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      Genetics of Acromegaly and Gigantism

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          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.

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          Most cited references 192

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          Medical progress: Acromegaly.

           Shlomo Melmed (2006)
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            Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.

            The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the alpha subunit of the G protein (Gs alpha) that stimulates cAMP formation. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gs alpha gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hybridization. We detected one of two activating mutations within exon 8 of the Gs alpha gene in tissues from all four patients, including affected endocrine organs (gonads, adrenal glands, thyroid, and pituitary) and tissues not classically involved in the McCune-Albright syndrome. In two of the patients, histidine was substituted for arginine at position 201 of Gs alpha, and in the other two patients cysteine was substituted for the same arginine residue. In each patient the proportion of cells affected varied from tissue to tissue. In two endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Mutations within exon 8 of the Gs alpha gene that result in increased activity of the Gs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome. Somatic mutation of this gene early in embryogenesis could result in the mosaic population of normal and mutant-bearing tissues that may underlie the clinical manifestations of this disease.
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              High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium.

              Prevalence data are important for assessing the burden of disease on the health care system; data on pituitary adenoma prevalence are very scarce. The objective of the study was to measure the prevalence of clinically relevant pituitary adenomas in a well-defined population. This was a cross-sectional, intensive, case-finding study performed in three regions of the province of Liège, Belgium, to measure pituitary adenoma prevalence as of September 30, 2005. The study was conducted in specialist and general medical practitioner patient populations, referral hospitals, and investigational centers. Three demographically and geographically distinct districts of the province of Liège were delineated precisely using postal codes. Medical practitioners in these districts were recruited, and patients with pituitary adenomas under their care were identified. Diagnoses were confirmed after retrieval of clinical, hormonal, radiological, and pathological data; full demographic and therapeutic follow-up data were collected in all cases. Sixty-eight patients with clinically relevant pituitary adenomas were identified in a population of 71,972 individuals; the mean (+/- sd) prevalence was 94 +/- 19.3 cases per 100,000 population (95% confidence interval, 72.2 to 115.8). The group was 67.6% female and had a mean age at diagnosis of 40.3 yr; 42.6% had macroadenomas and 55.9% underwent surgery. Prolactinomas comprised 66% of the group, with the rest having nonsecreting tumors (14.7%), somatotropinomas (13.2%), or Cushing's disease (5.9%); 20.6% had hypopituitarism. The prevalence of pituitary adenomas in the study population (one case in 1064 individuals) was more than 3.5-5 times that previously reported. This increased prevalence may have important implications when prioritizing funding for research and treatment of pituitary adenomas.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                29 March 2021
                April 2021
                : 10
                : 7
                Affiliations
                [1 ]Department of Endocrinology, Jagiellonian University Medical College, 31-008 Cracow, Poland; boguslawskaania@ 123456gmail.com
                [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
                Author notes
                Article
                jcm-10-01377
                10.3390/jcm10071377
                8036715
                33805450
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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