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Naia Grandgeorge, Giovanni Barchetti, Solange Grunenwald, Fabrice Bonneville and Philippe Caron

Objective

Primary SMSa treatment can be associated with hormonal control and tumor shrinkage in patients with GH-secreting pituitary adenomas. The aim of this study was to evaluate whether regular MRI follow-up was necessary in patients with acromegaly-treated and responsive to first-generation long-acting SMSa.

Patients and methods

In this retrospective monocentric study we included patients with GH/IGF-1 hypersecretion and pituitary adenomas with normal visual field, primarily treated with first-generation long-acting SMSa between 1995 and 2015 and regularly monitored (clinical evaluation, GH/IGF-1 levels and pituitary MRI) for at least 3 years.

Results

We included 83 patients (32 men and 51 women, mean age at diagnosis 50 ± 12 years) with mean GH = 19.3 ± 25.6 ng/mL, IGF-1 = 284 ± 110% ULN and pituitary adenoma height = 12.9 ± 4.7 mm. Mean follow-up was 8.9 ± 4.9 years in 36 controlled patients and 2.0 ± 1.6 years in 47 partial responders to SMSa alone. No significant increase in pituitary adenoma height was observed. Pituitary adenoma height decreased significantly in controlled patients (diagnosis: 11.9 ± 4.8 mm, SMSa: 9.6 ± 3.3 mm, P < 0.001), and in partially responders (diagnosis: 13.6 ± 4.5 mm, SMSa: 11.5 ± 4.5 mm, P < 0.001).

Conclusion

During SMSa treatment, no significant increase in GH-secreting adenoma size was observed. Primary SMSa treatment was associated with a significantly decrease in adenoma height in our population. Our cohort data suggest that regular MRI follow-up does not seem relevant in patients with acromegaly who are responsive to SMSa treatment.

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Yunting Lin, Yanna Cai, Jianan Xu, Chunhua Zeng, Huiying Sheng, Yang Yu, Xiuzhen Li and Li Liu

Objective

X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR.

Methods and results

For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband.

Conclusions

This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

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Lotte Kleinendorst, Ozair Abawi, van der Kamp Hetty J, Mariëlle Alders, Meijers-Heijboer Hanne E J, Elisabeth F C van Rossum, van den Akker Erica L T and van Haelst Mieke M

Objective

Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe.

Design

Comprehensive epidemiologic analysis and systematic literature review.

Methods

We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants.

Results

Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95–1.72).

Conclusions

This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.

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Jacques Young, Magalie Haissaguerre, Oceana Vieira-Pinto, Olivier Chabre, Eric Baudin and Antoine Tabarin

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in term of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS, and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced co-morbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to 1) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and; 2) the tumoral status, ranging from resectable ACTH secreting tumors, to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and includes variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasizing the operational effectiveness of care.

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Yutaka Takahashi

Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor-induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

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L T van Hulsteijn, R Pasquali, F Casanueva, M Haluzik, S Ledoux, M P Monteiro, J Salvador, F Santini, H Toplak and O M Dekkers

Objective

The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up for the Obesity Guideline of the European Society of Endocrinology.

Design

Systematic review and meta-analysis of the literature.

Methods

A search was performed in MEDLINE, EMBASE, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% confidence intervals (95% CI).

Results

Sixty-eight studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI: 9.7–18.9) and 14.6% (95% CI: 9.2–20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI: 0.3–1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI: 37.6–48.0) and 32.7% (95% CI: 23.1–43.0), respectively. Heterogeneity was high for all analyses.

Conclusions

The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.

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Giorgia Pepe, Domenico Corica, Luisa de Sanctis, Mariacarolina Salerno, Maria Felicia Faienza, Daniele Tessaris, Gerdi Tuli, Iris Scala, Laura Penta, Angela Alibrandi, Giovanni Battista Pajno, Tommaso Aversa and Malgorzata Wasniewska

Objective: to evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents.

Design: prospective multicenter study.

Methods: 101 DS patients with SH (TSH 5-10 mIU/L; FT4 12–22 pmol/L), aged 2-17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up.

Results: 37/101 patients displayed autoantibodies positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, p=0.001; 32.4% vs 7.8%, p=0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, p=0.028). Gender, median BMI (SDS), height (SDS), FT4 and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (p=0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (p=0.02); 37.8% of group A vs 51.5% of group B still had SH condition (p=0.183). Logistic regression suggested autoimmunity (OR=3.2) and baseline TSH values (OR=1.13) as predictive factors of the evolution from SH to OH.

Conclusions: In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

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Maximilian Eichner, Henri Wallaschofski, Ulf Schminke, Henry Völzke, Marcus Dörr, Stephan B Felix, Matthias Nauck and Nele Friedrich

Objective

Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown.

Design

The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP).

Methods

Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed.

Results

Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase −0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta −0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found.

Conclusions

The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.

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Yaelle Elfassy, Alice Bongrani, Pierre Levy, Frantz Foissac, Soraya Fellahi, Céline Faure, Chloé McAvoy, Jacqueline Capeau, Joëlle Dupont, Bruno Fève, Rachel Levy, Jean-Philippe Bastard and the Metasperme group

Objective

Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples.

Design

Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016.

Methods

Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP.

Results

Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS.

Conclusions

These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.

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Lucie Coppin, Margaux Dufosse, Pauline Romanet, Sophie Giraud, Marie-Odile North, Catherine Cardot Bauters, Françoise Borson-Chazot, Laurence Duchesne, Mélanie Métallo, Tonio Lovecchio, Anne Barlier and Marie-Françoise Odou

Objective

Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease.

Design and methods

The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT).

Results

From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance.

Conclusion

We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.