scholarly journals Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues

2013 ◽  
Vol 168 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Josep Oriola ◽  
Tomás Lucas ◽  
Irene Halperin ◽  
Mireia Mora ◽  
Ma José Perales ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Conventional Treatment ◽  
Poor Response ◽  
Germline Mutations ◽  
Somatostatin Analogues ◽  
Age At Diagnosis ◽  
Somatostatin Analogue ◽  
Endocrine Tumors ◽  
Peg Treatment ◽  
Aip Gene

ObjectiveMost cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment.Design and methodsFifty patients with acromegaly (22 males/28 females, age 51±18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification.ResultsSequence changes of potential different significance that could be considered as mutations or variations of unknown significance (VUS) of the AIP gene were found in four patients (8%). In two cases, two different mutations previously described were found: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment.ConclusionsAIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.

scholarly journals A Rare Case of Thyrotropin Secreting Pituitary Macroadenoma Primarily Treated With Somatostatin Analogue

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A568-A568
Author(s):  
Arwa Mahmoud Elsheikh ◽  
G Edward Vates ◽  
Ismat Shafiq
Keyword(s):  
Pituitary Adenoma ◽  
Medical Treatment ◽  
Thyroid Function ◽  
Pituitary Adenomas ◽  
Rare Case ◽  
Somatostatin Analogues ◽  
Primary Treatment ◽  
Alpha Subunit ◽  
Somatostatin Analogue ◽  
Pituitary Macroadenoma

Abstract Introduction/Background: Thyrotropin secreting pituitary adenomas (TSH-oma) are a rare cause of hyperthyroidism. They account for <1% of the cases of hyperthyroidism with a reported incidence of 2.8 per 1 million in Sweden. Diagnosis is suspected by the presence of elevated T4 and T3 in the setting of an unsuppressed TSH level. The presence of large pituitary adenoma is highly suggestive of the diagnosis and can be differentiated from thyroid hormone resistance by elevated alpha subunit and SHBG levels. Trans-sphenoidal surgery is the definitive treatment. Peri-operative medical treatment with somatostatin analogues is indicated to achieve euthyroidism and prevent surgical risks and thyroid storm. The use of somatostatin analogues as a primary treatment for TSH-oma is still under investigation. We hereby report a rare case of TSH-oma where somatostatin analogues successfully resulted in normalization of thyroid function and tumor size reduction. Clinical Case: A 61 years old gentleman with a history of hypothyroidism diagnosed three years before presentation to the Pituitary clinic. He was treated with Levothyroxine. On clinical examination, he had mild tremor and warm sweaty palms with no stigmata of Grave’s disease. The thyroid function test showed elevated free T4 of 3.6 ng/dl (0.9-1.7), elevated free T3 of 8.6 pg/ml (2.0-4.4), and a high TSH level of 9.10 μIU/ml (0.27-4.20). His prolactin level was mildly elevated at 24.8 ng/ml(4.0-15.2). Testosterone, IGF-1, and cortisol levels were normal. An MRI of his pituitary gland showed large pituitary macroadenoma with supra-sellar extension and mild compression of the optic nerve. He had an elevated alpha subunit of 5.6 ng/ml (<1.37) and a high SHBG level of 198 nmol/l(10-80). TSH adenoma was diagnosed and he was planned for trans-sphenoidal surgery. Pre-operative treatment with somatostatin analogue Lanerotide 90 mg monthly injection was initiated. Interestingly normal thyroid function was observed approximately 1 month after his first injection. Repeat MRI showed a considerable decrease in the size of the pituitary macroadenoma. The patient opted to hold on to surgery and to continue on medical treatment. His thyroid function remains normal 15 months after initiation of treatment and his MRI continues to show stable pituitary adenoma. Conclusion: Somatostatin analogues can be used as a primary treatment for thyrotropin secreting pituitary adenomas when the patient is unable or unwilling to undergo surgery. It is use is associated with normalization of thyroid function and in some cases with a reduction in the adenoma size.

scholarly journals Long term treatment of a thyrotropin-secreting microadenoma with somatostatin analogues

2010 ◽  
Vol 54 (5) ◽  
pp. 502-506 ◽  
Author(s):  
Alma Prieto-Tenreiro ◽  
Patricia Díaz-Guardiola
Keyword(s):  
Pituitary Adenomas ◽  
Somatostatin Analogs ◽  
Somatostatin Analogues ◽  
Term Treatment ◽  
Somatostatin Analogue ◽  
Delay In Diagnosis ◽  
First Line Therapy ◽  
Long Term Treatment ◽  
Primary Hyperthyroidism

Thyrotropin (TSH) secreting pituitary adenomas (TSH-omas) account for < 1% of all pituitary adenomas and are a rare cause of hyperthyroidism. The diagnosis is often made at the stage of macroadenoma because of the aggressive nature of the tumor and due to the fact that patients are mistakenly treated for more common primary hyperthyroidism for a long time. First line therapy is transsphenoidal resection of the tumor, which can cure one-third of the patients completely. However, if surgery is not possible or curative, pituitary radiotherapy and/or somatostatin analogs (SSA) can be useful. We report the case of a 54-year-old woman treated 20 years earlier for a mistakenly suspected primary hyperthyroidism. Given the persistence of symptoms she was studied further and was diagnosed with a thyrotropinoma. Despite the delay in diagnosis and prior thyroid ablation, a microadenoma was found. As transsphenoidal surgery was not considered effective, medical therapy with a somatostatin analogue was initiated. Currently, at four years of follow-up, the patient continues on this treatment and remains euthyroid and asymptomatic. We report a case of successful long-term treatment with SSA, after unsuccessful surgery.

scholarly journals The Dose of Somatostatin Analogues during Pre-Surgical Treatment Is a Key Factor to Achieve Surgical Remission in Acromegaly

Endocrines ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 241-250
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Héctor Pian ◽  
Ignacio Ruz-Caracuel ◽  
Alberto Acitores Cancela ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Surgical Treatment ◽  
Surgical Outcomes ◽  
Pituitary Adenomas ◽  
Somatostatin Analogues ◽  
Beneficial Effects ◽  
Key Factor ◽  
Long Acting ◽  
First Time ◽  
Endocrine Complications

Purpose: to determine whether pre-surgical treatment using long-acting somatostatin analogues (SSAs) may improve surgical outcomes in acromegaly. Methods: retrospective study of 48 patients with acromegaly operated by endoscopic transsphenoidal approach and for first time. Surgical remission was evaluated based on the 2010 criteria. Results: most patients, 83.3% (n = 40), harbored macroadenomas and 31.3% (n = 15) invasive pituitary adenomas. In this case, 14 patients were treated with lanreotide LAR and 6 with octreotide LAR, median monthly doses of 97.5 [range 60–120] and 20 [range 20–30] mg, respectively, for at least 3 months preoperatively. Presurgical variables were comparable between pre-treated and untreated patients (p > 0.05). Surgical remission was more frequent in those pre-treated with monthly doses ≥90 mg of lanreotide or ≥30 mg of octreotide than in untreated or pre-treated with lower doses (OR = 4.64, p = 0.025). However, no differences were found between pre-treated and untreated patients when lower doses were included or between those treated for longer than 6 months compared to those untreated or pre-treated for shorter than 6 months. Similarly, no differences were found either in terms of surgical or endocrine complications (OR = 0.65, p = 0.570), independently of the doses and the duration of SSA treatment (p > 0.05). Conclusions: the dose of SSAs is a key factor during pre-surgical treatment, since the beneficial effects in surgical remission were observed with monthly doses equal or higher than 90 mg of lanreotide and 30 mg of octreotide, but not with lower doses.

scholarly journals Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)

1999 ◽  
pp. 475-480 ◽  
Author(s):  
N Hai ◽  
N Aoki ◽  
A Matsuda ◽  
T Mori ◽  
S Kosugi
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Family Members ◽  
Premature Stop Codon ◽  
Germline Mutations ◽  
Endocrine Tumors ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine tumors involving the parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in families with MEN1. DESIGN: Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. METHODS: Full-length sequencing of the open reading frame and exon-intron boundaries in the MEN1 gene was performed with probands of familial MEN1. Family members were examined for the identified mutation in the proband. RESULTS: We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectability of MEN1 mutations in familial MEN1 among studies that examined more than 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carriers in the course of the present study in those families. CONCLUSIONS: Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members of MEN1, should be considered as a standard procedure and categorized as belonging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.

scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis
Keyword(s):  
Tumor Suppressor ◽  
Neuroendocrine Tumors ◽  
Pituitary Adenomas ◽  
Wide Spectrum ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

scholarly journals Modern views on the genetic determinism of GH-secreting pituitary adenomas (literature review and own data)

2021 ◽  
Vol 17 (1) ◽  
pp. 11-19
Author(s):  
R. Nikolaiev ◽  
L. Rostomyan ◽  
A. Beckers ◽  
O. Khyzhnyak ◽  
M. Mykytyuk ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Genetic Analysis ◽  
Pituitary Adenomas ◽  
Young Age ◽  
Mccune Albright Syndrome ◽  
Men1 Gene ◽  
Men 1 ◽  
Albright Syndrome ◽  
Aip Gene ◽  
Mccune Albright

Background. This article presents a review of the current literature on the role of the genetic component in the etiology and pathogenesis of hormone-active pituitary adenomas secreting growth hormone (GH) and clinically manifesting by acromegaly and/or gigantism (multiple endocrine neoplasia 1 (MEN-1), McCune-Albright syndrome, Carney complex, X-linked acrogigantism (X-LAG), familial isolated pituitary adenoma — FIPA). Materials and methods. To identify mutations in the AIP gene and to verify FIPA, 26 patients of the Ukrainian population (19 women and 7 men) were examined in whom acromegaly was diagnosed in adolescence or young age, and genetic analysis was performed. To determine the genetic determinism in the development of GH-secreting pituitary adenoma and differential diagnosis of FIPA and MEN-1 syndromes by sequencing method (MLPA — ligation-dependent probe amplification), the genes MLPA, P244-C1 were studied involving exons 1–6 MEN1 gene, (MLPA, P017-D1) AIP gene. Results. Among those examined, only two patients had AIP gene mutations. In one patient, genetic screening for MEN1 gene mutation was negative and no clinical symptoms suggestive of McCune-Albright syndrome were detected. A variant heterozygous missense c.714C>G (p.Cys238Trp) was found in the AIP gene. This AIP gene assay is compatible with a genetic predisposition to develop pituitary adenoma. The offspring of this patient has a 50% chance of inheriting this variant, acromegaly, hypersomatotropinemia, MEN-1 syndrome, familial isolated pituitary adenoma. Another patient was diagnosed with MEN syndrome type 1 (Wermer syndrome): insulinoma, parathyroid gland adenomas (2), primary hyperparathyroidism with a heterozygous c.134A>G variant (p.Glu45Gly) found in the MEN1 gene. The presence of the c.l34A>G (p.Glu45Gly) class variant 4 is likely to be pathogenic. The prevalence of this variant in the general population is unknown, so it is very rare. Conclusions. The genetic analysis is appropriate in pediatric and young patients or those with GH-secreting macro/giant pituitary adenoma diagnosed at a young age (under 35), regardless of family history. In patients with a history of a disease, genetic analysis is recommended in any case to identify FIPA and to predict the further course of the disease and the effectiveness of treatment with somatostatin analogues.

scholarly journals Effects of combination therapy: somatostatin analogues and dopamine agonists on GH and IGF1 levels in acromegaly

2015 ◽  
Vol 88 (3) ◽  
pp. 310-313 ◽  
Author(s):  
Ana Valea ◽  
Cristina Ghervan ◽  
Mara Carsote ◽  
Andra Morar ◽  
Iulia Iacob ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Combination Therapy ◽  
Dopamine Agonist ◽  
Normal Level ◽  
Dopamine Agonists ◽  
Somatostatin Analogues ◽  
Somatostatin Analogue ◽  
Endocrine Disorder ◽  
Excessive Secretion

 Background and aims. Acromegaly is a complex endocrine disorder caused by excessive secretion of GH, secondary to a GH secreting pituitary adenoma or a mixed pituitary adenoma secreting GH and PRL.Methods. The aim of this study was to evaluate the effects of combination therapy: dopamine agonist and somatostatin analogue on GH and IGF1 levels in a group of 30 patients with acromegaly. Cabergoline in a dose of 2 mg/week and 4 mg/week respectively was associated with Sandostatin LAR in a dose of 20 mg/month and 30 mg/months respectively. Eight patients were treated with Lanreotide 30 mg/week and Cabergoline 2 mg/week and 3 patients were treated with Bromocriptine 10 mg/day and Sandostatin LAR 30 mg/month.Results. Combination therapy: Cabergoline and Sandostatin achieved normal levels of IGF1  in 32% of the patients, better results being obtained after 12 months of treatment in the group treated with 4 mg Cabergoline/week. In 37% of cases the levels of IGF1 decreased by 50% after 12 months of treatment. In the group treated with Cabergoline and Somatuline a normal level of IGF1 was achieved in 25% of patients after 12 months of treatment. The outcome for the group treated with Sandostatin and Bromocriptine was similar to that obtained under Cabergoline 2 mg/week. There was no significant correlation between the level of GH and the type or dose of dopamine agonist used.Conclusions. In conclusion, combination therapy consisting of dopamine agonist and somatostatin analogue achieves a significant reduction of IGF1 levels in patients with mixed adenomas secreting GH and PRL. A decrease in IGF1 levels is directly correlated with the dose of Cabergoline used. 

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