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Grigoris Effraimidis

Prediction models are of a great assistance for predicting the development of a disease, detecting or screening undiagnosed patients, predicting the effectiveness of a treatment and helping towards better decision-making. Recently, three predictive scores in the field of Autoimmune Thyroid Disease (AITD) have been introduced: The Thyroid Hormones Event Amsterdam-THEA score: a predictive score of the development of overt AITD, the Graves' Events After Therapy-GREAT score: a prediction score for the risk of recurrence after antithyroid drugs withdrawal and the Prediction Graves’ Orbitopathy-PREDIGO score: a prediction score for the development of Graves’ Orbitopathy in newly diagnosed patients with Graves’ hyperthyroidism. Their construction, clinical applicability, the possible preventative measurements which can be taken to diminish the risks and the potential future developments which can improve the accuracy of the predictive scores are discussed in this review.

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Victoria Zeghbi Cochenski Borba, Tatiana Lemos Costa, Carolina Aguiar Moreira and Cesar Luiz Boguszewski

Objective

This paper reviews the main mechanisms, diagnostic criteria, treatment options and available data on sarcopenia in endocrine and non-endocrine disorders. The literature notes the presence of sarcopenia as a comorbid condition or a complication of another clinical situation and not a disease that only affects elderly patients.

Method

We performed a literature review, focusing on the following: mechanisms related to sarcopenia in elderly patients, and sarcopenia as it presents in the context of chronic and endocrine diseases; diagnostic tools and methods; aspects of sarcopenia and treatment options specific to chronic diseases and endocrine disorders respectively.

Results

Sarcopenia in chronic and endocrine disorders shares many mechanisms with sarcopenia affecting elderly patients, but certain diseases can have a predominant aspect that leads to sarcopenia. The prevalence of sarcopenia varies, depending on different diagnostic criteria, from around 12 to 60% in chronic illnesses and 15 to 90% in endocrine disorders. The interplay between sarcopenia, chronic diseases and elderly patients requires further study, to clarify the impact of each, in terms of prognosis and mortality.

Conclusion

Awareness of the presentation of sarcopenia in the context of other diseases and ages (and not just the elderly) is fundamental to ensure that preventive measures can be deployed.

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Alfredo Berruti, Rossella Libè, Marta Laganà, Hester Ettaieb, Mohamad Anas Sukkari, Jérôme Bertherat, Richard A Feelders, Salvatore Grisanti, Jérôme Cartry, Gherardo Mazziotti, Sandra Sigala, Eric Baudin, Harm Haak, Mouhammed Amir Habra and Massimo Terzolo

Introduction

Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent.

Objective

The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis.

Methods

This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States.

Results

Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19–4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range.

Conclusion

Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

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Yamina Dassa, Hélène Crosnier, Mathilde Chevignard, Magali Viaud, Claire Personnier, Isabelle Flechtner, Philippe Meyer, Stéphanie Puget, Nathalie Boddaert, Sylvain Breton and Michel Polak

Objectives

Childhood traumatic brain injury (TBI) is a public health issue. Our objectives were to determine the prevalence of permanent pituitary hormone deficiency and to detect the emergence of other pituitary dysfunctions or central precocious puberty several years after severe TBI.

Design

Follow-up at least 5 years post severe TBI of a prospective longitudinal study.

Patients

Overall, 66/87 children, who had endocrine evaluation 1 year post severe TBI, were included (24 with pituitary dysfunction 1 year post TBI).

Main outcome measures

In all children, the pituitary hormones basal levels were assessed at least 5 years post TBI. Growth hormone (GH) stimulation tests were performed 3–4 years post TBI in children with GH deficiency (GHD) 1 year post TBI and in all children with low height velocity (<−1 DS) or low IGF-1 (<−2 DS). Central precocious puberty (CPP) was confirmed by GnRH stimulation test.

Results

Overall, 61/66 children were followed up 7 (5–10) years post TBI (median; (range)); 17/61 children had GHD 1 year post TBI, and GHD was confirmed in 5/17 patients. For one boy, with normal pituitary function 1 year post TBI, GHD was diagnosed 6.5 years post TBI. 4/61 patients developed CPP, 5.7 (2.4–6.1) years post-TBI. Having a pituitary dysfunction 1 year post TBI was significantly associated with pituitary dysfunction or CPP more than 5 years post TBI.

Conclusion

Severe TBI in childhood can lead to permanent pituitary dysfunction; GHD and CPP may appear after many years. We recommend systematic hormonal assessment in children 1 year after severe TBI and a prolonged monitoring of growth and pubertal maturation. Recommendations should be elaborated for the families and treating physicians.

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Tulay Guran, Gozde Yesil, Serap Turan, Zeynep Atay, Emine Bozkurtlar, AghaRza Aghayev, Sinem Gul, Ilker Tinay, Basak Aru, Sema Arslan, M Kutay Koroglu, Feriha Ercan, Gulderen Y Demirel, Funda S Eren, Betul Karademir and Abdullah Bereket

Context

Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown.

Patients and methods

Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics.

Results

We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility.

Conclusion

Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

Free access

Frederic Castinetti, Thierry Brue and Oskar Ragnarsson

Treatment of Cushing’s disease (CD) is one of the most challenging tasks in endocrinology. The first-line treatment, transsphenoidal pituitary surgery, is associated with a high failure rate and a high prevalence of recurrence. Re-operation is associated with an even higher rate of a failure and recurrence. There are three main second-line treatments for CD – pituitary radiation therapy (RT), bilateral adrenalectomy and chronic cortisol-lowering medical treatment. All these treatments have their limitations. While bilateral adrenalectomy provides permanent cure of the hypercortisolism in all patients, the unavoidable chronic adrenal insufficiency and the risk of development of Nelson syndrome are of concern. Chronic cortisol-lowering medical treatment is not efficient in all patients and side effects are often a limiting factor. RT is efficient for approximately two-thirds of all patients with CD. However, the high prevalence of pituitary insufficiency is of concern as well as potential optic nerve damage, development of cerebrovascular disease and secondary brain tumours. Thus, when it comes to decide appropriate treatment for patients with CD, who have either failed to achieve remission with pituitary surgery, or patients with recurrence, the pros and cons of all second-line treatment options must be considered.

Free access

Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan and Roger Bouillon

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Open access

Balachandran Kumarendran, Dana Sumilo, Michael W O’Reilly, Konstantinos A Toulis, Krishna M Gokhale, Chandrika N Wijeyaratne, Arri Coomarasamy, Wiebke Arlt, Abd A Tahrani and Krishnarajah Nirantharakumar

Objective

Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs without PCOS and to examine the role of obesity in the observed findings.

Design

Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK.

Methods

76 978 women with PCOS and 143 077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models.

Results

Median patient age was 30 (IQR: 25–35) years; median follow-up was 3.5 (IQR: 1.4–7.1) years. We found 298 OSA cases in PCOS women vs 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10 000 person years, respectively. Women with PCOS were at increased risk of developing OSA (adjusted HR = 2.26, 95% CI: 1.89–2.69, P < 0.001), with similar HRs for normal weight, overweight and obese PCOS women.

Conclusions

Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

Free access

Hermann L Müller

This review presents an update on current concepts of pathogenesis, diagnostics, multidisciplinary treatment and follow-up care, with special focus on neuropsychological sequelae of childhood-onset craniopharyngioma (CP) based on most recent publications on these topics. Recent insight in molecular pathogenesis of CP opens new perspectives on targeted therapy. Further research to elucidate pathogenic mechanisms and to prevent hypothalamic involvement of CP is warranted. Surgical treatment strategies should be based on a multidisciplinary approach involving experienced teams aiming at posterior hypothalamus-sparing treatment for prevention of quality of life impairments. Centralization of CP treatment in experienced ‘centers of excellence’ is recommended. However, such centralization includes high thresholds concerning infrastructure not achievable in all health systems. Alternatives such as multicenter-based networks used for reference assessments should be considered to assure high standards of treatment quality. Irradiation is efficient in preventing further growth or recurrence in CP patients with residual tumor. Proton beam therapy – available on a wider range in the near future – will help to avoid radiooncological side effects. Novel insights into neuropsychological sequelae after CP should be the basis for the development of future therapeutic neuropsychological interventions. Due to the rareness of the disease, common international efforts in research and treatment are recommended and should lead to an international registry for childhood-onset CP, as a first step toward efficient coordination of scientific and clinical initiatives.