title: Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome.
abstract: BACKGROUND
  Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues.
  
  
  METHODS
  Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases.
  
  
  RESULTS
  HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD.
  
  
  CONCLUSIONS
  We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.
authors.affiliation: Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.|Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.|Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Hendrica
authors.initials: H
authors.lastname: Belge
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.affiliation: Division of Nephrology, Grand hôpital de Charleroi, Gilly, Belgium.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cambier
authors.affiliation: Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Benoit
authors.affiliation: Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.|Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Johann
authors.initials: J
authors.lastname: Morelle
authors.affiliation: Division of Nephrology, Centre hospitalier de Valenciennes, Valenciennes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bloch
authors.affiliation: Division of Nephrology, Centre hospitalier de Valenciennes, Valenciennes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vanhille
authors.affiliation: Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.|Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pirson
authors.affiliation: Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium.|Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Demoulin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003638:Deafness / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D006801:Humans; D007011:Hypoparathyroidism / Q000175:diagnosis* / Q000235:genetics; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D012189:Retrospective Studies; D013577:Syndrome; D014564:Urogenital Abnormalities / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human
keywords: GATA-3; hypoparathyroidism, deafness and renal dysplasia syndrome; inherited kidney disease