Case Of Alveolar Capillary Dysplasia Research Articles

Further refinement of the differentially methylated distant lung-specific FOXF1 enhancer in a neonate with alveolar capillary dysplasia

Heterozygous SNVs or CNV deletions involving the FOXF1 gene, or its distant enhancer, are causative for 80–90% of cases of alveolar capillary dysplasia with misalignment of pulmonary veins. Recently, we proposed bimodal structure and parental functional dimorphism of the lung-specific FOXF1 enhancer, with Unit 1 having higher activity on the paternal chr16 and Unit 2 on the maternal chr16. Here, we describe a novel unusually sized pathogenic de novo copy-number variant deletion involving a portion of the FOXF1 enhancer on maternal chr16 that implies narrowing Unit 2 to an essential ~ 9-kb segment. Using a restrictase-based assay, we found that this enhancer segment is weakly methylated at ApT adenine, with about twice the frequency of methylation on the maternal versus paternal chr16. Our data provide further insight into the FOXF1 enhancer structure and function.

Rapid genome diagnosis of alveolar capillary dysplasia leading to treatment in a child with respiratory and cardiac failure.

Alveolar capillary dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-mo-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema. The etiology of his condition was unknown, lung biopsy was contraindicated because of his medical fragility, and discussions were held to move to palliative care. Rapid whole-genome sequencing (rWGS) was performed. In 2 d it resulted, revealing a novel FOXF1 gene pathogenic variant that led to the presumptive diagnosis of atypical ACD. Cases of atypical ACD have been reported with survival in patients using medical therapy or lung transplantation. Based on the rWGS diagnosis and more favorable potential of atypical ACD, aggressive medical treatment was pursued. The patient was discharged home after 67 d in the hospital; he is currently doing well more than 30 mo after his initial presentation with only one subsequent hospitalization and no requirement for lung transplantation. Our case reveals the potential for use of rWGS in a critically ill child in which the diagnosis is unknown. rWGS and other advanced genetic tests can guide clinical management and expand our understanding of atypical ACD and other conditions.

A CLINICAL CASE OF CONGENITAL ALVEOLAR CAPILLARY DYSPLASIA: USE OF HIGH THROUGHPUT SEQUENCING TO VERIFY A DIAGNOSIS

The aim of the study was to establish the role of pathological clinical and laboratory characteristics of the course of the neonatal period, the data of morphological and molecular genetic studies in the thanatogenesis of a case of alveolar capillary dysplasia (ACD) in a newborn. ACD is a rare lethal neonatal lung developmental disorder, the development of
 which is caused in most cases by point mutations in the FOXF1 gene or deletion in the q24.1 region of chromosome 16.
 High-throughput whole-exome sequencing was performed in the child Sh. using the Illumina-IDT Exome Enrichment Protocol on the NextSeq 550 sequencer. A key role in the thanatogenesis of severe respiratory failure was existing alveolocapillary dysplasia in a child, which was confirmed by morphological data. Genetic analysis did not reveal pathogenic variants in FOXF1, PLXNB2, DOCK8, MPRIP, ESRP1, SLC50A1, and ZMYND11 genes, as well as deletions in regions L17941 and L29692 q24.1 of chromosome 16. In order to identify LINC01081 and LINC01082 deletions,
 it is necessary to develop additional bioinformatic algorithms.

A case of Alveolar capillary dysplasia with misalignment of pulmonary veins（ACD/MPV） with no extrapulmonary complications histologically diagnosed by pathological autopsy

A case of Alveolar capillary dysplasia with misalignment of pulmonary veins（ACD/MPV） with no extrapulmonary complications histologically diagnosed by pathological autopsy

A Case of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (ACD/MPV): The Importance of Early Genetic Testing

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, lethal condition caused by irregular pulmonary vascular maturation. Almost all cases present in the newborn period with ensuing respiratory decline within a couple days of life, ultimately leading to nearly 100% neonatal mortality. While the gold standard for diagnosis is lung biopsy, the identification of the Forkhead Box F1 (FOXF1) gene as the main genetic cause of ACD/MPV has allowed for a definitive diagnosis to be made without performing a high-risk procedure in a critically-ill neonate. This case report describes an ACD/MPV patient with hyperinsulinemia and refractory hypoglycemia as well as multiple anomalies who was found to have a novel pathogenic variant in the FOXF1 gene, identified via exome with copy number analysis, which results in premature protein termination (NM 001451.2 c.637 dup, p.Val213Glyfs*82). Our patient showcases the importance of early genetic testing to diagnose ACD/MPV given the substantial risk in obtaining a lung biopsy in a patient with hypoxemic respiratory failure, severe pulmonary hypertension, and vasodilator-induced pulmonary edema.

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation

BackgroundAlveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients.Case presentationWe herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2–40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels.ConclusionsUnusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

Analysis of the risk factors of persistent pulmonary hypertension in neonates

Objective To investigate the high risk factors of persistent pulmonary hypertension (PPHN) in preterm and full-term neonates. Methods Fifty-six newborns with PPHN were divided into preterm neonates group and the full-term neonates group according to their gestational ages.The relationship between PPHN and high risk factors such as the primary diseases, mother′s complications during pregnancy, and the prognosis were analyzed retrospectively in each group.A retrospective review of lung samples of 3 neonates who died of respiratory failure were carried out. Results Thirty-one (55.36%) out of 56 neonates with PPHN including 27 preterm and 29 full-term newborns had parenchyma diseases.The first and the second primary diseases were meconium aspiration syndrome (MAS, 9/29 cases, 31.03%) and congenital heart diseases (8/29 cases, 27.59%) in the full-term group, and respiratory distress syndrome (RDS, 16/27 cases, 59.26%) and infection (8/27 cases, 29.63%) in preterm group, respectively.There were 15 cases (55.56%) whose mothers had complications during pregnancy among the 27 preterm neonates, and 8 cases (27.59%) among the 29 full-term neonates.The morbidity of mothers′ complications during pregnancy in preterm neonates was higher than that in full-term neonates (χ2=4.519, P=0.034). The mortality rate was 33.33% (9/27 cases) in the preterm neonates group while 27.59% (8/29 cases) in the full-term neonates group.There was no significant difference in mortality rate between each group (χ2=0.218, P=0.640). The primary diseases were RDS (9/9 cases, 100%) and MAS (4/8 cases, 50%) in preterm and full-term neonates who died of PPHN, respectively.One case of pulmonary hypertensive vascular remodeling, 1 case of alveolar capillary dysplasia (ACD) and 1 case of interstitial pneumonia were found in 3 lung samples of neonates died of PPHN. Conclusions The ratio of preterm increased in neonates with PPHN.RDS and infection were the first two primary diseases in preterm neonates with PPHN.MAS was the first primary disease in full-term neonates with PPHN.Primary pulmonary hypertension should be considered for neonates with severe PPHN. Key words: Persistent pulmonary hypertension; Infant, newborn; Risk factor; Primary persistent pulmonary hypertension

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

FOXgene cluster defects in alveolar capillary dysplasia associated with congenital heart disease

The objective was to report two new patients with the diagnosis of alveolar capillary dysplasia and congenital heart disease, to describe the associated cardiac defects seen in these cases and in the literature, and to consider recent genetic advances concerning the FOX transcription factor gene cluster in chromosome 16q24.1q24.2. We retrospectively analysed the records of all patients with congenital heart disease and alveolar capillary dysplasia seen in the Pediatric Cardiology Department between 2005 and 2010. We reviewed all literature published in the English language relating to cases of alveolar capillary dysplasia and congenital heart disease. Two infants with alveolar capillary dysplasia and cardiac malformation were identified: one had an atrioventricular septal defect and a de novo balanced reciprocal translocation t(1;16)(q32;q24), the second infant had a ventricular septal defect. Analysis of 31 cases of the literature including these new cases showed a predominant association of alveolar capillary dysplasia with obstructive left heart disease (35%), as well as an atrioventricular septal defect (29%). FOX gene cluster defects were identified in eight of these patients. Genetic background of alveolar capillary dysplasia is discussed in the light of the balanced reciprocal translocation t(1;16)(q32;q24) identified in the first child of this report. Alveolar capillary dysplasia should be suspected in neonates with congenital heart disease and unexpectedly elevated pulmonary vascular resistances, especially in cases of obstructive left heart disease or atrioventricular septal defect. Detecting FOX gene cluster defects should be considered in infants with alveolar capillary dysplasia with or without congenital heart disease.

A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.

Alveolar capillary dysplasia associated with duodenal atresia: Ultrasonographic findings of enlarged, highly echogenic lungs and gastric dilatation in a third‐trimester fetus

We report a case of alveolar capillary dysplasia, wherein duodenal atresia was diagnosed during the third trimester. A 36-year-old mother was referred to our hospital for polyhydramnios at 31 weeks' gestation. Duodenal atresia was suspected from the ultrasonographic findings, which showed gastric dilation. Other findings noted were enlarged, highly echogenic lungs, a spherical heart and an increased lung-thorax transverse area ratio. A male infant was born at 37 weeks' gestation. The findings of serial radiography of the infant's upper gastrointestinal tract were compatible with the diagnosis of duodenal atresia; however, he developed persistent pulmonary hypertension of the newborn eight hours after birth and died at five days of age. The autopsy revealed alveolar capillary dysplasia and duodenal obstruction. We propose that the detection of duodenal atresia should prompt the physician to conduct a thorough ultrasonographic examination to rule out associated anomalies, such as alveolar capillary dysplasia, which can be detected by the presence of highly echogenic lungs.

ALVEOLAR CAPILLARY DYSPLASIA: ABSENCE OF CD117 IMMUNOREACTIVITY OF PUTATIVE HEMANGIOBLAST PRECURSOR CELLS

Alveolar capillary dysplasia is a rare cause of irreversible persistent pulmonary hypertension in newborns resulting from failure of formation of peripheral capillary loops with consequent reduction in the blood-gas barrier. The basic defect in morphogenesis is unknown, although it is postulated that there is a structural abnormality of the hemangioblast precursors of the primitive lung mesenchyme in the septal regions of the developing lung leading to abnormal vasculogenesis. Two cases of alveolar capillary dysplasia evaluated immunohistochemically showed uniform CD117 negativity in the septal interstitial cells forming the pulmonary capillaries. A series of 12 control cases showed positive immunoreactivity for CD117 in a subset of septal interstitial cells forming the putative hemangioblast precursor cells. This novel finding is a useful adjunctive diagnostic tool and may support the hypothesis that absence of putative CD117-positive hemangioblast precursor cells is a key structural defect. This defect results in abnormal vasculogenesis and consequent failure of formation of an adequate blood-gas barrier.

A Rare Case of Aortic Coarctation and Ventricular Septal Defect Combined with Alveolar Capillary Dysplasia

We report a rare case of alveolar capillary dysplasia (ACD) associated with severe aortic coarctation, hypoplastic aortic arch, and mild hypoplasia of the left ventricle. After successful coarctation repair, pulmonary hypertension persisted, and despite only minor anomalies on the x-ray, chest computed tomography (CT) revealed the presence of primary lung disease. Review of the literature suggests that ACD may be associated with left heart obstructions. Chest CT is applicable to diagnose ACD precociously.

Alveolar Capillary Dysplasia with Congenital Misalignment of Pulmonary Vessels

Alveolar capillary dysplasia with misalignment of pulmonary vessels is an uncommon congenital cause of persistent pulmonary hypertension of the newborn. It is universally fatal, and diagnosis is entirely dependent upon surgical lung biopsy. We present a case of alveolar capillary dysplasia with misalignment of pulmonary vessels occurring in a full-term neonate, emphasizing that early involvement of the thoracic surgeon for a histological diagnosis allows expensive and ineffective treatments to be avoided.

Alveolar capillary dysplasia: a six-year single center experience

Alveolar capillary dysplasia is a fatal disorder of the lung that requires lung biopsy for diagnosis. We reviewed the course of patients with alveolar capillary dysplasia following implementation of an early lung biopsy strategy between 1997-2002. We performed immunohisto-chemical studies on all tissue specimens. We diagnosed 7 cases of alveolar capillary dysplasia. We diagnosed 6/7 cases of alveolar capillary dysplasia pre-mortem by early lung biopsy. Median time between admission and lung biopsy was 6.5 days. All patients survived lung biopsy but died following withdrawal of active therapy after confirmation of the tissue diagnosis. In 1 patient we demonstrated histological findings of alveolar capillary dysplasia and congenital acinar dysplasia. Two patients were first cousins. One patient underwent pulmonary angiography with rapid filling of the pulmonary veins before passage of contrast through the capillary bed. Five patients were supported with extracorporeal membrane oxygenation and 2/5 patients survived decannulation. During the same period 8 patients required ECMO for acute hypoxic respiratory failure. Four out of 8 were diagnosed with alveolar capillary dysplasia. Early lung biopsy was performed with low risk and high diagnostic yield for alveolar capillary dysplasia. Alveolar capillary dysplasia occurs frequently in neonates who require ECMO support for refractory pulmonary hypertension. We have added an additional familial case and suggest a novel angiographic finding.

Dysplasie alvéolo-capillaire avec défaut d’alignement des vaisseaux pulmonaires: Revue de la littérature à propos d’un nouveau cas

Alveolar capillary dysplasia (ACD), with or without pulmonary vein misalignment is a uniformly fatal cause of persistent pulmonary hypertension and respiratory failure, first described in 1981. We report the case of ACD in a full term newborn with post mortem pathologic confirmation. Sixty five cases have been reported in the literature, most are sporadic, but a few cases of familial ACD suggest an autosomal recessive inheritance. In 55% of the reported cases of ACD other cardiovascular, digestive or urogenital anomalies were associated. ACD is presumed to be a primary capillary disorder. It affects full-term neonates who exhibit respiratory distress during the early post natal period due to pulmonary hypertension and die within 3 weeks of birth. Histologic findings include a decrease in the number of alveolar capillaries, which are placed centrally within the intralobular septa, ectatic veins accompany the bronchovascular bundles instead of being in their normal position in the interlobular septum, and muscularized pulmonary arteries extend to the distal level. Prognosis is very poor, intravenous prostacyclin with inhaled nitric oxide have been reported in the cases with the best survival.