that myasthenia gravis (MG) has a mild clinical expression when associated with autoimmune thyroid diseases (AITD). In the present study we have investigated the frequency of thyroid-associated ophthalmopathy (TAO) in patients with Graves' disease (GD) associated with MG as compared with GD patients without MG. A total of 418 patients with GD were studied, 31 with MG and 387 without MG. TAO was evaluated by physical examination, exophthalmometry, computerized tomography, and computerized visual fields assessment. The overall prevalence of TAO was similar in GD patients with MG (61.2%) and in those without MG (56.4%). When the analysis was restricted to GD patients with ocular MG, a greater frequency of TAO was found (84.6%), compared with GD patients without MG or with GD patients with generalized MG, although the differences did not reach the statistical significance. GD patients with MG had a significantly greater prevalence (12.9%) of euthyroid ophthalmopathy (clinically overt ophthalmopathy without previous and/or current hyperthyroidism) than those without MG (3.1%; p = 0.003). The results suggest a preferential association between the ocular manifestations of GD and MG, which may be due to immunological cross-reactivity against common autoimmune targets in the eye muscle as well as to a common genetic background.
    Thyroid 10/2000; 10(9):799-802. · 3.54 Impact Factor
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    ABSTRACT: Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (orbitopathy), which presents with varying degrees of severity. Graves' disease clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear. We have studied the family history of 114 consecutive, ethnically mixed patients with severe Graves' ophthalmopathy (GO). Patients were selected by unambiguous single ascertainment. Seventy-seven percent of patients were female and 59% smoked. The mean age at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-degree relative affected with either Graves' disease (GD) or Hashimoto's thyroiditis (HT). The segregation ratio for AITD in nuclear families in our ascertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only). Hence, the higher prevalence of AITD among relatives of Graves' ophthalmopathy patients agreed with the known genetic predisposition to AITD and this predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all second-degree relatives) and the segregation ratio for GO was 0. These data did not support a major role for familial factors in the development of severe Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for association with Graves' ophthalmopathy. These were negative except for the HLA and CTLA-4 genes, which were found to be weakly associated with GO giving similar relative risk (RR) as in GD patients without ophthalmopathy. These data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophthalmopathy. Smoking remains one example of such potential external insults.
    Thyroid 10/2000; 10(9):791-8. · 3.54 Impact Factor

Publication Stats

2k Citations
238.09 Total Impact Points

Institutions

  • 2013
    • Boston Children's Hospital
      • Division of Endocrinology
      Boston, MA, United States
  • 2010–2012
    • Massachusetts General Hospital
      • Department of Surgery
      Boston, Massachusetts, United States
  • 2007–2012
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1997–2003
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
  • 1990–2001
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 1993
    • Università degli Studi del Sannio
      Benevento, Campania, Italy