Smoot L B, Obler D, McElhinney D B, Boardman K, Wu B-L, Lip V, Mullen M P
Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Arch Dis Child. 2009 Jul;94(7):506-11. doi: 10.1136/adc.2007.133082. Epub 2009 Apr 8.
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.
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.
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.
肺动脉高压（PAH）与编码转化生长因子-β家族两个成员的基因突变有关，即骨形态发生蛋白受体2（BMPR2）和激活素受体样激酶1（ALK1），后者也与遗传性出血性毛细血管扩张症（HHT）相关。关于儿童PAH的遗传学，以及携带ALK1突变的年轻患者PAH的临床特征，我们了解得相对较少。
在随后的基因筛查中发现，三名分别于4岁、16岁和17岁被诊断为PAH的个体存在ALK1的非同义突变。所有先证者均符合HHT的标准，尽管其中两名在HHT被诊断之前就已出现PAH。详细的家族史显示，所有三个家族中都有亲属患有HHT，两个家族有PAH的推测家族史，其中一个家族有多名家庭成员在年轻时死于PAH。该系列中的所有三名患者均有体循环或超体循环右心室压力以及显著升高的肺血管阻力，最初对氧气和/或吸入一氧化氮无反应。所有患者均有肺动静脉畸形和体循环动脉血氧饱和度降低。
本报告强调了与可变PAH表型相关的ALK1突变，包括肺动静脉畸形和早年出现的严重PAH。对于HHT患者，尤其是那些已鉴定出ALK1突变的患者，可能需要进行超声心动图筛查以检测右心室压力升高。对于特发性PAH的儿童和青少年，应了解其HHT的临床特征或家族史；当出现此类特征时，ALK1筛查可能是合适的。
