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Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a GNAS mutation.

ABSTRACT: Germline loss-of-function GNAS mutations are associated with multiple phenotypes, depending on the parental origin of the mutant allele. Here, we describe an infantile lethal form of atypical pseudohypoparathyroidism type 1a or 1c with severe Albright's hereditary osteodystrophy phenotype, underlying the extremely variable expressivity of this syndrome.

SUBMITTER: Leclercq V

PROVIDER: S-EPMC6186887 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a <i>GNAS</i> mutation.

Leclercq Valérie V Benoit Valérie V Lederer Damien D Delaunoy Melanie M Ruiz Marcela M de Halleux Claire C Robaux Olivier O Wanty Catherine C Maystadt Isabelle I

Clinical case reports 20180816 10

Germline loss-of-function <i>GNAS</i> mutations are associated with multiple phenotypes, depending on the parental origin of the mutant allele. Here, we describe an infantile lethal form of atypical pseudohypoparathyroidism type 1a or 1c with severe Albright's hereditary osteodystrophy phenotype, underlying the extremely variable expressivity of this syndrome. ...[more]

PMID: 30349702

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Project description:Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha-stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein-coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid-stimulating hormone [TSH], growth hormone-releasing hormone [GHRH], calcitonin) and severe obesity. Paternally-inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally-inherited (GnasE1+/-p) versus maternally-inherited (GnasE1+/-m) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/-p mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/-m mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/-p and GnasE1+/-m mice could potentially be related to changes in the bone microenvironment driven by calcitonin-resistance within GnasE1+/-m osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast-osteoclast coupling. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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: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.

Dataset Information

Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a GNAS mutation.

Publications

Case report: An infantile lethal form of Albright hereditary osteodystrophy due to a <i>GNAS</i> mutation.

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