Review articleScreening for genetic causes of growth hormone hypersecretion
Introduction
Modern genetic sequencing techniques have made genetic tests for patients with pituitary disease more accessible in routine clinical practice. Nevertheless, the indications for genetic screening in a distinct disease phenotype are continually evolving, which can make testing choices difficult for both the clinician and the patient.
Pituitary lesions are the most frequent cause of chronic growth hormone (GH) excess. When GH excess occurs before the closure of the epiphyseal plates it leads to increased linear growth and gigantism; GH excess leads to acromegaly when it occurs after epiphyseal closure. Pituitary gigantism and acromegaly can be due to isolated somatotropinomas or form part of complex syndromes, although sporadic non-familial presentation remains by far the most common form [1].
Despite recent advances over the last 20 years the genetic etiology of most pituitary adenomas is unknown [1], [2]. Traditionally it is considered that about 5% of pituitary adenomas present in familial syndrome settings, most frequently multiple endocrine neoplasia (MEN) type 1 due to mutations in the MEN1 gene or familial isolated pituitary adenomas (FIPA) in which 15–20% have mutations in the AIP gene. Rarer hereditary forms of pituitary adenomas include Carney complex, MEN4, and X-linked acrogigantism (X-LAG) as detailed in Table 1. Based on the characteristic phenotypes produced in these conditions, various recommendations can be made regarding the optimal choice of genetic tests.
Section snippets
Multiple endocrine neoplasia type 1 syndrome
The MEN1 gene that encodes the protein menin is mutated in patients with MEN1 syndrome [3]. Both familial and sporadic forms can be observed and 2.7% of all pituitary adenomas are estimated to be a part of this syndrome [4]. Pituitary adenomas are diagnosed in 30–40% of MEN1 patients, being more frequent in familial cases than sporadic. In about 17% of cases the pituitary tumor is the presenting manifestation of MEN1 [5]. Most MEN1- associated pituitary tumors are prolactinomas (50–60%), while
Recommendations for genetic screening
Pituitary adenomas have a prevalence about 1:1000 [63], but only 2–5% occur in familial settings [1]. Screening for genetic causes of pituitary adenomas is usually limited to familial cases or patients with associated syndromic pathologies in the same individual or in affected family members. Genetic tests in unselected sporadic pituitary adenoma population showed low prevalence for almost all known pituitary adenoma-associated genes discussed above [64]. Therefore, genetic screening in
Conclusion
Scientific and technological advances have led to an increasing availability of genetic testing in clinical practice. A number of genetic mutations and molecular abnormalities are implicated in pituitary tumorigenesis. A decision strategy for genetic testing in GH-secreting pituitary adenoma cases is proposed in Fig. 1. The algorithm is based on clinical evaluation and family history, and includes the main pituitary adenoma predisposition genes: MEN1, AIP, PRKAR1A, and more recently described
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Acknowledgements
The authors would like to thank Prof. Adrian F. Daly for discussions and suggestions regarding the topic covered.
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