Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

Autor: Iacovazzo D; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Caswell R; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK., Bunce B; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK., Jose S; Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK., Yuan B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA., Hernández-Ramírez LC; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, 20892, USA., Kapur S; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Caimari F; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Evanson J; Department of Radiology, Barts Health NHS Trust, London, EC1A 7BE, UK., Ferraù F; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Dang MN; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Gabrovska P; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK., Larkin SJ; Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 2JD, UK., Ansorge O; Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 2JD, UK., Rodd C; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, R3T 2 N2, Canada., Vance ML; Department of Endocrinology, University of Virginia, Charlottesville, 22908, USA., Ramírez-Renteria C; Endocrinology Service and Experimental Endocrinology Unit, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, UNAM, Mexico City, 06720, Mexico., Mercado M; Endocrinology Service and Experimental Endocrinology Unit, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, UNAM, Mexico City, 06720, Mexico., Goldstone AP; Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, W12 0HS, London, UK., Buchfelder M; Department of Neurosurgery, University of Duisburg-Essen, Essen, 45141, Germany., Burren CP; Department of Paediatric Endocrinology, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8HW, UK., Gurlek A; Department of Endocrinology and Metabolism, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey., Dutta P; Department of Endocrinology, PGIMER, Chandigarh, 160012, India., Choong CS; Department of Pediatric Endocrinology, Princess Margaret Hospital for Children, Subiaco, 6008, Australia., Cheetham T; Newcastle University c/o Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne, NE1 4LP, UK., Trivellin G; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, 20892, USA., Stratakis CA; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, 20892, USA., Lopes MB; Department of Pathology, University of Virginia, Charlottesville, 22908, USA., Grossman AB; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX1 2JD, UK., Trouillas J; Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, 69500, France., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.; Department of Pediatrics, Baylor College of Medicine Houston, Houston, TX, 77030, USA.; Human Genome Sequencing Center, Baylor College of Medicine Houston, Houston, TX, 77030, USA.; Texas Children's Hospital, Houston, TX, 77030, USA., Ellard S; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK., Sampson JR; Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK., Roncaroli F; Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, M13 9PL, UK., Korbonits M; Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK. m.korbonits@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2016 Jun 01; Vol. 4 (1), pp. 56. Date of Electronic Publication: 2016 Jun 01.
DOI: 10.1186/s40478-016-0328-1
Abstrakt: 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.
Databáze: MEDLINE