@article {113, title = {Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.}, journal = {Endocrine}, volume = {51}, year = {2016}, month = {2016 Feb}, pages = {236-44}, abstract = {

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 {\texttimes} 23.9 {\texttimes} 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 {\texttimes} 58.1 {\texttimes} 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

}, keywords = {Adenoma, Child, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Pituitary Neoplasms, Treatment Outcome}, issn = {1559-0100}, doi = {10.1007/s12020-015-0804-6}, author = {Naves, Luciana A and Daly, Adrian F and Dias, Luiz Augusto and Yuan, Bo and Zakir, Juliano Coelho Oliveira and Barra, Gustavo Barcellos and Palmeira, Leonor and Villa, Chiara and Trivellin, Giampaolo and J{\'u}nior, Armindo Jreige and Neto, Flor{\^e}ncio Figueiredo Cavalcante and Liu, Pengfei and Pellegata, Natalia S and Stratakis, Constantine A and Lupski, James R and Beckers, Albert} } @article {50, title = {Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.}, journal = {Acta Neuropathol Commun}, volume = {4}, year = {2016}, month = {2016 06 01}, pages = {56}, abstract = {

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8~\%) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101\&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial~acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Female, Gene Duplication, Germ-Line Mutation, Gigantism, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Pituitary Neoplasms, Receptors, G-Protein-Coupled, Treatment Outcome, Young Adult}, issn = {2051-5960}, doi = {10.1186/s40478-016-0328-1}, author = {Iacovazzo, Donato and Caswell, Richard and Bunce, Benjamin and Jose, Sian and Yuan, Bo and Hern{\'a}ndez-Ram{\'\i}rez, Laura C and Kapur, Sonal and Caimari, Francisca and Evanson, Jane and Ferra{\`u}, Francesco and Dang, Mary N and Gabrovska, Plamena and Larkin, Sarah J and Ansorge, Olaf and Rodd, Celia and Vance, Mary L and Ram{\'\i}rez-Renteria, Claudia and Mercado, Mois{\'e}s and Goldstone, Anthony P and Buchfelder, Michael and Burren, Christine P and Gurlek, Alper and Dutta, Pinaki and Choong, Catherine S and Cheetham, Timothy and Trivellin, Giampaolo and Stratakis, Constantine A and Lopes, Maria-Beatriz and Grossman, Ashley B and Trouillas, Jacqueline and Lupski, James R and Ellard, Sian and Sampson, Julian R and Roncaroli, Federico and Korbonits, M{\'a}rta} } @article {202, title = {Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.}, journal = {Int J Cancer}, volume = {137}, year = {2015}, month = {2015 Jul 15}, pages = {320-31}, abstract = {

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5\% (4/266) of all patients, 4\% (3/77) of all familial cases and 7\% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.

}, keywords = {Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Child, Colorectal Neoplasms, DNA Polymerase II, DNA-Directed DNA Polymerase, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Isoenzymes, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Phospholipase D, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult}, issn = {1097-0215}, doi = {10.1002/ijc.29396}, author = {Spier, Isabel and Holzapfel, Stefanie and Altm{\"u}ller, Janine and Zhao, Bixiao and Horpaopan, Sukanya and Vogt, Stefanie and Chen, Sophia and Morak, Monika and Raeder, Susanne and Kayser, Katrin and Stienen, Dietlinde and Adam, Ronja and N{\"u}rnberg, Peter and Plotz, Guido and Holinski-Feder, Elke and Lifton, Richard P and Thiele, Holger and Hoffmann, Per and Steinke, Verena and Aretz, Stefan} } @article {189, title = {X-linked acrogigantism syndrome: clinical profile and therapeutic responses.}, journal = {Endocr Relat Cancer}, volume = {22}, year = {2015}, month = {2015 Jun}, pages = {353-67}, abstract = {

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Chromosomes, Human, X, Female, Gigantism, Humans, Infant, Male, Pituitary Neoplasms, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-15-0038}, author = {Beckers, Albert and Lodish, Maya Beth and Trivellin, Giampaolo and Rostomyan, Liliya and Lee, Misu and Faucz, Fabio R and Yuan, Bo and Choong, Catherine S and Caberg, Jean-Hubert and Verrua, Elisa and Naves, Luciana Ansaneli and Cheetham, Tim D and Young, Jacques and Lysy, Philippe A and Petrossians, Patrick and Cotterill, Andrew and Shah, Nalini Samir and Metzger, Daniel and Castermans, Emilie and Ambrosio, Maria Rosaria and Villa, Chiara and Strebkova, Natalia and Mazerkina, Nadia and Gaillard, St{\'e}phan and Barra, Gustavo Barcelos and Casulari, Luis Augusto and Neggers, Sebastian J and Salvatori, Roberto and Jaffrain-Rea, Marie-Lise and Zacharin, Margaret and Santamaria, Beatriz Lecumberri and Zacharieva, Sabina and Lim, Ee Mun and Mantovani, Giovanna and Zatelli, Maria Chaira and Collins, Michael T and Bonneville, Jean-Fran{\c c}ois and Quezado, Martha and Chittiboina, Prashant and Oldfield, Edward H and Bours, Vincent and Liu, Pengfei and W de Herder, Wouter and Pellegata, Natalia and Lupski, James R and Daly, Adrian F and Stratakis, Constantine A} } @article {326, title = {SEQCHIP: a powerful method to integrate sequence and genotype data for the detection of rare variant associations.}, journal = {Bioinformatics}, volume = {28}, year = {2012}, month = {2012 Jul 01}, pages = {1745-51}, abstract = {

MOTIVATION: Next-generation sequencing greatly increases the capacity to detect rare-variant complex-trait associations. However, it is still expensive to sequence a large number of samples and therefore often small datasets are used. Given cost constraints, a potentially more powerful two-step strategy is to sequence a subset of the sample to discover variants, and genotype the identified variants in the remaining sample. If only cases are sequenced, directly combining sequence and genotype data will lead to inflated type-I errors in rare-variant association analysis. Although several methods have been developed to correct for the bias, they are either underpowered or theoretically invalid. We proposed a new method SEQCHIP to integrate genotype and sequence data, which can be used with most existing rare-variant tests.

RESULTS: It is demonstrated using both simulated and real datasets that the SEQCHIP method has controlled type-I errors, and is substantially more powerful than all other currently available methods.

AVAILABILITY: SEQCHIP is implemented in an R-Package and is available at http://linkage.rockefeller.edu/suzanne/seqchip/Seqchip.html.

}, keywords = {Adenoma, Case-Control Studies, Colorectal Neoplasms, Genetic Association Studies, Genetic Variation, Genotype, Humans, Phenotype, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/bts263}, author = {Liu, Dajiang J and Leal, Suzanne M} }