HDR syndrome: Large cohort and systematic review.

Laurence Heidet, Stanislas Lyonnet, Nicolas Rive Le Gouard, Valentin Lafond-Rive, Laurence Jonard, Natalie Loundon, Sophie Achard, Isabelle Mosnier, Frederic Brioude, Margaux Serey Gaut, Sandrine Marlin

Journal: Clinical genetics 2024;106(5):564-573

PMID: 38940299

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Abstract

HDR syndrome is a rare disease characterized by hypoparathyroidism, deafness, and renal dysplasia. An autosomal dominant disease caused by heterozygous pathogenic GATA3 variants, the penetrance of each associated condition is variable. Literature reviews have provided some answers, but many questions remain, in particular what the relationship is between genotype and phenotype. The current study examines 28 patients with HDR syndrome combined with an exhaustive review of the literature. Some conditions such as hearing loss are almost always present, while others described as rare initially, do not seem to be so rare after all (genital malformations and basal ganglia calcifications). By modeling pathogenic GATA3 variants found in HDR syndrome, we found that missense variations appear to always be located in the same area (close to the two Zinc Finger domain). We describe new pathogenic GATA3 variants, of which some seem to always be associated with certain conditions. Many audiograms were studied to establish a typical audiometric profile associated with a phenotype in HDR. As mentioned in the literature, hearing function should always be assessed as early as possible and follow up of patients with HDR syndrome should include monitoring of parathyroid function and vesicoureteral reflux in order to prevent complications.

Address: Centre de Référence «Surdités Génétiques», Fédération de Médecine Génomique; Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; UF de Génomique Chromosomique, Département de Génétique médicale, Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France.; Laboratory of Embryology and Genetics of Malformations, Imagine Institute, INSERM UMR 1163, Université de Paris Cité, Paris, France.; Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.; Centre de Référence «Surdités Génétiques», Fédération de Médecine Génomique; Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; Centre de Recherche en Audiologie (CREA), Hôpital Necker-Enfants Malades, AP-HP, Paris, France.; Service d'ORL Pédiatrique et de Chirurgie Cervico-Faciale, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; Unité Fonctionnelle implants auditifs, Centre Référent Implant Cochléaire Adulte Ile de France, Centre Constitutif Maladies rares, Surdités génétiques de l'adulte, Hôpital Pitié-Salpetrière, AP-HP, Sorbonne Université, Paris, France.; Laboratory of Embryology and Genetics of Malformations, Imagine Institute, INSERM UMR 1163, Université de Paris Cité, Paris, France.; Explorations Fonctionnelles Endocriniennes-Biologie Moléculaire, Hôpital des Enfants Armand Trousseau, AP-HP, Sorbonne Université, Paris, France.; Centre de Référence «Surdités Génétiques», Fédération de Médecine Génomique; Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; Centre de Recherche en Audiologie (CREA), Hôpital Necker-Enfants Malades, AP-HP, Paris, France.; Centre de Référence «Surdités Génétiques», Fédération de Médecine Génomique; Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Paris, France.; Laboratory of Embryology and Genetics of Malformations, Imagine Institute, INSERM UMR 1163, Université de Paris Cité, Paris, France.; Centre de Recherche en Audiologie (CREA), Hôpital Necker-Enfants Malades, AP-HP, Paris, France.

DOI: 10.1111/cge.14583

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MeSH Terms: Humans, Hypoparathyroidism, GATA3 Transcription Factor, Phenotype, Male, Female, Hearing Loss, Sensorineural, Genetic Association Studies, Nephrosis, Child, Genetic Predisposition to Disease, Mutation, Child, Preschool, Cohort Studies