History

There is wide variation in the clinical presentation of pulmonary hypoplasia, depending on the extent of hypoplasia and other associated anomalies.^[16]

The history may include poor fetal movement or amniotic fluid leakage and oligohydramnios. The neonate may be asymptomatic or may present with severe respiratory distress or apnea that requires extensive ventilatory support. In older children, dyspnea and cyanosis may be present upon exertion, or a history of repeated respiratory infections may be noted.

Physical

The external chest may appear normal or may be small and bell shaped, with or without scoliosis. A mediastinal shift is observed toward the involved side, and dullness upon percussion is heard over the displaced heart. In right-sided hypoplasia, the heart is displaced to the right, which may lead to a mistaken diagnosis of dextrocardia. Breath sounds may be decreased or absent on the side of hypoplasia, especially over the bases and axilla.

Some infants may present with otherwise asymptomatic tachypnea, and other may have severe respiratory distress at birth requiring ventilatory support. Pneumothorax, either spontaneous or associated with mechanical ventilation, may occur.

Infants with secondary pulmonary hypoplasia may have associated congenital anomalies or features suggestive of neuromuscular diseases. Such patients may have myopathic facies, with a V-shaped mouth, muscle weakness, and growth restriction. Multiple genetic syndromes associated with primary pulmonary hypoplasia are reported in the literature such as Scimitar Syndrome, Trisomy 21, and Pena-Shokeir Syndrome (fetal akinesia).^{[28, 29]}

Compression deformities due to prolonged oligohydramnios, contractures, and arthrogryposis may be present. The Potter facies (hypertelorism, epicanthus, retrognathia, depressed nasal bridge, low set ears) suggest the possibility of lung hypoplasia caused by the associated renal defects.

Abdominal masses, such as cystic renal diseases and an enlarged bladder, must be sought. Associated anomalies of the cardiovascular, gastrointestinal (eg, tracheoesophageal fistula, imperforate anus, communicating bronchopulmonary foregut malformation), and genitourinary systems, as well as skeletal anomalies of the vertebrae, thoracic cage, and upper limbs, may be found upon examination.^[30]

Causes

The causes of primary pulmonary hypoplasia have not been identified. As mentioned above, Sonic hedgehog (Shh) appears to play a role in pulmonary branching morphogenesis. Shh knockout transgenic mice had severely hypoplastic lungs with loss of cartilaginous rings.^{[9, 11]}Experimental models suggest deficiencies in certain factors and/or their receptors can result in abnormal lung growth (see Table 1). These findings suggest that primary pulmonary hypoplasia likely results from disruptions in signaling during embryologic phase of lung development but needs further study.

Causes of secondary pulmonary hypoplasia include conditions that can result in small fetal thoracic volume, prolonged oligohydramnios, decreased fetal breathing movements, and congenital heart disease with poor pulmonary blood flow (see Table 2). Condition such as congenital diaphragmatic hernia, large pleural effusions and congenital pulmonary malformations also lead to the development of pulmonary hypoplasia due to mass effect.^[1]

Table 1. Factors and/or Their Receptors Possibly Involved with Abnormal Lung Growth (Open Table in a new window)

Transcription Factors	Growth Factors
Thyroid transcription factor-1 (TTF-1)^[12]	Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2)^[15]
GATA-4^[20]	Insulinlike growth factors (IGF-1 and IGF-2) and their receptors (IGF-1R and IGF-2R)^[18]
FOG-2^[23]	Epidermal growth factors and its receptor family (eg, ErbB receptors)^[21]
Hepatocyte nuclear factor (HNF3ß10)	Mitogen-activated protein kinases
	Connective tissue growth factor^[31]

Table 2. Causes of Secondary Pulmonary Hypoplasia (Open Table in a new window)

Small Fetal Thoracic Volume	Prolonged Oligohydramnios	Decreased Fetal Breathing Movements	Congenital Heart Diseases With Poor Pulmonary Blood Flow
CDH	Fetal renal agenesis	Central nervous system (CNS) lesions	Tetralogy of Fallot
Cystic adenomatoid malformation (CAM)	Urinary tract obstruction	Lesions of the spinal cord, brain stem, and phrenic nerve	Hypoplastic right heart
Pulmonary sequestration	Bilateral renal dysplasia	Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)	Pulmonary artery hypoplasia
Pleural effusions with fetal hydrops, hydrothorax	Bilateral cystic kidneys	Arthrogryposis multiplex congenital secondary to fetal akinesia	Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
Thoracic neuroblastomas	Prolonged rupture of membranes (PROM)	Maternal depressant drugs	Trisomies 18 and 21
Malformations of the thorax (eg, asphyxiating thoracic dystrophy)	Premature PROM
Diaphragmatic anomalies (eg, abdominal wall defects, eventration of the diaphragm)	Potter syndrome
Musculoskeletal disorders (eg, achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta)
Abdominal masses causing compression

Differential Diagnoses

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Media Gallery

Chest radiograph of a newborn with primary pulmonary hypoplasia of the right lung showing shift of the mediastinum to the right hemithorax.
CT scan of the same patient (a newborn with primary pulmonary hypoplasia of the right lung) showing absence of the right lung. Note branching of the left lower lobe bronchus (horizontal arrow) and absence of airways in the right side (vertical arrow).
A posteroanterior radiograph of a 3-month-old infant with primary pulmonary hypoplasia of the right lung.
Lateral view of the same patient (a 3-month-old infant with primary pulmonary hypoplasia of the right lung) showing one dome of the diaphragm.
Bronchogram of the same patient (a 3-month-old infant with primary pulmonary hypoplasia of the right lung) showing absence of the airways in the right side and presence of the left main bronchus and its branches.
A chest radiograph of a 14-year-old child with primary pulmonary hypoplasia of the right side causing secondary scoliosis.
A chest radiograph of a newborn with achondroplasia and small chest causing hypoplasia of both lungs.
A chest radiograph of a newborn with diaphragmatic hernia in the right hemithorax shortly after birth.
CT scan of the same child (a newborn with diaphragmatic hernia in the right hemithorax shortly after birth) showing the presence of abdominal contents in the right hemithorax. Note the presence of the left lower bronchus and its main branches (horizontal arrow) and absence of the right lower lobe bronchus. The liver in the right hemithorax is indicated by the upper arrow.
A chest radiograph of a 10-month-old child after repair of a right diaphragmatic hernia showing loss of lung volume in the right hemithorax.
MRI of the same patient (a 10-month-old child after repair of a right diaphragmatic hernia) showing loss of right lung volume and smaller right pulmonary artery than the left pulmonary artery (arrow).

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Table 1. Factors and/or Their Receptors Possibly Involved with Abnormal Lung Growth

Transcription Factors	Growth Factors
Thyroid transcription factor-1 (TTF-1)^[12]	Vascular endothelial growth factor receptors (VEGFR1 and VEGFR2)^[15]
GATA-4^[20]	Insulinlike growth factors (IGF-1 and IGF-2) and their receptors (IGF-1R and IGF-2R)^[18]
FOG-2^[23]	Epidermal growth factors and its receptor family (eg, ErbB receptors)^[21]
Hepatocyte nuclear factor (HNF3ß10)	Mitogen-activated protein kinases
	Connective tissue growth factor^[31]

Table 2. Causes of Secondary Pulmonary Hypoplasia

Small Fetal Thoracic Volume	Prolonged Oligohydramnios	Decreased Fetal Breathing Movements	Congenital Heart Diseases With Poor Pulmonary Blood Flow
CDH	Fetal renal agenesis	Central nervous system (CNS) lesions	Tetralogy of Fallot
Cystic adenomatoid malformation (CAM)	Urinary tract obstruction	Lesions of the spinal cord, brain stem, and phrenic nerve	Hypoplastic right heart
Pulmonary sequestration	Bilateral renal dysplasia	Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)	Pulmonary artery hypoplasia
Pleural effusions with fetal hydrops, hydrothorax	Bilateral cystic kidneys	Arthrogryposis multiplex congenital secondary to fetal akinesia	Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
Thoracic neuroblastomas	Prolonged rupture of membranes (PROM)	Maternal depressant drugs	Trisomies 18 and 21
Malformations of the thorax (eg, asphyxiating thoracic dystrophy)	Premature PROM
Diaphragmatic anomalies (eg, abdominal wall defects, eventration of the diaphragm)	Potter syndrome
Musculoskeletal disorders (eg, achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta)
Abdominal masses causing compression

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Author

Terry W Chin, MD, PhD Associate Clinical Professor, Department of Pediatrics, University of California, Irvine, School of Medicine; Associate Director, Cystic Fibrosis Center, Attending Staff Physician, Department of Pediatric Pulmonology, Allergy, and Immunology, Memorial Miller Children's Hospital

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Federation for Clinical Research, American Thoracic Society, California Society of Allergy, Asthma and Immunology, California Thoracic Society, Clinical Immunology Society, Los Angeles Pediatric Society, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Nandini Kataria, MD Fellow in Pediatric Pulmonology, Miller Children’s and Women’s Hospital Long Beach, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush Children's Hospital, Rush University Medical Center

Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Additional Contributors

Susanna A McColley, MD Professor of Pediatrics, Northwestern University, The Feinberg School of Medicine; Director of Cystic Fibrosis Center, Head, Division of Pulmonary Medicine, Children's Memorial Medical Center of Chicago

Susanna A McColley, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Sleep Disorders Association, American Thoracic Society

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from Genentech for consulting; Partner received consulting fee from Boston Scientific for consulting; Received honoraria from Gilead for speaking and teaching; Received consulting fee from Caremark for consulting; Received honoraria from Vertex Pharmaceuticals for speaking and teaching.

Khanh Van Lai, MD Fellow in Pediatric Pulmonology, Miller Children's Hospital, University of California, Irvine, School of Medicine

Khanh Van Lai, MD is a member of the following medical societies: American Thoracic Society

Disclosure: Nothing to disclose.

Bich-Trang Hoa, MD Fellow in Pediatric Pulmonology, Miller Children's Hospital, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The current authors would like to acknowledge the contributions of the following to this article:

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester School of Medicine and Dentistry; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center;

Girija Natarajan, MD, Assistant Professor, Division of Neonatology, Children's Hospital of Michigan, Wayne State University School of Medicine; and

Ibrahim Abdulhamid, MD, Associate Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Pulmonary Medicine, Clinical Director of Pediatric Sleep Laboratory, Children's Hospital of Michigan

Disclosure: Nothing to disclose.