Table 1.

Developmental lung diseases associated with pulmonary hypertension.

Developmental defect	Vascular pathology	Diagnosis and treatment
Alveolar capillary dysplasia (ACD) with or without misalignments of veins (MPV)	Reduction of alveolar capillaries, thickening of alveolar septal tissue, and failure of the capillaries to make contact with the alveolar epithelium. Familial cases occur. Genomic and genetic deletions of the FOX transcription factor gene cluster at 16p24.1 and inactivating point mutations of FOXF1 were identified	Usually diagnosed post mortem by histological examination. Positive family history? Genetic testing. Symptomatic treatment to decrease PVR (O2, iNO, ECMO), bilateral lung transplant
Bronchopulmonary dysplasia (BPD)	Pre- and postnatal impact of exogenous risk factors on a structural and functional immature lung lead to postnatal impairment of angiogenesis and alveolarization associated with abnormal vascular function (increased tone, altered reactivity, impaired metabolism) and structure (smooth muscle cell proliferation, altered extra cellular matrix structure)	Defined by criteria based on supplemental oxygen at 36 weeks postmenstrual age. Typical chest X-ray findings. Supportive treatment including respiratory support, O2, corticosteroids, in case of PH sildenafil, diuretics (hydrochlothiazide, spironolactone), and ERA might be considered
Congenital diaphragmatic hernia (CDH)	Developmental defect leading to severe vascular remodeling and rarefication of the vascular bed. The defect is associated with variable degrees of lung hypoplasia	Clinical and radiological diagnosis. Surgical repair. Supportive treatment involves ventilation with permissive hypercapnia, HFOV, surfactant, pre- or postnatal glucocorticoids without clear benefit. Early repair on ECMO might be beneficial
Lung hypoplasia (primary and secondary)	Genetic abnormalities, severe reduction in amniotic fluid leading to reduced prenatal alveolar and vascular development. Secondary to congenital pulmonary malformations (CPAM, etc.)	Diagnosis by HR-CT depending on underlying cause. Supportive treatment (consider mechanical ventilation including HFOV, iNO, and surfactant). PH-specific medications often with only minimal effect
Pulmonary interstitial glycogenosis (PIG)	Rare non-lethal pediatric form of interstitial lung disease, possible male predominance. Infants present with respiratory distress	Diffuse interstitial infiltrates on chest radiography. Lung biopsy with histological cytoplasmic accumulation of glycogen in interstitial cells and associated lung growth abnormalities. Corticosteroids have been used with various efficacies. Spontaneous regression in some cases
Pulmonary alveolar proteinosis (PAP)	Rare lung disease in which abnormal accumulation of surfactant occurs within the alveoli, interfering with gas exchange and affecting lung growth. Possible cause anti-GM-CSF autoantibodies. GM-CSF receptor mutations in hereditary PAP	PAS-positive dense bodies in the distal airways on lung biopsy. Supportive treatment including repeated bronchioalveolar lavage and lung transplantation. GM-CSF might be considered in autoimmune PAP. Transplantation of macrophage progenitors in hereditary PAP (experimental)
Pulmonary lymphangiectasia	Rare developmental pulmonary disorder characterized by pulmonary subpleural, interlobar, perivascular and peribronchial lymphatic dilatation	Pleural (chylous) effusions with or without generalized edema. Radiologic progression of generalized hazy infiltrates in the neonatal period to a more perihilar interstitial pattern with hyperinflation (X-ray, CT, MRI). Lymphangiectasia on lung biopsy (periartierial, subpleural, interlobar). Supportive and symptomatic treatment (respiratory support, drainage). MCT nutrition. Octreotide and antiplasmin (experimental)
Surfactant protein (SP) abnormalities (SP-B and SP-C deficiency, ATP-binding cassette A3 mutation, thyroid transcription factor 1/Nkx2.1 homeobox mutation)	Genetic inheritance of surfactant deficiency leading to impaired lung development	Diagnosis by genetic testing. Might present as interstitial lung disease on chest imaging. Surfactant replacement has only temporary effect, lung transplantation. Supportive treatment. Corticosteroids might show some effect. Hydroxychloroquine (experimental, SP-C deficiency)