Should children and grandchildren of a female patient who is an Alpha 1 antitrypsin (A1AT) ZZ carrier be tested for Alpha 1 antitrypsin deficiency?

Testing for Alpha-1 Antitrypsin Deficiency in Children and Grandchildren of ZZ Carriers

Testing should be discussed with children and grandchildren of a female patient with Alpha-1 antitrypsin ZZ genotype, acknowledging that testing could reasonably be accepted or declined (Type B recommendation). 1

Understanding the Risk and Testing Recommendations

For Children (Offspring)

• Children of a ZZ carrier have a 100% chance of being at least heterozygous (carriers)
• The risk of being homozygous (ZZ) depends on the genotype of the other parent
• American Thoracic Society/European Respiratory Society guidelines specifically recommend:
  • Type B recommendation for testing offspring: "Testing should be discussed, acknowledging that it could reasonably be accepted or declined" 1
  • Rationale: "Offspring can be homozygous only if the other parent is at least heterozygous. This potentially low prevalence rate for homozygosity coupled with potential adverse psychosocial effects warrants that testing be discussed rather than be recommended" 1

For Grandchildren (Distant Relatives)

• Considered "distant relatives" in the guideline classification
• Type B recommendation: Testing should be discussed but not mandated 1
• Rationale: "Distant relatives of a homozygote proband may have normal AAT alleles, be heterozygous, or be homozygous (a low likelihood). The low likelihood of being homozygous coupled with potential adverse psychosocial effects warrants a Type B recommendation" 1

Benefits of Testing

1. Early identification of disease risk:

   • Allows implementation of preventive measures before organ damage occurs 2
   • Enables early monitoring for liver and lung complications

2. Lifestyle modifications for identified carriers:

   • Smoking avoidance/cessation (critical for preventing lung disease)
   • Avoidance of occupational respiratory hazards
   • Reduced alcohol consumption to protect the liver

3. Medical interventions for those identified with deficiency:

   • Earlier access to augmentation therapy for those with emphysema
   • More vigilant monitoring for liver disease
   • Appropriate vaccination (pneumococcal, influenza)

Potential Harms and Limitations

1. Psychosocial impact:

   • Potential anxiety, distress, and altered family dynamics
   • Possible effects on the parent-child relationship 1

2. Discrimination concerns:

   • Insurance and employment discrimination risks
   • Stigmatization concerns

3. Variable penetrance:

   • Not all individuals with ZZ genotype develop clinical disease
   • Only about 10% of ZZ neonates develop liver disease, with approximately 3% progressing to severe disease 3

Testing Approach

1. Initial screening:

   • Serum AAT quantification (simple and cost-effective)
   • Be aware that AAT is an acute phase protein and levels may be falsely normal during inflammation 4

2. Confirmatory testing:

   • Phenotyping by isoelectric focusing for abnormal variants
   • Genotyping by PCR to identify S and Z alleles 5
   • Consider full gene sequencing for rare variants if clinical suspicion is high

Special Considerations for Different Age Groups

Children

• Growth and development monitoring
• Liver function testing
• Education about avoiding smoking and environmental toxins

Adolescents

• Targeted education about smoking avoidance
• Career counseling regarding occupational exposures
• Psychological support during identity formation

Adults

• Regular pulmonary function testing
• Liver monitoring
• Genetic counseling for reproductive planning

Common Pitfalls to Avoid

1. Assuming complete penetrance - Not all ZZ individuals develop disease 2
2. Overlooking psychological impact - Testing should include counseling support
3. Neglecting family screening - A systematic approach to family testing is important
4. Focusing solely on lung manifestations - Liver disease is also a significant concern
5. Misinterpreting normal AAT levels - Levels may be falsely normal during inflammation

In conclusion, while testing children and grandchildren of a ZZ carrier should be discussed, the decision should balance the benefits of early detection against potential psychosocial harms. The testing process should include appropriate genetic counseling and follow-up care for those identified with deficiency.