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Auli Karhu - One of the best experts on this subject based on the ideXlab platform.
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familial isolated Pituitary Adenomas fipa and the Pituitary Adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein aip gene
Endocrine Reviews, 2013Co-Authors: Albert Beckers, Lauri A Aaltonen, Adrian Daly, Auli KarhuAbstract:Pituitary Adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary Adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of Pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of Pituitary Adenoma development exist. Recent years have seen two separate, complimentary advances in inherited Pituitary tumor research. The clinical condition of familial isolated Pituitary Adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated Pituitary Adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of Pituitary Adenomas and represent a clinical entity with homogeneous or heterogeneous Pituitary Adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a Pituitary Adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large Pituitary Adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning Pituitary Adenomas, Cushing disease, and other infrequent clinical Adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of Pituitary Adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with Pituitary Adenomas.
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molecular diagnosis of Pituitary Adenoma predisposition caused by aryl hydrocarbon receptor interacting protein gene mutations
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marianthi Georgitsi, Ralf Paschke, Outi Vierimaa, Anniina Raitila, Karoliina Tuppurainen, Auli Karhu, Markus J Makinen, Wolfgang Saeger, Rob B Van Der Luijt, Timo SaneAbstract:Pituitary Adenomas are common neoplasms of the anterior Pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause Pituitary Adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of Pituitary Adenomas. To evaluate the role of AIP in Pituitary Adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in Pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected Pituitary Adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of Pituitary Adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 Adenomas: 12 AIP mutation-positive versus 38 mutation-negative Pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
Timo Sane - One of the best experts on this subject based on the ideXlab platform.
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large genomic deletions in aip in Pituitary Adenoma predisposition
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Marianthi Georgitsi, Elina Heliovaara, Ralf Paschke, Ajith Kumar, Marc Tischkowitz, Outi Vierimaa, P I Salmela, Timo Sane, Ernesto De Menis, Salvatore CannavoAbstract: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 ge...
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molecular diagnosis of Pituitary Adenoma predisposition caused by aryl hydrocarbon receptor interacting protein gene mutations
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marianthi Georgitsi, Ralf Paschke, Outi Vierimaa, Anniina Raitila, Karoliina Tuppurainen, Auli Karhu, Markus J Makinen, Wolfgang Saeger, Rob B Van Der Luijt, Timo SaneAbstract:Pituitary Adenomas are common neoplasms of the anterior Pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause Pituitary Adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of Pituitary Adenomas. To evaluate the role of AIP in Pituitary Adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in Pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected Pituitary Adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of Pituitary Adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 Adenomas: 12 AIP mutation-positive versus 38 mutation-negative Pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
Marianthi Georgitsi - One of the best experts on this subject based on the ideXlab platform.
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large genomic deletions in aip in Pituitary Adenoma predisposition
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Marianthi Georgitsi, Elina Heliovaara, Ralf Paschke, Ajith Kumar, Marc Tischkowitz, Outi Vierimaa, P I Salmela, Timo Sane, Ernesto De Menis, Salvatore CannavoAbstract: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 ge...
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molecular diagnosis of Pituitary Adenoma predisposition caused by aryl hydrocarbon receptor interacting protein gene mutations
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marianthi Georgitsi, Ralf Paschke, Outi Vierimaa, Anniina Raitila, Karoliina Tuppurainen, Auli Karhu, Markus J Makinen, Wolfgang Saeger, Rob B Van Der Luijt, Timo SaneAbstract:Pituitary Adenomas are common neoplasms of the anterior Pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause Pituitary Adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of Pituitary Adenomas. To evaluate the role of AIP in Pituitary Adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in Pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected Pituitary Adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of Pituitary Adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 Adenomas: 12 AIP mutation-positive versus 38 mutation-negative Pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
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Pituitary Adenoma predisposition caused by germline mutations in the aip gene
Science, 2006Co-Authors: Outi Vierimaa, Marianthi Georgitsi, P I Salmela, Rainer Lehtonen, Pia Vahteristo, Antti Kokko, Anniina Raitila, Karoliina Tuppurainen, Tapani Ebeling, Ralf PaschkeAbstract:Pituitary Adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with Pituitary Adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with Pituitary Adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of Pituitary Adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene.
Ralf Paschke - One of the best experts on this subject based on the ideXlab platform.
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large genomic deletions in aip in Pituitary Adenoma predisposition
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Marianthi Georgitsi, Elina Heliovaara, Ralf Paschke, Ajith Kumar, Marc Tischkowitz, Outi Vierimaa, P I Salmela, Timo Sane, Ernesto De Menis, Salvatore CannavoAbstract: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 ge...
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molecular diagnosis of Pituitary Adenoma predisposition caused by aryl hydrocarbon receptor interacting protein gene mutations
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marianthi Georgitsi, Ralf Paschke, Outi Vierimaa, Anniina Raitila, Karoliina Tuppurainen, Auli Karhu, Markus J Makinen, Wolfgang Saeger, Rob B Van Der Luijt, Timo SaneAbstract:Pituitary Adenomas are common neoplasms of the anterior Pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause Pituitary Adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of Pituitary Adenomas. To evaluate the role of AIP in Pituitary Adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in Pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected Pituitary Adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of Pituitary Adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 Adenomas: 12 AIP mutation-positive versus 38 mutation-negative Pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
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Pituitary Adenoma predisposition caused by germline mutations in the aip gene
Science, 2006Co-Authors: Outi Vierimaa, Marianthi Georgitsi, P I Salmela, Rainer Lehtonen, Pia Vahteristo, Antti Kokko, Anniina Raitila, Karoliina Tuppurainen, Tapani Ebeling, Ralf PaschkeAbstract:Pituitary Adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with Pituitary Adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with Pituitary Adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of Pituitary Adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene.
Outi Vierimaa - One of the best experts on this subject based on the ideXlab platform.
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large genomic deletions in aip in Pituitary Adenoma predisposition
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Marianthi Georgitsi, Elina Heliovaara, Ralf Paschke, Ajith Kumar, Marc Tischkowitz, Outi Vierimaa, P I Salmela, Timo Sane, Ernesto De Menis, Salvatore CannavoAbstract: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 ge...
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molecular diagnosis of Pituitary Adenoma predisposition caused by aryl hydrocarbon receptor interacting protein gene mutations
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Marianthi Georgitsi, Ralf Paschke, Outi Vierimaa, Anniina Raitila, Karoliina Tuppurainen, Auli Karhu, Markus J Makinen, Wolfgang Saeger, Rob B Van Der Luijt, Timo SaneAbstract:Pituitary Adenomas are common neoplasms of the anterior Pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause Pituitary Adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of Pituitary Adenomas. To evaluate the role of AIP in Pituitary Adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in Pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected Pituitary Adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of Pituitary Adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 Adenomas: 12 AIP mutation-positive versus 38 mutation-negative Pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.
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Pituitary Adenoma predisposition caused by germline mutations in the aip gene
Science, 2006Co-Authors: Outi Vierimaa, Marianthi Georgitsi, P I Salmela, Rainer Lehtonen, Pia Vahteristo, Antti Kokko, Anniina Raitila, Karoliina Tuppurainen, Tapani Ebeling, Ralf PaschkeAbstract:Pituitary Adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with Pituitary Adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with Pituitary Adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of Pituitary Adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene.