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Open access

Susanne Thiele, Ralf Werner, Annika Stubbe, Olaf Hiort, and Wolfgang Hoeppner


Hypophosphataemic rickets (HR) comprise a clinically and genetically heterogeneous group of conditions, defined by renal-tubular phosphate wasting and consecutive loss of bone mineralisation. X-linked hypophosphataemia (XLH) is the most common form, caused by inactivating dominant mutations in PHEX, a gene encompassing 22 exons located at Xp22.1. XLH is treatable by anti-Fibroblast Growth Factor 23 antibody, while for other forms of HR such as therapy may not be indicated. Therefore, a genetic differentiation of HR is recommended.


To develop and validate a next-generation sequencing panel for HR with special focus on PHEX.

Design and methods:

We designed an AmpliSeq gene panel for the IonTorrent PGM next-generation platform for PHEX and ten other HR-related genes. For validation of PHEX sequencing 50 DNA-samples from XLH-patients, in whom 42 different mutations in PHEX and 1 structural variation have been proven before, were blinded, anonymised and investigated with the NGS panel. In addition, we analyzed one known homozygous DMP1 mutation and two samples of HR-patients, where no pathogenic PHEX mutation had been detected by conventional sequencing.


The panel detected all 42 pathogenic missense/nonsense/splice-site/indel PHEX-mutations and in one the known homozygous DMP1 mutation. In the remaining two patients, we revealed a somatic mosaicism of a PHEX mutation in one; as well as two variations in DMP1 and a very rare compound heterozygous variation in ENPP1 in the second patient.


This developed NGS panel is a reliable tool with high sensitivity and specificity for the diagnosis of XLH and related forms of HR.

Open access

Carmina Teresa Fuss, Katharina Brohm, Max Kurlbaum, Anke Hannemann, Sabine Kendl, Martin Fassnacht, Timo Deutschbein, Stefanie Hahner, and Matthias Kroiss

Objective: Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored diagnostic utility of steroid panel analysis.

Design: Retrospective cohort study of 187 paired SIT samples (2009-2018). Diagnosis of PA (n=103) and EH (n=84) was established based on clinical routine workup without using LC-MS/MS values.

Setting: Tertiary care center.

Methods: LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion.

Results: Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95%-CI 89.0-98.4; specificity: 87%, 95%-CI 77.8-93.3; area under the curve (AUC) 0.955, 95%-CI 0.924-0.986; PPV: 90%, 95%-CI 83.7-93.9) and 69 ng/L for LC-MS/MS (79%, 95%-CI 69.5-86.1; 89%, 95%-CI 80.6-95.0; 0.902, 95%-CI 0.857-0.947; 90%, 95%-CI 82.8-94.4). Other steroids did not improve SIT.

Conclusions: Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

Open access

Davide Calebiro

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. They play a fundamental role in the endocrine system, where they mediate the effects of several hormones and neurotransmitters. As a result, alterations of GPCR signalling are a major cause of endocrine disorders such as congenital hypothyroidism or Cushing’s syndrome. My group develops innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy, which allow us to investigate GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using this innovative approach, we have contributed to elucidate some long debated questions about the mechanisms of GPCR signalling and their involvement in human disease. Among other findings, these studies have led to the unexpected discovery that GPCRs are not only signalling at the cell surface, as previously assumed, but also at various intracellular sites. This has important implications to understand how hormones and neurotransmitters produce specific responses in our cells and might pave the way to innovative treatments for common diseases like diabetes or heart failure.

Open access

Bastiaan Sol, Jeroen M.k. de Filette, Gil Awada, Steven Raeymaeckers, Sandrine Aspeslagh, C.e. Andreescu, Bart Neyns, and Brigitte Velkeniers


Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.


We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.


Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.


ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

Open access

Claire L Wood, Kieren G Hollingsworth, Eric Hughes, Sadhanandham Punniyakodi, Robert Muni-Lofra, Anna Mayhew, Rod T. Mitchell, Michela Guglieri, Timothy D Cheetham, and Volker Straub



Pharmacological doses of glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD). Delayed puberty and bone fragility are consequences of GC treatment. The aim of this study was to determine the acceptability of a 2-year pubertal induction regimen using 4-weekly testosterone injections and examine changes in physique, bone integrity, muscle pathology (assessed by magnetic resonance imaging) and muscle function.


15 prepubertal males with DMD, aged 12-17 years and receiving GC, were treated with an incremental testosterone regimen for 2 years. Participants completed a Treatment Satisfaction Questionnaire (TSQM). Data on BMI, bone density, muscle pathology and function were collected at baseline and 2 years later.


Testosterone injections were well tolerated, with high TSQM scores. Baseline BMI z-score was 2.16 (0.90) and 1.64 (1.35) 2 years later. Median testosterone levels were 9.7nmol/l (IQR 5.7-11.1) 6 – 9 months after the last injection with an associated increase in testicular volume. Lumbar spine z-score was 0.22 (SD 2.21) at baseline and 0.35 (SD 2.21) after 2 years. Upper and lower limb muscle contractile cross sectional area increased in all participants during the trial (p=0.05 and p<0.01 respectively). There was a reduction in T2 relaxation times in most muscle groups with stable upper limb muscle function.


Incremental monthly testosterone injections were well tolerated, promoted endogenous testosterone production and had a positive impact on the skeleton and contractile muscle bulk with evidence suggesting a beneficial impact on the underlying disease process.

Open access

Anuradhaa Subramanian, Jan Idkowiak, Konstantinos A Toulis, Shakila Thangaratinam, Wiebke Arlt, and Krishnarajah Nirantharakumar

Context: The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.

Objective: To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.

Data Sources: We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.

Study selection and extraction: Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described.

Results: Seven studies (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.

Conclusions: Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

Open access

Anastasia Gant Kanegusuku, Katherine Araque, Joanna Klubo-Gwiezdzinska, and Steven J Soldin


Open access

John-Paul Fuller-Jackson, Aimee L Dordevic, Iain J Clarke, and Belinda A Henry


Retrospective studies suggest that women have more active brown adipose tissue (BAT) than men, but little is known of the effect of fluctuating sex steroids across the menstrual cycle on thermogenesis in women.


To characterise the effects of sex and sex steroids on BAT activity we recruited healthy weight men (n = 14) and women at two stages of the menstrual cycle (luteal, n = 9; follicular, n = 11).


Infrared thermography measured supraclavicular temperature to index BAT thermogenesis in response to both cold (immersion of one hand in water at 15°C) and meal (Ensure, 10 kcal/kg body weight) stimuli.


Adaptive BAT temperature responses were greater (P < 0.05) in women than men, irrespective of stage of menstrual cycle. Whereas during cold exposure, the increase in BAT temperature was abrogated (P < 0.05) in women during follicular phase compared to men and women during luteal phase. Plasma concentrations of progesterone, 17β-estradiol, testosterone and cortisol were measured. Regression analyses demonstrated that baseline BAT temperature was positively correlated (P < 0.05) with progesterone levels, but was inversely associated (P < 0.05) with cortisol concentration. Both cold- and meal-induced changes in BAT temperature mildly correlated (P = 0.07; P < 0.05) with 17β-estradiol levels, but not with testosterone concentrations.


Baseline supraclavicular temperature is elevated in women during the luteal phase of the menstrual cycle, which correlated with elevated progesterone concentrations. Women exhibited greater thermogenic responses than men, irrespective of the state of the menstrual cycle, which was associated with plasma levels of 17β-estradiol. We conclude that sex steroids may regulate BAT thermogenesis in healthy adults.

Open access

Claire L Wood, Michael Cole, Malcolm Donaldson, David P Dunger, Ruth Wood, Niamh Morrison, John Ns Matthews, Simon Hs Pearce, and Timothy D Cheetham


First line treatment of thyrotoxicosis in young people is thionamide antithyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control.


A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2-16 years with newly diagnosed thyrotoxicosis at 15 UK centres.


Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4y outcome (remission/relapse).


Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60·2% in BR and 63·8% in DT patients; adjusted difference 4·3%, 95% CI (-7·8 to 16·4);p=0.48. Proportions for FT4 were 79·2% in BR and 85·7% in DT patients; adjusted difference 6·8%, (-0·2 to 15·6);p=0·13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y.


This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.

Open access

Friso de Vries, Mees Bruin, Angelica Cersosimo, Charlotte N van Beuzekom, S Faisal Ahmed, Robin P Peeters, Nienke R Biermasz, Olaf Hiort, and Alberto M Pereira


Given that volumes of patients and interventions are important criteria to qualify as a reference centre (RC) for the European Reference Network on Rare Endocrine Conditions (Endo-ERN), the present study aimed to evaluate the data that were reported in the original application against subsequent assessments of activity and review the criteria that may define RCs using two main thematic groups (MTGs): Pituitary and Thyroid, as examples.


Review of content in application forms and continuous monitoring data and of a survey distributed to RCs. A list of ‘key procedures’ for the assessment of performance of RCs was composed with the help of the Pituitary and Thyroid MTG chairs.


In the original application, the number of undefined procedures ranged from 20 to 5500/year (Pituitary) and from 10 to 2700/year (phyroid) between applicants. In the survey, the number of key procedures per centre ranged from 18 to 150/year (Pituitary) and from 20 to 1376/year (Thyroid). The median numbers of new patients reported in the continuous monitoring program were comparable with the application and survey; however, some centres reported large variations.


Monitoring of clinical activity in an ERN requires clear definitions that are optimally aligned with clinical practice, diagnosis registration, and hospital IT systems. This is a particular challenge in the rare disease field where the centre may also provide expert input in collaboration with local hospitals. Application of uniform definitions, in addition to condition-specific clinical benchmarks, which can include patient-reported- as well as clinician-reported outcome measures, is urgently needed to allow benchmarking of care across Endo-ERN.