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

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

Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males.

A heterozygous missense mutation of the islet β cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset β cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the unstable MAFA protein. Here, we develop a S64F MafA mouse model to determine how β cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafAS64F/+) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca2+ signaling, DNA damage, aging, and senescence. MAFAS64F production in male human β cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFAWT. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-biased manner

Unusual AIP mutation and phenocopy in the family of a young patient with acromegalic gigantism.

This is the peer reviewed version of the following article: Syed Ali, I., et al. (2018). "Unusual AIP mutation and phenocopy in the family of a young patient with acromegalic gigantism." Endocrinology, Diabetes & Metabolism Case Reports 2018., which has been published in final form at https://doi.org/10.1530/EDM-17-0092. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsEarly-onset acromegaly causing gigantism is often associated with aryl-hydrocarbon-interacting receptor protein (AIP) mutation, especially if there is a positive family history. A15y male presented with tiredness and visual problems. He was 201 cm tall with a span of 217 cm. He had typical facial features of acromegaly, elevated IGF-1, secondary hypogonadism and a large macroadenoma. His paternal aunt had a history of acromegaly presenting at the age of 35 years. Following transsphenoidal surgery, his IGF-1 normalized and clinical symptoms improved. He was found to have a novel AIP mutation destroying the stop codon c.991T>C; p.*331R. Unexpectedly, his father and paternal aunt were negative for this mutation while his mother and older sister were unaffected carriers, suggesting that his aunt represents a phenocopy. Learning points: Typical presentation for a patient with AIP mutation with excess growth and eunuchoid proportions.Unusual, previously not described AIP variant with loss of the stop codon.Phenocopy may occur in families with a disease-causing germline mutation

Risk category system to identify pituitary adenoma patients with AIP mutations.

Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk category system for aryl hydrocarbon receptor-interacting protein (AIP) mutations in patients with pituitary adenomas.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex

“Disclaimer: this is not the definitive version of record of this article. This manuscript has been accepted for publication inEuropean Journal of Endocrinology, but the version presented here has not yet been copy-edited, formatted or proofed. Consequently, Bioscientifica accepts no responsibility for any errors or omissions it may contain. The definitive version is now freely available at https://doi.org/10.1530/EJE-17-0227 2017.

Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation-Positive Child

UK India Education Research Initiative and the British Council (75-2014; to P.D.)Council of Scientific and Industrial Research, University Grants Commission, for financial support (2061330632; to A.R.).Medical Research Council (MR/M018539/1; to M.K

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Identification and characterisation of novel genetic mutations in familial and sporadic neuroendocrine tumours of the endocrine pancreas, thyroid and pituitary gland

A variable proportion of neuroendocrine tumours arise in the setting of familial tumour-predisposing conditions as a result of a genetic mutation. Owing to de novo mutations or incomplete penetrance, predisposing mutations can also be identified in patients with sporadic clinical presentation. While several advances have been made in the identification of the causative genes for the more common inheritable endocrine neoplasia syndromes, in rare instances the causative mutations remain to be identified. In this thesis, I aimed at identifying and characterising novel pathogenic genetic mutations in familial and sporadic neuroendocrine tumours affecting the endocrine pancreas (familial insulinomatosis), the thyroid (familial medullary thyroid carcinoma) and the pituitary gland (X-linked acrogigantism - XLAG). In the first chapter, I describe the identification of a novel germline mutation in the islet-enriched transcription factor MAFA (c.191C>T, p.S64F) as the cause of a sexually dimorphic phenotype of familial insulinomatosis and diabetes mellitus, a condition characterised by either hyperinsulinaemic hypoglycaemia secondary to multiple pancreatic insulinomas (i.e. insulinomatosis – occurring predominantly in females) or non-insulin-dependent diabetes mellitus (occurring prevalently in males). After establishing a suitable in vitro β cell model, I showed that the mutation impairs phosphorylation at the N-terminal transactivation domain of MAFA, resulting in impaired glucose-stimulated insulin secretion as well as reduced cell proliferation and increased susceptibility of β cells to apoptosis. Studies of glucose metabolism in vivo highlighted defective early phase insulin secretion exclusively in males, while female carriers of the MAFA mutation showed hyperinsulinism, confirming the sexually biased nature of these phenotypes. In the second chapter, I have described the phenotype of two related families with autosomal dominant inheritance of medullary thyroid carcinoma (MTC), a neuroendocrine tumour arising in the thyroid gland. While the vast majority of familial MTC cases are secondary to mutations in the RET gene, no such mutations were identified in these families. Instead, by employing next-generation sequencing techniques and linkage analysis, I provided strong evidence that the disease in these families maps to a discrete region of chromosome 4. High-density array comparative genomic hybridisation eventually allowed to identify a novel microdeletion on chromosome 4p. The deletion was found to segregate with the disease in all 14 affected subjects over three different generations. Furthermore, prospective genetic screening for this deletion allowed to identify two previously unrecognised carriers who were affected with MTC and have been successfully treated with surgery. The potential mechanisms linking this deletion with MTC development have been discussed. Lastly, in the third chapter, I have characterised the clinical features of XLAG, a condition of early-onset pituitary gigantism secondary to Xq26.3 microduplications. By describing a patient with a unique microduplication, I provided definitive evidence linking the disease with the GPR101 gene, encoding an orphan G protein-coupled receptor which is highly expressed in the hypothalamus. Furthermore, while the disease occurs as a result of a germline microduplication in females, I demonstrated that affected males have somatic mosaicism, and that testing of DNA from alternative tissues should be considered to confirm the diagnosis in cases with typical phenotype and negative testing on leukocyte-derived DNA. I have described the unique histopathological features of XLAG-related pituitary tumours and have ruled out a role of GPR101 point variants in patients with acromegaly. Finally, using RNA in situ hybridisation, I have shown that Gpr101 colocalises with Ghrh in the arcuate hypothalamic nucleus in mice, implicating this GPCR in the hypothalamic regulation of growth hormone secretion