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Alveolar Capillary Dysplasia

Alveolar capillary dysplasia (ACD) is a rare and almost uniformly lethal form of pulmonary dysplasia that is mostly associated with misalignment of the pulmonary veins. Most neonates suffering from ACD also show extra-pulmonary malformations. Treatment is not available. The majority of ACD patients develops cardiorespiratory failure within the first 48 hours of life and doesn't live beyond the neonatal period. Lung transplantation is the only chance for survival. The condition is usually caused by de novo mutations of the gene encoding for the FOXF1 transcription factor, which presumably affects fetal lung development.


Presentation

Respiratory distress is a characteristic, yet unspecific symptom of ACD that is often present at birth. Accordingly, neonatal 5- and 10-minutes APGAR scores are usually low. In some cases though, symptom onset may be somewhat delayed, neonates may achieve good APGAR scores and not develop respiratory distress until several hours after birth [1]. In any case, the patients' condition deteriorates rapidly and they develop pulmonary hypertension and respiratory failure [2]. Oxygen saturation on pulse oximetry is well below reference ranges and affected infants suffer from persistent hypoxemia. Consequently, cyanotic skin color can be observed. If chest radiographs are obtained, a pneumothorax may be recognized [1] [2]. The pathophysiological events leading to pneumothorax in ADC patients are not yet understood [3]. In most cases, ACD patients develop fatal cardiorespiratory failure within the first 48 hours of life [3] [4].

Of note, further congenital abnormalities are not uncommon in ACD patients. In a cohort of seven patients diagnosed with ACD between 1997 and 2005 in the United Kingdom, at least five suffered from additional malformations, e.g., intestinal malrotation, Hirschsprung's disease, renal pelvis dilatation, congenital genital malformation, atrioventricular septal defect, and left ventricular hypertrophy [5]. The prevalence of extra-pulmonary malformations in ACD patients has been estimated to 40% for the gastrointestinal tract, 32% for the genitourinary system, and 16% for the cardiovascular system [6]. The combination of ACD with congenital heart disease is particularly drastic since cardiac disorders may cause hemodynamic instability and add to cardiorespiratory failure.

Fishing
  • Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134 10 kb upstream (5'; centromeric) of FOXF1.[ncbi.nlm.nih.gov]
  • Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134   10 kb upstream (5′; centromeric) of FOXF1.[orca.cf.ac.uk]
Tachypnea
  • It is characterized by tachypnea (rapid breathing), dyspnea (labored breathing), cyanosis (blue-colored lips or skin), quickly leading to respiratory failure and death.[xpertdox.com]
Cyanosis
  • Abstract After surgical repair of an aortic coarctation a term infant presented with severe pulmonary hypertension and cyanosis unresponsive to treatment including extracorporeal membrane oxygenation.[ncbi.nlm.nih.gov]
  • It is characterized by tachypnea (rapid breathing), dyspnea (labored breathing), cyanosis (blue-colored lips or skin), quickly leading to respiratory failure and death.[xpertdox.com]
  • Symptoms of ACD include: Lack of oxygen in blood stream (Hypoxia) Bluish discoloration of skin, lips and nail beds (Cyanosis) High blood pressure in the lungs (Pulmonary Hypertension) Shortness of breath Intestinal defects Urinary tract and kidney dysfunction[patientworthy.com]
  • They experience shortness of breath, their lips, skin, and fingernails often appear bluish (cyanosis), and they have persistent pulmonary hypertension that does not respond to treatment.[child-foundation.org]
  • The newborn patient exhibits cyanosis and acidosis due to the persistence of fetal circulatory pattern of right-to-left shunting of blood through a patent ductus arteriosus (patent ductus arteriosus) and at times a patent foramen ovale (patent foramen[en.termwiki.com]
Withdrawn
  • Because of the lethal prognosis, extracorporeal membrane oxygenation was withdrawn and the patient expired. This is the first description of an association between omphalocele and alveolar capillary dysplasia.[ncbi.nlm.nih.gov]
  • Because of the lethal prognosis, extracorporeal membrane oxygenation was withdrawn and the patient expired. CONCLUSIONS: This is the first description of an association between omphalocele and alveolar capillary dysplasia.[repository.ubn.ru.nl]

Workup

The clinical presentation often raises suspicion of persistent fetal circulation and secondary pulmonary hypertension [5] [7]. This condition is much more common than ACD and in order to distinguish both entities, it is necessary to obtain a surgical lung biopsy sample. Histologically, ACD is characterized by severely hypoplastic alveolar capillaries, medial hypertrophy in small pulmonary arteries with abnormal muscular extensions into intra-acinar vessels and malposition of pulmonary veins adjacent to the aforementioned arteries. Both the density of alveolar capillaries as well as their proximity to the epithelial wall are significantly decreased. By contrast, the density of alveoli is only mild to moderately reduced. The interstitium is typically thickened by embryonal mesenchyme and interlobular septa are often widened [5].

Genetic analyses may also be helpful to determine whether a child is suffering from ACD or other forms of pulmonary dysplasia that may be associated with a better prognosis [1]. In the vast majority of patients, heterozygous point mutations of FOXF1 or genomic deletion copy-number variants of chromosomal region 16q24.1 comprising the FOXF1 gene have been detected [8]. Sequence anomalies vary from patient to patient, though, and distinct molecular biological techniques may have to be applied to precisely characterize the underlying genomic defect. Also, FOXF1 mutations may not be detected in all cases and it cannot be ruled out that additional genes are involved in the pathogenesis of ACD, ACD with misalignment of the pulmonary veins or intermediate type pulmonary dysplasia, which is why the diagnosis shouldn't be based on the results of genetic analyses alone [1] [9]. Indeed, the identification of sequence anomalies involving FOXF1 should prompt to realize a surgical lung biopsy [1].

Treatment

Neonates usually require immediate intubation and mechanical ventilation. Nitrous oxide therapy may be applied to counteract increasing pulmonary hypertension, but is generally insufficient to assure adequate blood oxygenation. ADC-associated pulmonary hypertension is generally refractory to any treatment, but isolated cases of prolonged survival due to permanent therapy with nitrous oxide and analog of prostacyclin epoprostenol have been reported [6]. Of note, prolonged survival refers to survival of the neonatal period. To date, very few ACD patients have survived for more than a few months, even if extracorporeal membrane oxygenation was used to oxygenate blood independent of lung function [1].

However, all the aforementioned measures may help to bridge the time until a lung transplantation can be carried out. According to current knowledge, lung transplantation is the only chance for survival. Although there are only isolated case reports, it has been shown that ADC patients may survive after lung transplantation [10].

Prognosis

Severe ACD leads to early death; affected children don't usually survive beyond the neonatal period. Unfortunately, even less severe ACD considerably interferes with pulmonary gas exchange and is incompatible with long-term survival. The average age at death of patients in the small cohort mentioned above was 18 days [5]. The only chance for longer survival is a lung transplantation, but many patients are ineligible for lung transplantation due to their poor general condition [10]. Exceptionally long survival without lung transplantation was reported for a Japanese girl who only died after eight months [6].

Etiology

ACD has been related to mutations of the FOXF1 gene and its upstream enhancer [8] [11] [12]. The exact role of FOXF1 has not yet been clarified, but it is known that FOXF1 encodes for a transcription factor presumably involved in embryonic organogenesis, particularly in lung development, and that its expression is regulated by non-coding RNA genes LINC01081 and LINC01082 [8] [13]. In detail, both heterozygous point mutations and genomic deletion copy-number variants of FOXF1 have been detected in ACD patients. These sequence anomalies presumably arise de novo and are almost exclusively found on the maternal chromosome - a fact that highly suggests genomic imprinting [8]. Still, cases of familial recurrence have been reported and it has been speculated that the disease may rarely be inherited in an autosomal recessive pattern [9].

Epidemiology

To date, less than a hundred cases of ACD have been reported. Melly and colleagues pointed out multiple clinical and histological similarities between ACD and congenital alveolar dysplasia, and were able to show that some patients diagnosed with the latter have probably been suffering from ACD or an ACD/congenital alveolar dysplasia mixed type [5]. Also, ADC may have been mistaken on several occasions for idiopathic persistent pulmonary hypertension of the newborn [3]. In any case, even if some ACD patients have been misdiagnosed with other forms of pulmonary dysplasia, the overall case number for ACD remains very low.

Sex distribution
Age distribution

Pathophysiology

Under physiological conditions, oxygen molecules reaching the alveoli can easily diffuse into alveolar capillaries because these small vessels are located at a very short distance from the alveolus' innner surface. Indeed, the alveolar wall is only one cell thick. In order to assure an adequate supply of oxygen to all tissues, considerable amounts of hemoglobin have to be oxygenated when passing through the alveolar capillaries. This can only be achieved if oxygen diffusion is facilitated through a large alveolar surface area into a rich network of adjacent capillaries.

In ADC patients, the gas exchange is impeded by severe abnormalities of the air-blood barrier. The aforedescribed mechanism is disturbed in two respects: On the one hand, capillary apposition is significantly decreased and oxygen molecules are required to diffuse a long distance to reach these small blood vessels. On the other hand, capillary density is significantly reduced. Thus, the overall surface available for the gas exchange is minimized [5]. Although alveolar dysplasia is not a defining criterion of ADC, alveolar density is often diminished in affected individuals [5]. This condition further aggravates the dysfunction of the air-blood barrier.

Prevention

Prenatal sonography and magnetic resonance imaging are of major importance in the workup of suspected pulmonary dysplasia [2]:

  • While thoracic cage and intrathoracic compression are the most common causes of abnormal fetal lung development, neither is to be expected in case of ACD. Nevertheless, severe reductions in lung volume can be measured and indicate a primary lung disorder. Lung volumes can be assessed sonographically.
  • In order to further characterize pulmonary malformations, subsequent magnetic resonance imaging is recommended. In T2-weighted images, hypointense areas can be clearly noted in lungs affected by ADC.

Because neither of those findings allows for a reliable prenatal diagnosis of ADC, chorionic villous sampling may be indicated to confirm DNA sequence anomalies affecting the FOXF1 gene [4]. As has been mentioned above, mutations triggering ADC generally arise de novo and are not inherited from either parent. Thus, irrespective of whether a decision to continue or abort the pregnancy is taken, parents are to be informed of the low likelihood of recurrence in future pregnancies. It should be noted, though, that familial accumulation has occasionally been described and seems to account for approximately 10% of all cases [1].

Summary

ACD is a rare congenital disease and "a unique form of pulmonary dysplasia" that has first been described by Janney et al. in 1981. Besides malformation and ingrowth of alveolar capillaries, anomalies of the bronchovascular bundles were found in the affected infant [7]. When other case reports were published later, it became clear that non-capillary vascular abnormalities are a rather common feature of ACD. To date, about 80 cases of ACD have been reported in the literature, with the majority of affected individuals being diagnosed with alveolar capillary dysplasia with misalignment of the pulmonary veins or ACD/MPV instead of sole ACD [5]. Additionally, gastrointestinal and cardiac malformations are common in ACD patients.

Respiratory problems are apparent at birth. Because the pulmonary gas exchange is severely limited, affected neonates rapidly develop pulmonary hypertension and respiratory, failure and need to be intubated. Unfortunately, neither mechanical ventilation nor extracorporeal membrane oxygenation nor pharmacological therapy suffice to assure an adequate oxygenation of hemoglobin and tissues, and the vast majority of patients dies within a few days or weeks.

Genetic analyses are helpful to support a suspicion of ADC and to facilitate decisions upon the detection of pulmonary anomalies in prenatal examinations. They are, however, not yet considered the gold standard for diagnosis. Instead, diagnosis of ACD relies on the histological examination of lung parenchyma, and while the respective specimens may be obtained by surgical lung biopsy, many cases are only confirmed post mortem [1].

Patient Information

Alveolar capillary dysplasia (ACD) is a rare form of pulmonary dysplasia, i.e., malformation of the lung. In order to understand how this type of dysplasia interferes with respiration, a basic understanding of the structure of the lung is required: In healthy individuals, inhaled oxygen diffuses into blood after reaching an alveolus, a tiny sac within the lung that is also called the basic unit of ventilation. This tiny sac is delimited by a very thin cellular layer and the smallest blood vessels of the lung are located immediately behind this layer. Consequently, the distance to be covered by an oxygen molecule to reach the bloodstream is very short. Within the healthy human lung, there are millions of such alveoli and they are surrounded by millions of capillaries prepared to absorb oxygen.

In patients suffering from ACD, the distance between the inner alveolar surface and surrounding capillaries is greatly increased. Furthermore, the overall number of capillaries and, to a lesser extent, of alveoli, is reduced. Thus, the gas exchange is severely impaired and the patient is unable to absorb sufficient oxygen to supply all their tissues. According to current knowledge, this condition results from gene mutations that are not inherited from the parents but rather arise de novo in very early stages of development. No recommendations can be given on any methods to avoid this kind of mutations.

Because humans depend on respiration and gas exchange from birth, affected neonates show symptoms of respiratory distress as soon as they are born or within hours afterwards. Even though all possible measures are taken to facilitate oxygen uptake and gas exchange, it is not yet possible to meet the demands of the child who suffers from ACD. Unfortunately, most patients don't survive beyond the neonatal period and very few cases are known in which the affected infants survived thanks to lung transplantation. Unfortunately, their poor general condition usually renders them ineligible for this surgical intervention.

References

Article

  1. Castilla-Fernandez Y, Copons-Fernández C, Jordan-Lucas R, et al. Alveolar capillary dysplasia with misalignment of pulmonary [corrected] veins: concordance between pathological and molecular diagnosis. J Perinatol. 2013; 33(5):401-403.
  2. Zirpoli S, Munari AM, Rustico M, et al. Fetal-MRI prenatal diagnosis of severe bilateral lung hypoplasia: alveolar capillary dysplasia case report. J Prenat Med. 2016; 10(3-4):15-19.
  3. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med. 2011; 184(2):172-179.
  4. Prothro SL, Plosa E, Markham M, Szafranski P, Stankiewicz P, Killen SA. Prenatal Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. J Pediatr. 2016; 170:317-318.
  5. Melly L, Sebire NJ, Malone M, Nicholson AG. Capillary apposition and density in the diagnosis of alveolar capillary dysplasia. Histopathology. 2008; 53(4):450-457.
  6. Kodama Y, Tao K, Ishida F, et al. Long survival of congenital alveolar capillary dysplasia patient with NO inhalation and epoprostenol: effect of sildenafil, beraprost and bosentan. Pediatr Int. 2012; 54(6):923-926.
  7. Janney CG, Askin FB, Kuhn C, 3rd. Congenital alveolar capillary dysplasia--an unusual cause of respiratory distress in the newborn. Am J Clin Pathol. 1981; 76(5):722-727.
  8. Szafranski P, Gambin T, Dharmadhikari AV, et al. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet. 2016; 135(5):569-586.
  9. Benevides GN, Picciarelli de Lima P, Felipe-Silva A, Lovisolo SM, Pereira de Melo AM. Recurrence of alveolar capillary dysplasia with misalignment of pulmonary veins in two consecutive siblings. Autops Case Rep. 2015; 5(1):21-27.
  10. Boston US, Fehr J, Gazit AZ, Eghtesady P. Paracorporeal lung assist device: an innovative surgical strategy for bridging to lung transplant in an infant with severe pulmonary hypertension caused by alveolar capillary dysplasia. J Thorac Cardiovasc Surg. 2013; 146(4):e42-43.
  11. Parris T, Nik AM, Kotecha S, et al. Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A. 2013; 161a(4):764-770.
  12. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009; 84(6):780-791.
  13. Szafranski P, Dharmadhikari AV, Wambach JA, et al. Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A. 2014; 164a(8):2013-2019.

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Last updated: 2019-07-11 20:18