Alveolar capillary dysplasia

Alveolar capillary dysplasia (ACD) is a rare, congenital diffuse lung disease characterized by abnormal blood vessels in the lungs that cause highly elevated pulmonary blood pressure and an inability to effectively oxygenate and remove carbon dioxide from the blood. ACD typically presents in newborn babies within hours of birth as rapid and labored breathing, blue-colored lips or skin, quickly leading to respiratory failure and death. Atypical forms of ACD have been reported with initially milder symptoms and survival of many months before the onset of respiratory failure or lung transplantation. Most cases of ACD are caused by mutations affecting the gene FOXF1 or its nearby enhancer region. Exactly how these mutations lead to abnormal lung development is unknown. Abnormal lung development is characterized by thickened alveolar interstitium, misplacement of pulmonary capillaries away from the alveolar surface, and fewer capillaries overall. This results in poor gas exchange and pulmonary hypertension. There is evidence for connections between pulmonary arteries and systemic vessels, which would additionally contribute to poor blood oxygenation. ACD is typically diagnosed by examination of lung tissue under a microscope, either from lung biopsy or an autopsy. The characteristic findings of misplaced pulmonary veins adjacent to pulmonary arteries, and abnormal alveolar and capillary development confirm the diagnosis. FOXF1 genetic testing is also available, which can confirm the diagnosis without invasive testing. There are no effective treatments for severe ACD. Standard therapy, which includes mechanical ventilation, pulmonary vasodilators, and possibly ECMO, provide only temporary improvement in symptoms with disease progression returning within hours. For babies with atypical ACD, response to medical therapy is more sustained, lasting for several months. For those that can be stabilized, definitive treatment is bilateral lung transplantation. ACD is a rare disease. About 100 cases have been reported. The first case was reported in 1981. ACD is a congenital disease whose symptoms appear within hours to days after birth. Babies with ACD usually have no symptoms at the time of birth, but soon after will begin to breathe rapidly, showing increased work of breathing, and may have blue discoloration around the lips, arms, or legs, especially when feeding or crying. If an echocardiogram is performed, marked thickening of the right ventricle will be seen, resulting from highly elevated pulmonary blood pressure. ACD is generally resistant to treatment. Babies who have persistent symptoms that are poorly relieved by standard therapies for neonatal pulmonary hypertension is commonly observed in ACD. Atypical forms of ACD have been reported with only mildly rapid breathing shortly after birth. They may present with the above symptoms of ACD at several months of age. Their symptoms may improve with standard pulmonary hypertension therapies for weeks to months before symptoms return. Babies born with ACD usually have other congenital abnormalities affecting the heart, the intestines, urinary system, or genitals. Most cases of ACD are caused by deletions or point mutations involving the gene FOXF1 on chromosome 16 or an area near the FOXF1 gene that regulates its expression. ACD is an autosomal dominant disorder, meaning only one disease-causing mutation affecting FOXF1 or its regulator region is needed to cause ACD. Evidence strongly suggests that the FOXF1 regulatory region is imprinted, which might affect disease severity and may permit some to carry the disease with few or no symptoms.