Publications by authors named "Márta Korbonits"

251 Publications

Management of children and young people with idiopathic pituitary stalk thickening, central diabetes insipidus, or both: a national clinical practice consensus guideline.

Lancet Child Adolesc Health 2021 Jun 29. Epub 2021 Jun 29.

London Centre for Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital and University College London Hospitals, London, UK; Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Programme, Great Ormond Street Hospital Institute of Child Health, University College London, London, UK.

Unexplained or idiopathic pituitary stalk thickening or central diabetes insipidus not only harbours rare occult malignancies in 40% of cases but can also reflect benign congenital defects. Between 2014 and 2019, a multidisciplinary, expert national guideline development group in the UK systematically developed a management flowchart and clinical practice guideline to inform specialist care and improve outcomes in children and young people (aged <19 years) with idiopathic pituitary stalk thickening, central diabetes insipidus, or both. All such cases of idiopathic pituitary stalk thickening and central diabetes insipidus require dynamic pituitary function testing, specialist pituitary imaging, measurement of serum β-human chorionic gonadotropin and alpha-fetoprotein concentrations, chest x-ray, abdominal ultrasonography, optometry, and skeletal survey for occult disease. Stalk thickening of 4 mm or more at the optic chiasm, 3 mm or more at pituitary insertion, or both, is potentially pathological, particularly if an endocrinopathy or visual impairment coexists. In this guideline, we define the role of surveillance, cerebrospinal fluid tumour markers, whole-body imaging, indications, timing and risks of stalk biopsy, and criteria for discharge. We encourage a registry of outcomes to validate the systematic approach described in this guideline and research to establish typical paediatric stalk sizes and the possible role of novel biomarkers, imaging techniques, or both, in diagnosis.
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http://dx.doi.org/10.1016/S2352-4642(21)00088-2DOI Listing
June 2021

GHRH secretion from a pancreatic neuroendocrine tumor causing gigantism in a patient with MEN1.

Endocrinol Diabetes Metab Case Rep 2021 Jun 1;2021. Epub 2021 Jun 1.

Department of Endocrinology, Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.

Summary: A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.

Learning Points: It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.
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http://dx.doi.org/10.1530/EDM-20-0208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240703PMC
June 2021

Cabergoline reduces 3-methoxytyramine in a SDHC patient with metastatic paraganglioma and prolactinoma.

Endocrinol Diabetes Metab Case Rep 2021 Jun 1;2021. Epub 2021 Jun 1.

Department of Endocrinology, University College London Hospital, London, UK.

Summary: We observed a novel therapeutic response with cabergoline in a male patient with a dopamine-secreting head and neck paraganglioma (HNPGL), macroprolactinoma and germline succinate dehydrogenase C mutation (SDHC). The macroprolactinoma was treated with cabergoline which gave an excellent response. He was found to have raised plasma 3-methoxytyramine of 1014 pmol/L (NR: 0-180 pmol/L); but it was unclear if this was a drug-induced phenomenon from dopamine agonist (DA) therapy. Cabergoline was stopped for 4 weeks and the 3-methoxytyramine level increased significantly to 2185 pmol/L, suggesting a biochemical response of his HNPGL. Subsequently, Gallium-68 Dotatate PET and MRI (Gallium-68 Dotatate PET/MRI) demonstrated a second lesion in the sacrum. Both the HNPGL and metastatic sacral deposit received external beam radiotherapy with a good biochemical and radiological response.

Conclusion: Our case report highlights the rare potential of germline SDHC mutations causing metastatic paraganglioma and concurrent pituitary tumours. Cabergoline treatment may lower elevated 3-methoxytyramine levels and, therefore, mask the biochemical evidence of metastatic disease but also may have therapeutic relevance in dopamine-secreting pheochromocytomas/paragangliomas (PPGLs).

Learning Points: Several neuroendocrine tumours (NETs) express dopamine D2 and D4 receptors. In this case report, cabergoline significantly reduced plasma 3-methoxytyramine level in a patient with functional HNPGL. Cabergoline might have therapeutic relevance in dopamine-secreting PPGLs. Paragangliomas associated with SDHC mutation classically present with asymptomatic non-functional HNPGL and have rare metastatic potential. The association of pheochromocytoma or paraganglioma and pituitary adenoma is now a well-described rare association (<1%), designated as the three P association. While the three P association is most commonly seen with succinate dehydrogenase B and D mutations, it has also been described in patients with SDHA and SDHC mutations. Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease.
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http://dx.doi.org/10.1530/EDM-21-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240717PMC
June 2021

Serum inflammation-based scores in endocrine tumors.

J Clin Endocrinol Metab 2021 Apr 10. Epub 2021 Apr 10.

Department of Medicine, Division of Endocrinology and Center for Endocrine Tumors Leiden (CETL), Leiden University Medical Center, Leiden, The Netherlands.

Context: Serum inflammation-based scores reflect systemic inflammatory response and/or patients' nutritional status, and may predict clinical outcomes in cancer. While these are well-described and increasingly used in different cancers, their clinical usefulness in the management of patients with endocrine tumors is less known.

Evidence Acquisition: A comprehensive PubMed search was performed using the terms "endocrine tumor", "inflammation", "serum inflammation-based score", "inflammatory-based score", "inflammatory response-related scoring", "systemic inflammatory response markers", "Neutrophil-to-lymphocyte ratio", "Neutrophil-to-platelet ratio", "Lymphocyte-to-monocyte ratio", "Glasgow Prognostic Score", "Neutrophil-Platelet Score", "Systemic Immune-Inflammation Index", and "Prognostic Nutrition Index" in clinical studies.

Evidence Synthesis: The Neutrophil-to-Lymphocyte Ratio and the Platelet-to-Lymphocyte Ratio are the ones most extensively investigated in patients with endocrine tumors. Other scores have also been considered in some studies. Several studies focused in finding whether serum inflammatory biomarkers may stratify the endocrine tumor patients' risk and detect those at risk for developing more aggressive and/or refractory disease, particularly after endocrine surgery.

Conclusions: In this review, we summarize the current knowledge on the different serum inflammation-based scores and their usefulness in predicting the phenotype, clinical aggressiveness, disease outcomes and prognosis in patients with endocrine tumors. The value of such serum inflammation-based scores in the management of patients with endocrine tumors has been emerging over the last decade. However, further research is necessary to establish useful markers and their cut-offs for routine clinical practice for individual diseases.
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http://dx.doi.org/10.1210/clinem/dgab238DOI Listing
April 2021

Genetics of Acromegaly and Gigantism.

J Clin Med 2021 Mar 29;10(7). Epub 2021 Mar 29.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (, , , , , , , ) as well as familial cases with currently unknown genes, while somatic mutations in are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with mutations or duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune-Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.
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http://dx.doi.org/10.3390/jcm10071377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036715PMC
March 2021

Posterior pituitary tumours: patient outcomes and determinants of disease recurrence or persistence.

Endocr Connect 2021 Apr;10(4):387-400

Department of Endocrinology, Postgraduate Institute of Medical Education and Research, (PGIMER), Chandigarh, India.

Objective: Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery.

Methods: We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010-2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours.

Results: Patients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence.

Conclusion: PPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.
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http://dx.doi.org/10.1530/EC-20-0621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142326PMC
April 2021

Molecular characterization of DICER1-mutated pituitary blastoma.

Acta Neuropathol 2021 06 1;141(6):929-944. Epub 2021 Mar 1.

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.
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http://dx.doi.org/10.1007/s00401-021-02283-6DOI Listing
June 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

The clinical aspects of pituitary tumour genetics.

Endocrine 2021 03 4;71(3):663-674. Epub 2021 Feb 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

Background: Pituitary tumours are usually benign and relatively common intracranial tumours, with under- and overexpression of pituitary hormones and local mass effects causing considerable morbidity and increased mortality. While most pituitary tumours are sporadic, around 5% of the cases arise in a familial setting, either isolated [familial isolated pituitary adenoma, related to AIP or X-linked acrogigantism], or in a syndromic disorder, such as multiple endocrine neoplasia type 1 or 4, Carney complex, McCune-Albright syndrome, phaeochromocytoma/paraganglioma with pituitary adenoma, DICER1 syndrome, Lynch syndrome, and USP8-related syndrome. Genetically determined pituitary tumours usually present at younger age and show aggressive behaviour, and are often resistant to different treatment modalities.

Subject: In this practical summary, we take a practical approach: which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient.

Conclusion: The identification of the causative mutation allows genetic and clinical screening of relatives at risk, resulting in earlier diagnosis, a better therapeutic response and ultimately to better long-term outcomes.
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http://dx.doi.org/10.1007/s12020-021-02633-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016799PMC
March 2021

Patients with rare endocrine conditions have corresponding views on unmet needs in clinical research.

Endocrine 2021 03 3;71(3):561-568. Epub 2021 Feb 3.

Department of Paediatric Endocrinology, Ghent University Hospital, and Ghent University, Ghent, Belgium.

Purpose: European Reference Network on Rare Endocrine Conditions' (Endo-ERN) mission is to reduce and ultimately abolish inequalities in care for patients with rare endocrine conditions in Europe. This study assesses which themes related to rare endocrine conditions are prioritized by patients for clinical research.

Methods: A survey was developed, translated into 22 different European languages, and distributed to patients with rare endocrine conditions. Patients were asked to give priority scores to listed prespecified topics: fertility, heritability, tiredness, daily medicine intake, sleep quality, physical discomfort, and ability to work, partake in social life, and sports. They were also asked to suggest further important areas for research in open fields.

Results: After data cleaning, 1378 survey responses were analyzed. Most responses were received from Northern (47%) and Western Europeans (39%), while Southern (11%) and Eastern Europe (2%) were underrepresented. Respondents were most interested in research concerning ability to participate in social life and work. Patients suggested key areas to work: long-term side effects of medical treatments and quality of life. Some priorities differed between disease groups, both for prespecified and open topics and reflected aspects of patients' individual conditions.

Conclusions: With this large survey, Endo-ERN gained insight into patients' unmet needs in scientific research. Patients prioritized research on ability to work and participation in social activities, though needs differ between the disease groups. Clinical experts should incorporate the results of this survey into the design of future studies on rare endocrine conditions. We aim to utilize these results in designing patient-reported outcome measures for the disease areas covered by Endo-ERN.
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http://dx.doi.org/10.1007/s12020-021-02618-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016771PMC
March 2021

Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours.

Int J Mol Sci 2021 Jan 22;22(3). Epub 2021 Jan 22.

Endocrine Signalling Group, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.

Patients harbouring mutations in genes encoding C-type natriuretic peptide (CNP; ) or its receptor guanylyl cyclase B (GC-B, ) suffer from severe growth phenotypes; loss-of-function mutations cause achondroplasia, whereas gain-of-function mutations cause skeletal overgrowth. Although most of the effects of CNP/GC-B on growth are mediated directly on bone, evidence suggests the natriuretic peptides may also affect anterior pituitary control of growth. Our previous studies described the expression of and in a range of human pituitary tumours, normal human pituitary, and normal fetal human pituitary. However, the natriuretic peptide system in somatotropes has not been extensively explored. Here, we examine the expression and function of the CNP/GC-B system in rat GH3 somatolactotrope cell line and pituitary tumours from a cohort of feline hypersomatotropism (HST; acromegaly) patients. Using multiplex RT-qPCR, all three natriuretic peptides and their receptors were detected in GH3 cells. The expression of was significantly enhanced following treatment with either 100 nM TRH or 10 µM forskolin, yet only expression was sensitive to forskolin stimulation; the effects of forskolin and TRH on expression were PKA- and MAPK-dependent, respectively. CNP stimulation of GH3 somatolactotropes significantly inhibited and expression, but dramatically enhanced expression at the same time point. Oestrogen treatment significantly enhanced expression of and in GH3 somatolactotropes, but inhibited CNP-stimulated cGMP accumulation. Finally, transcripts for all three natriuretic peptides and receptors were expressed in feline pituitary tumours from patients with HST. expression was negatively correlated with pituitary tumour volume and expression, but positively correlated with and expression. Collectively, these data provide mechanisms that control expression and function of CNP in somatolactotrope cells, and identify putative transcriptional targets for CNP action in somatotropes.
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http://dx.doi.org/10.3390/ijms22031076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865297PMC
January 2021

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

Eur J Endocrinol 2021 Apr;184(4):553-563

Department of Endocrinology, University of Medicine and Pharmacy Craiova, Craiova, Romania.

Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH.

Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry.

Methods: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits.

Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement.

Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.
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http://dx.doi.org/10.1530/EJE-20-1249DOI Listing
April 2021

Identification of a TMEM127 variant in a patient with paraganglioma and acromegaly.

Endocrinol Diabetes Metab Case Rep 2020 Sep 23;2020. Epub 2020 Sep 23.

Department of Endocrinology, Diabetes and Clinical Nutrition, Luzerner Kantonsspital, Luzern, Switzerland.

Summary: The coincidence of a pheochromocytoma or paraganglioma and a pituitary adenoma in the same patient is a rare condition. In the last few years SDHx and MAX mutations have been identified and discussed as a potential causal connection in cases of coincidence. We describe a case of a middle-aged female patient which presented with acromegaly, a growth hormone-secreting pituitary adenoma and a symptomatic neck paraganglioma. The patient was cured by surgery from both the pituitary tumour and the paraganglioma and is well after ten years follow-up. Due to the unusual coexistence of two neuroendocrine tumours, further molecular genetic testing was performed which revealed a variant in the TMEM127 gene (c245-10C>G).

Learning Points: Pheochromocytoma/paraganglioma and coexisting functioning pituitary adenoma are a very rare condition. An appropriate treatment of each tumour entity with a multi-disciplinary approach and regular follow-up is needed. The possibility of a hereditary disease should be considered and genetic workup is recommended. Genetic testing should focus primarily on the genes with mutations related to pheochromocytomas and paragangliomas. Next-generation sequencing with multi-gene panel testing is the currently suggested strategy. Genes associated with paragangliomas and pituitary adenomas are SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and MEN1, while case reports with VHL, RET and NF1 may represent coincidences. Variants of uncertain significance may need ongoing vigilance, in case novel data become available of these variants.
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http://dx.doi.org/10.1530/EDM-20-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576664PMC
September 2020

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

T Kocjan, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Ljubljana, Slovenia.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Sensitivity and specificity of the macimorelin test for diagnosis of AGHD.

Endocr Connect 2021 Jan;10(1):76-83

University of Arizona College of Medicine and Creighton School of Medicine, Barrow Pituitary Center, Barrow Neurological Institute, Phoenix, Arizona, USA.

Objective: The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints.

Design: Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18-66 years with BMI <37 kg/m2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D).

Methods: Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0-1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL.

Results: For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807-1), 0.9924 (0.9807-1), 0.9916 (0.9786-1), and 0.9950 (0.9861-1), respectively.

Conclusions: Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).
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http://dx.doi.org/10.1530/EC-20-0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923131PMC
January 2021

Clinical Outcomes and Complications of Pituitary Blastoma.

J Clin Endocrinol Metab 2021 Jan;106(2):351-363

Minneapolis, Minnesota, USA.

Context: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome.

Objective: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases.

Design And Setting: A multi-institutional case series is presented from tertiary pediatric oncology centers.

Patients: Patients included children with pituitary blastoma.

Interventions: Genetic testing, surgery, oncologic therapy, endocrine support are reported.

Outcome Measures: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes.

Results: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities.

Conclusions: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.
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http://dx.doi.org/10.1210/clinem/dgaa857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823240PMC
January 2021

Pre-operative serum inflammation-based scores in patients with pituitary adenomas.

Pituitary 2021 Jun 24;24(3):334-350. Epub 2020 Nov 24.

Department of Medicine, Division of Endocrinology and Center for Endocrine Tumors Leiden (CETL), Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Objective: Full blood count (FBC) and serum inflammation-based scores reflect systemic inflammation and predict outcomes in cancer, but little is known in pituitary adenomas (PAs). We aimed to characterise FBC and inflammation-based scores in PA patients and investigate their usefulness in predicting challenging disease course.

Methods: We studied 424 PA patients first operated at our centre with available pre-operative biochemical data. Patients with infection, malignancies, autoimmune or haematological conditions were excluded. Inflammation-based scores studied: Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic Immune-Inflammation Index (SII), Neutrophil-Platelet Score (NPS), Prognostic Nutrition Index (PNI), and Glasgow Prognostic Score (GPS).

Results: Cushing's disease patients had more platelets, leucocytes, neutrophils and monocytes, and higher NLR, NPS and SII. Serum inflammation-based scores didn't differ among non-Cushing PA subtypes. The glucocorticoid excess severity influenced leucocyte, eosinophil, basophil and platelet counts, and GPS in Cushing's disease. Patients with functioning non-Cushing PAs with suprasellar extension, cavernous sinus invasion and hypopituitarism had GPS ≥ 1, while NPS ≥ 1 was associated with suprasellar extension. More invasive and difficult to treat corticotrophinomas were associated with fewer platelets pre-operatively (< 299.5 × 10/L predicting multimodal treatment). Non-functioning PA patients who suffered apoplexy had more leucocytes, neutrophils and monocytes, higher GPS ≥ 1 and fewer platelets; re-operated cases had fewer lymphocytes, higher NLR and PLR.

Conclusions: Serum inflammation-based scores may predict invasive/refractory PAs: GPS and PNI in non-functioning and functioning non-Cushing PAs; NPS in functioning non-Cushing PAs; NLR and PLR in non-functioning PAs. Platelets < 299.5 × 10/L predict multimodal treatment in Cushing's disease. Further studies are needed to confirm these observations.
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http://dx.doi.org/10.1007/s11102-020-01112-5DOI Listing
June 2021

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

J Clin Endocrinol Metab 2021 Mar;106(4):1183-1194

Department of Endocrinology, Skåne University Hospital, Malmö, Lund University, Sweden.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors.

Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs.

Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored.

Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs.

Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.
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http://dx.doi.org/10.1210/clinem/dgaa749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993578PMC
March 2021

AIP variant causing familial prolactinoma.

Pituitary 2021 Feb 3;24(1):48-52. Epub 2020 Oct 3.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.
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http://dx.doi.org/10.1007/s11102-020-01085-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864850PMC
February 2021

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2021 Jan;106(1):e192-e203

Department of Paediatrics, University of Cambridge, Cambridge, UK.

Background: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear.

Methods: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC.

Results: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively.

Conclusions: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.
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http://dx.doi.org/10.1210/clinem/dgaa694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990061PMC
January 2021

ACQUIRED ECTOPIC POSTERIOR PITUITARY BRIGHT SPOT DUE TO VASCULOTOXIC SNAKEBITE.

AACE Clin Case Rep 2020 Sep-Oct;6(5):e207-e211. Epub 2020 May 4.

Department of Endocrinology, PGIMER, Chandigarh, India.

Objective: Vasculotoxic envenomation is an uncommon cause of hypopituitarism. Most described cases have varying extent of anterior pituitary dysfunction, but posterior pituitary involvement is extremely rare.

Methods: Clinical, biochemical, and radiologic evaluation of a young female who presented with secondary amenorrhea was performed. A brief literature review of envenomation-induced hypopituitarism is included.

Results: A 26-year-old female presented with secondary amenorrhea since the age of 20 years. She had normal stature. Her past medical history was significant for a vasculotoxic snakebite 12 years back requiring hemodialysis, but no hormonal testing was done at that time. Current evaluation showed anterior hypopituitarism. An insulin-induced hypoglycemia test confirmed deficiencies of cortisol and growth hormone axes (peak values 348 nmol/L and 0.03 ng/mL). There was no diabetes insipidus. Magnetic resonance imaging revealed a hypoplastic anterior pituitary with an ectopic posterior pituitary. In view of normal stature and secondary amenorrhea, a diagnosis of envenomation-induced hypopituitarism with ectopic posterior pituitary (EPP) was made. A brief literature review of envenomation-induced hypopituitarism showed both acute and delayed presentation, male predominance, and variable lag period (weeks to years). Nearly half of all patients were asymptomatic. The most common axis involved in acute presentation was the cortisol axis, whereas the thyroid and gonadotroph axes were commonly involved in delayed hypopituitarism.

Conclusion: Vasculotoxic envenomation is a rare cause of acquired hypopituitarism. EPP in the index case was probably due to the "axonal dieback" phenomenon and subsequent regeneration of the axons at a more caudal site. This case, being the first instance of acquired EPP following envenomation, expands the spectrum of envenomation-induced hypopituitarism.
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http://dx.doi.org/10.4158/ACCR-2020-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511110PMC
May 2020

The role of the tumour microenvironment in the angiogenesis of pituitary tumours.

Endocrine 2020 12 18;70(3):593-606. Epub 2020 Sep 18.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Purpose: Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines.

Methods: Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel.

Results: Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters.

Conclusions: M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs.
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http://dx.doi.org/10.1007/s12020-020-02478-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674353PMC
December 2020

Update on the Genetics of Pituitary Tumors.

Endocrinol Metab Clin North Am 2020 09;49(3):433-452

Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

Pituitary adenomas are common intracranial neoplasms, with diverse phenotypes. Most of these tumors occur sporadically and are not part of genetic disorders. Over the last decades numerous genetic studies have led to identification of somatic and germline mutations associated with pituitary tumors, which has advanced the understanding of pituitary tumorigenesis. Exploring the genetic background of pituitary neuroendocrine tumors can lead to early diagnosis associated with better outcomes, and their molecular mechanisms should lead to novel targeted therapies even for sporadic tumors. This article summarizes the genes and the syndromes associated with pituitary tumors.
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http://dx.doi.org/10.1016/j.ecl.2020.05.005DOI Listing
September 2020

Unusual Combination of MEN-1 and the Contiguous Gene Deletion Syndrome of CAH and Ehlers-Danlos Syndrome (CAH-X).

J Endocr Soc 2020 Aug 27;4(8):bvaa077. Epub 2020 Jun 27.

Division of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland.

The contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, and . Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described mutation (c.784-9G > A), a homozygous complete deletion of (c.1-?_1488+? del), as well as a large deletion of the neighboring gene (c.11381-?_11524+?). The deletion includes the complete gene and exons 35 through 44 of the gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges.
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http://dx.doi.org/10.1210/jendso/bvaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371387PMC
August 2020

XAF1 as a modifier of p53 function and cancer susceptibility.

Sci Adv 2020 Jun 24;6(26):eaba3231. Epub 2020 Jun 24.

School of Medicine, University of Sao Paulo, Sao Paulo, SP, Brazil.

Cancer risk is highly variable in carriers of the common R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma ( = 0.003) and subsequent malignancies ( = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic variants, whereas -E134* is markedly attenuated in this activity. We propose that cosegregation of E134* and R337H mutations leads to a more aggressive cancer phenotype than R337H alone, with implications for genetic counseling and clinical management of hypomorphic mutant carriers.
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http://dx.doi.org/10.1126/sciadv.aba3231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314530PMC
June 2020

The tumour microenvironment of pituitary neuroendocrine tumours.

Front Neuroendocrinol 2020 07 15;58:100852. Epub 2020 Jun 15.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address:

The tumour microenvironment (TME) includes a variety of non-neoplastic cells and non-cellular elements such as cytokines, growth factors and enzymes surrounding tumour cells. The TME emerged as a key modulator of tumour initiation, progression and invasion, with extensive data available in many cancers, but little is known in pituitary tumours. However, the understanding of the TME of pituitary tumours has advanced thanks to active research in this field over the last decade. Different immune and stromal cell subpopulations, and several cytokines, growth factors and matrix remodelling enzymes, have been characterised in pituitary tumours. Studying the TME in pituitary tumours may lead to a better understanding of tumourigenic mechanisms, identification of biomarkers useful to predict aggressive disease, and development of novel therapies. This review summarises the current knowledge on the different TME cellular/non-cellular elements in pituitary tumours and provides an overview of their role in tumourigenesis, biological behaviour and clinical outcomes.
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http://dx.doi.org/10.1016/j.yfrne.2020.100852DOI Listing
July 2020

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

Clin Endocrinol (Oxf) 2020 08 18;93(2):146-153. Epub 2020 May 18.

Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus C, Denmark.

Context: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved.

Objective: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant.

Methods: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants.

Results: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons.

Conclusions: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.
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http://dx.doi.org/10.1111/cen.14207DOI Listing
August 2020

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms.

Endocr Rev 2020 12;41(6)

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK.

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.
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http://dx.doi.org/10.1210/endrev/bnaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441741PMC
December 2020

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial.

Lancet Diabetes Endocrinol 2020 04 25;8(4):278-291. Epub 2020 Feb 25.

Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address:

Background: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids.

Methods: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994.

Findings: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01).

Interpretation: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation.

Funding: Barts Charity and Merck Serono.
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http://dx.doi.org/10.1016/S2213-8587(20)30021-8DOI Listing
April 2020
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