Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia.

BACKGROUND: Pulmonary arterial hypertension (PAH) has been linked to mutations in genes encoding two members of the transforming growth factor-beta family, BMPR2 and ALK1, the latter of which is also associated with hereditary haemorrhagic telangiectasia (HHT). Relatively little is known about the genetics of childhood PAH, or about the clinical features of PAH in young patients with an ALK1 mutation. METHODS AND RESULTS: Three individuals diagnosed with PAH at 4, 16 and 17 years of age were found on subsequent genetic screening to have non-synonymous mutations of ALK1. All probands met criteria for HHT, although two presented with PAH before HHT was diagnosed. Extended family history revealed relatives with HHT in all three kindreds, a presumptive family history of PAH in two, one with multiple family members dying from PAH at young ages. All three patients in this series had systemic or suprasystemic right ventricular pressure and significantly elevated pulmonary vascular resistance, initially not responsive to oxygen and/or inhaled nitric oxide. All patients had pulmonary arteriovenous malformations and systemic arterial desaturation. CONCLUSION: This report highlights ALK1 mutations associated with a variable PAH phenotype, including pulmonary arteriovenous malformations and severe PAH presenting early in life. Echocardiographic screening for elevated right ventricular pressure may be indicated in patients with HHT, particularly those with an identified ALK1 mutation. Clinical features or a family history of HHT should be elicited in children and adolescents with idiopathic PAH; ALK1 screening may be appropriate when such features are present.

Double outlet right ventricle: aetiologies and associations.

BACKGROUND: Double outlet right ventricle (DORV), a clinically significant congenital heart defect, occurs in 1-3% of individuals with congenital heart defects. In contrast to other major congenital heart defects, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV. We analysed reported cases in the medical literature to address these issues. METHODS: We queried the PubMed database using key words "double outlet right ventricle" and "DORV" for case reports, epidemiologic analyses and animal studies with this cardiac anomaly. The anatomic subtype of DORV was classified according to criteria of Van Praagh. RESULTS: Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11. DORV was reported in many uncommon or rare non-chromosomal syndromes. Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV. Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis. CONCLUSIONS: The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping.