Volume 69, Number 6 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright © 2014 by Lippincott Williams & Wilkins

CME REVIEW ARTICLE

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 CreditsTM can be earned in 2014. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.

Isolated Unilateral Pulmonary Agenesis and Other Fetal Thoracic Anomalies Bronwyn C. Russell, BS,* Paul Whitecar, MD,† and Joshua F. Nitsche, MD, PhD‡ *Medical Student, †Associate Professor, and ‡Assistant Professor, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC Importance: Although the diagnostic workup and management regimens for many of the common fetal thoracic lesions have been well described, the understanding of pulmonary agenesis is more limited. A better understanding of the published reports of this condition is essential to provide proper care for these complicated pregnancies. Objective: The aims of this study were to provide a better understanding of the difficulties in the diagnosis and management of fetal thoracic lesions and to consolidate what is known about unilateral pulmonary agenesis. Evidence Acquisition: We performed a review of the English medical literature covering the last 20 years (1993–2013) in PubMed, MEDLINE, and MD Consult using search terms pulmonary agenesis, pulmonary aplasia, unilateral pulmonary agenesis, unilateral pulmonary aplasia, lung agenesis, lung aplasia, unilateral lung agenesis, and unilateral lung aplasia. Results: Prenatal diagnosis of pulmonary agenesis and other fetal thoracic lesions can be particularly challenging given that many anomalies have similar appearance on ultrasound. Fetal magnetic resonance imaging has been used in several of the reported cases to clarify the diagnosis. Once confirmed, there are several important prognostic factors to consider in the management of unilateral pulmonary agenesis. Poor prognostic factors include right-sided agenesis, the presence of genetic abnormalities, and other associated congenital anomalies. Conclusion and Relevance: Fetal magnetic resonance imaging can be a useful imaging modality when the diagnosis is unclear after ultrasound imaging. The management of cases with a poor prognosis should be guided by the nature of the associated anomalies. Cases of isolated pulmonary agenesis have an overall good prognosis and can be managed conservatively during pregnancy, with consideration of delivery at a tertiary care facility in case postnatal respiratory issues arise. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to distinguish unilateral pulmonary agenesis from other thoracic congenital anomalies, identify the main predictors of prognosis for unilateral pulmonary agenesis, and identify the congenital anomalies that can be associated with unilateral pulmonary agenesis.

The embryonic development of the respiratory system begins during the sixth week of gestation, when the respiratory diverticulum begins to form along the All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Correspondence requests to: Joshua F. Nitsche, MD, PhD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: [email protected].

ventral surface of the foregut. This diverticulum elongates caudally, but becomes separated from the foregut, which will ultimately form the esophagus, by the esophagotracheal septum. During the seventh week of gestation, the respiratory diverticulum begins to branch and form the bronchial buds, and further branching into higher-order airways continues until the seventh month of pregnancy. Development of the respiratory tree is generally divided into 3 stages: (1) the pseudoglandular period, (2) the canalicular period, and (3) the alveolar period. As the lung progresses through these stages,

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the airways become more canalized and increasingly vascularized to ultimately permit efficient gas exchange after birth. Abnormalities of the respiratory tree can arise from disruption of this process at any point during that time; however, the earlier insults lead to more serious pathology.1 With the advances in obstetrical ultrasound and prenatal diagnosis, many of the anomalies that arise from and around the respiratory tree can be diagnosed before birth. In clinical practice, the most commonly seen thoracic anomalies include congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS), and congenital high airway obstruction (CHAOS). Although it is not strictly speaking an inherent abnormality of the thorax, a congenital diaphragmatic hernia (CDH) is often considered with these entities because the resultant intrathoracic bowel can have similar impact on the anatomy of other thoracic structures. Other more rare anomalies include bronchogenic cysts, esophageal duplication cysts, teratoma, neuroblastoma, and pulmonary agenesis. The latter is the focus of this review. Typically, these anomalies present with an echogenic mass within the thorax and/or mediastinal shift on ultrasound. Arriving at a clear diagnosis can be difficult because many of the anomalies have a similar echogenic and/or cystic appearance. This difficulty is illustrated in the cases presented below. CASE 1 A 36-year-old woman, gravida 3, para 2, 0 preterm birth, 0 abortion, and 2 living children, with a spontaneously conceived pregnancy confirmed by a firsttrimester ultrasound was referred to our practice after discovery of a large multicystic chest mass and accompanying mediastinal shift on an ultrasound performed in her primary obstetrician’s office. She had 2 prior uncomplicated pregnancies that ended in spontaneous vaginal deliveries at term. The initial ultrasound performed at our office at 31 weeks demonstrated a discrete cystic and echogenic area in the left hemithorax with moderate rightward displacement of the mediastinum. A dominant fluid-filled cyst was noted within the mass. The stomach and the liver visualized were within the abdomen. She was given the diagnosis of a type I CPAM, and the CPAM volume ratio (CVR) was calculated to be 0.3. A fetal echocardiogram confirmed normal cardiac anatomy. Antenatal fetal surveillance was started at 32 weeks. Serial ultrasound demonstrated a progressive increase in size with a maximum CVR of 2.1 found at 36 weeks. No evidence of hydrops was noted, and antenatal fetal testing remained reassuring.

An induction of labor was undertaken at 39 weeks, after which she had an uncomplicated spontaneous vaginal delivery of a male infant weighing 3696 g. The Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The infant experienced no respiratory distress and was maintained on room air until he underwent resection of the CPAM on day of life 2. He developed a superficial wound infection on day of life 5, which resolved with antibiotic therapy. The infant was discharged home on day of life 9. CASE 2 A 31-year-old gravida 1, para 0, with a spontaneously conceived pregnancy was referred to our office for further evaluation of a pleural effusion. Her initial ultrasound performed in our office at 20 weeks of gestation demonstrated a left-sided pleural effusion and a moderate rightward mediastinal shift. The contents of the left hemithorax were noted to have an echotexture similar to that of a normal lung. No evidence of hydrops was noted at that time. A follow-up ultrasound was performed at 24 weeks without any interval change in the ultrasound findings. Because the diagnosis was still in doubt, with CPAM, BPS, and CDH all on the differential, a fetal magnetic resonance imaging (MRI) was performed at 26 weeks. This demonstrated a CDH with the bowel extending into the left side of the chest. A fetal echocardiogram was performed and confirmed normal cardiac anatomy and function. On subsequent ultrasounds, the observed to expected lung-head ratio was calculated and found to vary between 75% and 85%, indicating a low risk for significant pulmonary hypoplasia. She went into spontaneous labor at 38 weeks but experienced arrest of the first stage of labor and delivered a female infant weighing 3112 g via low transverse cesarean delivery without further complication. The infant was immediately intubated at delivery and maintained on mechanical ventilation until she underwent an uncomplicated CDH closure on day of life 5. She was extubated and transitioned to nasal cannula on day of life 11. She was discharged home on day of life 17. CASE 3 A 34-year-old woman, gravida 2, para 1, 0 preterm birth, 0 abortion, 1 live child, with a spontaneously conceived pregnancy confirmed by a 9-week ultrasound was referred to our practice because of a suspected fetal chest abnormality. Before her referral, she received regular prenatal care and had a normal first-trimester screen.

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Pulmonary Agenesis and Fetal Thoracic Lesions • CME Review Article

Her first pregnancy 3 years prior was uncomplicated, resulting in a spontaneous vaginal delivery at term. She was referred because a routine ultrasound done by her primary physician at 18 weeks demonstrated a mediastinal shift. Our initial ultrasound confirmed the presence of a mediastinal shift with the heart in the anterior left side of the chest and a large, slightly echogenic and indistinct mass filling the entire chest cavity. No gross abnormalities of the heart were seen, and the diaphragm and remaining anatomy appeared normal. Fetal echocardiogram demonstrated abnormal position of the heart but normal structure and function. Although the etiology of the mediastinal shift was unclear at that time, CPAM, CDH, and CHAOS were all considered. An MRI was obtained at 24 weeks in an attempt to clarify the diagnosis. It was most consistent with, but not diagnostic of, CPAM. Weekly ultrasounds were performed to monitor for an increase in the size of the mass and the development of hydrops fetalis. The mediastinal shift remained stable, fetal growth was appropriate, and there were no signs of hydrops through 28 weeks of pregnancy. Two additional echocardiograms were performed and raised concern for narrowing of the aorta, possibly from external compression or congenital coarctation. Because the serial ultrasound still did not clearly establish a diagnosis, another MRI was performed at 28 weeks. It demonstrated agenesis of the left main stem bronchus and lung with a normal trachea and right main stem bronchus with a large but normal-appearing right lung. Overexpansion of the right lung caused the mediastinal shift to the left. No other structural abnormalities were noted. She received twice-weekly fetal testing beginning at 32 weeks and underwent an induction of labor at 37 weeks. She had a normal spontaneous vaginal delivery of a male infant without complications. The neonate weighed 3140 g and had Apgar score of 7 at 1 minute and 9 at 5 minutes. Soon after birth, he developed increased work of breathing and subcostal retractions requiring continuous positive airway pressure and eventual intubation at 8 minutes of life. After stabilization and transfer to the neonatal intensive care unit, an echocardiogram was performed and showed a slightly narrowed aortic arch but was without evidence of coarctation. The infant required ventilation until day of life 2, when he was transitioned to continuous positive airway pressure, then supplemental oxygen via nasal cannula. He was off all respiratory support by day of life 6 and was discharged home on day of life 9 in stable condition. The infant had follow-up at 2 weeks of life. He was growing appropriately, was without respiratory symptoms, and had

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been tolerating feedings well at the time of this report. DIFFERENTIAL DIAGNOSIS OF THORACIC LESIONS Case 1 illustrates a classic presentation of CPAM, which appears as an echogenic mass within the chest. It is estimated to have an incidence of 1 in 25,000 to 1 in 35,000 live births.2 Stocker3 most recently proposed 5 categories of CPAM: type 0 (bronchia), type I (bronchial/bronchiolar), type II (bronchiolar), type III (bronchiolar/alveolar), and type IV (peripheral). Types I, II, and III are the most common, representing 50%, 40%, and 10% of postnatal cases of CPAM, respectively.2 Types I and II are usually associated with a favorable outcome. The prognosis of type III lesions is more variable, with a larger proportion of fetuses developing hydrops.2 Type I and type II lesions often have large fluid-filled cysts within the lesion. This combination of an echogenic soft tissue with anechoic fluid-filled areas can be very similar in appearance to the intrathoracic stomach or bowel seen in CDH or the heterogenous appearance of several less common intrathoracic tumors such as a teratoma or neuroblastoma. Type III CPAM is generally solid and homogenous appearing on ultrasound and not dissimilar to BPS or CHAOS in appearance. Once confirmed, the size of the CPAM is typically monitored by determining the CVR, in which the volume of the CPAM (length  width  height  0.52) is divided by the head circumference. Values greater than 1.6 are associated with an 80% risk for hydrops and require close ultrasound monitoring.4 Bronchopulmonary sequestration is a mass of pulmonary tissues without communication to the bronchial tree that receives vascular supply from the systemic circulation. There are 2 main types of BPS, intralobar (75% of cases) and extralobar (25% of cases).5 Intralobar lesions share the same pleural covering as the normal lung, whereas extralobar lesions are surrounded by a separate pleural covering and can be seen in the abdomen.5 Definitive diagnosis of a BPS with ultrasound requires identification of a systemic feeding vessel with Doppler sonography, which is not always identifiable prenatally. Without clear identification of such a vessel, it is not possible to distinguish a BPS from a type III CPAM. Thoracic teratomas can appear similar to BPS; however, teratomas are often more heterogenous in appearance and contain higher-density structures, such as bone or cartilage, which can cause acoustic shadowing. Unlike CPAM, no prognostic conventions, such as CVR, have been described for BPS. However, the risk

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for hydrops and pulmonary hypoplasia correlates with the size of the mass. Case 2 illustrates a common presentation of CDH that is thought to be caused by failure of the pleuroperitoneal folds to close at 9 to 10 weeks of gestation.1 It has an incidence of approximately 1 in 220 births, with left-sided herniation being most common (85%–90%), followed by right-sided (10%–15%) and bilateral (2%)herniation.6 The defect leads to herniation of the bowel, the stomach, and sometimes the liver, into the thorax. The displaced viscera can cause a shift in the mediastinum and compress developing lung tissue. If this compression is severe, it can lead to fatal pulmonary hypoplasia. Congenital diaphragmatic hernia can be confused with CPAM, either type I when the bowel is fluid filled, which can be mistaken for macrocysts, or type III when the bowel is decompressed, which can be confused with a microcystic CPAM. Once confirmed, the prognosis of a CDH is typically determined by calculating the area of the lung contralateral to the CDH at the level of the 4-chamber view and dividing it by the head circumference to determine the lung-head ratio. Normative values are now available for fetuses without CDH so that the observed to expected lung head ratio (LHR) can also be determined, which has improved prognostic strength when compared with LHR not adjusted for gestational age.7 Although an observed to expected LHR of greater than 45% indicates an excellent chance of survival, few fetuses with values of less than 25% survive.7 Although the true incidence of CHAOS is unknown, it is thought to be significantly less common than CPAM, BPS, or CDH. Although there are several different causes of obstruction in CHAOS, such as laryngeal atresia, tracheal atresia, or laryngeal cysts, all have the same appearance on ultrasound.8 The obstruction traps fetal lung fluid and leads to overexpansion of the lungs. This in turn leads to inversion of the diaphragm and an anterior shift of the mediastinum. The main alternative diagnosis on the differential of CHAOS is bilateral type III CPAM because it demonstrates both bilateral echogenic masses and a mediastinal shift. However, bilateral CPAM is exceedingly rare, which should prompt one to consider CHAOS in this situation. Conventions to predict prognosis, such as CVR and LHR, are not necessary because each case of CHAOS requires an ex-utero intrapartum treatment procedure to establish a surgical airway before removal from the placental circulation. Pulmonary agenesis is a very rare condition that is estimated to affect 1 of 15,000 births.9–11 An established classification of pulmonary defects that was originally described by Schneider,12 and later modified

by Boyden,13 has 3 groupings: (1) pulmonary agenesis, which has complete absence of lung tissue, bronchi, and vasculature; (2) pulmonary aplasia, which has complete absence of lung tissue with a rudimentary bronchus; and (3) pulmonary hypoplasia, which has lung tissue and bronchi that are underdeveloped. Pulmonary agenesis can be bilateral or unilateral. Although bilateral agenesis is incompatible with life, the prognosis for unilateral agenesis is quite variable. Pulmonary agenesis is suspected to result from a disruption of normal lung bud development that begins during the sixth week of gestation. Inadequate blood supply due to underdeveloped bronchial arteries has been proposed as a possible mechanism for the insult.14 This could also explain why associated anomalies tend to be on the ipsilateral side, because many of the structures of the head and the neck develop from the first 2 branchial arches. This is in contrast to lung hypoplasia, which commonly occurs from space-restricting lesions or oligohydramnios.11,14 LITERATURE REVIEW Although pulmonary agenesis is more common than CPAM, the sonographic findings, associated conditions, natural history, and management of pulmonary agenesis are less well defined than those of other thoracic lesions. To gain a better grasp on this clinical entity, we performed a systematic review of the English medical literature covering the last 20 years (1993–2013) in PubMed, MEDLINE, and MD Consult using search terms pulmonary agenesis, pulmonary aplasia, unilateral pulmonary agenesis, unilateral pulmonary aplasia, lung agenesis, lung aplasia, unilateral lung agenesis, and unilateral lung aplasia. Cases with hypoplasia were excluded from the review. Reference lists from relevant articles were also examined for potential cases. This yielded a total of 55 articles, with a total of 96 cases described.9–11,14–65 The compiled list of reported cases is provided in Table 1. EPIDEMIOLOGY Of the 96 cases described, 23 were individuals with isolated unilateral pulmonary agenesis (24%), whereas the remaining 73 were individuals with unilateral pulmonary agenesis in association with multiple other anomalies (76%). A summary of the reported cases with regard to neonate sex, time and modality of diagnosis, sidedness, genetic testing results, associated anomalies, and mortality is provided in Table 2. Of note, when considering all 96 reported cases of unilateral pulmonary agenesis, there were more females affected (55%), there were more right-sided lesions

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Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Conway et al25

Banerjee et al19 Berkenstadt et al20 Borja et al21 Boulton and Force22 Chen et al23 Chen et al24 Chiang et al25 Chou et al26

Aggarwal et al15 Al-Owain et al16 Alsaadi et al17 Backer et al18

Guo et al9 Meller et al10 Bentsianov et al11

Reference

F M F F M F F F M M F F F F F M F M M F M M M M M F M F M F F M F F M F

F

4

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

F M F

Sex

1 2 3

Case No.

TABLE 1 Individual Case Characteristics

NR Birth 10 mo postnatal 1.7 y postnatal 13 d postnatal 2 mo postnatal 1 y postnatal 3.5 y postnatal 6 mo postnatal 4 mo postnatal 7 wk postnatal 6 wk postnatal 13 d postnatal 4 mo postnatal 23 y postnatal 22 wk gestation 5 mo postnatal NR 30 wk gestation Birth Birth 3 d postnatal Prenatal 1 d postnatal Prenatal 2 mo postnatal 3 d postnatal Prenatal 10 d postnatal 2 d postnatal Prenatal 3 d postnatal 1 d postnatal Prenatal 2 mo postnatal Birth

4 wk postnatal

5 y postnatal 22 wk gestation 5 y postnatal

Age of Diagnosis

NR Vici syndrome NR NR NR NR NR NR Trisomy 21 NR NR NR NR NR NR NR NR NR Normal karyotype NR NR 15q12 deletion 9q deletion 22q11 deletion NP Normal karyotype 46XY/45X NP NP NP NP Trisomy 21 Trisomy 21 NP NP 22q11.2 deletion

NR

NR NR NR

Genetic Testing

Right Left Left Left Right Right Right Right Left Right Right Right Right Right Left Right Right Left Right Right Left Left Left Left Left Right Right Right Right Right Right Right Right Right Right Left

Right

Left Right Left

Side of Aplasia Echocardiography, CXR US CXR, CT scan, bronchoscopy CXR, CT scan, bronchoscopy NR CT scan CXR, CT scan NR NR NR NR NR NR NR NR NR NR NR CXR US, autopsy CXR, MRI NR US NR CT scan NR NR NR NR NR NR NR NR NR NR NR NR NR NR CXR, CT scan

Modality of Diagnosis

NR NR NR A D A A A A D A A A A A TOP A A D D A D A D A D A D D D A D D D A NR

A

A A A

Status

(Continued on next page)

Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes None Yes No Yes Yes Yes Yes Yes NR Yes NR Yes Yes Yes Yes Yes Yes Yes Yes Yes NR Yes

No

Yes No No

Associated Anomaly

Pulmonary Agenesis and Fetal Thoracic Lesions • CME Review Article 339

14

59 60 61 62 63 64

Hastings et al39

77 78 79

Ootaki et al52

Nonaka et al50 Nowotny et al51

65 66 67 68 69 70 71 72 73 74 75 76

Kuwashima and Kaji43 Malcon et al44 Managoli et al45 Mohan et al46 Musleh et al47 Nazaroglu et al48 Nazir et al49

Heffron et al40 Kitagawa et al41 Krivchenya et al42

58

41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

Case No.

Hanna et al38

Downard et al28 Eroglu et al29 Fischer et al30 Fitoz et al31 Fuster et al32 Gabarre et al33 Gerard-Blanluet et al34 Gokhan et al35 Greenough et al36 Guven et al37

CunninghamandMann

Reference

TABLE 1. (Continued)

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. M M M

M M M F M M M M M M M F

F F F F F F

F

M F F F F M M F F F F M NR M F NR M

Sex

2 mo postnatal 6 d postnatal 1 d postnatal

Birth 8 y postnatal Birth 15 y postnatal 8 y postnatal 3 mo postnatal 2 mo postnatal 8 mo postnatal 9 mo postnatal 22 wk gestation 34 wk gestation Prenatal

20 wk gestation 21 wk gestation 20 wk gestation Birth Birth 3 mo postnatal

Birth

Birth Birth Birth Birth Birth Birth Birth 19 wk gestation 22 mo postnatal Birth 22 d postnatal 43 y postnatal 14 wk gestation Birth Birth 20 wk gestation 7 y postnatal

Age of Diagnosis

NR NR NR

NR NR NR NR NR NR NR NR NR NR Normal karyotype NR

Heterozygous 9p22.31 deletion (ROR2 gene) Normal karyotype* Normal karyotype Normal karyotype NR NR NR

Normal karyotype VACTERL syndrome VACTERL syndrome VACTERL syndrome VACTERL syndrome VACTERL syndrome NP Normal karyotype NR Goldenhar syndrome 22q11.2 deletion NR Normal karyotype Normal karyotype NR Goldenhar syndrome NR

Genetic Testing

Right Right Left

Right Left Left Right Left Right Left Left Left Right Right Right

Left Left Right Right Right Right

Right

Right Right Left Left Right Left Right Right Right Left Left Left Left Right Right Left Right

Side of Aplasia

US, MRI US, CXR, MRI US, CT scan CXR, US CXR CXR, digital subtraction cardiopulmonogram US, MRI, CXR, CT scan CXR, CT scan Autopsy CXR, CT scan NR CXR, CT scan CXR, CT scan CXR, CT scan CXR, CT scan US, MRI US, CXR, CT scan US, CXR, CT scan, bronchoscopy NR CT scan CT scan

Autopsy NR NR NR Autopsy NR NR US, CXR, CT scan CXR, CT scan CXR, CT scan CXR, CT scan, MRI Routine medical examination Transvaginal ultrasound Autopsy CXR, autopsy US, CT scan CXR, bronchoscopy, pulmonary angiography NR

Modality of Diagnosis

Yes Yes Yes

Yes No Yes No No No Yes Yes Yes No No No

Yes Yes Yes Yes Yes No

Yes

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes No

Associated Anomaly

A D A

NR A D A A A A A A A A A

A D A A A A

D

A NR NR NR D D D A NR A NR A A TOP D A NR

Status

340 Obstetrical and Gynecological Survey

*A 15Mb deletion within 15q11.2 was detected but not thought to be related to the fetal anomalies. A, alive; CT, computed tomography; CXR, chest x-ray; D, deceased; F, female; M, male; NP, not performed; NR, not reported; TOP, termination of pregnancy; US, ultrasound; VACTERL, vertebral anomalies, anal atresia, cardiac anomalies, tracheo-esophageal fistula, renal anomalies, limb anomalies.

A A A TOP D A Yes No No No Yes Yes US, CXR, CT scan Bronchoscopy, CT scan US, MRI US Autopsy Fluoroscopy, CXR, bronchoscopy Right Right Left Left Left Right F F M NR F F

Sicuranza and Figueroa60 Steadland et al61 Thomas et al62 Trivedi et al63 Viora et al64 Zhang et al65

Ratan and Grover56 Rathkopf et al57 Roque et al58 Sharma et al59

91 92 93 94 95 96

Prenatal 1.5 y postnatal 21 wk gestation 23 wk gestation 4 mo postnatal 18 mo postnatal

NR NR NR Normal karyotype NR NR

CXR, CT scan NR US, CXR, CT scan CXR CXR CXR, US NR CXR, CT CXR, CT scan CXR, CT scan NR M M NR F F F F F F F F Pahuja and Lee53 Palma et al54 Pu et al55

80 81 82 83 84 85 86 87 88 89 90

Birth Birth Birth Birth Birth 15 d postnatal 6 mo Birth 13 y postnatal 10 y postnatal Birth

NR NR NR NR NR NR NR Normal karyotype NR NR NR

Right Left Right Right Right Right Right Right Right Left Right

Yes Yes Yes Yes Yes Yes No Yes No No Yes

D A D A A D A D A A A

Pulmonary Agenesis and Fetal Thoracic Lesions • CME Review Article

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(62%), and a little more than half of affected individuals were alive at the time of the report (57%). Only a small minority (21%) were detected prenatally, whereas most were detected between birth and 2 weeks of age (39%) and 2 weeks and 1 year of age (23%). Genetic testing was performed in a minority of cases (30%). Identified genetic abnormalities included abnormal karyotype, chromosome deletions, and mutations associated with known genetic syndromes. When comparing cases with isolated pulmonary agenesis with cases associated with other congenital anomalies, several distinctions become apparent. Diagnosis prenatally and before age of 1 year was more common in cases with other congenital anomalies, presumably because of the increased scrutiny these fetuses/children receive. Genetic abnormalities seem to be more common in cases with multiple anomalies (70% of the 27 cases tested); however, it is difficult to make a clear comparison because genetic testing was performed in only 3 of the 23 cases of isolated pulmonary agenesis. In addition, whereas 37% of individuals with multiple anomalies had died, all of the reported cases of isolated pulmonary agenesis were alive at the time of the report. ROLE OF MRI When a thoracic abnormality is identified by ultrasound, it may be difficult to identify the specific etiology because many thoracic lesions, such as CDH, CPAM, CHAOS, and pulmonary agenesis, have similar echogenicity. Fetal MRI has the potential to overcome the diagnostic difficulties with ultrasound because it is able to visualize multiple planes simultaneously and better differentiate between various tissue types.66–68 For example, in CDH, left-sided herniation is more common than right-sided herniation, and it is necessary to recognize the bowel in chest or liver herniation. Although nonperistaltic bowel loops can be confused with CPAM and the liver shares similar echogenicity with lung tissue on ultrasound, each has characteristic signal intensities on MRI that make it readily identifiable.67–70 In addition, the location and size of the diaphragmatic hernia can be more easily identified on MRI.69,70 Furthermore, in some cases, type III CPAM can be difficult to distinguish from normal lung tissue with ultrasound. However, on MRI, CPAM will show higher signal intensity than normal lung tissue throughout gestational age.69 The central abnormality in CHAOS is laryngotracheal atresia, which leads to overdistension of the lungs with fluid. Visualization of this primary lesion itself is virtually impossible with standard ultrasound, requiring the diagnosis to be made by the detection

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TABLE 2 Characteristics of Reported Cases of Pulmonary Agenesis Parameter Sex Male Female Not reported Time of diagnosis Prenatal Birth to 2 wk 2 wk to 1 y 1 y to 5 y 6 y to 10 y After 10 y Not reported Side Left Right Genetic testing Not reported or performed Performed Normal Abnormal karyotype Deletion Known syndrome Patient status Alive Deceased Termination of pregnancy Not reported Total

Isolated Agenesis

Multiple Anomalies

Total

9 (39%) 12 (52%) 2 (9%)

30 (41%) 41 (56%) 2 (3%)

39 (41%) 53 (55%) 4 (4%)

7 (30%) 0 6 (26%) 2 (9%) 4 (17%) 4 (17%) 0

13 (18%) 37 (51%) 16 (22%) 5 (7%) 0 0 2 (3%)

20 (21%) 37 (39%) 22 (23%) 7 (7%) 4 (4%) 4 (4%) 2 (2%)

10 (43%) 13 (57%)

26 (36%) 47 (64%)

36 (38%) 60 (62%)

20 (87%) 3 (13%) 3 (100%) 0 0 0

46 (63%) 27 (37%) 8 (30%) 4 (14%) 7 (26%) 8 (30%)

66 (69%) 30 (31%) 11 (37%) 4 (13%) 7 (23%) 8 (27%)

22 (96%) 0 1 (4%) 0 23 (24%)

35 (48%) 27 (37%) 2 (3%) 9 (12%) 73 (76%)

55 (57%) 27 (28%) 3 (3%) 11 (12%) 96

of the secondary lung overdistention. However, the improved anatomic resolution of MRI allows the primary laryngotracheal atresia to be identified along with the secondary effects of bilaterally enlarged lungs, with a homogeneously higher signal for gestational age; diaphragmatic eversion; and a distended, fluid-filled trachea and bronchi.71 In addition to its improved diagnostic capabilities, MRI also offers the potential to improve prediction of prognosis in these different thoracic lesions discussed above. The outcomes for fetuses and neonates with thoracic lesions depend primarily on how much normal lung tissue is present at the time of birth. Magnetic resonance imaging has the ability to accurately evaluate residual normal lung volume.72–75 In the case of CDH, MRI has been shown to be superior to ultrasound in predicting survival.76 ASSOCIATED ANOMALIES AND PROGNOSIS For unilateral pulmonary agenesis, which, by nature of the abnormality, has a significant amount of normal lung tissue remaining, prognosis depends on several other factors, the most important being the presence

of other anomalies that carry a worse prognosis. Rightsided agenesis also denotes a worse prognosis. The reason for this is unknown but may be due to the greater displacement of the mediastinum with overexpansion of the left lung.10,11 Pulmonary agenesis can be associated with cardiac, tracheal, skeletal, renal, gastrointestinal, limb, and facial abnormalities. Cardiac manifestations include atrial septal defect (ASD), ventricular septal defect, patent ductus arteriosus, total anomalous pulmonary venous return, pulmonary artery sling, and persistent left superior vena cava.9,12,18,20,23,25–27,29–31,38,39,49,52,54–56,58,65 Tracheal stenosis and tracheoesophageal fistulas have also been reported along with unilateral pulmonary agenesis.14,18,22,24,41,53,61,65 Skeletal abnormalities such as vertebral dysplasia, scoliosis, and extra ribs have been reported.9,14,23,29,30,36,43,45,55,58,60 Reported associated renal anomalies include horseshoe kidneys, hypoplasia, or renal agenesis.14,23,29,34,43,45,49,52,55,58 Associated gastrointestinal anomalies have been seen throughout the tract from esophageal atresia to imperforate anus.14,22,24,28,34,38,40,42,49,61,65 Limb and facial defects including cleft palate and lip, microtia, micrognathia, syndactyly, and digit malposition have been

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Pulmonary Agenesis and Fetal Thoracic Lesions • CME Review Article

described.14–16,20,23,25,27,30,31,36,38,39,45,49,55,58 Pulmonary agenesis is also included as a component in several syndromes including Goldenhar syndrome, Vici syndrome, and the VACTERL sequence. Reports of pulmonary agenesis in trisomy 21 and microdeletions in 22q11.2 (DiGeorge syndrome) have also been described.39 Surgical repair is often required in those individuals with multiple anomalies, the most common of which are for cardiac and tracheal conditions. Outcomes of these operations are varied. Of those with normal or unknown genetics, there were 19 cases of significant heart anomalies, and 11 underwent corrective surgery, with 9 surviving.9,25,26,39,49,52,54,65 Of the remaining 8 who did not have surgery,14,23,26,39,58 only 1 survived.49 Combined cardiac and tracheal conditions accounted for 14 patients, all of whom underwent surgery, with 8 surviving18,55 and 6 deceased.18,26,52,55,65 Tracheal conditions were found in 8 patients, 6 of whom underwent surgery, with 5 surviving.18,22,41,61 The 2 individuals who did not undergo surgery did not survive.24,53 In the 4 patients in whom abnormal karyotypes were found, 1 underwent ASD/ ventricular septal defect repair and survived,26 2 with trisomy 21 did not undergo surgery and did not survive,26 whereas 1 with trisomy 21 underwent a tracheostomy and survived.18 The results of those with chromosomal deletions were mixed: 2 who did not undergo surgery did not survive,26,38 1 who did not undergo surgery survived,26 1 who underwent an aortoplasty did not survive,26 1 who underwent surgery for ASD/total anomalous pulmonary venous return repair survived,39 and 2 outcomes were not reported.27,31 Of the 8 individuals withgenetic abnormalities correlated with known syndromes, only 1 underwent surgery. One survived36; 2 did not survive12; and in 5 cases, the outcome was not reported, including the one who underwent surgery.14,16,30 On the basis of our literature review, patients with isolated unilateral pulmonary agenesis, as was seen in case 3, have a much improved prognosis compared with those with other structural anomalies.44 Although there are concerns related to diminished lung capacity, many individuals live without limitations, as evidenced by the number of cases diagnosed incidentally later in childhood and into adulthood. There is also concern for recurrent pulmonary infections in these patients because they may be both more susceptible to initial infection and less able to clear established infections given the altered anatomy.49 In that regard, good pulmonary hygiene and vaccination against common respiratory pathogens will be important for long-term health in these individuals. Although review of the literature suggests an overall good prognosis, there is limited information regarding the long-term outcomes in people with isolated pulmonary agenesis.

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SUMMARY Establishing the definitive diagnosis of fetal thoracic anomalies with ultrasound can be challenging because nearly all of the possible clinical entities have a similar sonographic appearance and all can cause a mediastinal shift. Although more thoroughly described anomalies such as CPAM, BPS, CHAOS, and CDH are usually on the differential upon presentation, unilateral pulmonary agenesis is often not considered. Thus, it is important to consider pulmonary agenesis in the differential diagnosis or it will be missed. The difficulty in diagnosing isolated pulmonary agenesis prenatally is further complicated by the fact that the mediastinal shift may be subtle or not present at all. This likely explains why many cases go undiagnosed well into childhood and even adulthood, when these are discovered incidentally during an unrelated medical evaluation. As was demonstrated in cases 2 and 3, fetal MRI can be a useful adjunct to ultrasound in the assessment of a mediastinal shift.39,50,63 It is also important to perform a thorough assessment of the entire fetus when pulmonary agenesis is suspected, paying particular attention for malformations of the head, the neck, and cardiac structures. Because the sonographic findings of the pulmonary agenesis itself are subtle, the diagnosis is most often made during a detailed fetal anatomic assessment prompted by the discovery of more obvious malformations. The overall prognosis of fetuses and newborns with pulmonary agenesis is best predicted by the severity of the associated anomalies and the presence of genetic abnormalities. Because there were favorable outcomes in the few reported cases of prenatally diagnosed isolated pulmonary agenesis and many cases go undiagnosed until well after birth, the overall prognosis in such cases is likely very good. MANAGEMENT RECOMMENDATIONS 1. When an ultrasound demonstrates an echogenic mass, an isolated mediastinal shift, heart malposition, or inability to locate pulmonary arteries, pulmonary agenesis should be in the differential, along with CPAM, CDH, and CHAOS. 2. When anomalies are identified, particularly those of the head, the neck, and cardiac structures, assessment of the fetal thorax and the mediastinum is necessary to determine whether pulmonary agenesis is also present. If the nature of the mass or the cause of the mediastinal shift cannot be readily determined using ultrasound alone, a fetal MRI should be considered if the equipment and expertise are available.

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Obstetrical and Gynecological Survey

3. Parents should be counseled that the prognosis is guarded in cases of pulmonary agenesis associated with other anomalies and/or genetic abnormalities. 4. Although the prognosis is very good in cases of isolated pulmonary agenesis, it is prudent to arrange a prenatal consultation with a pediatric surgeon and arrange for delivery in a tertiary care center so that the appropriate care can be provided if complications do arise.

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