title: A Girl With Beckwith-Wiedemann Syndrome and Pseudohypoparathyroidism Type 1B Due to Multiple Imprinting Defects.
abstract: BACKGROUND
  Several patients with Beckwith-Wiedemann Syndrome (BWS) with multiple imprinting defects found by genetic analysis have been described. However, only two cases have been described with both genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects.
  
  
  METHODS
  The girl in this case presented at the age of 6 months with morbid obesity (body mass index, +7.5 SDS) and a large umbilical hernia. Genetic analysis showed BWS (hypomethylation of the KCNQ1OT1 gene). Calcium homeostasis was normal, and she had no signs of Albright hereditary osteodystrophy. At the age of 10 years, she presented with fatigue, and laboratory analyses showed marked hypocalcemia with signs of PTH resistance, but without evidence for Albright hereditary osteodystrophy, thus suggesting pseudohypoparathyroidism type 1B. Consistent with this diagnosis, methylation analysis of the GNAS complex revealed hypomethylation (about 20%) of the GNAS exon 1A, NESPAS, and GNASXL loci and hypermethylation (100% methylation) of the NESP locus.
  
  
  CONCLUSIONS
  Imprinting defects at several different loci can occur in some patients, thus causing multiple different diseases. Symptoms of pseudohypoparathyroidism type 1B may be absent at diagnosis of BWS, yet prolonged subclinical hypocalcemia and/or hyperphosphatemia can have negative consequences (eg, intracerebral calcifications, myocardial dysfunction). We therefore suggest that patients with an imprinting disorder should be monitored for elevations in PTH, and epigenetic analysis of the GNAS complex locus should be considered.
authors.affiliation: Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Laura J H
authors.initials: LJ
authors.lastname: Sonneveld
authors.affiliation: Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: M Claire
authors.initials: MC
authors.lastname: Woltering
authors.affiliation: Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.affiliation: Department of Pediatrics (B.B., L.J.H.S., M.C.W.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; Department of Clinical Genetics (H.B.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002864:Chromogranins; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D018392:Genomic Imprinting; D006554:Hernia, Umbilical / Q000209:etiology; D006801:Humans; D054559:Hyperphosphatemia / Q000209:etiology; D006996:Hypocalcemia / Q000209:etiology; D007223:Infant; D063766:Pediatric Obesity / Q000209:etiology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011547:Pseudohypoparathyroidism / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016372:RNA, Antisense / Q000378:metabolism
chemical_list: D002864:Chromogranins; C485621:KCNQ1OT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated; D016372:RNA, Antisense; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs