Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas.

Pituitary adenomas are benign tumors with variable functional characteristics that can have a significant impact on patients. The majority arise sporadically, but an inherited genetic susceptibility is increasingly being recognized. Recent advances in genetics have widened the scope of our understanding of pituitary tumorigenesis. The clinical and genetic characteristics of pituitary adenomas that develop in the setting of germline-mosaic and somatic GNAS mutations (McCune-Albright syndrome and sporadic acromegaly), germline MEN1 mutations (multiple endocrine neoplasia type 1), and germline PRKAR1A mutations (Carney complex) have been well described. Non-syndromic familial cases of isolated pituitary tumors can occur as familial isolated pituitary adenomas (FIPA); mutations/deletions of the AIP gene have been found in a minority of these. Genetic alterations in GPR101 have been identified recently as causing X-linked acro-gigantism (X-LAG) leading to very early-onset pediatric gigantism. Associations of pituitary adenomas with other tumors have been described in syndromes like multiple endocrine neoplasia type 4, pheochromocytoma-paraganglioma with pituitary adenoma association (3PAs) syndrome and some of their genetic causes have been elucidated. The genetic etiologies of a significant proportions of sporadic corticotropinomas have recently been identified with the discovery of USP8 and USP48 mutations. The elucidation of genetic and molecular pathophysiology in pituitary adenomas is a key factor for better patient management and effective follow-up.

Diagnosis and treatment of angiographically unclear coronary lesions.

Although selective coronary angiography is the gold standard diagnostic technique for coronary lesions, this method does not provide all information regarding pathophysiologic mechanisms. We herein describe a patient in their early 60s with a 3-month history of pronounced angina. Coronary angiography revealed a central line of illumination in the proximomedial segment of the right coronary artery, suggesting a chronic coronary dissection/recanalized thrombus, along with positive remodeling and TIMI grade 2 flow. Optical coherence tomography showed a recanalized thrombus and multiple lumens separated by thin septa. Because of the significantly reduced flow and signs of ischemia in the right coronary artery irrigation territory, we decided to perform percutaneous coronary intervention. Post-treatment optical coherence tomography indicated optimal apposition and expansion of the stents with positive remodeling of the blood vessel. We believe that decisions regarding treatment modalities should be guided by the presence or absence of ischemia. Lesions that are causing myocardial ischemia should be revascularized; otherwise, medical treatment can be utilized.

An analysis of published cases of cutting balloon use in spontaneous coronary artery dissection.

Introduction: SCAD involves a sudden tear or separation within the layers of the coronary artery wall, resulting in blood flow obstruction and subsequent myocardial ischemia. Materials and methods: A comprehensive literature search was conducted to identify relevant published cases of cutting balloon use in patients diagnosed with spontaneous coronary artery dissection. Electronic databases including PubMed, MEDLINE, Embase, Cochrane Library and Google Scholar were systematically searched from inception until the present using terms "cutting balloon," "SCAD," "acute coronary syndrome," "intramural hematoma," and "angioplasty." Results: A total of 32 published cases of cutting balloon use in spontaneous coronary artery dissection were analyzed in this study. The majority of the patients included in the analysis were female without prior history of cardiovascular disease. The median age of the SCAD population was approximately 46 years. The most frequently affected artery in SCAD cases was the Left Anterior Descending artery. Intravascular ultrasound was utilized more frequently than other modalities of adjunctive imaging techniques. The most frequent complication was the distal propagation of hematoma. Despite the successful dilation achieved with the cutting balloon, in some cases stenting was required to provide additional support. Conclusion: The results of this analysis demonstrate that cutting balloon use in SCAD cases yields favorable outcomes.

H2 FPEF score predicts atherosclerosis presence in patients with systemic connective tissue disease.

BACKGROUND: Cardiovascular diseases are common cause of morbidity and mortality in patients with systemic connective tissue diseases (SCTD) due to accelerated atherosclerosis which couldn't be explained by traditional risk factors (CVDRF). HYPOTHESIS: We hypothesized that recently developed score predicting probability of heart failure with preserved ejection fraction (H2 FPEF), as well as a measure of right ventricular-pulmonary vasculature coupling [tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio], are predictive of atherosclerosis in SCTD. METHODS: 203 patients (178 females) diagnosed with SCTD underwent standard and stress-echocardiography (SE) with TAPSE/PASP and left ventricular (LV) diastolic filling pressure (E/e') measurements, carotid ultrasound and computed tomographic coronary angiography. Patients who were SE positive for ischemia underwent coronary angiography (34/203). The H2 FPEF score was calculated according to age, body mass index, presence of atrial fibrillation, ≥2 antihypertensives, E/e' and PASP. RESULTS: Mean LV ejection fraction was 66.3 ± 7.1%. Atherosclerosis was present in 150/203 patients according to: 1) intima-media thickness>0.9 mm; and 2) Agatstone score > 300 or Syntax score ≥ 1. On binary logistic regression analysis, including CVDRF prevalence, echocardiographic parameters and H2 FPEF score, only H2 FPEF score remained significant for the prediction of atherosclerosis presence (χ2 = 19.3, HR 2.6, CI 1.5-4.3, p < 0.001), and resting TAPSE/PASP for the prediction of a SE positive for ischemia (χ2 = 10.4, HR 0.01, CI = 0.01-0.22, p = 0.004). On ROC analysis, the optimal threshold value for identifying patients with atherosclerosis was a H2 FPEF score ≥2 (Sn 60.4%, Sp 69.4%, area 0.67, SE = 0.05, p < 0.001). CONCLUSIONS: H2 FPEF score and resting TAPSE/PASP demonstrated clinical value for an atherosclerosis diagnosis in patients diagnosed with SCTD.

Prevalence and progression of carbohydrate disorders in patients with pheochromocytoma/paraganglioma: retrospective single-center study.

BACKGROUND: Carbohydrate disorders are the most frequent metabolic disorders, affecting a significant proportion of patients with pheochromocytoma. OBJECTIVE: A retrospective study assessed the prevalence and progression of carbohydrate disorders in 204 patients (92 men, 112 women) with histologically proven pheochromocytoma diagnosed in a single specialized tertiary center during a 40-year period (1978-2017). One hundred were followed-up after tumor removal. RESULTS: Carbohydrate disorders were diagnosed in 49.5% of cases: 30.4% with diabetes and, 19.1% prediabetes. Subjects with carbohydrate disorders had significantly greater age at diagnosis and higher 24-hour urine metanephrine and normetanephrine concentrations than those with normal glucose tolerance. One-third of patients with diabetes achieved good glycemic control under oral treatment (54% on metformin monotherapy). One-third of patients overall required preoperative insulin treatment. Postoperative follow-up (100 patients; 5-year mean duration) showed reduced prevalence of diabetes (13% vs. 33%; P=0.0007) and prediabetes (12% vs. 24%; P=0.027). Almost 60% of subjects initially diagnosed with carbohydrate disorders recovered normal glucose tolerance after surgery; these subjects had significantly higher preoperative urine metanephrine/normetanephrine levels than those with persistent diabetes/prediabetes. Correlation analysis revealed a moderate negative relationship between urine metanephrine/normetanephrine concentration and the outcome of the carbohydrate disorders (Spearmen's Rho=-0.507; P=0.013). There was no significant difference according to pre- or postoperative prevalence of obesity (15% vs. 16%; P=0.845) or dyslipidemia (46% vs. 39%; P=0.316). CONCLUSIONS: Carbohydrate disorders affect approximately 50% of pheochromocytoma patients; 30% develop overt diabetes, which may be the only clinical manifestation in some rare cases. Pheochromocytoma-related diabetes is more likely to affect patients with predominant adrenaline secretion. It is often easy to control and usually requires oral antidiabetic treatment. Reversibility of carbohydrate disorders depend on severity, preoperative metanephrine level, age and weight.

Global longitudinal strain as a marker for systolic function in patients with pheochromocytomas.

Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (-16.54 ± 1.83 vs -19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (-16.64 ± 1.49 vs -19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA).

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.

Cystic Echinococcosis of the Breast - Diagnostic Dilemma or just a Rare Primary Localization.

INTRODUCTION: Although the liver and lung are the most frequently affected organs in cystic echinococcosis, the cysts may develop in any viscera and tissues. Breast is a rare primary localization with few cases described in the literature. We present an updated and systematic review and discuss the possible mechanisms of spreading, diagnostic and treatment options. MATERIALS AND METHODS: We performed a literature search in PUBMED using the key words 'hydatid disease', 'cystic echinococcosis' and 'breast echinococcosis' without time limitation. Only studies reporting breast cystic echinococcosis were included. RESULTS: Overall, 121 cases with cystic echinococcosis and 2 with alveolar echinococcosis were reported. A total of 52 cases were included in the analysis. The mean size of cysts was 5.5 cm (range 1.7-12). The most common clinical presentation was painless lump presented from 4 months to 19 years before the final diagnosis. Most cases had isolated breast CE, few cases had synchronous localizations ­ femoral, thigh and lung, and previous liver CE. Most were active CL and CE1-2 cysts (72%). Ultrasound was used in 83%, followed by mammography (35%). Fine needle aspiration was reported in 27 cases with positive finding in 59%. CONCLUSIONS: In cases with cystic breast lesions from endemic regions we recommend the US as a gold standard. CT and MRT are more accurate but expensive tools without the potential to change the surgical tactic. In contrast to the other localizations of CE, complete excision of the cysts is the best diagnostic and treatment approach.

Dataset for determining rational taxation value with incompatible criteria of economic efficiency and equity.

This article is essentially a dataset necessary for analysing the taxation. The data analysis has allowed to determine the optimal taxation model, when the criteria of economic efficiency and equity are incompatible. The dataset has allowed the use of the method of successive concessions in tax optimization. The practical significance of the dataset lies in the ability to simultaneously improve the efficiency and equity in taxation. The dataset was obtained by using the method of expert estimates. A group of experts was asked to rank the taxes established by the Tax Code of the Russian Federation, in descending order of importance. Only strict rankings were allowed. The consistency of expert opinion was evaluated using the Kendall coefficient of concordance. The data set was supplemented with the expert ranking data of the basic principles of taxation, such as the principle of equity; the principle of certainty and accuracy of taxes; the principle of ease of tax collection for taxpayers; the principle of efficiency; the principle of commitment. The dataset can be used in the future to determine a rational amount of taxation depending on the established criteria.

Asymmetric Dimethylarginin (ADMA) as a Marker of Endothelial Dysfunction in Primary Aldosteronism.

BACKGROUND: Recent studies have revealed a higher rate of cardiovascular complications in primary aldosteronism (PA) compared to patients with essential hypertension (EH). Asymmetric dimethylarginine (ADMA) is a marker of endothelial dysfunction that could contribute to increased cardiovascular risk in patients with PA. OBJECTIVES: The aim of this study was to compare the levels of ADMA among patients with PA, controls with EH and healthy participants. Methods: Serum ADMA levels were determined, using commercially available competitive enzyme-linked immunosorbent assay. METHODS: Serum ADMA levels were determined, using commercially available competitive enzyme-linked immunosorbent assay. RESULTS: Patients with PA had significantly higher concentrations of ADMA than healthy controls (0.488 ± 0.085 vs. 0.433 ± 0.053 µmol/L, P = 0.027). No difference was found in ADMA levels between cases with PA and EH (0.488 ± 0.085 vs. 0.476 ± 0.075 µmol/L, р = 0.636). The difference between patients with EH and normotensive controls did not reach statistical significance (P = 0.06). CONCLUSIONS: The lack of difference between ADMA levels in patients with PA and EH suggests that endothelial dysfunction is more likely related to hypertension per se than to the specific etiology of elevated blood pressure.

MANAGEMENT OF ENDOCRINE DISEASE: Pituitary 'incidentaloma': neuroradiological assessment and differential diagnosis.

Pituitary incidentalomas are a by-product of modern imaging technology. The term 'incidentaloma' is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke's cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.

McCune-Albright syndrome: a detailed pathological and genetic analysis of disease effects in an adult patient.

CONTEXT: McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging. OBJECTIVE: The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues. DESIGN: This was a comprehensive autopsy and genetic analysis. SETTING: The study was conducted at a tertiary referral university hospital. PATIENTS: An adult male patient with MAS and severe disease burden including gigantism was the subject of the study. INTERVENTION(S): Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues. MAIN OUTCOME MEASURE: Pathological findings and the presence of GNAS1 mutations were measured. RESULTS: The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas. CONCLUSIONS: This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1-related pathology across a wide range of affected organs.

Macroprolactinemia in a patient with invasive macroprolactinoma: a case report and minireview.

Background. Macroprolactin, the high-molecular prolactin isoform, is considered to be an inactive in vivo product with extrapituitary origin. Patients with macroprolactinemia are usually asymptomatic, with negative pituitary imaging. Based on these data, most authors do not recommend treatment and long-term followup in subjects with macroprolactinemia. However, there is evidence for overlapping clinical features among subjects with hyperprolactinemia due to monomeric or "big big" PRL isoform. Case Presentation. We present a 35-year-old female patient with secondary amenorrhea, mild obesity, hirsutism, headache and blurred vision. Hormonal evaluation revealed an extreme hyperprolactinemia (PRL = 10 610 mIU/L) almost exclusively due to macroprolactin isoform (MPRL = 10 107 mIU/L; recovery after PEG precipitation 4.7%) and hypogonadotropic hypogonadism. An invasive pituitary macroadenoma was visualized on MRI, and cabergoline therapy was initiated. Disappearance of clinical signs and symptoms, normalization of gonadotropin levels, and restoration of regular ovulatory menstrual cycles after 1 year of treatment are arguments in favor of preserved-macroprolactin bioactivity in this case. The significant decrease in MPRL levels and tumor volume in response to dopamine agonist therapy is suggestive for the tumoral origin of this isoform. Conclusions. Although macroprolactinemia is considered to be a benign condition, pituitary imaging, dopamine agonist treatment, and prolonged followup should be recommended in some particular cases.

Transforming growth factor ß1 is not a reliable biomarker for valvular fibrosis but could be a potential serum marker for invasiveness of prolactinomas (pilot study).

BACKGROUND: Transforming growth factor ß1 (TGFß1) signaling pathway is crucial for both human fibrogenesis and tumorigenesis. OBJECTIVE: This study aimed to investigate the usefulness of TGFß1 and matrix metalloproteinase 2 (MMP2) as potential circulating markers for fibrotic valvular heart disease (FVHD) and invasiveness as well as of Fetuin A as a marker for calcification in patients with prolactinomas. DESIGN: The study population consisted of 147 subjects divided into four groups: 30 dopamine agonist (DA)-treated prolactinoma patients with proven FVHD and three control groups with normal echocardiograms: 43 DA-treated patients, 26 naïve patients, and 48 healthy subjects. RESULTS: We observed significantly higher serum TGFß1 levels in all three patient groups than in the healthy subjects (21.4 ± 8.86 vs 19.1 ± 9.03 vs 20.7±11.5 vs 15.8 ± 7.2 ng/ml; P=0.032). Moreover, TGFß1 levels were significantly higher in patients with macroprolactinomas and invasive prolactinomas than in those with microprolactinomas and noninvasive tumors respectively. In addition, a strong positive linear relationship between TGFß1 levels and invasiveness score (ρ=0.924; P<0.001) and a moderate correlation between TGFß1 levels and tumor volume (r=0.546; P<0.002) were observed in patients with invasive prolactinomas. By contrast, prolactin (PRL) levels exhibited a better correlation with tumor volume (r=0.721; P<0.001) than with invasiveness score (ρ=0.436; P<0.020). No significant difference was observed in Fetuin A levels between patients with FVHD and healthy controls. Results concerning MMP2 were unclear. CONCLUSIONS: TGFß1, MMP2, and Fetuin A are not reliable biomarkers for valvular fibrosis and calcification in DA-treated patients with prolactinomas, but TGFß1 may represent a useful serum marker for tumor invasiveness. The simultaneous determination of TGFß1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior.

Clinical and genetic aspects of familial isolated pituitary adenomas.

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2-3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up.

Familial pituitary tumor syndromes.

OBJECTIVE: To summarize current knowledge on the clinical and genetic characteristics of familial pituitary tumor syndromes. METHODS: This review is based on a comprehensive search through the English-language literature with use of the following terms: "familial," "pituitary," "adenomas," and "tumors." RESULTS: Familial pituitary tumors are rare and constitute approximately 5% of all pituitary adenomas. Currently, there are 4 recognized inherited syndromes that involve pituitary tumorigenesis-multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 4 (MEN 4), Carney complex (CNC), and familial isolated pituitary adenomas (FIPA). MEN 1 and CNC have been known for several decades, and their clinical and molecular characteristics have been comprehensively studied. Many familial cases of pituitary adenomas can be attributed to mutations in MEN1 and PRKAR1A genes. The recently defined MEN 4 is extremely rare. Familial pituitary tumors that are not associated with MEN 1 and CNC have been united under a new term introduced in the 1990s-FIPA. About 15% to 25% of patients with FIPA harbor mutations in the AIP gene. CONCLUSION: Although rare, familial pituitary tumors present an opportunity to study inherited molecular and genetic mechanisms of pituitary tumorigenesis. A comprehensive understanding of their characteristics may provide a basis for early diagnosis and better management of affected patients.

Management of acromegaly.

Acromegaly is caused by hypersecretion of growth hormone and resultant overproduction of insulin-like growth factor-1 and is associated with increased mortality and morbidity. Successful treatment modalities have been developed and are used in a multistep approach allowing normal life expectancy as well as improved quality of life in an increasing number of patients.

Clinical and genetic aspects of familial isolated pituitary adenomas

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2-3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up.