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McCune Albright syndrome and bilateral adrenal hyperplasia: the GNAS mutation may only be present in adrenal tissue.

ABSTRACT: OBJECTIVE:Corticotropin (ACTH)-independent hypercortisolism due to bilateral adrenocortical hyperplasia (BAH) in infancy is an extremely rare condition that is often caused by McCune Albright syndrome (MAS). MAS is caused by an activating mutation of the GNAS gene which leads to increased cyclic (c) adenosine monophosphate (AMP) signaling. Most forms of BAH are linked to increased cAMP signaling. We report the case of an infant with MAS who had BAH. METHODS:Genomic DNA fragments from blood and adrenal tissue encompassing regions (exons 8 and 9) with the hot spot activating missense GNAS mutations were amplified by classical bidirectional Sanger sequencing. RESULTS:The infant was found to carry the most common GNAS mutation, in exon 8 (c.602G >A, p. R201H), only in her adrenocortical tissue, despite extensive skin and other findings. CONCLUSIONS:We conclude that infants with MAS, despite absence of the GNAS activating mutation in blood, may still have significant clinical findings, including ACTH-independent hypercortisolism. Molecular confirmation of the diagnosis should be sought at the tissue level in these patients.

SUBMITTER: Angelousi A

PROVIDER: S-EPMC6341467 | biostudies-literature | 2015 Jul-Sep

REPOSITORIES: biostudies-literature

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McCune Albright syndrome and bilateral adrenal hyperplasia: the GNAS mutation may only be present in adrenal tissue.

Angelousi Anna A Fencl Filip F Faucz Fabio R FR Malikova Jana J Sumnik Zdenek Z Lebl Jan J Stratakis Constantine A CA

Hormones (Athens, Greece) 20150701 3

<h4>Objective</h4>Corticotropin (ACTH)-independent hypercortisolism due to bilateral adrenocortical hyperplasia (BAH) in infancy is an extremely rare condition that is often caused by McCune Albright syndrome (MAS). MAS is caused by an activating mutation of the GNAS gene which leads to increased cyclic (c) adenosine monophosphate (AMP) signaling. Most forms of BAH are linked to increased cAMP signaling. We report the case of an infant with MAS who had BAH.<h4>Methods</h4>Genomic DNA fragments f ...[more]

PMID: 26188235

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Project description:ContextMcCune-Albright syndrome (MAS) is caused by sporadic mutations of the GNAS. Patients exhibit features of acromegaly. In most patients, GH-secreting pituitary adenomas have been held responsible for this presentation. However, surgical adenomectomy rarely eliminates excess GH production.ObjectiveThe aim of this study was to elucidate pituitary pathology in patients with MAS and to explain the basis of failure of adenomectomy to eliminate GH hypersecretion.Design and settingWe conducted a case series at the National Institutes of Health.Intervention(s)Interventions included medical therapy and transsphenoidal surgery.Patients and main outcome measuresWe studied clinical and imaging features and the histology and molecular features of the pituitary of four acromegalic MAS patients.ResultsWe identified widespread and diffuse pituitary gland disease. The primary pathological changes were characterized by hyperplastic and neoplastic change, associated with overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples of any type of histological area consistently revealed identical GNAS mutations in individual patients. The only patient with remission after surgery received complete hypophysectomy in addition to removal of multiple GH-secreting tumors.ConclusionsThese findings indicate developmental effects of GNAS mutation on the entire anterior pituitary gland. The pituitary of individual cases contains a spectrum of changes with regions of normal appearing gland, hyperplasia, and areas of fully developed adenoma formation, as well as transitional stages between these entities. The primary change underlying acromegaly in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, with or without development of somatotroph adenoma. Thus, successful clinical management, whether it is medical, surgical, or via irradiation, must target the entire pituitary, not just the adenomas evident on imaging.

Project description:McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of bone (FD), café-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome, and renal phosphate wasting. Café-au-lait spots usually appear in the neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal involvement is seen in approximately 50% of the patients with MAS. The disease results from somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however, should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is dictated by the tissues affected, and the extent to which they are affected. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS.

Project description:In a small number of cases, the development of ectopic residual adrenal lesions during embryogenesis causing Cushing's syndrome due to the production of excess cortisol has been reported. A 29-year-old woman was admitted to our hospital for fatigue and recent amenorrhea. Her plasma ACTH was <1.5 pg/mL, and her serum cortisol was 21.4 pg/mL after the 8 mg dexamethasone suppression test, revealing the presence of ACTH-independent Cushing's syndrome; however, her bilateral adrenal glands were atrophied. Abdominal CT revealed a 40-mm round tumor on the right renal hilum and remarkably accumulated 131I-labelled adosterol. CT and bone scintigraphy showed that 99mTc-methylene diphosphonate had accumulated in her dissymmetric skull at the right-frontoparietal region. The tumor on the right renal hilum was laparoscopically removed. Her cortisol levels rapidly decreased to below the normal range, and glucocorticoids were administered to rescue adrenal insufficiency. The resected tumor was yellowish in appearance and 4.5×3.0×2.8 cm in size. Immunohistochemical staining for SF-1, P450scc, CYP17A, CYP21A, and CYP11B1 indicated that this tumor produced cortisol. Exome sequencing analysis revealed that the GNAS heterozygous mutation (c.601C>T, p. Arg201Cys; accession number, NM_000516.5) was found in approximately 20% of the adrenal tumor sample. A mutation of GNAS, encoding the Gsα subunit that mediates GPCR signaling, causes the constitutive activation of adenylyl cyclase, resulting in hypersecretion of hormones regulated by the GPCR. GNAS mutation is one of the major genetic causes of cortisol-producing adrenal tumors independent of ACTH secretion. Considering the combination of GNAS mutation with one of the typical clinical triad characteristics, fibrous dysplasia of bone, we diagnosed this patient with McCune-Albright syndrome accompanied by ACTH-independent Cushing's syndrome caused by an ectopic residual adrenal tumor due to GNAS mutation. This case highlights that GNAS involves a previously unknown pathological mechanism in which inhibition of the natural elimination of remnant tissue leads to ectopic endocrine hypersecretion.

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McCune Albright syndrome and bilateral adrenal hyperplasia: the GNAS mutation may only be present in adrenal tissue.

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McCune Albright syndrome and bilateral adrenal hyperplasia: the GNAS mutation may only be present in adrenal tissue.

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