Elsevier

Growth Hormone & IGF Research

Volumes 30–31, October–December 2016, Pages 52-57
Growth Hormone & IGF Research

Review article
Screening for genetic causes of growth hormone hypersecretion

https://doi.org/10.1016/j.ghir.2016.10.004Get rights and content

Highlights

  • Genetically determined pituitary adenomas represent a small (5%) but clinically important group of tumors.

  • Genetically related pituitary tumors can present in an isolated or syndromic manner.

  • Mutations in the MEN1, AIP, PRKAR1A, CDKN1B, GNAS and SDHx genes can cause pituitary tumors.

  • X-linked acrogigantism (X-LAG) syndrome due to duplications involving GPR101 can be sporadic, mosaic or inherited.

Abstract

Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage. In addition to mutations or deletions, copy number variation at the GPR101 locus may also lead to mixed GH and prolactin secreting pituitary adenomas in the setting of X-linked acrogigantism (X-LAG syndrome). In X-LAG syndrome and in McCune Albright syndrome, mosaicism for GPR101 duplications and activating GNAS1 mutations, respectively, contribute to the genetic pathogenesis. As only 5% of pituitary adenomas have a known cause, efficient deployment of genetic testing requires detailed knowledge of clinical characteristics and potential associated syndromic features in the patient and their family.

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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