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HPAH represent less than 4% of PAH. Prevalence is estimated at < 1/million people.

HPAH develop usually in adults, and rarely in children; women are twice as likely as men to be affected. Usual age at diagnosis is mid thirties. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation.70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV).Rarely, clubbing and Raynaud phenomenon (mostly in females) have been observed. Hemoptysis has also been reported. HPAH patients have a severe clinical with less response to acute vasodilator challenge, lower cardiac index, and higher pulmonary vascular resistance. HPAH due to ACVRL1or TBX4gene mutations occurs more commonly in children with rapid progression and poor prognosis.

HPAH has been linked to mutations in BMPR2 ((2q33) in majority of cases. However, other genes implicated in HPAH have been described in few cases, and include ACVRL1 ((12q13)), KCNK3 (2p23),CAV1(7q31), TBX4 (17q21) and SMAD9(13q12) .

Patients displaying a sporadic PAH or a PAH occurring in a familial context, should be tested in priority for mutations in BMPR2 gene. If no mutations in BMPR2gene were identified in a patient displaying a familial form of PAH, mutations in all other PAH predisposing genes have to searched successively. All PAH predisposing genes are transmitted in an autosomal dominant manner with an incomplete penetrance. In the cases ofBMPR2 mutations the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers. Prenatal genetic testing and preimplantation diagnosis are considered in patients and asymptomatic relatives carriers of a mutation in PAH predisposing genes.