title: PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.
abstract: The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Trochet
authors.forename: Louise M
authors.initials: LM
authors.lastname: O'Brien
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.forename: Ha
authors.initials: H
authors.lastname: Trang
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.forename: Béatrice
authors.initials: B
authors.lastname: Laudier
authors.forename: Pär-Johan
authors.initials: PJ
authors.lastname: Svensson
authors.forename: Sabine
authors.initials: S
authors.lastname: Uhrig
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Stephan
authors.initials: S
authors.lastname: Niemann
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Claude
authors.initials: C
authors.lastname: Gaultier
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000150:complications / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000150:complications / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009030:Mosaicism; D020125:Mutation, Missense; D009423:Nervous System Neoplasms / Q000150:complications / Q000235:genetics*; D011247:Pregnancy; D012307:Risk Factors; D020182:Sleep Apnea, Central / Q000150:complications / Q000151:congenital* / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors