Journal of Clinical Medicine Review Genetics of Acromegaly and Gigantism Anna Bogusławska 1 and Márta Korbonits 2,* 1 Department of Endocrinology, Jagiellonian University Medical College, 31-008 Cracow, Poland; [email protected] 2 Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK * Correspondence: [email protected] Abstract: Growth hormone (GH)-secreting pituitary tumours represent the most genetically de- termined 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 Citation: Bogusławska, A.; and gigantism. Korbonits, M. Genetics of Acromegaly and Gigantism. J. Clin. Med. 2021, 10, Keywords: acromegaly; AIP; gigantism; FIPA; MEN1; somatotroph adenoma; pituitary neuroen- 1377. https://doi.org/10.3390/ docrine tumour; X-linked acrogigantism jcm10071377 Academic Editor: Shereen Ezzat 1. Introduction Received: 10 February 2021 Acromegaly is a rare, chronic disorder caused by excessive growth hormone (GH) Accepted: 19 March 2021 production. Common clinical manifestations include changes in appearance, headache, Published: 29 March 2021 joint pains as well as serious systemic complications such as metabolic, cardiovascular and osteoarticular comorbidities especially axial arthritis and higher risk of tumour growth Publisher’s Note: MDPI stays neutral (e.g., colon polyps and thyroid nodules) [1]. Cardiovascular diseases and cancer are mostly with regard to jurisdictional claims in responsible for an increased mortality in untreated patients [2,3]. Due to complications, published maps and institutional affil- quality of life is significantly reduced [4]. In childhood and adolescence, an excessive iations. GH secretion before complete epiphyseal closure leads to gigantism, characterised by abnormally tall stature. The prevalence of acromegaly is estimated between 28 to 137 per million people [5]. In most studies, females are slightly more (1:1.24) affected than males and the peak age of diagnosis is within the 5th decade of life [3,5]. The most common Copyright: © 2021 by the authors. cause of acromegaly and gigantism is growth hormone (GH) secreting pituitary adenoma Licensee MDPI, Basel, Switzerland. (PA), also called pituitary neuroendocrine tumour (PitNET) (Box1), which represents This article is an open access article approximately 9–13% of all PAs. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). J. Clin. Med. 2021, 10, 1377. https://doi.org/10.3390/jcm10071377 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1377 2 of 24 Box 1. Pituitary neuroendocrine tumour (PitNET). 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, therefore, 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 [7–9]. It was suggested that there is a risk that aligning adenohypophyseal tumours to other neuroendocrine tumours would raise unnecessary anxiety in patients and physicians less familiar with the disease, and for the time being suggested to carry on using the term adenoma with further discussion invited on this issue [10]. As PitNET is a valid term, in a scientific publication its use can be deemed appropriate. We acknowledge that both terms have advantages and disadvantages, and will use both terms in the review. Pituitary hyperplasia is encountered less commonly, mainly as part of genetic dis- orders such as Carney complex (CNC), McCune–Albright syndrome (MAS) or X-linked acrogigantism (XLAG). In rare cases (less than 1%), neuroendocrine tumours producing growth hormone releasing hormone (GHRH) or ectopic GH-secreting tumours have been described [11–13]. Altered growth hormone regulation resulting in GH excess can ac- company neurofibromatosis type 1, associated with optic pathway gliomas (OPG) [14]. Additionally, deficiency in the immunoglobulin superfamily member 1 (IGSF1), may result in somatotroph neurosecretory hyperfunction in adults [15]. Most somatotroph PitNETs develop sporadically; however, in nearly 46–49% of gi- gantism, the identifiable genetic background has been reported [16,17]. Hereditary GH- secreting pituitary tumours can manifest as an isolated manifestation, called familial isolated pituitary adenoma (FIPA), due to either loss-of-function mutations in aryl hy- drocarbon receptor interacting protein (AIP) or due to gain-of-function gene duplication in GPR101, causing XLAG. Hereditary pituitary tumours can also 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 [18–25] (Table1). J. Clin. Med. 2021, 10, 1377 3 of 24 Table 1. Germline and somatic GNAS mutations associated with acromegaly and gigantism (adapted from Gadelha et al. [26]). Gene Muta- Prevalence in Pituitary Prevalence in Mean Age of Diagnosis of Disease tion/Genetic Gene Location Phenotype Histopathology Tumours Acromegaly (%) GH Excess Alteration 50% in homogeneous FIPA More often 2nd decade of life (<30 4% in sporadic sparsely FIPA/AIP AIP 11q13.3 3.6% Isolated pituitary tumour years), male predominance, acromegaly granulated reduced SSTR 2 expression 29% in gigantism variant patients Often first years of life (<5 years) 0–4.4% in somatotroph female predominance, FIPA/X-linked acromegaly h/lactotroph GPR101 Xq26.3 1.6% Isolated pituitary tumour pituitary hyperplasia or acrogigantism 10% of gigantism pituitary tumour, males can be mosaic patients hyperplasia in or familial 25% of cases Multiple PAs and more often plurihormonal profile. More Hyperparathyroidism, Multiple 1.2% in acromegaly often pituitary pituitary tumour, 4th decade of life Endocrine MEN1 11q13.1 0.6–2.6% 1% of gigantism hyperplasia. In pancreatic female predominance Neoplasia type 1 patients some part of neuroendocrine tumours patients, poorly- differentiated PIT1- lineage tumours Hyperparathyroidism, Multiple More often pituitary tumour, Endocrine CDKN1B 12p13.1 rare rare Single cases pituitary pancreatic Neoplasia type 4 hyperplasia neuroendocrine tumours Classic triad: fibrosus 2nd decade of life McCune– More often Mosaic GNAS Only acromegaly/gigantism 5% of gigantism dysplasia, cafe- au-lait male predominance, Albright 20q13.3 pituitary mutation (20% of patients) patients macules, precocious pituitary hyperplasia, Syndrome hyperplasia puberty prolactin cosecretion somatotroph PRKAR1A 17q22-24 Only acromegaly/gigantism 1% among Acromegaly, cardiac and 3rd decade of life no gender Carney Complex h/lactotroph (12% but 75% asymptomatic gigantism patients cutaneous myxomas, predominance, hyperplasia pituitary CNC2 locus 2p16 elevation of GH and IGF-1 PPNAD, lentiginosis (majority) or tumour hyperplasia J. Clin. Med. 2021, 10, 1377 4 of 24 Table 1. Cont. Gene Muta- Prevalence in Pituitary Prevalence in Mean Age of Diagnosis of Disease tion/Genetic Gene Location Phenotype Histopathology Tumours Acromegaly (%) GH Excess Alteration SDHx SDHA 5p15.33 VHL Pituitary SDHB 1p36.13 Association between intracytoplasmic MEN1 Single cases adenoma and SDHC 1q23.3 rare rare PPGL and pituitary vacuoles RET PPGL association SDHD 11q23.1 tumour MAX 14q23.3 Neurofibromas, cafe Only acromegaly/gigantism- Neurofibromatosis au-lait macules, No visible pituitary NF1 17q11.2 around 10% in patients with rare - type 1 freckling, Lisch nodules, pathology NF1 and optic glioma optic glioma Deficiency of the X-link acromegalic facial No visible pituitary immunoglobulin IGSF1 Xq26.1 Only GH excess features Not estimated features organomegaly - pathology superfamily in adulthood member 1 no association has been smaller size, good response observed Sporadic soma- Somatic GNAS 20q13.3 Only acromegaly 40% Isolated pituitary tumour to medical treatment with between GNAS totropinomas mutation somatostatin analogues