2778

GNAS

AHO|C20orf45|GNAS1|GPSA|GSA|GSP|NESP|PHP1A|PHP1B|PHP1C|POH;GNAS complex locus;GNAS;GNAS complex locus

adenylate cyclase-stimulating G alpha protein|alternative gene product encoded by XL-exon|extra large alphas protein|guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1|guanine nucleotide regulatory protein|guanine nuc

20q13.3

protein-coding

The use of octreotide-LAR and cabergoline therapy has shown great promise in adults with acromegaly; however, the experience in pediatric patients has rarelybeen reported. We described a clinical course of a 15-year-old boy of McCune-Albright syndrome (MAS) with pituitary gigantism. At the age of 8 years, a growth hormone (GH) and prolactin (PRL) producing pituitary adenoma was diagnosed at our hospital. He also had multiple fibrous dysplasia, so that he was diagnosed as having MAS. The tumor was partially resected, and GNAS1 gene mutation (R201C)was identified in affected tissues. We introduced octreotide to suppress GH secretion (100 mug 2/day s.c). During therapy with octreotide, IGF-1 and GH levels could not be suppressed and the patient frequently complained of nausea from octreotide treatment. Therefore, the therapy was changed to monthly injections of octreotide-LAR at the age of 12.3 years and was partially effective. However, as defect of left visual field worsened due to progressive left optic canal stenosis, he underwent second neurological decompression of theleft optic nerve at 13.4 years of age. After surgery, in addition to octreotide-LAR, cabergoline (0.25 mg twice a month) was started. This regimen normalized serum levels of GH and IGF-1; however, he showed impaired glucose tolerance and gallstones at 15.7 years of age. Therefore, the dose of octreotide-LAR was reduced to 10 mg and the dose of cabergoline increased. This case demonstrated the difficulty of treating pituitary gigantism due to MAS. Theuse of octreotide-LAR and cabergoline should be considered even in pediatric patients; however, adverse events due to octreotide-LAR must be carefully examined.

BACKGROUND: Neuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiationin tumors frequently proceeds along the chromaffin lineage and that decreased oxygen (hypoxia) plays a role in this. Here we explore the utility of Neuro-Endocrine Secretory Protein 55 (NESP55), a novel member of the chromogranin family, as a marker for this process. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical analyses and in situ hybridizations were performed on human fetal tissues, mouse xenografts of human neuroblastoma cell lines, and on specimens of human neuroblastoma/ganglioneuroma. Effects of anaerobic exposure on gene expression by cultured neuroblastoma cells was analyzed with quantitative real-time PCR. Fetal sympathetic nervous system expression of NESP55 was shown to be specific for chromaffin cell types. In experimental and clinical neuroblastoma NESP55 immunoreactivity was specific for regions of chronic hypoxia. NESP55 expression also correlated strikingly with morphological evidence of differentiation and with other chromaffin-specific patterns of gene expression, including IGF2 and HIF2alpha. Anaerobic culture of five neuroblastoma cell linesresulted in an 18.9-fold mean up-regulation of NESP55. CONCLUSIONS/SIGNIFICANCE:The data confirms that chronic tumor hypoxia is a key microenvironmental factor for neuroblastoma cell differentiation, causing induction of chromaffin featuresand NESP55 provides a reliable marker for this neuronal to neuroendocrine transition. The hypoxia-induced phenotype is the predominant form of differentiation in stroma-poor tumors, while in stroma-rich tumors the chromaffin phenotype coexists with ganglion cell-like differentiation. The findings providenew insights into the biological diversity which is a striking feature of this group of tumors.

BACKGROUND: Autonomously functioning, "hot", thyroid nodules are not common in children and adolescents. Such nodules are not considered alarming because they are assumed to be benign adenomas. Herein, we present a 15-year-old girl with a papillary thyroid carcinoma of 3.5 cm in diameter, which was functionally autonomous and scintigraphically hot. PATIENT FINDINGS: The patient, initially referred to our Endocrine Unit because of a thyroid nodule, returned 6 months later for symptoms of hyperthyroidism. Hyperthyroidism was confirmed biochemically. Radioactive iodine ((131)I) thyroid scintigraphy was consistent with an autonomous thyroid nodule. As per guidelines, the patient underwent surgery and a pathological examination revealed papillary carcinoma, follicular variant. The excised nodule was examined for activating mutations of the thyrotropin receptor (TSHR), Gsalpha (GNAS1), H-RAS, N-RAS, K-RAS, and BRAF genes by direct sequencing. No mutations were found. Nevertheless, two combined nonfunctioning mutations were detected: a single-nucleotide polymorphism (SNP) of the TSHR gene, in exon 7, at codon 187 (AAT-->AAC, both encoding asparagine), and a SNP within exon 8 of the Gsalpha gene at codon 185 (ATC-->ATT, both encoding isoleucine). Both SNPs were also identified in the germline DNA of the patient. The same SNPs were sought in the parents and brother of our patient. Her father was heterozygous for the TSHR SNP, her mother heterozygous for the Gsalpha SNP, and her brother was wild type. CONCLUSIONS: This case demonstrates that the presence of hyperfunctioning thyroid nodule(s) does not rule out cancer and warrants careful evaluation, especially in childhood and adolescence to overlookmalignancy.

CONTEXT: pediatric adrenocortical tumors (ACTs) are rare and are frequently associated with tumor predisposition syndromes. Somatic GNAS1 mutations are associated with adrenocortical hyperplasia, but have not typically been reportedin ACTs. OBJECTIVE: We report on genetic and histopathological findings in a 3-month-old infant presenting with a unilateral cortisol-producing ACT with malignant features. METHODS: We performed a detailed clinical evaluation of the patient along with molecular genetic testing of genes associated with ACTs in both tumor tissue and peripheral lymphocytes. We also performed a histopathological analysis of the tumor tissue. RESULTS: The patient was found to have a p.R201C-activating mutation in exon 8 of the GNAS1 gene in adrenocorticaltumor tissue but not peripheral lymphocytes. This mutation is the characteristicgenetic change in McCune-Albright syndrome. In contrast to previously reported GNAS1-positive tumors characterized by bimodal diffuse and nodular adrenocortical hypertrophy, our patient had a single adrenocortical mass that showed features of malignancy, including areas of necrosis, microcystic degeneration, and venous and capsular microinvasion-changes that have been seen previously in Beckwith-Wiedemann syndrome. However, our patient did not have clinical featuresof Beckwith-Wiedemann syndrome. Further analysis revealed abnormal allele-specific hypomethylation of the KCNQ1OT1 gene in the tumor sample but notperipheral lymphocytes. CONCLUSION: This is a novel case of an activating GNAS1 mutation associated with an epigenetic alteration that may be related to adrenocortical tumorigenesis. Our findings may have implications in the molecular pathogenesis of pediatric ACTs.

Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptorinteracting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases.#CI- Copyright (c) 2013 S. Karger AG, Basel.