What are the pulmonary manifestations and management strategies for a pediatric or young adult patient with a 17q23.1q23.2 deletion or duplication?

Pulmonary Manifestations of 17q23.1q23.2 Deletion

Primary bilateral lung hypoplasia is the most critical pulmonary manifestation of 17q23.1q23.2 deletion, presenting in utero with a uniformly fatal prognosis when bilateral, and requires immediate neonatal intensive care with consideration for lung transplantation referral in severe cases. 1

Primary Pulmonary Manifestations

Lung Hypoplasia

• Bilateral primary lung hypoplasia represents the most severe pulmonary presentation, detected prenatally with no reports of fetal survival when bilateral 1
• The deletion involves a 2.14-2.2 Mb region encompassing the TBX4 gene, which is critical for lung development 1, 2
• Lung hypoplasia manifests with pulmonary interstitial emphysema and features of underdeveloped lung parenchyma 2
• Fetal biometry may show growth delay (typically 2-week delay) but measurements often remain above the 10th percentile, making prenatal detection challenging 1

Pulmonary Hypertension

• Pulmonary hypertension is a consistent finding in neonates with 17q23.1q23.2 deletion and lung involvement 2, 3
• The pulmonary hypertension results from both structural lung hypoplasia and vascular remodeling 2
• This complication contributes directly to respiratory failure and neonatal death soon after birth 2

Airway Abnormalities

• Mild tracheomalacia has been documented in patients with this deletion 3
• Respiratory distress at birth is common, requiring immediate neonatal intensive care unit admission 4

Genetic Mechanisms

TBX4 Haploinsufficiency

• The deletion creates haploinsufficiency of TBX4, a dosage-sensitive gene essential for lung and limb development 2, 3
• Novel putative regulatory non-coding single nucleotide variants in the predicted lung-specific enhancer upstream to TBX4 may modify phenotype severity 2
• A complex compound inheritance model suggests both non-coding and coding heterozygous TBX4 variants contribute to the lethal lung phenotype 2

Critical Region

• The critical region spans 17q23.1q23.2, with deletions ranging from 2.14-2.2 Mb 1, 2
• Breakpoints proximal to 17q23.1 appear associated with more severe cardiac and pulmonary involvement 5

Associated Systemic Features

Cardiac Manifestations

• Congenital heart defects are common and may compound pulmonary complications 6, 3
• Right-to-left shunting at the atrial level can occur with pulmonary hypertension, worsening hypoxemia 6

Neurological Features

• Microcephaly is present in most cases 4, 3, 5
• Hypotonia initially, followed by hypertonia and tremors from the second week of life 4
• Moderate to severe global developmental delay is expected 3, 5

Other Manifestations

• Micrognathia, ankyloglossia, small mouth, and high arch palate 4
• Poor feeding and poor weight gain in the neonatal period 4
• Sensorineural hearing loss may be present 3

Management Strategies

Immediate Neonatal Care

• Admit to neonatal intensive care unit immediately at birth for respiratory support 4
• Provide supplemental oxygen to maintain adequate saturation, as hypoxemia worsens pulmonary hypertension and bronchospasm 6
• Monitor for complications including hypoglycemia, presumed sepsis, and thrombocytopenia 4

Respiratory Support

• Initiate mechanical ventilation for respiratory failure secondary to lung hypoplasia 2
• Consider pulmonary arterial hypertension pharmacotherapy, though natural history is typically relentless despite treatment 7
• Oxygen therapy should target physiologic saturation levels to reduce pulmonary arterial pressure and airway constriction 6

Surgical Considerations

• Lung transplantation is the only potential route to long-term survival for patients with severe bilateral lung hypoplasia and should be discussed with families early 6, 7
• Referral to a pediatric lung transplantation center is recommended for infants with severe, life-threatening disease 6
• Perioperative management requires multidisciplinary coordination due to increased complication risk, including prolonged mechanical ventilation 7

Diagnostic Workup

• Perform thin-section CT scanning using the lowest radiation dose that provides adequate diagnostic information to characterize lung structure 6
• Echocardiography to assess pulmonary hypertension severity and cardiac anatomy 6
• Genetic testing with chromosomal microarray to confirm 17q23.1q23.2 deletion and identify additional genomic abnormalities 4, 2

Monitoring and Supportive Care

• Serial assessment of oxygen saturation, pulmonary arterial pressure, and right ventricular function 6
• Nutritional support is critical, as hypoxemic infants lack energy to feed and function at an increased metabolic rate 6
• Avoid dehydration and maintain adequate preload to prevent worsening of pulmonary hypertension 6

Prognosis

Survival Outcomes

• Primary bilateral lung hypoplasia has no reported cases of fetal survival 1
• Neonatal death soon after birth is typical when severe lung hypoplasia and pulmonary hypertension are present 2
• The phenotype severity correlates with deletion size and specific breakpoint locations 5

Prognostic Factors

• Presence of cardiac defects increases morbidity and affects developmental outcomes 5
• Extent of developmental delay appears related to proximal and distal breakpoints at 17q 5