Genetics of Acromegaly and Gigantism

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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Inherited endocrine syndromes and MEN

10.1093/med/9780198851899.003.0010 ◽

2021 ◽

pp. 651-702

Author(s):

Paul Newey

Keyword(s):

Renal Calculi ◽

Cowden Syndrome ◽

Carney Complex ◽

Endocrine Disorders ◽

Mccune Albright Syndrome ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Albright Syndrome

This chapter begins with genetic testing for monogenic endocrine disorders, and then goes on to define the diagnosis, treatment, and management of McCune-Albright syndrome, neurofibromatosis, von Hippel-Lindau disease, Carney complex, Cowden syndrome, and POEMS syndrome. It then goes on to the clinical features and management of MEN type 1 and MEN type 2, and MEN type 4. Inherited primary hyperparathyroidism, phaeochromocytoma-paraganglioma syndromes, and renal calculi.

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Modern views on the genetic determinism of GH-secreting pituitary adenomas (literature review and own data)

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY ◽

10.22141/2224-0721.17.1.2021.226425 ◽

2021 ◽

Vol 17 (1) ◽

pp. 11-19

Author(s):

R. Nikolaiev ◽

L. Rostomyan ◽

A. Beckers ◽

O. Khyzhnyak ◽

M. Mykytyuk ◽

...

Keyword(s):

Pituitary Adenoma ◽

Genetic Analysis ◽

Pituitary Adenomas ◽

Young Age ◽

Mccune Albright Syndrome ◽

Men1 Gene ◽

Men 1 ◽

Albright Syndrome ◽

Aip Gene ◽

Mccune Albright

Background. This article presents a review of the current literature on the role of the genetic component in the etiology and pathogenesis of hormone-active pituitary adenomas secreting growth hormone (GH) and clinically manifesting by acromegaly and/or gigantism (multiple endocrine neoplasia 1 (MEN-1), McCune-Albright syndrome, Carney complex, X-linked acrogigantism (X-LAG), familial isolated pituitary adenoma — FIPA). Materials and methods. To identify mutations in the AIP gene and to verify FIPA, 26 patients of the Ukrainian population (19 women and 7 men) were examined in whom acromegaly was diagnosed in adolescence or young age, and genetic analysis was performed. To determine the genetic determinism in the development of GH-secreting pituitary adenoma and differential diagnosis of FIPA and MEN-1 syndromes by sequencing method (MLPA — ligation-dependent probe amplification), the genes MLPA, P244-C1 were studied involving exons 1–6 MEN1 gene, (MLPA, P017-D1) AIP gene. Results. Among those examined, only two patients had AIP gene mutations. In one patient, genetic screening for MEN1 gene mutation was negative and no clinical symptoms suggestive of McCune-Albright syndrome were detected. A variant heterozygous missense c.714C>G (p.Cys238Trp) was found in the AIP gene. This AIP gene assay is compatible with a genetic predisposition to develop pituitary adenoma. The offspring of this patient has a 50% chance of inheriting this variant, acromegaly, hypersomatotropinemia, MEN-1 syndrome, familial isolated pituitary adenoma. Another patient was diagnosed with MEN syndrome type 1 (Wermer syndrome): insulinoma, parathyroid gland adenomas (2), primary hyperparathyroidism with a heterozygous c.134A>G variant (p.Glu45Gly) found in the MEN1 gene. The presence of the c.l34A>G (p.Glu45Gly) class variant 4 is likely to be pathogenic. The prevalence of this variant in the general population is unknown, so it is very rare. Conclusions. The genetic analysis is appropriate in pediatric and young patients or those with GH-secreting macro/giant pituitary adenoma diagnosed at a young age (under 35), regardless of family history. In patients with a history of a disease, genetic analysis is recommended in any case to identify FIPA and to predict the further course of the disease and the effectiveness of treatment with somatostatin analogues.

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A Case of McCune-Albright Syndrome Complicating Pituitary Adenoma and Fibrous Dysplasia

Orthopedics & Traumatology ◽

10.5035/nishiseisai.54.407 ◽

2005 ◽

Vol 54 (3) ◽

pp. 407-408

Author(s):

Yoshiyuki Masuda ◽

Fumihiro Miyaguchi ◽

Kyoji Hayashi ◽

Kazunori Yone ◽

Setsuro Komiya

Keyword(s):

Pituitary Adenoma ◽

Fibrous Dysplasia ◽

Mccune Albright Syndrome ◽

Albright Syndrome ◽

Mccune Albright

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Carney complex and McCune Albright syndrome: An overview of clinical manifestations and human molecular genetics

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2013.08.022 ◽

2014 ◽

Vol 386 (1-2) ◽

pp. 85-91 ◽

Cited By ~ 61

Author(s):

Paraskevi Salpea ◽

Constantine A. Stratakis

Keyword(s):

Molecular Genetics ◽

Clinical Manifestations ◽

Carney Complex ◽

Mccune Albright Syndrome ◽

Albright Syndrome ◽

Mccune Albright

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THE MCCUNE ALBRIGHT SYNDROME: A GENETICALLY DETERMINED SIGNAL TRANSDUCTION DISORDER

Pediatric Research ◽

10.1203/00006450-199305001-00026 ◽

1993 ◽

Vol 33 ◽

pp. S6-S7 ◽

Cited By ~ 1

Author(s):

A M Spiegel ◽

A Shenker ◽

L S Weinstein

Keyword(s):

Signal Transduction ◽

Mccune Albright Syndrome ◽

Albright Syndrome ◽

Genetically Determined ◽

Mccune Albright

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The role of molecular genetic methods in the diagnosis of McCune—Albright syndrome

Problems of Endocrinology ◽

10.14341/probl2017636360-368 ◽

2018 ◽

Vol 63 (6) ◽

pp. 360-368

Author(s):

Nadezhda V. Makazan ◽

Elizaveta M. Orlova ◽

Anna A. Kolodkina ◽

Maria A. Kareva ◽

Natalia Yu. Kalinchenko ◽

...

Keyword(s):

Peripheral Blood ◽

Somatic Mutations ◽

Molecular Genetic ◽

Mccune Albright Syndrome ◽

Gnas Gene ◽

Allele Specific ◽

Taqman Pcr ◽

Polymerase Chain ◽

Albright Syndrome ◽

Next Generation Sequencing Ngs

McCune-Albright syndrome (MAS) is a rare genetic disorder which is caused by somatic mutations in the GNAS gene. Clinical symptoms of MAS include café-au-lait skin pigmentation, fibrous dysplasia, and autonomous endocrine hyperfunction. Somatic character of the gene defects determines wide variety of syndrome manifestations, from mild forms with minimum presentation to severe conditions with aggressive course. Potential multicomponent form of the MAS syndrome necessitates the dynamic monitoring, including regular screening for possible components of the disease. Therefore, additional methods specifying the diagnosis of MAS syndrome, especially of its suppressed forms, should facilitate selection of patient management strategy and monitoring rate and/or complete exclusion of the diagnosis. Molecular genetic verification of the diagnosis may be one of these methods. Objective — the study was aimed at evaluating massive parallel sequencing (next generation sequencing, NGS) and real-time polymerase chain reaction using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR) in the diagnosis of somatic mutations R201C and R201H in the GNAS gene based on DNA obtained from the peripheral blood. Material and methods. The study included patients diagnosed with and suspected for MAS syndrome. Molecular genetic testing of R201C and R201H mutations in the GNAS gene based on DNA extracted from peripheral blood leukocytes was carried out by Next generation sequencing (NGS) and real-time polymerase chain reaction methods using the TaqMan technique for detection of somatic mutations (competitive allele-specific TaqMan PCR, CAST-PCR). Based on clinical data, patients were divided into groups depending on the severity of the disease and the number of MAS manifestations. The results were evaluated by comparing the rate of detected molecular genetic defects in the formed groups of patients. Results. Molecular genetic study included 39 children with MAS syndrome and 6 children with suspected MAS. R201C and R201H mutations in GNAS gene were detected in 16 patients with severe to moderate MAS 16 (41%) 39. No mutations were detected in other MAS patients and patients with suspected MAS. Conclusion. NGS and CAST-PCR methods can detect the presence of mutant alleles R201C and R201H of GNAS gene in DNA samples obtained from the blood in the case of severe to moderate MAS syndrome, but they cannot be recommended for MAS diagnosis based on the peripheral blood samples in children with mild signs of the syndrome or suspected diagnosis.

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