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Monogenic diabetes arises due to mutation in a single-gene and is recognized by their striking familial inheritance pattern. This form of diabetes is inherited in an autosomal dominant or recessive fashion, unlike polygenic Type 1 (autoimmune) or type 2 diabetes caused by the combined action of more than one gene [1-11]. Monogenic diabetes is classified into three main groups: Neonatal diabetes mostly presents in the first six months of birth, maturity onset diabetes of the young (MODY) and maternally inherited mitochondrial diabetes.\ud \ud These mutations run in the family and have a predictable course. Most of the monogenic diabetes is treated with oral medications like sulfonylurea rather than insulin. ABCC8/KCNJ11 gene mutations also cause monogenic diabetes. This gene mutation has been found in ~50% of congenital hyperinsulinemia (CHI) patients. In such cases diabetes commonly presents in the neonatal period (transient or permanent) or at adolescence / early adulthood [1]. \ud \ud We present a 58-year-old diabetic lady, who was detected with ABCC8 mutation during the cascade testing [8]. She was diagnosed with diabetes at the age of 12 [8]. Her son had history of neonatal hypoglycaemia and developed diabetes at the age of 15. He was the index case who was found to have ABCC8 mutation. The family has several other members diagnosed with diabetes. The aim of the article is to increase awareness and understanding of monogenic diabetes among the medical practitioners in adult population with diabetes so that the genetic testing can be offered in a cost effective manner.

Context\ud \ud 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).\ud \ud \ud \ud Objective\ud \ud 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.\ud \ud \ud \ud Design\ud \ud 12-year prospective, observational study.\ud \ud \ud \ud Participants & Setting\ud \ud 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.\ud \ud \ud \ud Interventions & Outcome\ud \ud 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).\ud \ud \ud \ud Results\ud \ud 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).\ud \ud \ud \ud Conclusions\ud \ud 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.

STUDY QUESTION: What prevents the fall in anti-Müllerian hormone (AMH) levels in polycystic ovary syndrome (PCOS) and what are the consequences of this for follicle progression in these ovaries? SUMMARY ANSWER: Exposure of granulosa cells (GCs) to high levels of androgens, equivalent to that found in PCOS, prevented the fall in AMH and was associated with dysregulated AMH-SMAD signalling leading to stalled follicle progression in PCOS. WHAT IS KNOWN ALREADY: In normal ovaries, AMH exerts an inhibitory role on antral follicle development and a fall in AMH levels is a prerequisite for ovulation. Levels of AMH are high in PCOS, contributing to the dysregulated follicle growth that is a common cause of anovulatory infertility in these women. STUDY DESIGN, SIZE, DURATION: Human KGN-GC (the cell line that corresponds to immature GC from smaller antral follicles (AF)) were cultured with a range of doses of various androgens to determine the effects on AMH production. KGN-GC were also treated with PHTPP (an oestrogen receptor β (ERβ) antagonist) to examine the relationship between AMH expression and the ratio of ERα:ERβ. The differential dose-related effect of AMH on gene expression and SMAD signalling was investigated in human granulosa-luteal cells (hGLC) from women with normal ovaries, with polycystic ovarian morphology (PCOM) and with PCOS. KGN-GC were also cultured for a prolonged period with AMH at different doses to assess the effect on cell proliferation and viability. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH protein production by cells exposed to androgens was measured by ELISA. The effect of PHTPP on the mRNA expression levels of AMH, ERα and ERβ was assessed by real-time quantitative PCR (qPCR). The influence of AMH on the relative mRNA expression levels of aromatase, AMH and its receptor AMHRII, and the FSH and LH receptor (FSHR and LHR) in control, PCOM and PCOS hGLCs was quantified by qPCR. Western blotting was used to assess changes in levels of SMAD proteins (pSMAD-1/5/8; SMAD-4; SMAD-6 and SMAD-7) after exposure of hGLCs from healthy women and women with PCOS to AMH. The ApoTox-Glo Triplex assay was used to evaluate the effect of AMH on cell viability, cytotoxicity and apoptosis. MAIN RESULTS AND THE ROLE OF CHANCE: Testosterone reduced AMH protein secreted from KGN-GC at 10-9-10-7 M (P

Glucagonomas are the functioning neuroendocrine tumors. These arise from pancreatic islet α-cells. These tumors are extremely rare and have an annual incidence of 1 per 20-40 million population 80% of glucagon-expressing tumors are sporadic, and 20% are associated with genetic syndromes such as Multiple Endocrine Neoplasia-type 1. Glucagonoma typically occurs in the distal pancreas, and around 85% are in the body or tail. It tends to be large at the time of diagnosis. Most reported cases of glucagonoma are malignant and about 65-75% patients present with metastatic disease. The liver is usually the first site of metastases, followed by the involvement of peripancreatic lymph nodes. The term Glucagonoma syndrome and glucagonoma are often interchangeably used, but in fact, these are two distinct entities. Glucagonoma syndrome comprises of necrolytic migratory erythema, hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, diarrhea, venous thrombosis and neuropsychiatric disturbances in the presence of a glucagon-producing tumor of the pancreas. Tumors secreting glucagon can occur without the glucagonoma syndrome. The glucagonoma secretion depends on the expression of protein convertase enzyme PC1/3 or PC2 within the tumor itself. As a result of this expression, the clinical manifestations can be variable. The tumor can either present with hyperinsulinemic hypoglycemia in a patient with a previous history of diabetes or with the features of the glucagonoma syndrome. In cases where a tumor is localized surgery is the curative treatment. Reduction of the tumor bulk, removal of the primary by surgery and targeted therapy for the hepatic metastases are the favored approach even when there is the metastasis.

Objective: \ud The risk of developing hyperparathyroidism (HPT) in adults after radiation exposure is higher than that of the general population. Extensive \ud follow up guidelines of United Kingdom Children’s Cancer Study group (UKCCSG) or Scottish intercollegiate guidelines network (SIGN) do not recommend \ud monitoring serum calcium or parathyroid hormone in patients treated for childhood malignancies.\ud The aim of this study was to examine the occurrence of HPT in a cohort of survivors of childhood malignancy attending a late effects clinic after their \ud treatment for haematological and non-haematological malignancies that included previous irradiation\ud Design and methods: \ud Study was performed in 105 patients attending a late effects clinic. These patients had received different modalities f treatment \ud including surgery, chemotherapy, radiotherapy and bone marrow transplant for haematological and non-haematological malignancies in their childhood with. \ud All patients had evaluation for thyroid and parathyroid disease with a clinical examination and biochemical investigations. Patients with hyperparathyroidism \ud were treated with parathyroidectomy in the absence of thyroid disease and positive localization on imaging. This resulted in normalization of serum calcium.\ud Conclusion:\ud This data suggests that there is a significant risk of hyperparathyroidism in young females with haematological malignancies who received \ud total body irradiation as a single fraction for bone marrow transplant.

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

There is evidence from animal studies that 1,25-dihyroxyvitamin D3 (1,25(OH)2D3) is essential for normal reproductive function. Vitamin deficient rats have reduced fertility and VDR null mutant mice demonstrate impaired folliculogenesis. One small uncontrolled study in humans has demonstrated that vitamin D replacement improves menstrual frequency and acne in women with polycystic ovary syndrome (PCOS). We have previously demonstrated that 1,25(OH)2D3 inhibits the production of oestradiol independently of progesterone in luteinised but not in non-luteinised granulosa cells. We have also demonstrated the presence of vitamin D receptors on luteinised granulosa cells and cells of the corpus luteum, peer-reviewed