title: Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.
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.
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Donato
authors.initials: D
authors.lastname: Iacovazzo
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bunce
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Jose
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Hernández-Ramírez
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Sonal
authors.initials: S
authors.lastname: Kapur
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Francisca
authors.initials: F
authors.lastname: Caimari
authors.affiliation: Department of Radiology, Barts Health NHS Trust, London, EC1A 7BE, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Evanson
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferraù
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Dang
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK.
authors.forename: Plamena
authors.initials: P
authors.lastname: Gabrovska
authors.affiliation: Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 2JD, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Larkin
authors.affiliation: Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 2JD, UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, R3T 2 N2, Canada.
authors.forename: Celia
authors.initials: C
authors.lastname: Rodd
authors.affiliation: Department of Endocrinology, University of Virginia, Charlottesville, 22908, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Vance
authors.affiliation: Endocrinology Service and Experimental Endocrinology Unit, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, UNAM, Mexico City, 06720, Mexico.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ramírez-Renteria
authors.affiliation: Endocrinology Service and Experimental Endocrinology Unit, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, UNAM, Mexico City, 06720, Mexico.
authors.forename: Moisés
authors.initials: M
authors.lastname: Mercado
authors.affiliation: Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, W12 0HS, London, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Goldstone
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Essen, 45141, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Department of Paediatric Endocrinology, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8HW, UK.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Burren
authors.affiliation: Department of Endocrinology and Metabolism, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey.
authors.forename: Alper
authors.initials: A
authors.lastname: Gurlek
authors.affiliation: Department of Endocrinology, PGIMER, Chandigarh, 160012, India.
authors.forename: Pinaki
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Department of Pediatric Endocrinology, Princess Margaret Hospital for Children, Subiaco, 6008, Australia.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Choong
authors.affiliation: Newcastle University c/o Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne, NE1 4LP, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cheetham
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, 20892, USA.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, 20892, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, 22908, USA.
authors.forename: Maria-Beatriz
authors.initials: MB
authors.lastname: Lopes
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX1 2JD, UK.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.affiliation: Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, 69500, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Trouillas
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Centre for Endocrinology, Barts and The London School of Medicine, London, EC1M 6BQ, UK. m.korbonits@qmul.ac.uk.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000172:Acromegaly / Q000150:complications / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D020440:Gene Duplication; D018095:Germ-Line Mutation; D005877:Gigantism / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D010911:Pituitary Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000594175:GPR101 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C103265:aryl hydrocarbon receptor-interacting protein
keywords: CNV mutation; GPR101; Gigantism; Pituitary; XLAG