Congenital Alveolar Capillary Dysplasia Research Articles

Congenital interstitial lung diseases: What the anesthesiologist needs to know.

Congenital interstitial lung diseases can affect both adults and children. Pediatric congenital interstitial lung diseases generally carry high risk for morbidly and mortality and include congenital alveolar capillary dysplasia with misalignment of pulmonary veins, congenital alveolar dysplasia, acinar dysplasia, congenital pulmonary lymphangiectasis, diffuse pulmonary lymphangiomatosis, neuroendocrine cell hyperplasia of infancy, pulmonary hemosiderosis, pulmonary alveolar proteinosis, and pulmonary interstitial glycogenosis. Given their usual non-specific clinical presentation, they are frequently misdiagnosed and recognized late, particularly in children who have been apparently healthy for several years (eg, diffuse pulmonary lymphangiomatosis). Some diseases have a very poor prognosis, whereas others have a benign course with appropriate treatment. The current manuscript reviews congenital interstitial lung diseases that typically affect neonates and young children and may be encountered by the pediatric anesthesiologist.

Congenital Alveolar Capillary Dysplasia and New Associations: A Case Series with a Report of New Associations and Literature Review

Congenital Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD-MPV) is a rare and a lethal cause of neonatal respiratory failure and severe hypoxemia, secondary to persistent pulmonary hypertension (PPHN). It is refractory to all standard medical therapies including High Frequency Ventilation (HFV), inspired Nitric Oxide (iNO), and Extracorporeal Membrane Oxygenation (ECMO). According to the Online Mendelian Inheritance in Man (OMIM), it is caused by heterozygous mutation in the FOXF1 gene on chromosome 16q24. Newer study has suggested that two other genes can cause (ESRP1) or function as modifiers (PLXNB2) of the ACDMPV phenotype. Most reported cases of ACD-MPV had multiple congenital non-lethal anomalies. Here, we report six cases of autopsyproven ACD-MPV from a single institution during a seven year period. Medical information was obtained from the electronic medical records. Pathology slides were read and confirmed by pediatric pathologists of two different university hospitals. Novel findings include an association with previously undescribed congenital anomalies and a sibling with congenital alveolar dysplasia without capillary dysplasia. All patients presented in the newborn period, with severe hypoxemia and echocardiogram (Echo)-confirmed PPHN. The vast majority of ACDMPV cases continue to be diagnosed by autopsy, after the infants have been subjected to extreme degree of intensive care. ACD-MPV needs to be considered as a diagnostic possibility when ECMO fails.

MG-117 Chromosome microarray and non-coding DNA copy number variants – a case of alveolar capillary dysplasia at FOXF1 locus

Background Chromosome microarray (CMA) analysis typically focuses on coding DNA (RefSeq and OMIM genes). Although non-coding intergenic and intronic variants may be critical in disease pathogenesis, copy number variants (CNV) in these regions are usually interpreted as variants of unknown clinical significance. Objective We present a case of a lethal neonatal condition in which the pathogenic CNV lies in a distant, upstream non-coding region. Design/method Chromosome microarray was performed in a newborn female with a prenatal diagnosis of AVSD, who presented with severe neonatal respiratory distress out of keeping with her cardiac issues. Results CMA analysis revealed a de novo 1.5 Mb deletion at 16q24.1. None of the 16 RefSeq genes mapping within the deleted region appeared causative. However, this deletion is located 157 kb upstream of FOXF1, a gene responsible for congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). The observed deletion encompasses a recently characterised distant regulator/enhancer of the FOXF1 gene. The pathological diagnosis of ACDMPV was confirmed posthumously. Conclusion This case highlights the importance of relevant clinical information for CMA interpretation, and the importance of the analysis of flanking regions if an identified CNV does not initially appear pathogenic. As our knowledge of epigenetics and the genomic landscape improves, an increasing number of non-coding CNVs are poised to gain clinical relevance. We suggest that a database of well-characterised non-coding regulatory regions be developed and incorporated into CMA analysis.

Long survival of congenital alveolar capillary dysplasia patient with NO inhalation and epoprostenol: Effect of sildenafil, beraprost and bosentan

The case is described herein of a patient with alveolar capillary dysplasia with double-outlet right ventricle and duodenal atresia who survived for a remarkably long time. The newborn girl was born at a gestational age of 36 weeks and weighed 1926 g. One min after delivery the Apgar score was 4. The patient had persistent pulmonary hypertension (PH) and needed nitric oxide inhalation and i.v. epoprostenol all through her life. Although other oral medications for PH were tried, they could not be used in practice because of gastrointestinal complications. The patient died on the 237 th day of life as a result of worsening PH associated with infection.

Aortic Coarctation Associated with Alveolar Capillary Dysplasia and Misalignment of the Pulmonary Veins

After surgical repair of an aortic coarctation a term infant presented with severe pulmonary hypertension and cyanosis unresponsive to treatment including extracorporeal membrane oxygenation. The atypical clinical course became apparent once the accompanying diagnosis of congenital alveolar capillary dysplasia with misalignment of the pulmonary veins had been established at autopsy. In infants with congenital heart defects and with refractory pulmonary hypertension unexplainable on anatomic findings, a lung biopsy at the time of cardiac repair should be considered to avoid further therapies that would not alter the uniformly fatal course of this rare lung disorder.

CONGENITAL ALVEOLAR CAPILLARY DYSPLASIA AND ASSOCIATED GASTROINTESTINAL ANOMALIES

Congenital alveolar capillary dysplasia is a rare cause of irreversible pulmonary hypertension with 100% mortality. We present three cases of congenital alveolar capillary dysplasia with associated gastrointestinal abnormalities. Three full-term neonates presented with pulmonary hypertension needing ventilatory support by oscillation. Of the three, two neonates subsequently needed extracorporeal membrane oxygenation. Abdominal distension associated with bilious aspirates was the gastrointestinal manifestation. One child had duodenal atresia and anorectal anomaly, one with intestinal malrotation and the other with a rare combination of intestinal malrotaion and total colonic Hirschsprung's disease. All three infants succumbed to pulmonary hypertension at mean age 34 days. The etiopathogenesis and pathology of this condition are discussed with a comprehensive review of the literature.

Persistent pulmonary hypertension of newborn due to congenital capillary alveolar dysplasia

Congenital alveolar capillary dysplasia is a rare and fatal cause of pulmonary hypertension in neonates. We report on a term baby with severe pulmonary hypertension unresponsive to high-frequency ventilation and nitric oxide. A diagnosis of alveolar capillary dysplasia was established on autopsy. We review the literature regarding pathophysiology, clinical presentations, associated malformations, and treatment trials.

Expanding the phenotype of alveolar capillary dysplasia (ACD)

To define the phenotype of congenital alveolar capillary dysplasia (ACD) as a first step toward mapping the responsible gene(s). Analysis of pathology reports and microscopic slides of 23 subjects with ACD and sequence analysis of two candidate genes. Our review of the pre- and postmortem records delineates both the natural history of this condition and the associated anomalies. Our collection of families corroborates the likely autosomal recessive nature of this condition in some families and provides additional data for genetic and prenatal counseling. Anomalies of many organ systems were detected either in the prenatal period or during the hospital course. However, some major anomalies were not detected until postmortem examination. Left-right asymmetry and gastrointestinal malrotation emerge as important, previously recognized but underappreciated phenotypic features of ACD. Finally, we used sequence analysis to exclude mutations in the coding region of two candidate genes, bone morphogenetic protein type II receptor (BMPR2) and endothelial monocyte-activating polypeptide II (EMAP II), as candidates for ACD. Understanding the clinical spectrum of ACD and the cloning of an "ACD gene" both have implications for counseling, for prenatal testing, and for understanding the molecular pathophysiology of ACD and other organ malformations that are associated with this condition.

Revisiting alveolar capillary dysplasia

Expanding the phenotype of alveolar capillary dysplasia (ACD)The Journal of PediatricsVol. 145Issue 5PreviewTo define the phenotype of congenital alveolar capillary dysplasia (ACD) as a first step toward mapping the responsible gene(s). Full-Text PDF

Bilateral tibial agenesis with ectrodactyly (OMIM 119100): Further evidence for autosomal recessive inheritance

We present further evidence for autosomal recessive inheritance of the bilateral tibial agenesis/ectrodactyly dysostosis. A consanguineous Turkish couple gave birth to three children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia and also had tibial agenesis and ectrodactyly. A second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of three unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of tibiae and symmetrical ectrodactyly of hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirms the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia. © 2001 Wiley-Liss, Inc.

Bilateral tibial agenesis with ectrodactyly (OMIM 119100): Further evidence for autosomal recessive inheritance

We present further evidence for autosomal recessive inheritance of the bilateral tibial agenesis/ectrodactyly dysostosis. A consanguineous Turkish couple gave birth to three children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia and also had tibial agenesis and ectrodactyly. A second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of three unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of tibiae and symmetrical ectrodactyly of hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirms the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia.

Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia).

Misalignment of the pulmonary veins with congenital alveolar capillary dysplasia, although rare, has been reported as a cause of persistent pulmonary hypertension of the newborn. Reported cases have been mainly...

Congenital Alveolar Capillary Dysplasia: Rare Cause of Persistent Pulmonary Hypertension

We report on a rare case of fatal congenital alveolar capillary dysplasia. The newborn boy of a 37 weeks' normal gestation suffered from persistent pulmonary hypertension without any cardiovascular malformation and died at the age of 4 weeks despite intensive treatment. The autopsy tissue was examined histologically, immunohistochemically, and ultrastructurally. Moreover, a three-dimensional tissue reconstruction based on serial sections was performed comparing the affected lung with normal lung tissue. We observed a unique pattern of pulmonary dysplasia: An extreme decrease of capillaries was localized centrally within thickened intra-acinar septa instead of capillaries intensely neighboring pneumocytes; ectatic veins normally running in the interlobular septa were found to accompany intralobular bronchovascular bundles, denying a clear distinction between pulmonary and bronchial veins; small muscular pulmonary arteries extended to the precapillary level and type 2 pneumocytes exceeded by far the type 1 pneumocytes, inverting the normal ratio. In summary, alveolar capillary dysplasia is assumed to be a primary capillary disorder of unknown origin, which possibly involves the regular differentiation of pneumocytes, according to the close alveolocapillary relationship during pulmonary ontogenesis. We consider the venous alterations as being part of the dysplasia, whereas the arterial phenomena might occur secondarily. Recent reports on affected siblings suggest a genetic component of pathogenesis.