title: Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene.
abstract: BACKGROUND
  Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder resulting from mutations in the PHOX2B gene located on chromosome 4p12.3, characterized by hypoventilation secondary to missing responses to both hypercapnia and hypoxia.
  
  
  METHODS
  Proband. A girl, hospitalised 5 times for respiratory failure from 6 weeks old, presented at 4 years of age severe cyanosis related to pneumonia. Tracheostomy was done, and she was discharged home using a portable positive pressure ventilator during sleep. Proband's father: The father was retrospectively found out to suffer from severe headache and excessive daytime sleepiness. Molecular genetic evaluation of PHOX2B gene was performed and casual polyalanine repeat expansion mutation c.741_755dup15 in exon 3 was found both in proband and her father in heterozygous form. The proband's grandmother died of respiratory failure after administration of benzodiazepine at the age of fifty years. Considering the grandmother's history, she is highly suspected of having had CCHS as well.
  
  
  CONCLUSIONS
  Repeated respiratory failure of girl was explained by PHOX2B mutation and Ondina curse. Proband´s father has incompletely penetrated PHOX2B heterozygous mutation as well and proband´s grandmother died probably from the consequences of drug interaction with PHOX2B mutated background as well. Both daughter and father currently require overnight mechanical ventilatory support. Although most PHOX2B mutations occur de novo, our case is a rare three generation family affected by autosomal dominant inheritance with incomplete penetrance manifested as the late-form of CCHS and proven PHOX2B mutation in two generations.
authors.affiliation: Department of Paediatrics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Klaskova
authors.affiliation: Institute of Molecular and Translational Medicine, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Drabek
authors.affiliation: Department of Respiratory Medicine, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Milada
authors.initials: M
authors.lastname: Hobzova
authors.affiliation: Department of Paediatrics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Vratislav
authors.initials: V
authors.lastname: Smolka
authors.affiliation: Department of Paediatrics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Seda
authors.affiliation: Center of Prenatal Diagnosis U.S.G.POL, s. r. o., Olomouc, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Hyjanek
authors.affiliation: Institute of Molecular and Translational Medicine, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Slavkovsky
authors.affiliation: Institute of Molecular and Translational Medicine, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Stranska
authors.affiliation: Department of Medical Genetics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Prochazka
mesh_terms: D002675:Child, Preschool; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics; D020182:Sleep Apnea, Central / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine
keywords: PHOX2B gene; congenital central hypoventilation syndrome; late-onset form; respiratory failure