What is the incidence of genetic abnormalities in fetuses with Congenital Pulmonary Airway Malformations (CPAMs)?

Incidence of Genetic Abnormalities in Fetuses with Congenital Pulmonary Airway Malformations

The incidence of genetic abnormalities in fetuses with Congenital Pulmonary Airway Malformations (CPAMs) is relatively low, with most cases being sporadic and non-hereditary without associated chromosomal abnormalities unless other fetal malformations are present.

Epidemiology and Genetic Associations

CPAMs represent approximately 30-40% of developmental lung bud anomalies that are diagnosed during pregnancy or in newborn infants 1. These malformations typically occur as:

• Sporadic, non-hereditary lung abnormalities
• No predilection for right or left lung
• No sex or race predisposition

Genetic Testing Considerations

While most CPAMs occur in isolation without genetic abnormalities, there are important considerations:

• Genetic testing should be offered when a fetus with CPAM is identified on ultrasound 2
• The first reported case of mosaic Klinefelter syndrome associated with CPAM type II was documented in a fetus with no other malformations 2
• Some CPAMs have shown somatic mutations in specific genes:
  • KRAS mutations have been confirmed in some CPAM cases 3
  • Other genetic susceptibilities linked to potential tumor development are being investigated 3

Associated Conditions and Complications

CPAMs can be associated with other conditions that may have genetic implications:

• When CPAMs are large enough to cause hydrops fetalis (occurs in about 5% of CPAM cases), there is a poor prognosis without treatment 4
• In newborns with severe childhood interstitial lung disease (chILD) syndrome, genetic testing is recommended for abnormalities associated with neonatal diffuse lung disease 4

Management Implications

The genetic profile of CPAMs may influence management decisions:

• For newborns with severe respiratory disease and CPAM, testing for genetic abnormalities associated with neonatal diffuse lung disease is strongly recommended 4
• In cases where CPAMs are associated with hydrops, intervention may be necessary, with options including:
  • Macrocystic type: fetal needle drainage or thoracoamniotic shunt placement
  • Microcystic type: maternal corticosteroid administration 4

Clinical Approach to Genetic Assessment

When a CPAM is identified on prenatal ultrasound:

1. Perform detailed anatomical survey to identify any additional malformations
2. Consider amniocentesis for genetic testing, especially if:
   • Other anomalies are present
   • Family history of genetic disorders exists
   • Hydrops fetalis develops

Pitfalls and Caveats

• Do not assume that isolated CPAMs have no genetic component - while most are sporadic, genetic testing should still be considered
• The risk of malignant transformation in some CPAMs may be related to underlying genetic mutations, highlighting the importance of genetic evaluation 3
• Long-term follow-up is essential for children with CPAMs, whether they undergo surgical resection or expectant management

While most CPAMs are sporadic without genetic abnormalities, the emerging evidence of specific genetic mutations in some cases and the documented association with conditions like mosaic Klinefelter syndrome suggest that genetic testing should be considered in the evaluation of fetuses with CPAMs, particularly when other anomalies are present or when hydrops develops.