Volumetric computed tomography measurements as predictors for outcomes in a cohort of Fournier's gangrene patients.

PURPOSE: This study evaluates the prognostic value of CT findings, including volumetric measurements, in predicting outcomes for patients with Fournier gangrene (FG), focusing on mortality, ICU admission, hospital stay length, and healthcare costs. METHODS: A retrospective study was conducted on 38 FG patients who underwent CT scans before surgical debridement. We analyzed demographic data, CT volumetric measurements, and clinical outcomes using logistic and linear regression models. RESULTS: No single CT measurement significantly predicted mortality or ICU admission. The best model for mortality prediction included age, air volume, NSTI score, and male sex, with an AUC of 0.911. Intubation likelihood was modeled with an AUC of 0.913 using age, NSTI score, and visceral to subcutaneous fat ratio. The ICU admission model achieved an AUC of 0.677. Hospital stay was predicted by air volume (ß = 0.0002656, p = 0.0505) with an adjusted R-squared of 0.1287. Air volume significantly predicted hospital costs (ß = 2.859, p = 0.00558), resulting in an adjusted R-squared of 0.2165. CONCLUSION: Volumetric CT findings provide valuable prognostic insights for FG patients, suggesting a basis for informed clinical decisions and resource allocation. Further validation in larger, multi-center studies is recommended to develop robust predictive models for FG outcomes.

Postoperative Medial Malleolar Fractures in Total Ankle Replacement Are Associated With Decreased Medial Malleolar Width and Varus Malalignment: A Case-Control Study.

BACKGROUND: There are limited data regarding risk factors associated with periprosthetic medial malleolar fractures in total ankle arthroplasty (TAA). This case-control study aimed to identify the risk factors and analyze the effect of prophylactic screw fixation in preventing a medial malleolar fracture after TAA. METHODS: A case-control study was conducted on 149 patients who underwent primary TAA. Twenty patients with postoperative medial malleolar fractures >4 weeks postoperatively (cases) were identified. An additional 129 patients (controls) were randomly selected from the TAA database. Radiographic evaluation included tibial component coronal alignment and postoperative medial malleolar width. Demographics and radiographic variables were compared between cohorts. Logistic regression was used to investigate the association between medial malleolar fracture and postoperative coronal alignment, medial malleolar width, and prophylactic fixation of the medial malleolus. RESULTS: Mean (SD) medial malleolar width was significantly smaller in the fracture cohort (8.52 mm [1.6]) than in the control group (11.78 mm [1.74]) (P < .001). Mean (SD) tibial component coronal alignment was 92.17 degrees (2.77) in the fracture cohort and 90.21 degrees (1.66) in the control group (P = .002). Regression analysis identified a significant negative association between postoperative medial malleolar width and the probability of fracture (OR = 0.06, 95% CI 0.01, 0.26, P < .001). Varus malalignment of the tibial component was positively associated with the probability of fracture (OR = 1.90, 95% CI 1.27, 2.86, P = .002). Prophylactic screw fixation resulted in more than 90% reduction in the odds of a fracture (OR = 0.04, 95% CI 0.01, 0.45, P = .01). ROC curve analysis determined a medial malleolar width of 10.3 mm as a potential threshold for predicting fracture. CONCLUSION: Decreased medial malleolar width and postoperative varus malalignment were associated with an increased risk of postoperative medial malleolar fracture. Therefore, surgeons should consider prophylactic screw fixation in patients with a medial malleolar width <10.3 mm or at risk of postoperative varus deformity.

ACR Appropriateness Criteria® Workup of Pleural Effusion or Pleural Disease.

Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Influence of Isolated Talonavicular and Subtalar Joint Arthrodesis on Hindfoot Kinematics and Range of Motion During Cadaveric Gait Simulation.

BACKGROUND: Isolated subtalar and talonavicular joint arthrodeses have been associated with adjacent joint arthritis and altered hindfoot kinematics during simplified loading scenarios. However, the effect on kinematics during dynamic activity is unknown. This study assessed changes in subtalar and talonavicular kinematics after isolated talonavicular (TNiso) and subtalar (STiso) arthrodesis, respectively, during stance simulations. METHODS: Fourteen midtibia specimens received either a TNiso or STiso arthrodesis, with 7 randomized to each group. A 6-degree-of-freedom robot sequentially simulated the stance phase for the intact and arthrodesis conditions. Bootstrapped bias-corrected 95% CIs of the talonavicular and subtalar joint kinematics were calculated and compared between conditions. RESULTS: The TNiso decreased subtalar inversion, adduction, and plantarflexion in late stance (P < .05). The subtalar range of motion in the sagittal and coronal planes decreased by 40% (P = .009) and 46% (P = .002), respectively. No significant changes in talonavicular joint kinematics were observed after isolated subtalar arthrodesis; however, the range of motion was reduced by 61% (P = .007) and 50% (P = .003) in the coronal and axial planes, respectively. CONCLUSION: In this model for arthrodesis, changes in subtalar kinematics and motion restriction were observed after isolated talonavicular arthrodesis, and motion restriction was observed after isolated subtalar arthrodesis. Surprisingly, talonavicular kinematics did not appear to change after isolated subtalar arthrodesis. CLINICAL RELEVANCE: Both joint fusions substantially decrease the motion of the reciprocal adjacent joint. Surgeons should be aware that the collateral costs with talonavicular fusion appear higher, and it has a significant effect on subtalar kinematics during the toe-off phase of gait.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

The spectrum of growth hormone excess in Carney complex and genotype-phenotype correlations.

CONTEXT: Carney complex (CNC) is a familial neoplasia syndrome associated with growth hormone (GH) excess (GHE). OBJECTIVE: To describe the frequency of GHE in a large cohort of patients with CNC, and to identify genotype-phenotype correlations. METHODS: Patients with CNC with at least one biochemical evaluation of GH secretion at our center from 1995-2021 (n=140) were included in the study. Diagnosis of GHE was based on levels of insulin-like growth factor-1 (IGF-1), GH suppression during oral glucose tolerance test (OGTT), GH stimulation after thyrotropin (TRH) administration and overnight GH secretion. RESULTS: Fifty patients (35.7%) had GHE and 28 subjects (20%) had symptomatic acromegaly, with median age at diagnosis of 25.3 and 26.1 years respectively. Most of the patients (99.3%) had a PRKAR1A gene defect. There was a higher risk of GHE in patients harboring a variant that led to no expression of the affected allele [Hazard risk (HR): 3.06, 95% Confidence Intervals (CI): 1.2-7.8] and for patients harboring the hotspot variant c.491_492delTG (HR: 2.10, 95%CI: 1.1-4.1). Almost half of patients with CNC had an abnormal finding on pituitary imaging. CNC patients with an abnormal pituitary imaging had higher risk of GHE (HR: 2.94, 95%CI: 1.5-5.8), especially when single or multiple adenoma-like lesions were identified. Management of patients with symptomatic acromegaly involved surgical and medical approaches. CONCLUSION: Dysregulation of GH secretion is a common finding in CNC. The clinical spectrum of this disorder and its association with genetic and imaging characteristics of the patient make prompt diagnosis and management more successful.

Evaluation and Utilization of Flow Artifacts at CT.

Flow artifacts are commonly encountered at contrast-enhanced CT and can be difficult to discern from true pathologic conditions. Therefore, radiologists must be comfortable distinguishing flow artifacts from true pathologic conditions. This is of particular importance when evaluating the pulmonary arteries and aorta, as a flow artifact may be mistaken for a pulmonary embolism or dissection flap. Understanding the mechanics of flow artifacts and how these artifacts are created can help radiologists in several ways. First, this knowledge can help radiologists appreciate how the imaging characteristics of flow artifacts differ from true pathologic conditions. This information can also help radiologists better recognize the clinical conditions that predispose patients to flow artifacts, such as pneumonia, chronic lung damage, and altered cardiac output. By understanding when flow artifacts may be confounding the interpretation of an examination, radiologists can then know when to pursue other troubleshooting methods to assist with the diagnosis. In these circumstances, the radiologist can consider several troubleshooting methods, including adjusting the imaging protocols, recommending when additional imaging may be helpful, and suggesting which imaging study would be the most beneficial. Finally, flow artifacts can also be used as a diagnostic tool when evaluating the vascular anatomy, examples of which include the characterization of shunts, venous collaterals, intimomedial flaps, and alternative patterns of blood flow, as seen in extracorporeal membrane oxygenation circuits. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.

A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

Practical Implications of the American Society for Radiation Oncology Radiation Oncology Case Rate Program Proposal for Radiation Oncologists.

The American Society for Radiation Oncology has proposed the Radiation Oncology Case Rate Program (ROCR) to advocate for fair reimbursement for radiation oncologists. ROCR would replace Medicare fee-for-service with a case rate payment for each of the 15 most common cancer types treated with external beam or stereotactic radiation therapy. This topic discussion attempts to provide a concise overview of the practical implications for radiation oncologists should the ROCR payment program be legislated by Congress and subsequently implemented by the Center for Medicare and Medicaid Services. This topic discussion covers the practical changes to billing and reimbursement, the Health Equity Achievement in Radiation Therapy payment, the Quality of Care requirement, and the available tool to calculate the effect of the ROCR based on an individual practice's case mix.

Comparing Lung Cancer Screening Strategies in a Nationally Representative US Population Using Transportability Methods for the National Lung Cancer Screening Trial.

Importance: The National Lung Screening Trial (NLST) found that screening for lung cancer with low-dose computed tomography (CT) reduced lung cancer-specific and all-cause mortality compared with chest radiography. It is uncertain whether these results apply to a nationally representative target population. Objective: To extend inferences about the effects of lung cancer screening strategies from the NLST to a nationally representative target population of NLST-eligible US adults. Design, Setting, and Participants: This comparative effectiveness study included NLST data from US adults at 33 participating centers enrolled between August 2002 and April 2004 with follow-up through 2009 along with National Health Interview Survey (NHIS) cross-sectional household interview survey data from 2010. Eligible participants were adults aged 55 to 74 years, and were current or former smokers with at least 30 pack-years of smoking (former smokers were required to have quit within the last 15 years). Transportability analyses combined baseline covariate, treatment, and outcome data from the NLST with covariate data from the NHIS and reweighted the trial data to the target population. Data were analyzed from March 2020 to May 2023. Interventions: Low-dose CT or chest radiography screening with a screening assessment at baseline, then yearly for 2 more years. Main Outcomes and Measures: For the outcomes of lung-cancer specific and all-cause death, mortality rates, rate differences, and ratios were calculated at a median (25th percentile and 75th percentile) follow-up of 5.5 (5.2-5.9) years for lung cancer-specific mortality and 6.5 (6.1-6.9) years for all-cause mortality. Results: The transportability analysis included 51 274 NLST participants and 685 NHIS participants representing the target population (of approximately 5 700 000 individuals after survey-weighting). Compared with the target population, NLST participants were younger (median [25th percentile and 75th percentile] age, 60 [57 to 65] years vs 63 [58 to 67] years), had fewer comorbidities (eg, heart disease, 6551 of 51 274 [12.8%] vs 1 025 951 of 5 739 532 [17.9%]), and were more educated (bachelor's degree or higher, 16 349 of 51 274 [31.9%] vs 859 812 of 5 739 532 [15.0%]). In the target population, for lung cancer-specific mortality, the estimated relative rate reduction was 18% (95% CI, 1% to 33%) and the estimated absolute rate reduction with low-dose CT vs chest radiography was 71 deaths per 100 000 person-years (95% CI, 4 to 138 deaths per 100 000 person-years); for all-cause mortality the estimated relative rate reduction was 6% (95% CI, -2% to 12%). In the NLST, for lung cancer-specific mortality, the estimated relative rate reduction was 21% (95% CI, 9% to 32%) and the estimated absolute rate reduction was 67 deaths per 100 000 person-years (95% CI, 27 to 106 deaths per 100 000 person-years); for all-cause mortality, the estimated relative rate reduction was 7% (95% CI, 0% to 12%). Conclusions and Relevance: Estimates of the comparative effectiveness of low-dose CT screening compared with chest radiography in a nationally representative target population were similar to those from unweighted NLST analyses, particularly on the relative scale. Increased uncertainty around effect estimates for the target population reflects large differences in the observed characteristics of trial participants and the target population.

Influence of Joint Line Level on Clinical Outcomes and Range of Motion in Total Ankle Arthroplasty.

BACKGROUND: Ankle arthritis leads to an elevated joint line compared to the nonarthritic ankle, as measured by the "joint line height ratio" (JLHR). Previous work has shown that the JLHR may remain elevated after total ankle arthroplasty (TAA). However, the clinical impact of this has yet to be determined. This study assessed the correlation between postoperative JLHR, post-TAA range of motion (ROM), and 1-year Patient-Reported Outcome Measurement Information System (PROMIS) scores. METHODS: A retrospective review of 150 patients who underwent primary TAA was performed. Preoperative and postoperative JLHR, as well as postoperative dorsiflexion, plantarflexion, and total ROM, was calculated on weightbearing radiographs at a minimum of 1-year follow-up. Correlation between JLHR, post-TAA ROM, and 1-year PROMIS scores was investigated using Pearson correlation and multiple linear regression models. Interobserver reliability for the JLHR was also calculated. RESULTS: Interobserver reliability for the JLHR was excellent (r = 0.98). Mean (SD) JLHR changed from 1.66 (0.45) to 1.55 (0.26) after TAA (P < .001), indicating that the joint line was lowered after TAA. An elevated joint line was correlated with decreased post-TAA dorsiflexion (r = -0.26, P < .001), total ROM (r = -0.18, P = .025), and worse 1-year PROMIS physical function (r = -0.22, P = .046), pain intensity (r = 0.22, P = .042), and pain interference (r = 0.29, P = .007). There was no correlation between the JLHR and post-TAA plantarflexion (r = -0.025, P = .76). Regression analysis identified a 0.5-degree reduction in post-TAA dorsiflexion with each 0.1-unit increase in JLHR (Coeff. = -5.13, P = .005). CONCLUSION: In this patient cohort, we found that an elevated joint line modestly correlated with decreased postoperative dorsiflexion, total ROM, and worse 1-year PROMIS scores. These data suggest that effort likely should be made toward restoring the native joint line at the time of TAA. In addition, future studies investigating the clinical outcomes after TAA may consider including a measure of joint line height, such as the JLHR, because we found it was associated with patient-reported outcomes. LEVEL OF EVIDENCE: Level III, retrospective review of prospectively collected data.

The utility of IGF1 in the evaluation of pediatric patients with endogenous hypercortisolemia.

BACKGROUND: Cushing Disease (CD) is a rare endocrine disorder associated with impaired growth hormone (GH) and short stature. Insulin-like growth factor-1 (IGF-1) is a marker of GH secretion. METHODS: Patients with young onset CD (<21 years old) and available IGF-1 levels at diagnosis and/or follow-up were studied (total = 194, diagnosis = 174, follow-up = 104). IGF-1 was reported as z-score (IGF1z). RESULTS: IGF1z was lower than expected in the general population (median IGF1z: -0.92 [-1.54, 0.07], p < 0.0001) at diagnosis and remained low at follow-up (median: -1.13 [-1.78, -0.66], p < 0.0001). There was no correlation of IGF1z at diagnosis with BMI; there was a weak correlation with height (rs = 0.19, p = 0.035). IGF1z was inversely correlated with markers of hypercortisolemia, including morning (rs = -0.31, p < 0.0001) and midnight cortisol (rs = -0.30, p < 0.0001), and with insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR, rs = -0.27, p < 0.01). CONCLUSIONS: IGF-1 levels in CS are on the lower side of the normal range during active disease and remain low at one year after treatment. IGF-1 levels correlated mainly with markers of hypercortisolemia rather than the short stature of patients and should not be used in the assessment of growth in this population. IMPACT: We report that IGF-1 levels in childhood during active hypercortisolemia and up to 1 year after resolution are on the lower side of the normal range. Our results demonstrate that IGF-1 levels during active hypercortisolemia correlate mainly with markers of Cushing syndrome. This report adds data to the current literature where reports of IGF-1 in Cushing syndrome have shown variable results. Understanding the lack of utility of IGF-1 in assessing growth parameters in the pediatric Cushing syndrome population is important for physicians caring for these patients who should not use IGF-1 for diagnostic or treatment decisions.

GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism.

GPR101 is a G protein-coupled receptor (GPCR) implicated in a rare form of genetic gigantism known as X-linked acrogigantism, or X-LAG. In particular, X-LAG patients harbor microduplications in the long arm of the X-chromosome that invariably include the GPR101 gene. Duplications of the GPR101 gene lead to the formation of a new chromatin domain that causes over-expression of the receptor in the pituitary tumors of the patients. Notably, GPR101 is a constitutively active receptor, which stimulates cells to produce the second messenger cyclic AMP (cAMP) in the absence of ligands. Moreover, GPR101 was recently reported to constitutively activate not only the cAMP pathway via Gs, but also other G protein subunits (Gq/11 and G12/13). Hence, chemicals that block the constitutive activity of GPR101, known as inverse agonists, have the potential to be useful for the development of pharmacological tools for the treatment of X-LAG. In this study, we provide structural insights into the putative structure of GPR101 based on in-house built homology models, as well as third party models based on the machine learning methods AlphaFold and AlphaFold-Multistate. Moreover, we report a molecular dynamics study, meant to further probe the constitutive activity of GPR101. Finally, we provide a structural comparison with the closest GPCRs, which suggests that GPR101 does not share their natural ligands. While this manuscript was under review, cryo-electron microscopy structures of GPR101 were reported. These structures are expected to enable computer-aided ligand discovery efforts targeting GPR101.

Paediatric Cushing syndrome: a prospective, multisite, observational cohort study.

BACKGROUND: Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management. METHODS: In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants' clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment. FINDINGS: Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0-3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4-13·6] vs 13·0 years [10·5-15·3] for Cushing disease vs 13·4 years [11·0-13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19-2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60-2·56] for Cushing disease vs 2·22 [1·42-2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7-18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6-5·7]) or Cushing disease (3·9 [2·3-6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease. INTERPRETATION: This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition. FUNDING: Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.

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

Introduction: Germline loss-of-function variants in PAM, 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). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%. Results: We identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing's disease (2/7, 29%), compared to prolactinomas (1/12, 8%). Conclusion: This is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing's disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol.