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Open access

Hoda Gad, Einas Elgassim, Ibrahim Mohammed, Ahmad Yaser Alhaddad, Hussein Ahmed Hussein Zaky Aly, John-John Cabibihan, Abdulaziz Al-Ali, Kishor Kumar Sadasivuni, Aliyaa Haji, Neila Lamine, Adnan Khan, Ioannis N Petropoulos, Georgios Ponirakis, Alise Kalteniece, Maryam Ferdousi, Shazli Azmi, Uazman Alam, Wajeeha Abuhelaiqa, Amin Jayyousi, Dabia AlMohanadi, Khaled Baagar, and Rayaz A Malik

Objective

Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes.

Methods

A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days.

Results

CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0–37.5) vs 38.6 (29.2–46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9–37.5) vs 37.5 (29.2–46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8–41.7) vs 35.4 (28.1–44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = –0.342, P = 0.031). Duration in level 1 (181–250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05).

Conclusions

Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Open access

Nathalia Liberatoscioli Menezes Andrade, Mariana Ferreira de Assis Funari, Alexsandra Christianne Malaquias, Paulo Ferrez Collett-Solberg, Nathalia L R A Gomes, Renata Scalco, Naiara Castelo Branco Dantas, Raissa C Rezende, Angelica M F P Tiburcio, Micheline A R Souza, Bruna L Freire, Ana C V Krepischi, Carlos Alberto Longui, Antonio Marcondes Lerario, Ivo J P Arnhold, Alexander A L Jorge, and Gabriela Andrade Vasques

Objective

Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.

Design and methods

We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.

Results

We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n  = 4), SHOX (n  = 3), FGFR3 (n  = 2), NPR2 (n  = 2), ACAN (n  = 2), and COL2A1 (n  = 1) or involved in the RAS/MAPK pathway: NF1 (n  = 2), PTPN11 (n  = 1), CBL (n  = 1), and BRAF (n  = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.

Conclusion

A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.

Open access

Alexander Heinzel, Dirk Müller, Hanneke M van Santen, Sarah C Clement, Arthur B Schneider, and Frederik A Verburg

Background

Childhood cancer survivors (CCS) who received radiation therapy exposing the thyroid gland are at increased risk of developing differentiated thyroid cancer (DTC). Therefore, the International Guideline Harmonization Group (IGHG) on late effects of childhood cancer therefore recommends surveillance. It is unclear whether surveillance reduces mortality.

Aim

The aim of this study was to compare four strategies for DTC surveillance in CCS with the aim of reducing mortality: Strategy-1, no surveillance; Strategy-2, ultrasound alone; Strategy-3, ultrasound followed by fine-needle biopsy (FNB); Strategy-4, palpation followed by ultrasound and FNB.

Materials and methods

A decision tree was formulated with 10-year thyroid cancer-specific survival as the endpoint, based on data extracted from literature.

Results

It was calculated that 12.6% of CCS will develop DTC. Using Strategy-1, all CCS with DTC would erroneously not be operated upon, but no CCS would have unnecessary surgery. With Strategy-2, all CCS with and 55.6% of CCS without DTC would be operated. Using Strategy-3, 11.1% of CCS with DTC would be correctly operated upon, 11.2% without DTC would be operated upon and 1.5% with DTC would not be operated upon. With Strategy-4, these percentages would be 6.8, 3.9 and 5.8%, respectively. Median 10-year survival rates would be equal across strategies (0.997).

Conclusion

Different surveillance strategies for DTC in CCS all result in the same high DTC survival. Therefore, the indication for surveillance may lie in a reduction of surgery-related morbidity rather than DTC-related mortality. In accordance with the IGHG guidelines, the precise strategy should be decided upon in a process of shared decision-making.

Open access

Luca Persani, Martine Cools, Stamatina Ioakim, S Faisal Ahmed, Silvia Andonova, Magdalena Avbelj-Stefanija, Federico Baronio, Jerome Bouligand, Hennie T Bruggenwirth, Justin H Davies, Elfride De Baere, Iveta Dzivite-Krisane, Paula Fernandez-Alvarez, Alexander Gheldof, Claudia Giavoli, Claus H Gravholt, Olaf Hiort, Paul-Martin Holterhus, Anders Juul, Csilla Krausz, Kristina Lagerstedt-Robinson, Ruth McGowan, Uta Neumann, Antonio Novelli, Xavier Peyrassol, Leonidas A Phylactou, Julia Rohayem, Philippe Touraine, Dineke Westra, Valeria Vezzoli, and Raffaella Rossetti

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11–490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

Open access

Rachel Forfar, Mashal Hussain, Puneet Khurana, Jennifer Cook, Steve Lewis, Dillon Popat, David Jackson, Ed McIver, Jeff Jerman, Debra Taylor, Adrian JL Clark, and Li F Chan

The overproduction of adrenocorticotropic hormone (ACTH), in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), leads to significant morbidity. Current treatment with glucocorticoids does not adequately suppress plasma ACTH, resulting in excess adrenal androgen production. At present, there is no effective medical treatment in clinical use that would directly block the action of ACTH. Such a therapy would be of great clinical value. ACTH acts via a highly selective receptor, the melanocortin-2 receptor (MC2R) associated with its accessory protein MRAP. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and the high degree of ligand specificity suggest that antagonism of this receptor could provide a useful therapeutic strategy in the treatment of conditions of ACTH excess. To this end, we screened an extensive library of low-molecular-weight drug-like compounds for MC2R antagonist activity using a high-throughput homogeneous time-resolved fluorescence cAMP assay in Chinese hamster ovary cells stably co-expressing human MC2R and MRAP. Hits that demonstrated MC2R antagonist properties were counter-screened against the β2 adrenergic receptor and dose–response analysis undertaken. This led to the identification of a highly specific MC2R antagonist capable of antagonising ACTH-induced progesterone release in murine Y-1 adrenal cells and having selectivity for MC2R amongst the human melanocortin receptors. This work provides a foundation for the clinical investigation of small-molecule ACTH antagonists as therapeutic agents and proof of concept for the screening and discovery of such compounds.

Open access

Peter Wolf, Alexandre Dormoy, Luigi Maione, Sylvie Salenave, Jacques Young, Peter Kamenický, and Philippe Chanson

Objective

Pasireotide is a second-generation somatostatin receptor ligand (SRL) used for treating acromegaly. Its clinical use is limited by adverse effects on glucose homeostasis. The aim of this study was to evaluate longitudinal changes in beta-cell function and insulin sensitivity associated with pasireotide in patients not controlled by first-generation SRLs.

Design

We performed a retrospective study.

Methods

The efficacy (growth hormone (GH)/insulin-like growth factor (IGF-1) concentrations; tumor size) and effect on glucose homeostasis were analyzed in 33 patients. Longitudinal data on oral glucose tolerance tests were available before, shortly (mean ± s.d., 6.1 ± 3.8 months) and long term (24.4 ± 11.1 months) after initiation of pasireotide in 14 patients. Insulin secretion (insulinogenic index; disposition index) and insulin sensitivity were calculated by validated indices.

Results

Pasireotide-induced diabetes occurred in 12 patients (36%). It was mediated by impaired insulin secretion, which occurred shortly after initiation of treatment and then remained stable on long term (insulinogenic index, median (min; max), 80 (12; 542) vs 16 (6.4; 101) vs 25 (3.7; 396) pmol/mmol, respectively; P = 0.028; disposition index, 1.45 (0.42; 4.88) vs 0.53 (0.17; 2.63) vs 0.60 (0.22; 1.71), respectively; P = 0.024). No significant changes in insulin sensitivity were observed, despite a marked reduction of GH/IGF-1 concentrations. Older age and a worse glycemic control at baseline were the strongest predictors for hyperglycemia and the need for antidiabetic treatment.

Conclusion

Worsening of glycemic control during pasireotide therapy is caused by an impaired insulin secretion, whereas insulin sensitivity is not affected. These findings might be important for the choice of antidiabetic treatment for pasireotide-induced hyperglycemia.

Significance statement

Pasireotide, a second-generation SRL used for treating acromegaly, may be associated with glucose metabolism impairment. In a retrospective study of 33 patients, we observed that treatment with pasireotide was associated with normalization of serum IGF-1 in almost 60% of patients, but one-third of patients developed diabetes. In the patients who stopped pasireotide because of hyperglycemia, HbA1c promptly decreased. Longitudinal data in 14 patients show that diabetes is mediated by impaired insulin secretion, which occurred shortly and then remained stable on long term, while no significant changes in insulin sensitivity were observed, despite a marked reduction of GH/IGF-1 concentrations. Older age and a worse glycemic control at baseline were the strongest predictors for hyperglycemia.

Open access

Yuntao Song, Jiaxin Wang, Yanli Zhu, Guohui Xu, Tianxiao Wang, and Bin Zhang

Objective

The central neck lymph node (LN) status is important for the treatment strategy of papillary thyroid cancer (PTC), while the diagnosis is difficult. This study aims to evaluate the diagnostic value of fine-needle aspiration (FNA) and its washout thyroglobulin (FNA-Tg) detection in central neck LN metastasis.

Methods

Central neck LNs with FNA cytology (FNA-C) and FNA-Tg measurements from a tertiary hospital were included. Tg levels were correlated with histopathological or follow-up results. The diagnostic performance of FNA-C, FNA-Tg, and combining FNA-C and FNA-Tg for detecting LN metastasis was assessed.

Results

A total of 132 LNs in the central neck from 129 patients were studied. The median FNA-Tg concentration of 74 metastatic LNs was 552.5 ng/mL, whereas, in 58 benign LNs, the median Tg concentration was 0.1 ng/mL (P < 0.001). Receiver operating characteristic analysis (area under the curve, 0.861) was used, and a cutoff value of 14.6 ng/mL was obtained. There was no significant increase in the diagnostic accuracy when FNA-Tg was used or combined with FNA-C, compared with FNA-C alone. The size, location of LNs, the presence of the ipsilateral thyroid gland, and Hashimoto's thyroiditis did not affect the incidence of misdiagnosis.

Conclusions

FNA-C is the gold standard for evaluating central neck metastasis in PTC patients. Measurement of Tg levels in FNA washout does not improve the diagnostic accuracy any further.

Open access

Izabelle Lövgren, Azadeh Abravan, Abigail Bryce-Atkinson, and Marcel van Herk

Brain tumours make up nearly one-third of paediatric malignancies. Over time, advancements in oncological treatments like radiotherapy have helped reduce normal-tissue toxicity when treating cancers in the brain. However, clinicians are still facing a trade-off between treatment efficacy and potential side effects. The aim of this review is to address the late effects of cranial irradiation on the neuroendocrine system and to identify factors that make patients more vulnerable to radiation-induced endocrine sequelae. Radiation damage to the hypothalamic–pituitary axis, which orchestrates hormone release, can lead to endocrinopathy; up to 48.8% of children who have undergone cranial irradiation develop a hormone deficiency. This may lead to further health complications that can appear up to decades after the last treatment, lowering the patients’ quality of life and increasing long-term costs as lifelong hormone replacement therapy may be required. Growth hormone deficiency is the most common sequelae, followed by either thyroid or gonadotropic hormone deficiency. Adrenocorticotropic hormone deficiency tends to be the least common. Identified factors that increase the risk of late endocrine deficiency include total radiation dose, age at treatment, and time since last treatment. However, as there are various other factors that may potentiate the damage, a universal solution proven to be most effective in sparing the endocrine tissues is yet to be identified. Until then, accounting for the identified risk factors during treatment planning may in some cases help reduce the development of endocrine sequelae in childhood cancer survivors.

Open access

Sílvia Santos Monteiro, Tiago Silva Santos, Ana Martins Lopes, José Carlos Oliveira, Cláudia Freitas, and André Couto Carvalho

Purpose

The levothyroxine absorption test (LT4AT) is an important tool for distinguishing hypothyroidism due to malabsorption from ‘pseudomalabsorption’ conditions. Our aim was to review our institution’s LT4AT results and assess its role in the management of patients with refractory hypothyroidism.

Methods

We performed a retrospective study of all patients evaluated for refractory hypothyroidism who underwent LT4AT in our tertiary center between 2014 and 2020. Its results and the impact on thyroid function management during follow-up were assessed.

Results

Ten female patients were included with a mean age of 40 years (min-max: 26–62). Mean weight was 72 kg (min–max: 43–88) and baseline LT4 dosage ranged from 2.5 to 5.3 µg/kg/day. The most common causes of hypothyroidism were postsurgical in 50% (n  = 5) and autoimmune in 20% (n  = 2). During LT4AT, normal LT4 absorption was found in all but one individual (mean FT4 increase of 231%, min–max: 85–668). The only patient with objective LT4 absorption impairment (maximal increase of 48% by hour 5) presented also Helicobacter pylori gastritis and prior history of ‘intestinal surgery’ during childhood. No adverse events were reported during any of the LT4ATs. During follow-up (median 11.5 months (IQR 23)), three patients obtained euthyroidism and six had improved their hypothyroidism state.

Conclusions

The LT4AT is an effective and safe way to assess refractory hypothyroidism and provides valuable information to distinguish LT4 malabsorption from ‘pseudomalabsorption’. Our data suggest that most patients with suspicious LT4 malabsorption perform normally during LT4AT. This test provides relevant information for better management of patients with refractory hypothyroidism.

Open access

Herjan J T Coelingh Bennink, Jan Krijgh, Jan F M Egberts, Maria Slootweg, Harm H E van Melick, Erik P M Roos, Diederik M Somford, Yvette Zimmerman, Iman J Schultz, Noel W Clarke, R Jeroen A van Moorselaar, and Frans M J Debruyne

The purpose of androgen deprivation therapy (ADT) in prostate cancer (PCa), using luteinizing hormone-releasing hormone agonists (LHRHa) or gonadotrophin-releasing hormone antagonists, is to suppress the levels of testosterone. Since testosterone is the precursor of estradiol (E2), one of the major undesired effects of ADT is the concomitant loss of E2, causing among others an increased bone turnover and bone loss and an increased risk of osteoporosis and fractures. Therefore, the guidelines for ADT indicate to combine ADT routinely with bone-sparing agents such as bisphosphonates, denosumab or selective estrogen receptor modulators. However, these compounds may have side effects and some require inconvenient parenteral administration. Co-treatment with estrogens is an alternative approach to prevent bone loss and at the same time, to avoid other side effects caused by the loss of estrogens, which is the topic explored in the present narrative review. Estrogens investigated in PCa patients include parenteral or transdermal E2, diethylstilbestrol (DES), and ethinylestradiol (EE) as monotherapy, or high-dose estetrol (HDE4) combined with ADT. Cardiovascular adverse events have been reported with parenteral E2, DES and EE. Encouraging effects on bone parameters have been obtained with transdermal E2 (tE2) and HDE4, in the tE2 development program (PATCH study), and in the LHRHa/HDE4 co-treatment study (PCombi), respectively. Confirmation of the beneficial effects of estrogen therapy with tE2 or HDE4 on bone health in patients with advanced PCa is needed, with special emphasis on bone mass and fracture rate.