Article in press - uncorrected proof J. Perinat. Med. 33 (2005) 347–352
•
Copyright by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2005.067
Alveolar capillary dysplasia: a six-year single center experience
Pablo Eulmesekian, Ernest Cutz, Boriana Parvez, Desmond Bohn and Ian Adatia* Hospital for Sick Children, Toronto, Canada
Abstract 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 immunohistochemical 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. Conclusions: 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. Keywords: Congenital acinar dysplasia; congenital alveolar dysplasia; extra corporeal membrane oxygenation misalignment of pulmonary veins; nitric oxide persistent pulmonary hypertension of the newborn. *Corresponding author: Dr Ian ThomasKassam Adatia, MBChB Associate Professor of Pediatrics University of California San Francisco Children’s Hospital Department of Pediatrics, Division of Cardiology 505 Parnassus Ave Room M-655 San Fransisco, California 94143-0106, USA E-mail:
[email protected]
Abbreviations: ACD, Alveolar Capillary Dysplasia; PPHN, Persistent Pulmonary Hypertension of Newborn; HFOV, High Frequency Oscillatory Ventilation; MPV, Misalignment of Pulmonary Veins; CAD, Congenital Acinar Dysplasia; HLHS, Hypoplastic Left Heart Syndrome; IAS, Intact Atrium Septum; d, Days.
Introduction Alveolar capillary dysplasia with or without so-called ‘‘misalignment of the pulmonary veins’’ is a rare and thus far, fatal congenital abnormality of pulmonary vascular development, particularly the alveolar- capillary relationship. The complete histological features of alveolar capillary dysplasia were described first in 1981 w21x. Congenital alveolar dysplasia, described in 1948 w25x, may represent a variant w21x. Since 1981 approximately 84 cases have been reported and a clinically recognizable pattern of disease is emerging w9, 20, 41, 42x Alveolar capillary dysplasia is typified by relentless neonatal pulmonary hypertension, transient response to pulmonary vasodilators w12, 22, 24, 32, 39, 40x, a familial variant w1, 6, 24, 38, 43, 46x and an association with congenital cardiac w9, 16, 23, 28, 34x, gastrointestinal w2, 9–11, 17–19, 23, 28, 34, 37, 40, 42x, genitourinary w3, 21, 43–45x, limb w13, 38, 40, 46x and ocular anomalies w29x in 50–60% of cases. However, the diagnosis is confirmed rarely pre-mortem. In 1997 we began to evolve a strategy of early lung biopsy in neonates with recalcitrant pulmonary hypertension. In particular, early lung biopsy was undertaken in neonates with persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide therapy and 48–72 h of ECMO support. Therefore, we present a 6-year single center evaluation of lung biopsy in the diagnosis of alveolar capillary dysplasia.
Methods We reviewed retrospectively all available clinical and laboratory data of patients with histological proven alveolar capillary dysplasia between 1997–2002. In addition, we reviewed the respective databases to identify all neonates receiving extracorporeal membrane oxygenation (ECMO) and all neonates who underwent open lung biopsy.
Article in press - uncorrected proof 348 Eulmesekian et al., Alveolar capillary dysplasia
Table 1 Clinical data on ACD patients. Case
1
2
3
4
5
6
7
Presenting Diagnosis HFOV Nitric Oxide Associated Anomalies Histology
PPHN
PPHN
PPHN
PPHN
PPHN
PPHN
Yes Yes Intestinal Malrotation ACD MPV
Yes Yes
No Yes
Yes Yes
Yes Yes
HLHS IAS Yes Yes HLHS
ACD MPV
ACD MPV
ACD MPV
ACD MPV
ACD
Presentation age Admission age ECMO Age cannulated ECMO Age decannulated Age at Lung biopsy Age at Death
1d 2d 4d
2d 2d 3d
13 d 13 d
1d 1d 1d
1d 3d 4d
1d 1d 9d
ACD MPV CAD 1d 11 d
5d
6d
11 d
11 d
18 d
6d
Yes Yes
7d
20 d
9d
9d
36 d
13 d
8d
21 d
11 d
11 d
40 d
22 d
The lung biopsy samples were fixed in 10% neutral buffered formalin and embedded in paraffin. For histopathological assessment, paraffin sections were stained with heamatoxylineosin (H&E), periodic acid -Schiff (PAS) with and without diastase treatment, Masson trichrome and Movat stain for connective tissue elements. Stains for microorganisms included Gram stain, Grocott methanamine silver and Ziehl-Nielsen stain for mycobacteria. For immunohistochemical studies the indirect immunoperoxidase method was employed on formalin fixed- paraffin sections. The following primary monoclonal (MAb) or polyclonal antibodies were used on all biopsies: MAb against cytokeratin 7 (1:20 dilution, Dako Corporation, Carpinteria, CA) as a general epithelial cell marker; rabbit polyclonal antibody against collagen type IV (1:50 dilution Dako) as a maker for alveolar and capillary basement membrane; MAb against CD34 (Novocastra, Newcastle upon Tyne, UK) and rabbit polyclonal antibody against Factor 8 (1:500 dilution, Dako) as endothelial markers; MAb against surfactant protein B (SPB,1:20 dilution, Research Diagnostics, Flanders, NJ) as a marker for alveolar type 2 cells, and rabbit polyclonal antibody against CC10 (1:2000 dilution, Dako) as a marker for Clara cells. For transmission electron microscopy (TEM) studies, samples of lung were fixed in ‘‘universal fixative’’ (1% glutaraldehyde and 4% paraformaldehyde in 0,1 M phosphate buffer) and processed according to routine methodology. Lung biopsy specimens were stained with cytokeratin 7, collagen type 1V, CD34, UP1 and SP-B antibody as well as hemotoxylin and eosin and Movat’s stain. The study was approved by the hospital Research Ethics Board.
Results We identified 7 cases of alveolar capillary dysplasia. The clinical features and associated abnormalities are summarized in Table 1. The median age at presentation, admission, and death was 1 day (range 1 to 13 days),
2 days (range 1 to 13 days) and 11 days (range 6 to 40 days) respectively. Median age at lung biopsy was 11 days (range 7–36) and median time from admission until lung biopsy was 6.5 days (range 2–35). Four patients were males and three females. Six patients presented with cyanosis and cardiopulmonary distress with supra-systemic pulmonary artery hypertension. Patient 6 carried an antenatal diagnosis of hypoplastic left heart syndrome with intact atrial septum. After transcatheter left atrial decompression she was listed for cardiac transplantation. She underwent orthotopic cardiac transplantation on day 9 of life but could not be separated from cardiopulmonary bypass because of refractory supra- systemic pulmonary artery hypertension. Cardiopulmonary bypass was converted to ECMO. After 3 days on ECMO she was returned to the operating room to repair stenosis of the left atrial anastomosis. Six days later she tolerated decannulation but pulmonary artery pressures remained supra-systemic despite inhaled NO and high frequency oscillatory ventilation. She underwent lung biopsy and resection of an emphysematous right middle lobe eighteen days after decannulation. She died on day 40 of life. Patients 2 & 3 were first cousins. Patient 3 was the oldest patient at presentation in our series. She presented to us on day 13 of life. She was one of triplets, conceived by assisted fertilization, and discharged home after birth. Patient 5 presented with severe hypoxemia and supra-systemic pulmonary artery hypertension despite treatment with inhaled NO and high frequency oscillatory ventilation. Echocardiography demonstrated a large coronary sinus with a left superior vena cava but anomalous pulmonary veins could not be excluded. He was taken to the operating for cannulation for ECMO with direct inspection of the left atrium. Normal pulmonary venous connections were confirmed. The following day
Article in press - uncorrected proof Eulmesekian et al., Alveolar capillary dysplasia 349
the patient underwent cardiac catheterization with angiography while on ECMO support. Contrast injected in the distal right pulmonary artery demonstrated delayed passage through the capillary bed but before clearance, the right and left pulmonary veins and left atrium are opacified densely and rapidly (Figure 3). Five out of 7 patients received ECMO support. The median age at cannulation was 4 days (range 1 to 9 days) and median duration of ECMO support was 7 days (range 1 to 10 days). Two patients ( 2 and 6) tolerated decannulation from ECMO support and survived for a further 2 and 22 days respectively. All patients died at a median age of 11 days (range 6 to 40). Between 1997–2002 only 4 additional neonates required ECMO support for pulmonary hypertension (3 patients had meconium aspiration syndrome and 1 persistent neonatal pulmonary hypertension). Thus 4/8 (50%) neonates requiring ECMO support for persistent pulmonary hypertension of the newborn (excluding the patient 6 with hypoplastic left heart syndrome) suffered from alveolar capillary dysplasia. In 6/7 patients the diagnosis of alveolar capillary dysplasia was established pre mortem by lung biopsy. Patient 1 suffered a cerebral hemorrhage and active treatment was withdrawn before biopsy. The diagnosis was confirmed at autopsy. Lung biopsies were undertaken in the critical care unit (3/6) or the operating room. Two patients were biopsied while receiving ECMO support (patients 4 and 5) after ensuring the platelet count was 100=109/L and activated clotting time within 160–180 s. During the study period 10 neonates (median age 14 days range 7–35) underwent open lung biopsy and alveolar capillary dysplasia was diagnosed in 60%. Fatal pulmonary or vascular abnormalities were diagnosed in 3/4 without alveolar capillary dysplasia. One patient with a biopsy suggestive of pulmonary capillary hemangiomatosis has survived 5 years with continued pulmonary hypertension treated with phosphodiesterase inhibition. In all lung biopsies, the principal findings included marked paucity of intraacinar capillaries, increased separation between alveolar and capillary basement membrane and a failure of the intra-acinar capillary endothelium to contact the alveolar epithelium that forms the air-blood barrier. These microscopic features became more clearly defined on sections immunostained for CD34 (Figure 1) and collagen type IV, a basement membrane marker (Figure 2) and factor 8 (not shown) markers of endothelial cells. The widening of interalveolar septa was highlighted by immunostaining for cytokeratin (not shown). Immunostaining for SPB and CC10 revealed a normal pattern. The pulmonary arterioles showed medial hypertrophy and abnormal muscular extension into arterioles beyond the terminal bronchiole. The alveolar septa were thickened by excessive mesenchyme, interstitial edema and dilated lymphatics. The biopsy of patient 7 was remarkable and
Figure 1 (a) Section of lung biopsy from Case 2 immunostained with CD34 antibody shows marked reduction in peripheral capillary loops with most residual capillaries located in the middle of a thickened interalveolar septum. (b) For comparison, lung from an age matched control lung shows well developed alveolar capillary network.
demonstrated, in addition to the findings of alveolar capillary dysplasia, marked developmental arrest of the airspaces with findings reminiscent of congenital acinar dysplasia. Lung biopsy was performed without complication in all 6 patients. After confirmation of the diagnosis all patients died following withdrawal of active therapy.
Discussion We present the findings in 7 patients with alveolar capillary dysplasia from a single institution over six years. We established the diagnosis before death by lung biopsy in 86% of cases. Our findings suggest a higher incidence of the disease than expected from another recent single center experience of 6 cases spanning an 18 year period reported by Tibballs et al. w42x. We suggest that alveolar capillary dysplasia may be a more frequent cause of death from refractory neonatal pulmonary hypertension than hitherto realized. Premortem diagnosis by lung biopsy has been established in only 15 out of approximately 85 cases reported compared to 86% in the present series w20x. The advantages of early diagnosis include early discussion of prognosis with the parents and limitation of futile therapies. Presently, the disease is fatal with a maximum reported survival of 2–3 months w22, 24, 32x. However, as infant lung transplantation results improve, it is possible that early diagnosis with adjunct continuous pulmonary vasodilator therapy might bridge
Article in press - uncorrected proof 350 Eulmesekian et al., Alveolar capillary dysplasia
a patient to transplantation w8, 24x. Early lung biopsy may be especially pertinent to the management of certain neonates with hypoplastic left heart syndrome and intact atrial septum before embarking on complex staged surgery or cardiac transplantation w4, 23, 34, 36x. We have demonstrated that neonatal lung biopsy may be performed without serious adverse sequelae even in this unstable patient population. Diagnostic accuracy is improved with the use of appropriate immunohistochemical markers in addition to H&E and Movat stains w33x. Therefore, we would suggest proceeding to open lung biopsy if a neonate with idiopathic persistent pulmonary hypertension fails, despite maximal therapy, to improve after 72 h. Earlier biopsy may be indicated if associated congenital abnormalities are identified or ECMO therapy is required. Our experience suggests that with current management strategies 50% of neonates requiring ECMO for hypoxemia due to idiopathic pulmonary artery hypertension may have alveolar capillary dysplasia. As suggested by others, ECMO is not a contraindication to open lung biopsy w7, 20x and the use of immunohistochemical markers greatly facilitates the diagnosis. Although absent or delayed capillary blush following pulmonary arteriography in alveolar capillary dysplasia has been reported w19x, the angiographic findings in patient 5 are intriguing (Figure 3). They suggest that bronchial veins may act as an alternative pathway from pulmonary artery to pulmonary vein in areas of lung with a paucity of, or obstructed capillaries and permit deoxygenated pulmonary arteriolar blood to bypass severely
Figure 2 (a) Section of lung biopsy from Case 2 immunostained for collagen type IV showing paucity of alveolar capillaries and wide separation between alveolar and capillary basement membrane, (b) For comparison, lung from an age matched control lung shows well developed alveolar capillary network.
Figure 3 Right pulmonary arteriogram. The distal end of the catheter is seen in the right pulmonary artery. The catheter course (delineated by black arrows) is from the right femoral vein, IVC, right atrium, right ventricle, main pulmonary artery to right pulmonary artery. The catheter course differentiates the right pulmonary artery from right pulmonary veins (delineated by black arrow heads). Contrast is visualized in the capillary bed but before clearance, the right and left pulmonary veins are opacified densely. This suggests both an obstructed arteriolar vascular bed as well as decompressing vessels from pulmonary artery to pulmonary vein. These are most likely bronchial venules and may represent the ‘‘misaligned pulmonary veins’’ described histologically.
affected parts of the lung. Further, studies are required to elucidate whether this angiographic finding can be used to substantiate the diagnosis instead of, or prior to, lung biopsy. Of note bronchial veins that drain the trachea and main bronchi return to the systemic venous circulation whereas bronchial veins draining lobar, segmental and peripheral bronchi return to pulmonary veins w27x. In pulmonary veno-occlusive disease and severe congenital pulmonary vein stenosis these bronchial veins become congested and enlarged and may bypass obstructed pulmonary vasculature w5x. This adds credence to the suggestion of Cullinane et al., that the so called ‘‘misaligned pulmonary veins’’ are decompressing bronchial venules w13x. Lung biopsy from an area of lung without severe capillary obstruction may account for the descriptions of alveolar capillary dysplasia without ‘‘misalignment of the pulmonary veins’’ as in patient 6 and has been described previously w16, 31x. Congenital acinar dysplasia may present a similar clinical picture to alveolar capillary dysplasia and may ultimately be distinguishable only by lung biopsy. The lung biopsy findings, clinical presentation and a familial case of congenital acinar dysplasia have been described previously w14, 30, 35x. Patient 7 had findings of both alveolar capillary dysplasia with misalignment of pulmonary veins and congenital acinar dysplasia. These findings were facilitated by the use of immunohistochemical
Article in press - uncorrected proof Eulmesekian et al., Alveolar capillary dysplasia 351
markers, which improved the diagnostic accuracy of lung biopsy. To our knowledge we believe this is the first patient reported with these two coexisting congenital structural lung abnormalities. Galambos et al. w15x using a genetically engineered mouse model, have demonstrated that absence of vascular endothelial growth factor (VEGF) isoforms 164 and 188 leads to defective air-blood barrier formation and delayed airspace maturation in the developing lung. In particular the epithelial expression of VEGF isoform 188 directs the juxtaposition of the growing capillary endothelium that leads to the formation of the air blood barriers w15x. It is possible that congenital acinar dysplasia and alveolar capillary dysplasia represent part of a histological spectrum of pulmonary vascular and alveolar maldevelopment related to abnormal VEGF isoform expression in the developing lung. Finally, we have documented another affected family, which adds support for the genetic basis of the disease w1, 3, 6, 17, 24, 26, 38, 43, 46x. In conclusion, we suggest that an early lung biopsy strategy can be performed with low risk and high diagnostic yield in neonates with refractory pulmonary hypertension who fail to improve quickly. The diagnosis is facilitated by the use of special immunohistochemical markers that emphasize the alveolar capillary relationship. Alveolar capillary dysplasia may be more frequently a cause of fatal neonatal pulmonary hypertension than realized previously. Alveolar capillary and acinar dysplasia may represent a histological spectrum of disease unified by abnormal VEGF isoform expression. Finally, we have added an additional familial case to the literature and suggest an angiographic finding that is worthy of further evaluation.
References w1x Abdallah HI, N Karmazin, LA Marks: Late presentation of misalignment of lung vessels with alveolar capillary dysplasia. Crit Care Med 21(4) (1993) 628 w2x Adolph V, H Flageole, T Perreault, A Johnston, L Nguyen, S Youssef, G Guttman, JM Laberge: Repair of congenital diaphragmatic hernia after weaning from extracorporeal membrane oxygenation. J Pediatr Surg 30 (1995) 349 w3x Alameh J, A Bachiri, L Devisme, P Truffert, T Rakza, Y Riou, S Manouvrier, P Lequien, L Storm: Alveolar capillary dysplasia: a cause of persistent pulmonary hypertension of the newborn. Eur J Pediatr 161 (2002) 262 w4x Atz AM, JA Feinstein, RA Jonas, SB Perry, DL Wessel: Preoperative management of pulmonary venous hypertension in hypoplastic left heart syndrome with restrictive atrial septal defect. Am J Cardiol 83 (1999) 1224 w5x Becker AE, MJ Becker, JE Edwards: Dilated bronchial veins within pulmonary parenchyma. Arch Path 21 (1971) 256 w6x Boggs S, MC Harris, DJ Hoffman, R Goal, D McDonaldMcGinn, C Langston, E Zackal, E Ruchelli: Misalignment of pulmonary veins with alveolar capillary dysplasia: affect-
w7x
w8x
w9x
w10x
w11x
w12x
w13x
w14x
w15x
w16x
w17x
w18x
w19x
w20x
w21x
w22x
ed siblings and variable phenotype expression. J Pediatr 124(1) (1994) 125 Bond SJ, DJ Lee, DL Stewart, JJ Buchino: Open lung biopsy in pediatric patients on ECMO. J Pediatr Surg 33 (1998) 1327 Bridges ND, GB Mallory, CB Huddleston, CE Canter, TL Spray: Lung transplantation in infancy and early childhood. J Heart Lung Transplant 15 (1996) 895 Cassidy J, J Smith, A Goldman, S Haynes, E Smith, C Wright, S Haworth, P Davis, R Firmin, K Kasem, C Davis: The incidence and characteristics of neonatal irreversible lung dysplasia. J Pediatr 141 (2002) 426 Cater G, DW Thibeault, EC Beatty, HW Kilbride, M Huntrakoon: Misalignment of lung vessels and alveolar capillary dysplasia: a cause of persistent pulmonary hypertension. J Pediatr 114 (1989) 293 Chelliah BP, D Brown, M Cohen, AJ Talleyrand, S ShenSchwarz: Alveolar capillary dysplasia – a cause of persistent pulmonary hypertension unresponsive to a second course of extracorporeal membrane oxygenation. Pediatrics (1995) 1159 Christou H, I Adatia, LJV Marter, JW Kane, JE Thompson, AR Stark, DL Wessel, S Kourembanos: Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5’monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension. J Pediatr 130 (1997) 603 Cullinane C, P Cox, M Silver: Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Pediatr Pathol 12 (1992) 499 Davidson LA, P Batman, DG Fagan: Congenital acinar dysplasia: a rare cause of pulmonary hypoplasia. Histopathology 32 (1998) 57 Galambos C, Y-S Ng, A Ali, A Noguchi, S Lovejoy, PA D’Amore, DE deMello: Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms. Am J Respir Cell Mol Biol 27 (2002) 194 Garola RE, DW Thibeault: Alveolar capillary dysplasia, with and without misalignment of pulmonary veins: an association of congenital anomalies. Am J Perinatol 15 (1998) 103 Gutierrez C, A Rodriguez, S Palenzuela, C Forteza, JL Rosello: Congenital misalignment of pulmonary veins with alveolar capillary dysplasia causing persistent neonatal pulmonary hypertension: report of two affected siblings. Pediatr Dev Pathol 3 (2000) 271 Haraida S, H Lochbu¨hler, A Heger, A Nerlich, J Diebold, I Wiest, J Mu¨ller-Ho¨cker, U Lo¨hrs: Congenital alveolar capillary dysplasia: rare cause of persistent pulmonary hyper-tension. Pediatr Path Lab Med 17 (1997) 959 Hintz SR, JA Vincent, PT Pitlick, JR Fineman, RH Steinhorn, GE Kim, WE Benitz: Alveolar capillary dysplasia: diagnostic potential for cardiac catheterization. J Perinatology 19 (1999) 441 Inwald D, K Brown, F Gensini, M Malone, A Goldman: Open lung biopsy in neonatal and paediatric patients referred for extracorporeal membrane oxygenation (ECMO). Thorax 59(4) (2004) 328 Janney CG, FB Askin, C Kuhn: Congenital alveolar capillary dysplasia – an unusual cause of respiratory distress in the newborn. Am J Clin Path 76(3) (1981) 722 Kitayama Y, S Kamata, H Okuyama, N Usui, T Sawai, T Kobayashi, Y Fukui, A Okada: Nitric oxide inhalation therapy for an infant with persistent pulmonary hypertension
Article in press - uncorrected proof 352 Eulmesekian et al., Alveolar capillary dysplasia
w23x
w24x
w25x w26x
w27x
w28x
w29x
w30x
w31x w32x
w33x
w34x
caused by misalignment of pulmonary veins with alveolar capillary dysplasia. J Pediatr Surg 32 (1997) 99 Lane JR, E Siwik, T Preminger, E Stork, M Spector: Prospective diagnosis of alveolar capillary dysplasia in infants with congenital heart disease. Am J Cardiol 84 (1999) 618 Licht C, S Schickendantz, N Sreeram, G Arnold, R Rossi, A Vierzig, U Mennicken, B Roth: Prolonged survival in alveolar capillary dysplasia syndrome. Eur J Pediatr 163(3) (2004) 181 MacMahon HE: Congenital alveolar dysplasia of the lungs. Am J Path 24(4) (1948) 919 Manouvrier-Hanu S, L Devisme, I Farre, V Hue, L Storme, N Kacet, O Boute-Benejean, JP Farriaux: Pulmonary hypertension of the newborn and urogenital anomalies in two male siblings: a new family with misalignment of pulmonary vessels. Genetic Counseling 7 (1996) 249 Matthews AW, R Buchanan: A case of pulmonary venoocclusive disease and a new bronchoscopic sign. Respir Med 84 (1990) 503 McGaughran J, DJ Souter, CA Kuschel: Alveolar capillary dysplasia with antenatal anomalies mimicking trisomy 21. J Paediatr Child Health 37 (2001) 85 Merchak A, GT Lueder, FV White, FS Cole: Alveolar capillary dysplasia with misalignment of pulmonary veins and anterior segment dysgenesis of the eye: report of a new association and review of the literature. J Perinatol 21 (2001) 327 Moerman P, C Vanhole, H Devlieger, H Fryns: Severe primary pulmonary hypoplasia (‘‘acinar dysplasia’’) in sibs: a genetically determined mesodermal defect? J Med Genetics 35(11) (1998) 964 Newman B, E Yunis: Primary alveolar capillary dysplasia. Pediatr Radiol 21 (1990) 20 Parker TA, DD Ivy, JP Kinsella, F Torielli, SZ Ruyle, EH Thilo, SH Abman: Combined therapy with inhaled nitric oxide and intravenous prostacyclin in an infant with alveolar-capillary dysplasia. Am J Respir Care Med 155 (1997) 743 Pucci A, C Zanini, F Ferrero, R Arisio, A Valori, P Abbruzzese, M Forni: Misalignment of lung vessels: diagnostic role of conventional histology and immunohistochemistry. Virchows Arch 442(6) (2003) 597 Rabah R, JM Poulik: Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome. Pediatric and Developmental Pathology 4 (2001) 167
w35x Rutledge JC, P Jensen: Acinar dysplasia: a new form of pulmonary maldevelopment. Hum Pathol 17 (1986) 1290 w36x Rychik J, JJ Rome, MH Collins, WM DeCampli, TL Spray: The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 34 (1999) 554 w37x Sigalet DL, A Tierney, V Adolph, T Perreault, N Finer, R Hallgreen, JM Laberge: Timing of repair of congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation support. J Pediatr Surg 30 (1995) 1183 w38x Simonton S, B Chrenka: Familial persistent pulmonary hypertension in two siblings with phocomelia and alveolar capillary dysplasia (ACD) A new syndrome? Mod Pathol 6 (1993) 9 w39x Sirkin W, BP O’Hare, PN Cox, D Perrin, MM Silver: Alveolar capillary dysplasia: lung biopsy diagnosis, nitric oxide responsiveness, and bronchial generation count. Pediatric Pathology and Laboratory Medicine 17 (1997) 125 w40x Steinhorn RH, PN Cox, JR Fineman, NN Finer, EM Rosenberg, MM Silver, J Tyebkhan, MS Zwass, FC Morin: Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia. J Pediatr 130(3) (1997) 417 w41x Thibeault DW, RE Garcia, HW Kilbride: Alveolar capillary dysplasia: an emerging syndrome. J Pediatr 134 (1999) w42x Tibballs J, CW Chow: Incidence of alveolar capillary dysplasia in severe idiopathic persistent pulmonary hypertension of the newborn. J Paediatr Child Health 38 (2002) 397 w43x Vassa HB, M Malone, AJ Petros, RM Winter: Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (cogenital alveolar capillary dysplasia). J Med Genet 35 (1998) 58 w44x Vick RN, T Owens, KJ Moise, N Chescheir, TP Bukowski: Urethral atresia in a neonate with alveolar capillary dysplasia and pulmonary venous misalignment. Urology 55 (2000) 774 w45x Wagenvoort CA: Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Human Pathol 17(7) (1986) 727 w46x Witters I, K Devriendt, P Moerman, J Caudron, CV Hole, J-P Fryns: Bilateral tibial agenesis with ectrodactyly (OMIM 119100); further evidence for autosomal recessive inheritance. Am J Med Genet 104 (2001) 209
Received March 2, 2005. Accepted May 17, 2005.
