Diagnoses: Pulmonary hypertension of newborn due to alveolar capillary dysplasia and misalignment of anomalous veins. Rectal atresia, status post colostomy.


Discussion: Alveolar capillary dysplasia (hypoplasia) with misaligned veins

Introduction: This entity was first described in 1981 as a cause of persistent pulmonary hypertension of the newborn [1]. It is characterized histologically by poor development of capillaries and small veins. As a result, new venous channels develop in utero in the bronchovascular bundle. These channels then connect with larger, normally situated, pulmonary veins that have the usual connections to the heart.

Clinical features: This syndrome occurs in term babies of both sexes. Affected infants have normal Apgar scores at birth but develop cyanosis and difficulty breathing on the first or second day of life, sometimes later. In contrast to other types of persistent pulmonary hypertension of the newborn, which are often reversible, this condition is probably irreversible, death usually occurring by 3 to 4 weeks despite maximal life support including ECMO or nitric oxide (NO). Reports of 14 males and 7 females are summarized in Table 1. The patient presented here is case 3 of reference 13.

Table 1. Summary of Cases, Clinical Events, and Pathology

Case no. Sex [ref]

Age at death

*Radial alveolar count

Comment

1. F [1]

40 h

Normal

--

2. M [2]

30 h

Normal

--

3. F [3]

11 d

Normal

--

4. F [3]

10 d

Normal

--

5. M [4]

13 d

Low

Received **ECMO 10 d; twin sibling normal

6. M [4]

60 h

Low

--

7. M [5]

49 h

Normal

--

8. F [6]

12 d

Low

--

9. F [6]

30 d

Low

--

10. F [7]

5 wks

--

Sibling of case 11

11. M [7]

--

--

Received ECMO

12. M [8]

40 d

--

Disease patchy histologically. Prior female sibling affected

13. M [9]

28 d

--

2 courses of ECMO (20 d total)

14. M [10]

4 d

Low

--

15. M [11]

44 d

--

Disease patchy histologically. Onset day 42

16. M [12]

58 d

Low

***NO (50 d) and PGI2 (41 d) used together

17-21. 4M/1F [13]

19.2 ± 3.7 d

--

Four treated with ECMO, 5 treated with NO. Three diagnosed by lung biopsy

*A measure of alveolar number, **ECMO = Extracorporeal membrane oxygenation, ***NO = nitric oxide

Accompanying congenital anomalies are common (gastrointestinal, genitourinary, or vascular) but not consistent (Table 2).

Table 2. Congenital Anomalies in 8 of 14 Infants with Alveolar Capillary Dysplasia

Agangliosis or hypogangliosis, colon (3 cases) [4,5,13]

Single umbilical artery (2) [3,13]

Duodenal stenosis (annular pancreas) (2) [4,9]

Cor triatriatum [5]

Imperforate anus (2) [10,13]

Persistent left superior vena cava [7]

Absent gall bladder [13]

Retroesophageal subclavian artery [1]

Volvulus [4]

Tracheo-esophageal fistula [9]

Bilateral hydronephrosis (2) [3,8]

Polyhydramnios (2) [7,9]

Unilateral cryptorchism [9]

Phocomelia [13]

Bicornuate uterus [1]

Radiographic features: Patchy or diffuse opacities have been described as granular or hazy [10, 12].

Gross appearance: The lungs are usually of normal weight, size, and lobation. Main pulmonary artery and venous connections are normal.

Histologic findings: The changes are parenchymal and vascular. At low power, airways appear normal but the alveoli are poorly developed. Alveolar ducts are enlarged, and distal air spaces (quantified by the radial alveolar count) are described as diminished in number in all but the earliest reports. Air space walls are thickened by edematous, connective tissue and lined by flat to cuboid type II cells. Interlobular septa appear to be edematous and increased in number. Overall, the ratio of air space to parenchyma is decreased compared to normal [4].

Pulmonary arteries and arterioles course normally but have increased muscle. Dilated intra-acinar venules accompany the pulmonary arterioles. Airspace capillaries are decreased in number and do not make contact with the epithelial basement membrane. Anomalous centriacinar veins (so-called "misaligned" veins because they are not situated in the interlobular septa as are normal pulmonary veins) accompany bronchovascular bundles beginning with small bronchi and extending throughout the bronchiolar region. The "misaligned" veins often share the adventitia of the artery. Although they sometimes anastomose with bronchial veins, their size suggests that they have developed separately from the bronchial vessels [4]. They are believed to connect with proximal large veins that are located away from the arteries, as usual. The peripheral interlobular septa have few veins. There is no thickening of venous walls to indicate obstruction. Lymphatics, identified by their very thin walls, are moderately prominent in bronchovascular bundles, interlobular septa, and pleura. In some cases, the abnormality does not involve the entire lung [8, 11].

Summary of Histologic Features

Differential diagnosis: Other causes of pulmonary hypertension in the newborn include pulmonary venous obstruction related to cardiac anomalies, upper airway obstruction (especially in infants with late onset of symptoms) [7], sepsis, pneumonia, infant respiratory distress syndrome, and persistent fetal circulation [5].

Treatment and prognosis: Diagnosis has been established by lung biopsy in three infants [13]. Infants have transient, but not sustained, responses to standard measures to treat persistent hypertension including ECMO and NO. To date, all infants have died.

Proposed mechanism: In this entity, vascular development apparently lags behind air space development [1, 2]. The pulmonary hypertension is believed to be caused by hypoplasia of alveolar capillaries and small veins. Medial thickening of arteries and arterioles persists after birth. Venous return to the heart is probably effected via the anomalous veins that course in the bronchovascular bundle [6]. These veins then anastomose with proximal large pulmonary veins to return blood to the heart [4]. Spheres, 15 µm in diameter, injected into the pulmonary artery at autopsy fill small arteries but do not fill the anomalous veins, indicating the absence of direct A-V shunts [4]. Obstruction to blood flow is suggested by the prominent lymphatics, the interstitial edema, and the radiographic opacities. In normal intrauterine lung growth, capillaries develop rapidly during the canalicular phase after 16 weeks [14]. Possibly the abnormal development occurs at that time.

Summary of stages of intrauterine lung growth: A pseudoglandular phase, characterized by development of airways to the terminal bronchioles, lasts until 16 weeks' gestation. The canalicular phase, which lasts from 16 to 28 weeks, shows development of the acinus and its vessels. The saccular stage (28 to 36 weeks) shows subdivision of saccules by secondary crests. Alveoli with single capillaries in their walls develop after 36 weeks [14].

References

1. Janney C, Askin F, Kuhn III C. Congenital alveolar capillary dysplasia--an unusual cause of respiratory distress in the newborn. Am J Clin Pathol 1981; 76:722-727.

2. Khorsand J, Tennant R, Gillies C, Phillipps A. Congenital alveolar capillary dysplasia: a developmental vascular anomaly causing persistent pulmonary hypertension of the newborn. Ped Pathol 1985; 3:299-306.

3. Wagenvoort C. Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Hum Pathol 1986; 17:727-730.

4. Cater G, Thibeault D, Beatty Jr E, Kilbride H, Huntrakoon M. Misalignment of lung vessels and alveolar capillary dysplasia: a cause of persistent pulmonary hypertension. J Pediatr 1989; 114:293-300.

5. Langston C. Misalignment of pulmonary veins and alveolar capillary dysplasia. Ped Pathol 1991; 11:163-170.

6. Cullinane C, Cox P, Silver M. Persistent pulmonary hypertension of the newborn due to alveolar capillary dysplasia. Ped Pathol 1992; 12:499-514.

7. Abdallah H, Karmazin N, Marks L. Late presentation of misalignment of lung vessels with alveolar capillary dysplasia. Crit Care Med 1993; 21:628-630.

8. Boggs S, Harris M, Hoffman D, Goel R, McDonald-McGinn D, Langston C, Zackai E, et al. Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression. J Pediatr 1994; 124:125-128.

9. Chelliah B, Brown D, Cohen M, Talleyrand A, Shen-Schwarz S. Alveolar capillary dysplasia--a cause of persistent pulmonary hypertension unresponsive to a second course of extracorporeal membrane oxygenation. Pediatrics 1995; 96:1159-1161.

10. Ng P, Lewindon P, Siu Y, To K, Wong W. Congenital misalignment of pulmonary vessels: an unusual syndrome associated with PPHN. Acta Paediatr 1995; 84:349-353.

11. Oldenburg J, Van Der Pal H, Schrevel L, Blok A, Wagenvoort C. Misalignment of lung vessels and alveolar capillary dysplasia. Histopathology 1995; 27:192-194.

12. Parker T, Ivy D, Kinsella J, Torielli F, Ruyle S, Thilo E, Abman S. Combined therapy with inhaled nitric oxide and intravenous prostacyclin in an infant with alveolar-capillary dysplasia. Am J Respir Crit Care Med 1997; 155:743-746.

13. Steinhorn R, Cox P, Fineman J, Finer N, Rosenberg E, Silver M, Tyebkhan J, et al. Inhaled nitric oxide enhances oxygenation but not survival in infants with alveolar capillary dysplasia. J Pediatr 1997; 130:417-422.

14. Langston C, Kida K, Reed M, Thurlbeck W. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis 1984; 129:607-613.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 5/10/97

Copyright 1997 Martha L. Warnock. All rights reserved.