The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours.

Purpose: Heritable genetic contributions to familial and sporadic pituitary tumorigenesis are poorly understood. There is emerging evidence that germline variants in classical cancer susceptibility genes may increase the risk of pituitary tumour development. We aimed to identify and assess the rate of pathogenic germline variants in breast and colorectal cancer susceptibility genes that may promote pituitary tumorigenesis.

From bench to bedside in the sella: translational developments in pituitary tumour genetics.

The two most prevalent pituitary tumour types are pituitary adenomas (also referred to as pituitary neuroendocrine tumours or pitNETs) and craniopharyngiomas, collectively accounting for 98% of all pituitary tumours. The genetic basis of these pituitary tumours is partly understood. In pituitary adenomas, established predisposition genes in the germline setting are MEN1, PRKAR1A, AIP, CDKN1B, GPR101 and the SDHx genes, while somatic driver mutations are well described in GNAS in somatotrophinomas and in USP8 in corticotrophinomas.

FGFR1 variation in the divergent settings of congenital hypopituitarism and pituitary tumours.

Purpose: Pituitary tumours are relatively common, and familial in approximately 5% of cases. However, germline genetic contributions to pituitary tumour development are incompletely characterised. Preliminary evidence suggests pituitary tumours may be promoted by variants in pituitary organogenesis genes.

Aripiprazole use as a cause of dopamine agonist failure in the treatment of prolactinomas.

Prolactinomas are the most common hypersecretory pituitary adenoma. The traditional first-line therapy is dopamine agonists (DAs), which are highly effective and tolerated in the majority of cases. However, DAs have the potential for psychiatric complications, such as psychosis, impulse control disorders and anxiety/depression.

Improving detection of monogenic diabetes through reanalysis of GCK variants of uncertain significance.

Aims: To assess the utility of reanalysing GCK variants of uncertain significance (VUS) as an intervention to improve the detection of monogenic diabetes.

Methods: We examined GCK VUS in a local cohort of individuals with suspected monogenic diabetes and re-curated each variant against the recent ClinGen GCK-specific variant classification guidelines.

Results: Variant reanalysis achieved a new 'likely pathogenic' classification (i.

17α-Hydroxylase/17,20-lyase Deficiency (17-OHD): A Meta-analysis of Reported Cases.

Purpose: Homozygous pathogenic variants in the CYP17A1 gene result in defective activity of the steroidogenic enzymes 17α-hydroxylase/17,20-lyase resulting in the clinical syndrome 17-OHD characterized by hypertension, hypokalemia, and disorders of sexual development. Pathogenic variants of CYP17A1 lead to complete or partial loss of enzymatic activity and clinical presentations of varying severity. This study aimed to examine relationships between CYP17A1 genotype and clinical presentation in a global cohort.

variants in patients with thyrotrophinomas, cyclical Cushing's disease and prolactinomas.

Introduction: Germline loss-of-function variants in , encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC).

Methods: We performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing's disease).

Cabergoline-associated valvulopathy of the tricuspid valve in the treatment of prolactinoma.

Cabergoline-associated valvulopathy (CAV) is defined by the echocardiographic triad of moderate or severe regurgitation, valvular thickening and restricted valvular motion. While it is a well-described complication of dopamine agonist therapy in Parkinson's disease, only three convincing cases of CAV have previously been described in the treatment of prolactinoma, with none involving the tricuspid valve. We describe a case of CAV affecting the tricuspid valve, ultimately resulting in the patient's death.

Pituitary tumours: molecular and genetic aspects.

'Pituitary tumours' is an umbrella term for various tumours originating from different regions of the hypothalamic-pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare.

Dopamine agonist therapy for prolactinomas: do we need to rethink the place of surgery in prolactinoma management?

The current treatment paradigm for prolactinomas involves dopamine agonist (DA) therapy as the first-line treatment, with surgical resection reserved for cases where there is DA failure due to resistance or intolerance. This review highlights how DA therapy can be optimised to overcome its increasingly recognised pitfalls, whilst also addressing the potential for expanding the use of surgery in the management of prolactinomas. The first part of the review discusses the limitations of DA therapy, namely: DA resistance; common DA side effects; and the rare but serious DA-induced risks of cardiac valvulopathy, impulse control disorders, psychosis, CSF rhinorrhoea and tumour fibrosis.

Primary hyperparathyroidism in adults-(Part II) surgical management and postoperative follow-up: Position statement of the Endocrine Society of Australia, The Australian & New Zealand Endocrine Surgeons, and The Australian & New Zealand Bone and Mineral Society.

Objective: To develop evidence-based recommendations to guide the surgical management and postoperative follow-up of adults with primary hyperparathyroidism.

Methods: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing eight key questions.

Results: Diagnostic imaging does not determine suitability for surgery but can guide the planning of surgery in suitable candidates.

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

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.

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

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.

A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing's disease.

Background: Apart from PRKAR1A mutations in a subset of cyclical Cushing's syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing's syndrome has not been investigated. We speculated that cyclical Cushing's syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis.

Case Presentation: A 47-year-old man presented with mass effects from a sellar lesion.

Development and validation of a targeted gene sequencing panel for application to disparate cancers.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.

Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors.

Context: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain.

Objective: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls.

The Genomic Landscape of Sporadic Prolactinomas.

Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas.

Serum prolactin overestimation and risk of misdiagnosis.

Background: Falsely elevated prolactin measurements risk overdiagnosis, and unnecessary imaging and treatment.

Design: We conducted a clinical audit of 18 patients who presented with hyperprolactinaemia, followed by a laboratory audit of 40 split samples across a range of serum prolactin (5-5051 mIU/L). In each case (total n = 58), serum prolactin was measured on both Roche and Siemens platforms.