Context:Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.Objective:The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.Design:Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.Setting:The study was conducted at university hospitals.Patients:Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.Outcome:Outcomes included genetic screening and clinical characteristics.Results:Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.Conclusions:Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

The study quantifies the high level of risk experienced by students with Type 1 diabetes during the transition to university, in particular, female students and those moving to a new university healthcare provider.

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.

A naturally occurring ACTH receptor [melanocortin 2 receptor (MC2R)] mutation (F278C) has been identified in a subject with ACTH-independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild-type receptor-expressing cell lines. Dose responsiveness is similar between wild-type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild-type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the third cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.

Context Long-term outcomes of patients with Nelson’s syndrome (NS) have been poorly explored, especially in the modern era. Objective To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. Patients, design, and setting Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1–45) since NS diagnosis. Results Management of Cushing’s disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6–13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. Conclusions At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.

We report the use of stereotactic radiosurgery delivered through an adapted linear accelerator [stereotactic multiple arc radiation therapy (SMART)] for pituitary adenomas not cured by conventional therapy. All 21 patients had undergone conventional radiotherapy (45-50 Gy); 18 had also undergone prior surgery. This cohort comprised 13 patients with somatotrope adenomas, four with corticotrope adenomas, one with a lactotrope adenoma, and three with nonfunctioning pituitary adenomas (median follow-up: 33 months, range: 3-72 months). SMART has proven effective, safe, and rapidly acting. We observed an accelerated reduction in GH and IGF-I levels in acromegaly, with normalization of GH and IGF-I levels in 58%. Mean GH fell from 21.1 mU/liter to 7.9 mU/liter (7 ng/ml to 2.6 ng/ml, P < 0.01, median 25 months) faster than our predicted fall to 50% at 2 yr with conventional radiotherapy. Mean IGF-I fell from 624 ng/ml to 384 ng/ml (P < 0.001). Tumor growth was controlled in two of three nonfunctioning pituitary adenomas, and three of four corticotrope adenomas. There were no adverse effects from SMART. Notably there have been no visual sequelae or further loss of anterior pituitary function in this heavily pretreated group. Our data indicate that SMART is an effective complementary therapy for pituitary adenomas that have displayed a suboptimal response to conventional therapy including external irradiation.

Our data suggest that tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11 beta HSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.

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