Publications by authors named "Roderick J Clifton-Bligh"

87 Publications

A contemporary clinical approach to genetic testing for heritable hyperparathyroidism syndromes.

Endocrine 2021 Nov 13. Epub 2021 Nov 13.

Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia.

Purpose: The improved access and affordability of next generation sequencing has facilitated the clinical use of gene panel testing to test concurrently patients for multiple heritable hyperparathyroidism syndromes. However, there is little guidance as to which patients should be selected for gene panel testing and which genes should be included in such panels. In this review, we provide a practical approach to considering, interpreting and managing genetic testing for familial primary hyperparathyroidism (PHPT) syndromes and familial hypocalciuric hypercalcaemia (FHH) in patients with PTH-dependent hypercalcaemia. We discuss known genes implicated in PHPT and FHH, testing criteria and yields, pre-test counselling, laboratory considerations, and post-test management.

Methods: In addition to reviewing the literature, we conducted audits of local genetic testing data to examine the real-world yield of genetic testing in patients with PTH-dependent hypercalcaemia.

Results: Our local audits revealed a positive genetic testing rate of 15-26% in patients with suspected hyperparathyroidism syndromes.

Conclusion: Based on the particular testing criteria met, affected patients should be tested for variants in the genes currently implicated in PHPT (MEN1, CDC73, RET, CDKN1B, GCM2, CASR) and/or FHH (CASR, GNA11, AP2S1). Patients should be provided with pre- and post-test counselling, including consideration of potential implications for family members.
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http://dx.doi.org/10.1007/s12020-021-02927-3DOI Listing
November 2021

Risk stratification of indeterminate thyroid nodules using ultrasound and machine learning algorithms.

Clin Endocrinol (Oxf) 2021 Oct 13. Epub 2021 Oct 13.

Northern Clinical School, Faculty of Health and Medicine, University of Sydney, Australia.

Background: Indeterminate thyroid nodules (Bethesda III) are challenging to characterize without diagnostic surgery. Auxiliary strategies including molecular analysis, machine learning models, and ultrasound grading with Thyroid Imaging, Reporting and Data System (TI-RADS) can help to triage accordingly, but further refinement is needed to prevent unnecessary surgeries and increase positive predictive values.

Design: Retrospective review of 88 patients with Bethesda III nodules who had diagnostic surgery with final pathological diagnosis.

Measurements: Each nodule was retrospectively scored through TI-RADS. Two deep learning models were tested, one previously developed and trained on another data set, mainly containing determinate cases and then validated on our data set while the other one trained and tested on our data set (indeterminate cases).

Results: The mean TI-RADS score was 3 for benign and 4 for malignant nodules (p = .0022). Radiological high risk (TI-RADS 4,5) and low risk (TI-RADS 2,3) categories were established. The PPV for the high radiological risk category in those with >10 mm nodules was 85% (CI: 70%-93%). The NPV for low radiological risk in patients >60 years (mean age was 100% (CI: 83%-100%). The area under the curve (AUC) value of our novel classifier was 0.75 (CI: 0.62-0.84) and differed significantly from the chance-level (p < .00001).

Conclusions: Novel radiomic and radiologic strategies can be employed to assist with preoperative diagnosis of indeterminate thyroid nodules.
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http://dx.doi.org/10.1111/cen.14612DOI Listing
October 2021

International initiative for a curated variant database improving the diagnosis of hereditary paraganglioma and pheochromocytoma.

J Med Genet 2021 Aug 27. Epub 2021 Aug 27.

Genetics Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France

Background: is one of the major genes predisposing to paraganglioma/pheochromocytoma (PPGL). Identifying pathogenic variants in patients with PPGL is essential to the management of patients and relatives due to the increased risk of recurrences, metastases and the emergence of non-PPGL tumours. In this context, the 'NGS and PPGL (NGSnPPGL) Study Group' initiated an international effort to collect, annotate and classify variants and to provide an accurate, expert-curated and freely available variant database.

Methods: A total of 223 distinct variants from 737 patients were collected worldwide. Using multiple criteria, each variant was first classified according to a 5-tier grouping based on American College of Medical Genetics and NGSnPPGL standardised recommendations and was then manually reviewed by a panel of experts in the field.

Results: This multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB).

Conclusion: This international initiative by a panel of experts allowed us to establish a consensus classification for 223 variants that should be used as a routine tool by geneticists in charge of PPGL laboratory diagnosis. This accurate classification of genetic variants will help to clarify the diagnosis of hereditary PPGL and to improve the clinical care of patients and relatives with PPGL.
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http://dx.doi.org/10.1136/jmedgenet-2020-107652DOI Listing
August 2021

Translational Utility of Liquid Biopsies in Thyroid Cancer Management.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW 2052, Australia.

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly in lung, colorectal and breast cancer. In thyroid cancer, the role of liquid biopsy in either diagnosis or prognosis is beginning to translate from the lab to the clinic. In this review, we describe the evolution of liquid biopsies in detecting CTC, ctDNA and miRNA in thyroid cancer patients, together with its limitations and future directions in clinical practice.
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http://dx.doi.org/10.3390/cancers13143443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306718PMC
July 2021

Papillary thyroid microcarcinoma: Is active surveillance always enough?

Clin Endocrinol (Oxf) 2021 12 28;95(6):811-817. Epub 2021 Jun 28.

Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, Australia.

The incidence of papillary thyroid carcinoma (PTC) has increased over recent decades. This apparent epidemic has been attributed to the overdiagnosis of small PTC ≤10 mm in diameter (papillary thyroid microcarcinoma [PTMC]) incidentally detected on imaging for unrelated presentations. Although most PTMCs follow an indolent disease course, there is a small but significant proportion of cases that display more biologically aggressive features such as early metastasis and lymph node involvement. Management of PTMC diagnosed preoperatively should be distinguished from managing those PTMCs incidentally discovered after thyroidectomy. Here, we will focus on the challenge of managing the preoperative patient. Current guidelines recommend against routine biopsy of nodules ≤10 mm, even if they display highly suspicious features on ultrasound; however, it is not known how to identify those PTMCs at higher risk of disease progression. In view of their good prognosis even without surgical resection, active surveillance has emerged as an alternative to operative management for low-risk PTMC without lymph node involvement or distant metastasis. This review aims to summarise active surveillance data for PTMC and identify clinical features that may differentiate the indolent majority from those PTMCs that exhibit early disease progression and metastasis.
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http://dx.doi.org/10.1111/cen.14529DOI Listing
December 2021

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Nat Rev Endocrinol 2021 07 21;17(7):435-444. Epub 2021 May 21.

INSERM, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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http://dx.doi.org/10.1038/s41574-021-00492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205850PMC
July 2021

Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment.

J Clin Endocrinol Metab 2021 08;106(9):e3704-e3713

Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

Context: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable.

Objective: This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.

Methods: We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed.

Results: A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes.

Conclusion: Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
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http://dx.doi.org/10.1210/clinem/dgab263DOI Listing
August 2021

Multikinase inhibitors in thyroid cancer: timing of targeted therapy.

Nat Rev Endocrinol 2021 04 18;17(4):225-234. Epub 2021 Feb 18.

Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, NSW, Australia.

In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation.
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http://dx.doi.org/10.1038/s41574-020-00465-yDOI Listing
April 2021

The Sydney AFF Score: A Simple Tool to Distinguish Females Presenting With Atypical Femur Fractures Versus Typical Femur Fractures.

J Bone Miner Res 2021 05 16;36(5):910-920. Epub 2021 Feb 16.

Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Atypical femur fractures (AFF) are a rare but serious complication of long-term bisphosphonate use. Although clearly defined by ASBMR criteria, a proportion of patients with AFFs may go unrecognized and the use of qualitative fracture criteria may lead to uncertainty in AFF diagnosis, with significant therapeutic implications. A score that rapidly and accurately identifies AFFs among subtrochanteric femur fractures using quantitative, measurable parameters is needed. In a retrospective cohort of 110 female patients presenting with AFFs or typical femur fractures (TFFs), multiple logistic regression and decision tree analysis were used to develop the Sydney AFF score. This score, based on demographic and femoral geometry variables, uses three dichotomized independent predictors and adds one point for each: (age ≤80 years) + (femoral neck width <37 mm) + (lateral cortical width at lesser trochanter ≥5 mm), (score, 0 to 3). In an independent validation set of 53 female patients at a different centre in Sydney, a score ≥2 demonstrated 73.3% sensitivity and 69.6% specificity for AFF (area under the receiver-operating characteristic curve [AUC] 0.775, SE 0.063) and remained independently associated with AFF after adjustment for bisphosphonate use. The Sydney AFF score provides a quantitative means of flagging female patients with atraumatic femur fractures who have sustained an AFF as opposed to a TFF. This distinction has clear management implications and may augment current ASBMR diagnostic criteria. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4255DOI Listing
May 2021

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

J Clin Endocrinol Metab 2021 03;106(4):1163-1182

Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, Australia.

Context: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.

Objective: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.

Methods: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.

Results: Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.

Conclusion: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
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http://dx.doi.org/10.1210/clinem/dgaa957DOI Listing
March 2021

Aberrant Splicing of in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas.

J Endocr Soc 2020 Dec 16;4(12):bvaa071. Epub 2020 Jun 16.

Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.

Context: Germline mutations in the succinate dehydrogenase genes (///, -collectively, "") have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline mutation.

Methods: We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA.

Results: Germline WES revealed a novel intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type in a PGL and a somatic gain-of-function mutation in a GIST. The intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect.

Conclusions: This is the deepest intronic variant to be reported among the genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.
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http://dx.doi.org/10.1210/jendso/bvaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646550PMC
December 2020

Prophylactic central lymph node dissection informs the decision of radioactive iodine ablation in papillary thyroid cancer.

Am J Surg 2021 05 18;221(5):886-892. Epub 2020 Aug 18.

Department of Endocrine Surgery, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia; Cancer Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

Background: Prophylactic central lymph node dissection (CLND) in papillary thyroid cancer (PTC) is controversial. We aimed to investigate if prophylactic CLND aids risk stratification and contributes to the decision for postoperative RAI ablation.

Methods: Patients undergoing thyroidectomy for PTC and prophylactic CLND were identified from an endocrine surgical unit database. Pathology reports where reviewed for number and size of lymph nodes and patients stratified by risk according to the ATA guidelines.

Results: 426 patients were identified with PTC ≤4 cm and prophylactic CLND. 96 patients (23%) had central lymph node metastasis (CLNM) that qualified them for the intermediate risk group. In 17 patients (4%), the CLNM data led to upgrading independently of other histopathological characteristics. Correcting for multiple variables, CLNM was an independent factor contributing to RAI treatment.

Conclusion: Prophylactic CLND provides information to aid the selection of RAI ablation independent of primary cancer histology for risk stratification in 4% of patients. This benefit should be carefully balanced with the risk of CLND and patient treatment choice when deciding on management of PTC ≤4 cm.
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http://dx.doi.org/10.1016/j.amjsurg.2020.08.012DOI Listing
May 2021

Molecular Markers Guiding Thyroid Cancer Management.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Endocrine Surgical Unit, Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia.

The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC.
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http://dx.doi.org/10.3390/cancers12082164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466065PMC
August 2020

A Proposed Grading Scheme for Medullary Thyroid Carcinoma Based on Proliferative Activity (Ki-67 and Mitotic Count) and Coagulative Necrosis.

Am J Surg Pathol 2020 10;44(10):1419-1428

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research.

We investigated the prognostic value of a range of histologic parameters in medullary thyroid carcinoma (MTC) to design a grading system to predict overall survival. We assessed 76 patients with MTCs undergoing primary tumor resection for age, sex, tumor size, vascular space invasion, lymph node metastasis, multiple endocrine neoplasia type 2 (MEN2) status, mitotic count, Ki-67 proliferative index, spindled morphology, sheet-like growth pattern, coagulative necrosis, incipient necrosis, nuclear grade, multinucleation, prominent nucleoli, fibrosis, and amyloid deposition. In addition to the clinical features of age and the diagnosis of MEN2, the only histologic features that significantly predicted reduced overall survival were Ki-67 proliferative index, mitotic count, and the presence of coagulative necrosis. Using a combination of these 3 variables, we propose a 3-tiered grading system based solely on proliferative activity (Ki-67 proliferative index and mitotic count) and necrosis. There were 62 (82%) low-grade MTCs (low proliferative activity, no necrosis), 9 (12%) intermediate grade (low proliferative activity and necrosis present, or intermediate proliferative activity and no necrosis), and 5 (7%) high grade (intermediate proliferative activity and necrosis present, or high proliferative activity with or without necrosis). The mean overall survival was 193, 146, and 45 months, respectively (P=0.0001) for the 3 grades. The grading system remained prognostic when controlled for other factors associated with survival including age and known MEN2 syndrome. We conclude that this proposed grading system, which uses only a combination of proliferative activity (Ki-67 index, mitotic count) and coagulative necrosis, is a strong predictor of overall survival in MTC.
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http://dx.doi.org/10.1097/PAS.0000000000001505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641183PMC
October 2020

Congenital Hypoparathyroidism Associated With Elevated Circulating Nonfunctional Parathyroid Hormone Due to Novel PTH Mutation.

J Clin Endocrinol Metab 2020 07;105(7)

Cancer Genetics, Kolling Institute of Medical Research, Sydney, North South Wales, Australia.

Context: Familial hypoparathyroidism has a heterogeneous presentation where patients usually have low parathyroid hormone (PTH) levels due to impaired production or secretion. This contrasts with pseudohypoparathyroidism, in which PTH resistance is usually associated with an elevated serum PTH. High levels of circulating PTH can also be due to bioinactive PTH, which is difficult to distinguish from pseudohypoparathyroidism on biochemical grounds.

Case Description: We report on 2 sisters from consanguineous parents who presented with tetany at birth and were diagnosed with congenital hypocalcemia. Serum PTH levels were normal for many years, but progressively increased in midadulthood to greater than 100x the upper limit of normal on multiple assays. Homozygosity mapping was performed on 1 sister that demonstrated loss of heterozygosity (LOH) around PTH. Sequencing revealed a previously unreported variant, c.94T>C, predicting a codon change of p.Ser32Pro that is biologically inactive.

Conclusions: This case report shows a previously unreported unusual biochemical phenotype of a rising PTH in the context of a novel PTH mutation. This expands the evolving genotypes associated with hypoparathyroidism without established gene mutations.
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http://dx.doi.org/10.1210/clinem/dgaa279DOI Listing
July 2020

Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 04 11;110:83-97. Epub 2020 May 11.

Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA. Electronic address:

Background And Objectives: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.

Methods: Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.

Results: With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.

Conclusions: The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.
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http://dx.doi.org/10.1016/j.humpath.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655677PMC
April 2021

Multiple endocrine neoplasia: an update.

Intern Med J 2019 08;49(8):954-961

Department of Endocrinology and Diabetes, Royal North Shore Hospital, Sydney, New South Wales, Australia.

The multiple endocrine neoplasia (MEN) syndromes include MEN1, MEN2 (formerly MEN2A), MEN3 (formerly MEN2B) and the recently identified MEN4. Clinical presentations are varied and often relate to the overproduction of specific hormones. Understanding the genetics of each syndrome assists in determining screening timelines. Treatments for each manifestation are dependent on location, risk of recurrence or malignancy, hormone excess and surgical morbidity. Multidisciplinary management should include geneticists, genetic counsellors, endocrinologists and endocrine surgeons.
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http://dx.doi.org/10.1111/imj.14394DOI Listing
August 2019

Metabolomics in the Diagnosis of Pheochromocytoma and Paraganglioma.

Horm Metab Res 2019 Jul 15;51(7):443-450. Epub 2019 Jul 15.

Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, Australia.

Metabolomics refers to the detection and measurement of small molecules (metabolites) within biological systems, and is therefore a powerful tool for identifying dysfunctional cellular physiologies. For pheochromocytomas and paragangliomas (PPGLs), metabolomics has the potential to become a routine addition to histology and genomics for precise diagnostic evaluation. Initial metabolomic studies of tumors confirmed, as expected, succinate accumulation in PPGLs associated with pathogenic variants in genes encoding succinate dehydrogenase subunits or their assembly factors (). Metabolomics has now shown utility in clarifying variants of uncertain significance, as well as the accurate diagnosis of PPGLs associated with fumarate hydratase (), isocitrate dehydrogenase (), malate dehydrogenase () and aspartate transaminase (). The emergence of metabolomics resembles the advent of genetic testing in this field, which began with single-gene discoveries in research laboratories but is now done by standardized massively parallel sequencing (targeted panel/exome/genome testing) in pathology laboratories governed by strict credentialing and governance requirements. In this setting, metabolomics is poised for rapid translation as it can utilize existing infrastructure, namely liquid chromatography-tandem mass spectrometry (LC-MS/MS), for the measurement of catecholamine metabolites. Metabolomics has also proven tractable to diagnosis of SDH-deficient PPGLs using magnetic resonance spectroscopy (MRS). The future of metabolomics - embedded as a diagnostic tool - will require adoption by pathologists to shepherd development of standardized assays and sample preparation, reference ranges, gold standards, and credentialing.
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http://dx.doi.org/10.1055/a-0926-3790DOI Listing
July 2019

Checkpoint Inhibitor-Associated Autoimmune Diabetes Is Distinct From Type 1 Diabetes.

J Clin Endocrinol Metab 2019 11;104(11):5499-5506

Melanoma Institute Australia and the University of Sydney, Sydney, New South Wales, Australia.

Context: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis.

Case Series Description: Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti-programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti-PD-1-based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)-associated autoantibodies (DAAs) were present in two patients (both of whom had anti-glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy.

Conclusion: CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure.
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http://dx.doi.org/10.1210/jc.2019-00423DOI Listing
November 2019

MiRNA-3653 Is a Potential Tissue Biomarker for Increased Metastatic Risk in Pancreatic Neuroendocrine Tumours.

Endocr Pathol 2019 Jun;30(2):128-133

Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, Australia.

Pancreatic neuroendocrine tumours (PNETs) are relatively uncommon, accounting for 1-2% of all pancreatic neoplasms. Tumour grade (based on the Ki67 proliferative index and mitotic rate) is associated with metastatic risk across large cohorts; however, predicting the behaviour of individual tumours can be difficult. Therefore, any tool which could further stratify metastatic risk may be clinically beneficial. We sought to investigate microRNA (miRNA) expression as a marker of metastatic disease in PNETs. Tumours from 37 patients, comprising 23 with locoregional disease (L) and 14 with distant metastases (DM), underwent miRNA profiling. In total 506 miRNAs were differentially expressed between the L and DM groups, with four miRNAs (miR-3653 upregulated, and miR-4417, miR-574-3p and miR-664b-3p downregulated) showing statistical significance. A database search demonstrated that miRNA-3653 was associated with ATRX abnormalities. Mean survival between the two groups was correlated with mean expression of miRNA-3653; however, this did not reach statistical significance (p = 0.204). Although this is a small study, we conclude that miRNA-3653 upregulation may be associated with an increased risk of metastatic disease in PNETS, perhaps through interaction with ATRX and the alternate lengthening of telomeres pathway.
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http://dx.doi.org/10.1007/s12022-019-9570-yDOI Listing
June 2019

Bayesian approach to determining penetrance of pathogenic SDH variants.

J Med Genet 2018 11 10;55(11):729-734. Epub 2018 Sep 10.

Hormones and Cancer, Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Background: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C () genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).

Methods: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).

Results: Pathogenic variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in , 75 in and 12 in ), 13 are reported in ExAC (two in , nine in and two in ) accounting for 21% of subjects with variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for variants, 8.3% (95% CI 3.5% to 18.5%) for variants and 1.7% (95% CI 0.8% to 3.8%) for variants.

Conclusion: Pathogenic variants in are more penetrant than those in and . Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.
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http://dx.doi.org/10.1136/jmedgenet-2018-105427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252366PMC
November 2018

Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash Syndrome): A New Association.

J Clin Endocrinol Metab 2018 09;103(9):3119-3123

University of Sydney, Sydney, New South Wales, Australia.

Context: Hyperglucagonemia in the absence of glucagonomas is rare. Biallelic-inactivating mutations in the glucagon receptor gene (GCGR) cause glucagon cell hyperplasia and neoplasia (GCHN), also termed Mahvash syndrome. Here, we report the first case to our knowledge of GCHN presenting with hypercalcemia and demonstrate a unique relationship between calcium and α-cell hyperplasia.

Case Description: A 47-year-old man presented with severe PTH-independent hypercalcemia, 13.95 mg/dL (3.48 mmol/L). Imaging and extensive pathology tests yielded no conclusive cause. Glucagon levels >300 times the upper limit of normal were discovered. Subtotal pancreatectomy identified α-cell hyperplasia and neoplasia with metastatic disease in lymph nodes. Genomic analysis confirmed a homozygous missense variant in GCGR (Asp63Asn). This is a previously described pathologic variant and has a known association with GCHN.

Conclusions: Inactivating mutations of the glucagon receptor gene lead to nonfunctional hyperglucagonemia and are associated with GCHN. Homozygous or compound heterozygous GCGR mutations are associated with α-cell hyperplasia, a known precursor to pancreatic neuroendocrine tumors that can metastasize. Hypercalcemia is an unreported consequence of GCHN with an unclear mechanism.
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http://dx.doi.org/10.1210/jc.2018-01074DOI Listing
September 2018

An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter.

Thyroid 2018 07;28(7):891-901

1 Division of Infection and Immunity, Cardiff University , Cardiff, United Kingdom .

Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).

Methods: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.

Results: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02).

Conclusions: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.
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http://dx.doi.org/10.1089/thy.2017.0312DOI Listing
July 2018

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

Am J Surg Pathol 2019 01;43(1):35-46

Sydney Medical School, University of Sydney, Sydney.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.
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http://dx.doi.org/10.1097/PAS.0000000000001017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296846PMC
January 2019

The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma.

Eur J Endocrinol 2018 Feb 29;178(2):173-180. Epub 2017 Nov 29.

Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia.

Objective: Endocrine immune-related adverse events (endocrinopathies) are increasingly prevalent with the use of immune checkpoint inhibitors for the treatment of metastatic melanoma and other malignancies. There are no evidence-based guidelines for the screening or management of such patients. To describe the spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors.

Design: A prospective study conducted at Melanoma Institute Australia between April 2014 and October 2015.

Methods: A total of 177 patients were treated with (a) ipilimumab ( = 15), (b) anti-PD-1 (nivolumab, pembrolizumab) ( = 103) or (c) combination ipilimumab and anti-PD-1 ( = 59) and were screened and managed for the subsequent endocrinopathies. The main outcome measures were the incidence and kinetics of endocrinopathy by immunotherapy drug class.

Results: Thirty-one patients (18%) developed an endocrine immune-related adverse event (thyroid dysfunction: 14%, hypophysitis: 6% and autoimmune diabetes: 0.6%). Combination immunotherapy was more likely to result in a single or multiple endocrinopathy compared to anti-PD-1 monotherapy (27% vs 9% and 7% vs 0% respectively,  < 0.01). Endocrinopathies occurred after a median of 8 weeks from treatment commencement (range: 12-225 days), with combination immunotherapy resulting in significantly earlier onset compared to ipilimumab (median: 30 vs 76 days,  = 0.046). The majority of endocrinopathies were identified in asymptomatic patients with hormonal screening. There were no baseline predictors for endocrinopathy.

Conclusions: Combination immunotherapy has a greater risk of development of endocrinopathy compared to anti-PD-1 monotherapy. Regular biochemical profiling of patients, particularly within the first twelve weeks, results in early detection of endocrinopathy to minimise morbidity.
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http://dx.doi.org/10.1530/EJE-17-0810DOI Listing
February 2018

Clinical guidance for radioiodine refractory differentiated thyroid cancer.

Clin Endocrinol (Oxf) 2018 04 24;88(4):529-537. Epub 2017 Nov 24.

Department of Diabetes, Endocrinology & Metabolism, Royal North Shore Hospital Sydney, St Leonards, NSW, Australia.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.
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http://dx.doi.org/10.1111/cen.13508DOI Listing
April 2018

structural rearrangements in metastatic pheochromocytomas.

Endocr Relat Cancer 2018 01 3;25(1):1-9. Epub 2017 Oct 3.

The Peter MacCallum Cancer CentreEast Melbourne, Victoria, Australia

Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of activation in the majority of PC/PGL remains unclear. As promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated expression, each of which lacked promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the promoter, that are likely responsible for the activation of the normally tightly repressed expression in chromaffin cells.
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http://dx.doi.org/10.1530/ERC-17-0306DOI Listing
January 2018

Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.

BMC Cancer 2017 Jul 24;17(1):497. Epub 2017 Jul 24.

Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, 84132, USA.

Background: Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.

Methods: DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293).

Results: Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.

Conclusions: Our studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.
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http://dx.doi.org/10.1186/s12885-017-3486-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525311PMC
July 2017

Clinical, cellular, microscopic, and ultrastructural studies of a case of fibrogenesis imperfecta ossium.

Bone Res 2017 14;5:16057. Epub 2017 Mar 14.

Department of Endocrinology, Royal North Shore Hospital, St Leonards 2065, New South Wales, Australia; Faculty of Medicine, University of Sydney, Sydney 2006, New South Wales, Australia.

Fibrogenesis imperfecta ossium is a rare disorder of bone usually characterized by marked osteopenia and associated with variable osteoporosis and osteosclerosis, changing over time. Histological examination shows that newly formed collagen is abnormal, lacking birefringence when examined by polarized light. The case presented demonstrates these features and, in addition, a previously undocumented finding of a persistent marked reduction of the serum C3 and C4. Osteoblasts established in culture from a bone biopsy showed abnormal morphology on electron microscopy and increased proliferation when cultured with benzoylbenzoyl-ATP and 1,25-dihydroxyvitamin D, contrasting with findings in normal osteoblasts in culture. A gene microarray study showed marked upregulation of the messenger RNA (mRNA) for G-protein-coupled receptor 128 (GPR 128), an orphan receptor of unknown function and also of osteoprotegerin in the patient's osteoblasts in culture. When normal osteoblasts were cultured with the patient's serum, there was marked upregulation of the mRNA for aquaporin 1. A single pathogenetic factor to account for the features of this disorder has not been defined, but the unique findings described here may facilitate more definitive investigation of the abnormal bone cell function.
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http://dx.doi.org/10.1038/boneres.2016.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350113PMC
March 2017
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