Genetics of Acromegaly and Gigantism.

Anna Bogusławska,Márta Korbonits

doi:10.3390/jcm10071377

Abstract

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune–Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

Highlights

Is a rare, chronic disorder caused by excessive growth hormone (GH) production
In 2017 The International Pituitary Pathology Club suggested that the hormone-producing cells of the pituitary are a part of the neuroendocrine system and sometimes show invasive growth, proposed to use the phrase pituitary neuroendocrine tumour (PitNET) rather than pituitary adenoma, to highlight the similarity with other neuroendocrine neoplasms [6]
Hereditary pituitary tumours can be part of syndromic disease accompanied by other manifestations, often tumours of other endocrine organs, such as in multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), McCune–Albright syndrome (MAS), Carney complex (CNC), or phaeochromocytoma/paraganglioma (PPGL)-pituitary adenoma association [18,19,20,21,22,23,24,25] (Table 1)

Summary

Introduction

Is a rare, chronic disorder caused by excessive growth hormone (GH) production. The most common cause of acromegaly and gigantism is growth hormone (GH) secreting pituitary adenoma (PA), called pituitary neuroendocrine tumour (PitNET) (Box 1), which represents approximately 9–13% of all PAs. Box 1. In 2017 The International Pituitary Pathology Club suggested that the hormone-producing cells of the pituitary are a part of the neuroendocrine system and sometimes show invasive growth, proposed to use the phrase pituitary neuroendocrine tumour (PitNET) rather than pituitary adenoma, to highlight the similarity with other neuroendocrine neoplasms [6]. This suggestion has been met with some controversy [7,8,9]. Hereditary pituitary tumours can be part of syndromic disease accompanied by other manifestations, often tumours of other endocrine organs, such as in multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), MAS, CNC, or phaeochromocytoma/paraganglioma (PPGL)-pituitary adenoma association [18,19,20,21,22,23,24,25] (Table 1)

Isolated pituitary tumour

No visible pituitary pathology intracytoplasmic vacuoles

Findings

ATP Signalling