Article

Genetic analysis in young patients with sporadic pituitary macroadenomas:Beside AIP don't forget MEN1 genetic analysis.

T Cuny, Endocrinology, University Hospital of Nancy Brabois, Vandoeuvre-Les-Nancy, France.
European Journal of Endocrinology (Impact Factor: 3.69). 01/2013; DOI: 10.1530/EJE-12-0763
Source: PubMed

ABSTRACT CONTEXT: germline mutations in the AIP gene have been identified in young patients (age ≤ 30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of MEN1 mutations in such population. OBJECTIVE: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤ 30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS: 174 patients from Endocrinology Departments of 15 French University Hospital Centers were eligible for this study. RESULTS: 21/174(12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤ 18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were respectively identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients; they each accounted for 4/74 (5.4%) prolactinoma patients with mutations. Half of patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the 8 corticotroph-adenomas and a single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION: mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly prolactinomas, and together with AIP, we suggest genetic analysis of MEN1 in such population.

Full-text

Available from: Adrian Francis Daly, Dec 08, 2014
0 Followers
 · 
124 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case-reports. Objective: Improve knowledge of MEN1 natural history before 21 years old. Methods: Description of first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. Results: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), non-secreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%) and malignant thymic-NET in one (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n=9, 16%), hyperparathyroidism (n=38, 31%), gastrinoma (n=1, 33%), NSPT (n=5, 36%), and all cases of insulinoma, adrenal tumors and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. Conclusions: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.
    Journal of Clinical Endocrinology &amp Metabolism 01/2015; 100(4):jc20143659. DOI:10.1210/jc.2014-3659 · 6.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Pituitary adenomas are rare in children and adolescents. The response of macroprolactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in adults. Objective: We retrospectively analyzed data on a large cohort of young patients with macroprolactinomas. Patients and Methods: Patients < 20 years at macroprolactinoma diagnosis and seen in 3 tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the patients' status at their last visit, after a mean (± SD) follow-up of 8.2 ± 5.8 years, was assessed. Results: The cohort comprised 77 patients (26M, 51F). Mean age at diagnosis was 16.1±2.5 years (range, 4.5-20). In both sexes, the most frequent revealing symptom was a pubertal disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal PRL levels and maximal tumor diameter were significantly higher in boys than in girls (7168ng/ml, 202-40168 vs 1433ng/ml, 115-20000, p=0.002; and 33±14mm, 15-64 vs 19±9mm; 10-50, p<0.001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP or MEN1 was found in 14% of patients. Factors associated with resistance to DA were young age, higher PRL levels, larger volume and presence of a MEN1 (but not an AIP) mutation. Conclusion: Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and during adolescence. Like adults, young patients are very sensitive to DA, which should therefore be considered the first-line treatment. DA resistance is associated with higher PRL level and larger tumor size, both parameters being closely linked together. About 14% of these young patients have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance.
    Journal of Clinical Endocrinology &amp Metabolism 12/2014; 100(3):jc20143670. DOI:10.1210/jc.2014-3670 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pituitary adenomas are benign intracranial neoplasms that can result in morbidity owing to local invasion and/or excessive or deficient hormone production. The prevalence of symptomatic pituitary adenomas is approximately 1:1,000 in the general population. The vast majority of these tumours occur sporadically and are not part of syndromic disorders. However, germline mutations in genes known to predispose individuals to familial pituitary adenomas are found in a few patients with sporadic pituitary adenomas. Mutations in AIP (encoding aryl-hydrocarbon receptor-interacting protein) are the most frequently observed germline mutations. The prevalence of these mutations in patients with sporadic pituitary adenomas is ∼4%, but can increase to 8-20% in young adults with macroadenomas or gigantism, and also in children. Germline mutations in MEN1 (encoding menin) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas, which highlights the importance of the chromosome 11q13 locus in pituitary tumorigenesis. In this Review, we describe the clinical features of patients with sporadic pituitary adenomas that are associated with AIP or MEN1 mutations, and discuss the molecular mechanisms that might be involved in pituitary adenoma tumorigenesis. We also discuss genetic screening of patients with sporadic pituitary adenomas and investigations of relatives of these patients who also have the same genetic mutations.
    Nature Reviews Endocrinology 10/2014; 11(1). DOI:10.1038/nrendo.2014.181 · 12.96 Impact Factor