title: Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic.
  
  
  RESULTS
  We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n=2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations.
  
  
  CONCLUSIONS
  The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.
authors.affiliation: Division of Medical Genetics, University of Leicester, Leicester, UK.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Harrison
authors.forename: Rolf
authors.initials: R
authors.lastname: Berger
authors.forename: Sheila G
authors.initials: SG
authors.lastname: Haworth
authors.forename: Robert
authors.initials: R
authors.lastname: Tulloh
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Mache
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics* / Q000502:physiology; D030301:Activin Receptors, Type II; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution; D015703:Antigens, CD; D052006:Bone Morphogenetic Protein Receptors, Type II; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D000071063:Endoglin; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology
chemical_list: D015703:Antigens, CD; D018389:Codon, Nonsense; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II