title: Somatic GPR101 Duplication Causing X-Linked Acrogigantism (XLAG)-Diagnosis and Management.
abstract: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance.
  
  
  
  A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64-369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality.
  
  
  
  Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Celia
authors.initials: C
authors.lastname: Rodd
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Maude
authors.initials: M
authors.lastname: Millette
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Donato
authors.initials: D
authors.lastname: Iacovazzo
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Stiles
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Sayka
authors.initials: S
authors.lastname: Barry
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Evanson
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bunce
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Jose
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Trouillas
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Sampson
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Pediatrics and Child Health (C.R.), University of Manitoba, Winnipeg MB R3E 0Z2, Canada; Department of Pediatrics (M.M.), Centre mère-enfant Soleil, Centre Hospitalier de l'Université de Quebec, QC G1V 4G2, Canada; Endocrinology (D.I., C.E.S., S.B., J.E., M.K.), Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Pathology (S.A.), McGill University, Montreal QC H4A 2J1, Canada; Molecular Genetics (R.C., B.B., S.E.), University of Exeter, Exeter EX4 4SB, United Kingdom; Institute of Medical Genetics (S.J., J.S.), School of Medicine, Cardiff University, Cardiff CF10 3XQ, United Kingdom; Centre de Pathologie Est (J.T.), Hospices Civils de Lyon, University of Lyon, 69622 Lyon, France; and Neuropathology (F.R.), University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000077465:Cabergoline; D002675:Child, Preschool; D004873:Ergolines / Q000627:therapeutic use; D020440:Gene Duplication; D005877:Gigantism / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics*; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008297:Male; D010902:Pituitary Gland / Q000000981:diagnostic imaging*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: D004873:Ergolines; C000594175:GPR101 protein, human; D043562:Receptors, G-Protein-Coupled; D019382:Human Growth Hormone; D000077465:Cabergoline; C406545:pegvisomant