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Purpose The clinical outcome of COVID-19 disease is worse in males, and the reasons of this gender disparity are currently unclear, though evidences point to a combination of biological and gender-specific factors. A phenomenon unique to the female gender is the fetal cell microchimerism (FCM), defined as the presence of fetal microchimeric cells in maternal organs and in the circulation for years after delivery and usually evaluated by assessing the presence of male cells or DNA in a woman. In the present case–control study, we aimed to evaluate the possible effect of pregnancy and related FCM on the susceptibility to SARS-CoV-2 infection and on the clinical course and outcome of COVID-19. Methods One hundred twenty-three women with a previous male pregnancy, comprising 63 COVID-19 cases and 60 healthy controls were enrolled. The presence of blood male DNA was assessed by the amplification of the Y-chromosome specific gene SRY. Results The prevalence of male DNA of presumed fetal origin was significantly higher in healthy controls than in COVID-19 cases (70 vs 44.4%, P = 0.0044; OR 0.3429, 95% CI 0.1631–0.7207, P = 0.0047). Among women affected with COVID-19, the presence of male FCM did not significantly influence the severity of the disease, though the 8 deceased women studied were all FCM negative. Conclusion This is the first case–control study reporting the prevalence of FCM in COVID-19 and healthy women. Overall, our data seem to suggest a role for FCM in the protection towards the SARS-CoV-2 infection with a possible positive impact on clinical outcome.

Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter. Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.

Introduction: Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.

Thyroid dysfunctions are highly prevalent and can worsen underlying cardiopathies, but despite that the routine screening of thyroid function in the Emergency Department (ED) setting is not generally recommended.To understand if staff training and implementation of rapid TSH screening (rTSH) could improve the management of patients arrived in the ED. Specifically, we aimed at evaluating the prevalence of undiagnosed thyroid diseases among ED patients; the effects of educational meetings in the clinical decision-making process; the usefulness of rTSH, in terms of variation of either the clinical work out or the existing treatment.Retrospective case-control study of 9227 patients managed in the ED of an academic institution. rTSH was routinely available for all patients, who were divided into rTSH-YES and rTSH-NO groups.We included 4243 and 4984 patients in the rTSH-YES and rTSH-NO group, respectively. Trained personnel uncovered a high prevalence of undiagnosed thyroid dysfunction (7%). The diagnosis in the ED of heart failure, history of thyroid diseases, contrast media/amiodarone administration and female gender were independently associated with an increased likelihood to have thyroid dysfunction. The rTSH improved the clinical outcome by (a) appropriate treatment of an underlying clinical condition causing ED entrance, (b) appropriate prophylaxis in patients requiring contrast media, (c) uncovering incorrect treatments, with 60% of patients on levothyroxine requiring a dose reduction.The rTSH in the ED revealed a high prevalence of untreated thyroid disorders with a major impact on following interventions. The training of a multidisciplinary team is crucial in driving the correct decision-making process.

Introduction Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment. Methods Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. Results All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. Conclusions We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

Background: Radioiodine (RAI) is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs)...

BackgroundImmunosuppressive therapy of Graves’ orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC.Methodsof 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety.ResultsBaseline CAS decreased significantly in all groups (PConclusionsWe studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients’ quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

Resistance to Thyroid hormone beta (RTH-β) is a genetic syndrome characterized by impaired peripheral sensitivity to thyroid hormone (TH) due to heterozygous dominant-negative variants in the THRB gene, coding for TH receptor beta (TRβ).

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose. Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events. Results: Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p = 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome. Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON.

Background: The overall changes of ocular motility in Graves' orbitopathy (GO) are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the prese...

Thyroid hormone (TH) action is crucial for the development of several tissues.A number of syndromes are associated with reduced responsiveness to thyroid hormones, expanding the original definition of thyroid hormone resistance, firstly described by Refetoff and collaborators in 1967, which is characterized by elevated circulating levels of T4 and T3 with measurable serum TSH concentrations, as a consequence of mutations of thyroid hormone receptor beta (TRβ), recently named as RTHβ. More recently, another form of insensitivity to TH has been identified due to mutations in the thyroid hormone receptor alpha (TRα), named RTHα. In this chapter we will focus the discussion on the phenotype of RTHβ and RTHα. These diseases share the same pathogenic mechanism caused by dominant negative mutations in TH receptor genes that reduce T3 binding or affect the recruitment of cofactors. As a consequence, thyroid hormone actions are impaired at the tissue level. The phenotypic manifestations of RTHβ and RTHα are to some extent correlated with the degree of disruption and the tissue distribution of the TRs being characterized by variable coexistence of hypothyroid or thyrotoxic manifestations in RTHβ or by a congenital hypothyroid features in RTHα despite normal TSH and borderline low free T4.

Objectives Amiodarone-induced thyrotoxicosis (AIT) affects up to 3% of treated patients. Type 2 AIT (AIT2) is a destructive thyroiditis and is usually treated with medium-high oral doses of prednisone. As AIT may worsen the underlying heart disease, a rapid control of thyroid function is desirable. We aimed to determine whether a combined intravenous methylprednisolone (IVMP) pulses therapy associated to prednisone in the interpulse period can represent an efficient and safe alternative to urgent total thyroidectomy in patients with AIT2 not responsive to prednisone alone. Design and methods Patients presenting with a severe AIT2 studied in a tertiary referral Center from August 2018 to April 2019. We included four patients requiring a rapid improvement of thyroid function for their underlying cardiac disorders. The baseline doses of oral prednisone (range: 5–12.5 mg/day) and IVMP (range: 250–500 twice a week) were determined according to the severity of the thyrotoxicosis and were titrated based on clinical response. Results Combined treatment was effective in all patients in the prompt restoration of euthyroidism and no major adverse events were reported during the follow-up. In all cases, FT4 and FT3 levels normalized at 3–5 weeks of treatment. A permanent hypothyroidism was observed in one patient, 3 months after the discontinuation of treatment. Conclusions We report for the first time that the combined intravenous and oral steroid therapy is effective in patients with AIT2. The treatment is well tolerated and leads to a rapid improvement of thyroid function, avoiding urgent total thyroidectomy and favoring a quick functional recovery and rehabilitation of cardiac patients.

Thyroid hormone (TH) action is crucial for the development of several tissues. A number of syndromes are associated with reduced responsiveness to thyroid hormones, expanding the original definition of thyroid hormone resistance, firstly described by Refetoff and collaborators in 1967, which is characterized by elevated circulating levels of T4 and T3 with measurable serum TSH concentrations, as a consequence of mutations of thyroid hormone receptor beta (TRβ). Recently, other forms of insensitivity to TH have been identified: defects in cell surface transporters such as the monocarboxylate transporter 8 (MCT8), genetic disorders of thyroid hormone metabolism due to alterations of selenoprotein synthesis, which comprise the deiodinase enzymes, and finally, mutations in the thyroid hormone receptor alpha (TRα). Since the syndromes of TH insensitivity are characterized by extremely variable clinical manifestations and different molecular mechanisms, this group of thyroid disorders has been very recently reclassified and a novel nomenclature proposed.

The etiology of autoimmune diseases is the result of a complex interaction of the immune system with environmental and genetic factors, although the underlying mechanisms are not completely understood. A number of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a striking female predominance. Sexual dimorphism in autoimmunity can be explained at least in part by the role of sex hormones in the regulation of the immune system, whose cells express estrogen and androgen receptors. Furthermore, other mechanisms such as epigenetics may be involved in this multifaceted scenario. The rupture of this complex balance may contribute to the development of autoimmune diseases. In this chapter, we will focus on the effects of sex hormones and prolactin on the pathogenesis and development of autoimmunity.

The B cell activating factor (BAFF) is a member of the tumor necrosis factor family, which controls the survival/proliferation of B cells and is involved in the pathogenesis of a number of autoimmune diseases. The objective of the present study was to investigate the expression of BAFF and BAFF receptor (BAFF-R) in the thyroid tissue of patients affected with autoimmune thyroid disorders (AITD) or multinodular goiter (MNG) compared with those with normal thyroids.Immunohistochemistry was performed using a panel of antibodies against BAFF, BAFF-R, CD3, CD4, CD8, CD20, CD34, CD79a, CD1a, CD68, and CD163 on the thyroid sections of 27 patients affected with Graves' disease (GD), 23 with Hashimoto's thyroiditis (HT), 16 with nontoxic nodular goiter (NTG), and 15 with toxic nodular goiter (TG), submitted to total thyroidectomy between 2000 and 2011.The overall BAFF-R expression in thyrocytes was weak and not different in AITD and MNG. Conversely, a stronger BAFF expression was observed in MNG compared with AITD. BAFF and BAFF-R expression in the infiltrating lymphocytes was higher in AITD compared with MNG. Interestingly, in lymphocytes of follicular-like structures observed in HT, BAFF and BAFF-R were localized in the germinal center or in the mantle, respectively.This study shows that BAFF and BAFF-R are expressed in the thyrocytes derived from patients with either AITD or MNG, in addition to the expected expression of BAFF and its receptor in the infiltrating immune cells of GD and HT. These findings suggest a possible involvement of BAFF and its receptors in the pathophysiology of AITD.

BACKGROUND: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy.METHODS: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93.FINDINGS: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92-3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09-4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17-3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12-3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23-4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1-2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48).INTERPRETATION: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy.FUNDING: Novartis, Germany.

While pulsed intravenous methylprednisolone (iv-MP) has been shown to be effective and well tolerated in moderate to severe Graves' orbitopathy (GO), limited data are available on dysthyroid optic neuropathy (DON). The objective of this retrospective study was to investigate the efficacy of iv-MP in the treatment of DON and to seek parameters predictive of response.Twenty-four DON patients (40 eyes) treated with iv-MP from 2007 to 2012 were included in the study. Concurrent neurological or ophthalmologic diseases or signs of corneal exposure were considered as exclusion criteria. Iv-MP was administered daily for three consecutive days and repeated the following week. At six months, eyes not requiring surgery to preserve visual function were considered as responsive to treatment. Visual acuity, color sensitivity, visual field, and optic discs were analyzed at two and four weeks, and at 3, 6, and 12 months after treatment. Activity of GO was graded using a clinical activity score (CAS). Visual and clinical characteristics of the eyes responsive to iv-MP were studied by comparison to those of nonresponsive eyes.At six months, 17 of 40 (42.5%) eyes had complete visual recovery and were spared from surgical decompression. At two weeks, visual acuity, color sensitivity, and visual field improved significantly in almost all eyes, but GO inactivated (CAS4) only in the eyes that permanently responded to iv-MP (p0.01). The CAS at two weeks was a good predictor of response (cutoff ≥4; 66.7% sensitivity, 76.9% specificity). Optic disc swelling at diagnosis was highly predictive for unresponsiveness to iv-MP (34% sensitivity, 100% specificity). At baseline, high CAS (cutoff5; 40.2% sensitivity, 94.1% specificity) and severely altered visual field mean defect (cutoff ≤6.31 dB; 73.9% sensitivity, 58.8% specificity) were associated with unresponsiveness to steroids. No major side effects were observed.High-dose iv-MP was effective in permanently restoring visual function in about 40% of the eyes treated. When successful, it generally induced inactivation of the orbital disease within two weeks and normalization of visual function within one month. The presence of optic disc swelling at diagnosis and persistent active disease at two weeks were good predictors of unresponsiveness to steroids.

To define a method of quantifying axial proptosis in patients with Graves' orbitopathy (GO) and to validate a score that correlates with the orbital involvement and helps determine the degree of proptosis correction for elective orbital decompression.Retrospective, case series.The study included 50 patients (group A) and 29 control subjects who underwent orbital computed tomography (CT). The method was then validated in another group of 21 patients with GO (group B).The orbital area (OA) was measured manually on the central axial section of the CT scan at a level where the lens is visualized. The OA intersects the projection of the globe and delimitates the chord of an arch (globe chord [OC]). The area of the circular sector under the chord (CA) represents the portion of the globe within the orbit.A CA-to-OA ratio was calculated to reduce the error due to variability of the measurements and to perform correlations with some of the clinical parameters of GO.Measurement error was low (2%). We did not observe significant differences in the mean OA of patients with GO (783.6 ± 12.1 mm(2)) and controls (758.5 ± 20.4 mm(2); P = not significant). The OC value in patients with GO was 130.2 ± 11.5 mm(2), significantly lower than in controls (281.8 ± 9.7 mm(2); P0.0001). The CA-to-OA ratio also was lower in patients with GO than in controls (0.16 ± 0.01 vs. 0.38 ± 0.01; P0.0001). A significant correlation was found in patients with GO between the CA-to-OA ratio and proptosis (P0.001), lid fissure (P = 0.004), and intraocular pressure (P0.001). In group B, the CA-to-OA ratio was 0.18 ± 0.02, significantly different from that of controls (P0.0001) and inversely correlated with proptosis (P0.0001) and lid fissure (P0.045).By measuring the CA-to-OA ratio, we were able to quantify the degree of axial proptosis in patients with GO. The significant correlation of CA/OA with some orbital parameters confirms that this parameter also may be used as a measure of orbital involvement in GO.The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Pretibial myxedema (PTM) is a rare extrathyroidal manifestation of Graves' disease that requires treatment when the clinical picture is markedly evident. In addition to topical treatment with steroid ointments, there have been previous reports of subcutaneous injections of steroids. This procedure may cause nodular degeneration of the skin due to fat atrophy when standard needles are used. In the present study, we have tried a novel modality of treatment of PTM by injecting a solution of dexamethasone in the subcutaneous tissue using needles employed for mesotherapy. These needles are ≤4 mm long and deliver the medication within the dermis or the first layer of the subcutaneous fat. We have treated five patients, four with diffuse and one with elephanthiasic PTM. We utilized multiple injections of a solution of dexamethasone, lidocaine, and saline in the PTM plaque and in the pretibial area, both in the PTM plaque and in the area surrounding the lesions, once a week for three consecutive weeks. Two patients with a more severe form of PTM underwent another two cycles four to six weeks after initial treatment. Patients were studied before and after treatment by clinical assessment and ultrasound of the pretibial skin. The treatment was well-tolerated, with only moderate pain upon injection of the solution. One month after treatment, all patients showed improvement of PTM at clinical assessment and a reduction of the thickness of the lesions at ultrasound of ∼15%, involving mostly the dermis. Moreover, all patients reported amelioration of the leg appearance. The present study, although preliminary, shows that intralesion steroid injection with mesotherapy needles in PTM is effective and well tolerated, and does not cause undesired long-term modifications of the skin. More studies are warranted to standardize such treatment in larger groups of patients.

Context: Ig superfamily member1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods: All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone productionwasdelayed, aswerethe growth spurtandpubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Thyroid hormones (TH) are crucial for neuronal development, as untreated congenital hypothyroidism or genetic defects of TH transport cause severe neurological and cognitive impairment (Bernal, Nat Clin Pract Endocrinol Metab 3:249–259, 2007). TH modulate the division, the cell cycle, the migration, the maturation, and the differentiation of neuronal progenitors.

Objective: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle. Research Design and Methods: Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using P-31-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls. Results: The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P < 0.001). This substantial (similar to 35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates. Conclusions: Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.

Management of Graves’ orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO. In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20–30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients’ personal needs.

Summary In active Graves' orbitopathy (GO), proinflammatory cytokines predominate. Circulating thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) have been correlated with GO clinical activity and severity. In preliminary studies rituximab (RTX), an anti-CD 20 monoclonal antibody, has induced clinical improvement of active GO without a change in serum anti-thyroid antibodies. We have studied whether RTX in GO acts by affecting proinflammatory cytokines and thyroid and orbital-directed antibodies. Ten patients with GO were treated with RTX, administered twice intravenously (i.v.) (1000 mg) at days 1 and 15, and 20 with methylprednisolone, administered weekly i.v. (500 mg), for 16 weeks. Patients were studied before treatment, at B cell depletion and at 4, 8, 16, 20, 30 and 50 weeks. Peripheral lymphocytes, serum interleukin (sIL)-6, sIL-6r, chemokine (C-X-C motif) ligand 10 (CXCL10), TRAb and stimulating antibodies (TSAb) and autoantibodies against orbital calsequestrin, collagen XIII and flavoprotein subunit of succinate dehydrogenase (FP-SDH) were measured at baseline and after treatment. Serum IL-6 and sIL-6R concentrations did not change after RTX [P = not significant (n.s.)]. Serum CXCL10 increased after RTX at B cell depletion and at 30 weeks (P < 0·003). Serum TSAb did not change in relation to TRAb, nor did antibodies against orbital antigens (P = n.s.). In conclusion, this study shows that RTX in GO does not affect humoral reactions. The observed increase of serum CXCL10 concentrations at B cell depletion may result from cell lysis. We suggest that RTX may exert its effect in GO by inhibiting B cell antigen presentation.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of all pituitary adenomas. In the last years, the diagnosis has been facilitated by the routine use of ultra-sensitive TSH immunometric assays. Failure to recognise the presence of a TSHoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumour volume to further expand. The diagnosis mainly rests on dynamic testing, such as T3 suppression tests and TRH, which are useful in differentiating TSHomas from the syndromes of thyroid hormone resistance. The first therapeutical approach to TSHomas is the pituitary neurosurgery. The medical treatment of TSHomas mainly rests on the administration of somatostatin analogues, such as octreotide and lanreotide, which are effective in reducing TSH secretion in more than 90% of patients with consequent normalisation of FT4 and FT3 levels and restoration of the euthyroid state.