Long-term hormonal follow-up after human Puumala hantavirus infection.

OBJECTIVE: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE. DESIGN: Forty-seven of our recent cohort of 58 NE patients volunteered to be re-examined in order to estimate the burden of hormonal deficiency 4 to 8 years after the acute illness. Two patients had suffered from pituitary haemorrhage, but many others exhibited pituitary oedema during their acute infection. In this study, we searched for symptoms of hormonal deficiency, performed hormonal laboratory screening, and most patients underwent pituitary MRI examination. RESULTS: The pituitary size had diminished in all patients in whom MRI was performed (P < 0·001). One patient with acute phase haemorrhage had made a complete recovery while the other continued to require hormonal substitution. In addition, hormonal laboratory abnormalities were observed in nine other patients; these being attributable to several reasons, for example independent peripheral hormonal diseases, side effects of medication or other secondary causes such as obesity. None of them had signs of late-onset pituitary insufficiency caused by their previous NE. Health-related quality of life (mean and median 15D score) of patients was comparable to that of age-standardized general population. CONCLUSIONS: None of our patients had developed obvious late-onset hypopituitarism despite of the fact that pituitary gland can be affected during acute NE. We recommend requesting a history of hantavirus infection whenever the possibility of pituitary dysfunction is suspected at least in patients originating from regions with high NE infection rate.

[Treatment of primary hypothyroidism in adult patients]. / Aikuisen primaarisen hypotyreoosin hoito.

The diagnosis of hypothyroidism is based on the findings of an increased serum TSH (above the reference range) and decreased serum free T4 (below the reference range) concentration. Treatment of subclinical hypothyroidism is indicated if serum THS is above 10 mU/l. For less severe forms of subclinical hypothyroidism, the treatment should be individually tailored. The treatment of choice is synthetic human levothyroxine. The goals for treatment are amelioration of symptoms and normalization of TSH and free T4 concentrations.

[Multiple endocrine neoplasia type 1]. / Tyypin 1 multippeli endokriininen neoplasia eli MEN 1-oireyhtymi.

Multiple endocrine neoplasia type 1 (MEN1) is a complex multisystem disease characterized by the combined occurrence of endocrine tumours of the parathyroid glands, anterior pituitary gland and adrenal glands and the neuroendocrine tumours (NET) of duodenum, pancreas, thymus and bronchus. Malignancy occurs commonly (up to 30 %) and malignant NETs are important causes of the MEN1-related morbidity and mortality. Regular clinical, biochemical and radiologic screening for the syndrome-related tumours are the basis of the life-long surveillance. Early detection and adequate management of these tumours reduce risk of death and morbidity.

Acromegaly caused by a GHRH-producing pancreatic neuroendocrine tumor: a rare manifestation of MEN1 syndrome.

SUMMARY: Multiple endocrine neoplasia type 1 NM_001370259.2(MEN1):c.466G>C(p.Gly156Arg) is characterized by tumors of various endocrine organs. We report on a rare, growth hormone-releasing hormone (GHRH)-releasing pancreatic tumor in a MEN1 patient with a long-term follow-up after surgery. A 22-year-old male with MEN1 syndrome, primary hyperparathyroidism and an acromegalic habitus was observed to have a pancreatic tumor on abdominal CT scanning, growth hormone (GH) and insulin-like growth factor 1 (IGF1) were elevated and plasma GHRH was exceptionally high. GHRH and GH were measured before the treatment and were followed during the study. During octreotide treatment, IGF1 normalized and the GH curve was near normal. After surgical treatment of primary hyperparathyroidism, a pancreatic tail tumor was enucleated. The tumor cells were positive for GHRH antibody staining. After the operation, acromegaly was cured as judged by laboratory tests. No reactivation of acromegaly has been seen during a 20-year follow-up. In conclusion, an ectopic GHRH-producing, pancreatic endocrine neoplasia may represent a rare manifestation of MEN1 syndrome. LEARNING POINTS: Clinical suspicion is in a key position in detecting acromegaly. Remember genetic disorders with young individuals having primary hyperparathyroidism. Consider multiple endocrine neoplasia type 1 syndrome when a person has several endocrine neoplasia. Acromegaly may be of ectopic origin with patients showing no abnormalities in radiological imaging of the pituitary gland.

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1.

OBJECTIVE: MEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland. DESIGN/METHODS: We evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985-2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients. RESULTS: There were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm2, qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%. CONCLUSION: In this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients.

Young male patients are at elevated risk of developing serious central nervous system complications during acute Puumala hantavirus infection.

BACKGROUND: Our aim was to characterize clinical properties and laboratory parameters in patients with or without cerebrospinal fluid (CSF) findings suggestive of central nervous system (CNS) involvement, and especially those who developed serious CNS complications during acute nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) infection. METHODS: A prospective cohort of 40 patients with acute NE and no signs of major CNS complications was analyzed. In addition, 8 patients with major CNS complications associated with NE were characterized. We collected data of CNS symptoms, CSF analysis, brain magnetic resonance imaging (MRI) results, electroencephalography (EEG) recordings, kidney function, and a number of laboratory parameters. Selected patients were evaluated by an ophthalmologist. RESULTS: Patients with a positive CSF PUUV IgM finding or major CNS complications were more often males (p < 0.05) and they had higher plasma creatinine values (p < 0.001) compared to those with negative CSF PUUV IgM. The degree of tissue edema did not explain the CSF findings. Patients with major CNS complications were younger than those with negative CSF PUUV IgM finding (52.9 vs. 38.5 years, p < 0.05). Some patients developed permanent neurological and ophthalmological impairments. CONCLUSIONS: CNS and ocular involvement during and after acute NE can cause permanent damage and these symptoms seem to be attributable to true infection of the CNS rather than increased tissue permeability. The possibility of this condition should be borne in mind especially in young male patients.

The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas.

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to the development of pituitary adenomas. Here, we characterized AIP mutation positive (AIPmut+) and AIP mutation negative (AIPmut-) pituitary adenomas by immunohistochemistry. The expressions of the AIP-related proteins aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), cyclin-dependent kinase inhibitor 1B encoding p27(Kip1), and hypoxia-inducible factor 1-alpha were examined in 14 AIPmut+ and 53 AIPmut- pituitary adenomas to detect possible expression differences. In addition, the expression of CD34, an endothelial and hematopoietic stem cell marker, was analyzed. We found ARNT to be less frequently expressed in AIPmut+ pituitary adenomas (P = 0.001), suggesting that AIP regulates the ARNT levels. AIP small interfering RNA-treated HeLa, HEK293, or Aip-null mouse embryonic fibroblast cells did not show lowered expression of ARNT. Instead, in the pituitary adenoma cell line GH3, Aip silencing caused a partial reduction of Arnt and a clear increase in cell proliferation. We also observed a trend for increased expression of nuclear AHR in AIPmut+ samples, although the difference was not statistically significant (P = 0.06). The expressions of p27(Kip1), hypoxia-inducible factor 1-alpha, or CD34 did not differ between tumor types. The present study shows that the expression of ARNT protein is significantly reduced in AIPmut+ tumors. We suggest that the down-regulation of ARNT may be connected to an imbalance in AHR/ARNT complex formation arising from aberrant cAMP signaling.

The clinical value of [18F]fluoro-dihydroxyphenylalanine positron emission tomography in primary diagnosis, staging, and restaging of neuroendocrine tumors.

The study was set up to determine the clinical value of dihydroxyphenylalanine positron emission tomography-computed tomography ([(18)F]DOPA PET-CT) in patients with neuroendocrine tumors (NETs). Eighty-two patients with suspected/known NET were imaged with PET(-CT) using [(18)F]DOPA. Patients were divided into two groups: primary diagnosis/staging and restaging of disease. All patients without previous diagnosis of NET had biochemical proof of disease. The diagnostic accuracy of PET was assessed by comparing the histopathology and clinical follow-up. The overall accuracy of [(18)F]DOPA PET was 90%. In patients having PET for primary diagnosis/staging (n=32), the accuracy of PET was 88%, and for restaging 92% (n=61). The mean s.d. sizes of primary and metastatic lesions detected by PET were 26+/-11 and 16+/-9 mm respectively. In organ-region-specific analysis, the sensitivity and specificity were 100% in the primary diagnosis of pheochromocytoma (n=16) and metastases were found in all cases with recurrent disease (n=5). The accuracy for NET of gastrointestinal tract was 92% in restaging (n=24). For the NETs located in the head-neck-thoracic region (n=19), the overall accuracy of PET was 89% including 12 cases of recurrent medullary thyroid cancer with a sensitivity of 90%. In analysis of patients with biochemical proof of disease combined with negative conventional imaging methods, PET had positive and negative predictive value of 92% and 95% respectively. [(18)F]DOPA PET-CT provided important additional information in the diagnosis of pheochromocytoma and restaging of known NET. Both in primary diagnosis and in patients with formerly known NET and increasing tumor markers, [(18)F]DOPA PET-CT is a sensitive first-line imaging method.

Large genomic deletions in AIP in pituitary adenoma predisposition.

CONTEXT: Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings. OBJECTIVE: Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP. DESIGN: Here, we applied the multiplex ligation-dependent probe amplification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases. PATIENTS: The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing. RESULTS: Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found. CONCLUSIONS: The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe amplification could be considered if direct sequencing does not identify a mutation.

Characteristics and Outcomes of 79 Patients with an Insulinoma: A Nationwide Retrospective Study in Finland.

OBJECTIVE: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. DESIGN AND METHODS: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. RESULTS: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. CONCLUSIONS: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

Changes in cardiac repolarisation during spontaneous nocturnal hypoglycaemia in subjects with type 1 diabetes: a preliminary report.

AIMS: Experimental studies have revealed that hypoglycaemia can result in morphological changes in electrocardiographic repolarisation in subjects with type 1 diabetes. However, the influence of spontaneous nocturnal hypoglycaemia on repolarisation morphology in a 'real life' situation is not clear. METHODS: Adults with type 1 diabetes (n = 11) underwent continuous glucose monitoring with a subcutaneous sensor and digital 12-lead ECG recording for three nights. T-wave morphology was analysed with custom-made software during both hypoglycaemia (glucose <3.5 mmol/l at least 20 min) from ten consecutive heart beats in the middle of the deepest hypoglycaemia and from a control nonhypoglycaemic period (glucose ≥5.0 mmol/l) from the same recording. RESULTS: In the comparison of 10 hypoglycaemia-control pairs, heart rate (65 ± 12 beats/min during normoglycaemia versus 85 ± 19 beats/min during hypoglycaemia, p = 0.028) increased and the QTc interval (439 ± 5 vs. 373 ± 5 ms, respectively, p = 0.025) decreased significantly during hypoglycaemia. The spatial QRS-T angle (TCRT) was reduced, and the roughness of the T-wave loop (T-E) increased significantly (p = 0.037 for both) in the patients during hypoglycaemia. CONCLUSIONS: In adults with type 1 diabetes, spontaneous nocturnal hypoglycaemia results in morphological changes and increased heterogeneity of global cardiac repolarisation. These changes may contribute to the risk of 'dead in bed' syndrome encountered in young individuals with type 1 diabetes.

Effects of sustained insulin-induced hypoglycemia on cardiovascular autonomic regulation in type 1 diabetes.

Effects of hypoglycemia on cardiac autonomic regulation may contribute to the occurrence of adverse cardiac events. This study assessed the effects of sustained hyperinsulinemic hypoglycemia on cardiovascular autonomic regulation in type 1 diabetic patients and their nondiabetic counterparts. The study consisted of 16 type 1 diabetic patients and 8 age-matched healthy control subjects who underwent euglycemic and hypoglycemic clamp procedures in a random order. Heart rate variability was measured from continuous electrocardiogram recordings by time and frequency domain methods, along with Poincare plot analysis during both a hyperinsulinemic-euglycemic and hypoglycemic clamp at three different glucose levels (4.5-5.5, 3.0-3.5, and 2.0-2.5 mmol/l). Controlled hypoglycemia resulted in an increase of supine heart rate in both the diabetic patients (from 72 +/- 9 to 80 +/- 11 bpm, P < 0.01) and the control subjects (from 59 +/- 5 to 65 +/- 5 bpm, P < 0.05) and progressive reductions of the high-frequency spectral component and beat-to-beat heart rate variability (SD1; P < 0.05 in the diabetic patients and P < 0.01 in control subjects). No significant changes in heart rate variability occurred during the euglycemic clamp. We conclude that hypoglycemia results in a reduction of cardiac vagal outflow in both diabetic and nondiabetic subjects. Altered autonomic regulation may contribute to the occurrence of cardiac events during hypoglycemia.

A nationwide survey of mortality in acromegaly.

CONTEXT: Increased mortality in acromegaly has been confined to those with posttreatment basal GH of 2.5 microg/liter or greater, but the impact of IGF-I and pituitary radiotherapy on mortality has remained controversial. OBJECTIVE: The purpose of this nationwide survey was to examine the all-cause mortality of patients with acromegaly and evaluate the impact of treatment outcome and mode of treatment on survival. DESIGN, SETTING, AND PATIENTS: All-cause mortality of all patients with acromegaly diagnosed during January 1980 and December 1999 in the five university hospitals of Finland was followed up by the end of 2002 (12.5 +/- 5.6 yr) and compared with that of the general population by using age- and gender-adjusted standardized mortality ratios (SMRs). Logistic regression analysis was used to investigate factors related to mortality within the survey population. MAIN OUTCOME MEASURE: Mortality was the main outcome measure. RESULTS: Of the 334 patients, 56 (16.8%) had died during follow-up. SMR of the patients was 1.16 [confidence interval (CI) 0.85-1.54, not significant (NS)]. However, patients with basal serum GH concentration 2.5 microg/liter or greater (SMR 1.63, CI 1.10-2.35, P < 0.001) measured 5.2 +/- 4.4 yr after the initial treatment, and those irradiated (SMR 1.69, CI 1.05-2.58, P < 0.001) showed excess mortality. In a multivariate model, the effect of radiotherapy was of borderline significance only (P = 0.083). Posttreatment IGF-I levels, available for 72.2% of the patients, did not have impact on mortality. CONCLUSIONS: The posttreatment basal GH concentration less than 2.5 microg/liter in acromegalic patients is associated with a normal lifespan. Excess mortality is confined to poorly controlled patients and possibly those who have received conventional radiotherapy.

Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications.

Differentiated thyroid carcinomas (DTC) (papillary, follicular and follicular type of papillary) have a favourable prognosis, but a proportion of patients develop recurrences and eventually die of the disease. Various prognostic factors have been identified and been used to create the current staging classifications (AGES, AMES, MACIS, EORTC, UICC-TNM). We examined 499 DTC patients retrospectively to validate known prognostic factors that enable them to be recognised as having either a low or a high risk of death related to a recurrence of DTC, by reference to the current staging classifications. Sixty-nine of them (14%) had local or distant recurrences, the mean time to recurrence being 7.7 years. The 10-year disease-free survival rate was 80%, and the ten-year overall survival rate for the entire group was 91%, with a mean survival time of 8.7 years. Male gender, a follicular type of tumour, larger tumour size, extrathyroidal invasion outside the capsule and nodal metastases were all related to a higher incidence of tumour recurrence, and the follicular type of histology, age > 45 years, larger tumour size and local invasion entailed poorer survival. The AMES and to some extent the EORTC classification were not reproducible in this material, mainly because some prognostic variants were no longer encountered or were insufficient in number to allow reliable conclusions to be drawn. The MACIS staging classification leaves the definition of the intermediate and high risk groups too wide and is therefore not very reliable. Pooling of stages I and II improved the relevance of the TNM classification. All the current staging classifications are able to discern a low risk DTC group well. We achieved a highly accurate definition of risk in the present material using only two parameters, age (cut-off value 50 years) and extracapsular invasion of the thyroid gland.

Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and detection of viral antigen in the hypophysis.

We describe 3 cases of nephropathia epidemica (NE) that confirm that Puumala virus infection may cause hypophyseal injury. Autopsy revealed a hemorrhagic hypophysis positive for Puumala virus antigen in both neuroendocrine stromal and vascular endothelial cells in 1 patient, and 2 patients developed hypophyseal hemorrhage (diagnosed with magnetic resonance imaging) during or shortly after acute NE, both of whom developed panhypopituitarism.

MRI-guided laser ablation of neuroendocrine tumor hepatic metastases.

BACKGROUND: Neuroendocrine tumors (NET) represent a therapeutically challenging and heterogeneous group of malignancies occurring throughout the body, but mainly in the gastrointestinal system. PURPOSE: To describe magnetic resonance imaging (MRI)-guided laser ablation of NET liver metastases and assess its role within the current treatment options and methods. MATERIAL AND METHODS: Two patients with NET tumor hepatic metastases were treated with MRI-guided interstitial laser ablation (LITT). Three tumors were treated. Clinical follow-up time was 10 years. RESULTS: Both patients were successfully treated. There were no local recurrences at the ablation site during the follow-up. Both patients had survived at 10-year follow-up. One patient is disease-free. CONCLUSION: MRI-guided laser ablation can be used to treat NET tumor liver metastases but combination therapy and a rigorous follow-up schedule are recommended.

Autonomic cardiac regulation during spontaneous nocturnal hypoglycemia in patients with type 1 diabetes.

OBJECTIVE: Experimental clamp studies have suggested that hypoglycemia evokes a reduction of cardiac vagal control in patients with type 1 diabetes. However, there are limited data on the influence of spontaneous nocturnal hypoglycemia on cardiac autonomic regulation. RESEARCH DESIGN AND METHODS: Adults with type 1 diabetes (n = 37) underwent continuous glucose monitoring via a subcutaneous sensor as well as recording of R-R interval or electrocardiogram for 3 nights. Heart rate (HR) variability was analyzed during periods of hypoglycemia (glucose <3.5 mmol/L) (minimum length of 20 min) and a control nonhypoglycemic period (glucose >3.9 mmol/L) of equal duration and at the same time of night. RESULTS: The duration of hypoglycemic and control episodes (n = 18) ranged from 20 to 190 min (mean 71 min). HR (62 ± 7 vs. 63 ± 9 beats per min; P = 0.30) or the high-frequency component of HR power spectrum (2,002 ± 1,965 vs. 1,336 ± 1,506 ms(2); P = 0.26) did not change during hypoglycemia. Hypoglycemia resulted in a significant decrease in the low-frequency component of HR variability (2,134 ± 1,635 vs. 1,169 ± 1,029 ms(2), respectively; P = 0.006). The decline in the glucose concentration displayed a significant positive correlation with the decrease of the low-frequency component of HR variability (r = 0.48; P = 0.04). The latter was closely related to an increase in muscle sympathetic nerve activity recorded in 10 subjects during controlled sympathetic activation. CONCLUSIONS: Spontaneous nocturnal hypoglycemia in patients with type 1 diabetes results in a reduction of the low-frequency component of HR, which is best explained by excessive sympathetic activation without a concomitant withdrawal of vagal outflow.

Central nervous system-related symptoms and findings are common in acute Puumala hantavirus infection.

BACKGROUND: Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS) also called nephropathia epidemica (NE). Recent case reports and retrospective studies suggest that NE may damage the pituitary gland. Based on these observations, our goal was to explore the nature of this complication prospectively. METHODS: A total of 58 hospitalized patients with acute NE volunteered to participate. Central nervous system (CNS) symptoms were recorded, cerebrospinal fluid (CSF) samples were collected, human leukocyte antigen (HLA) haplotype was analyzed, brain magnetic resonance imaging (MRI) was acquired, and electroencephalography (EEG) was recorded. Patients with abnormal pituitary MRI finding were examined by an endocrinologist. RESULTS: Most patients experienced CNS symptoms, and half of the CSF samples were positive for PUUV IgM, elevated protein level, or leukocyte count. CSF of patients negative for DR15(2)-DQ6 haplotype was less frequently affected. MRI revealed pituitary hemorrhage in two patients; these two patients suffered sudden loss of vision associated with headache, and they both developed hypopituitarism. Only one patient required long-term hormonal replacement therapy. CONCLUSION: CNS-related symptoms and inflammation in the CSF are common in acute NE. Genetic properties of the host may predispose to CNS involvement. It does seem that pituitary injury and subsequent hormonal insufficiency may complicate the recovery.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.