What is the mode of inheritance for a pediatric patient with café au lait spots and axillary freckling, given a family history of the condition, including an affected nephew?

Mode of Inheritance for Café au Lait Spots with Axillary Freckling and Affected Nephew

The mode of inheritance for café au lait spots with axillary freckling in this pediatric patient, with an affected nephew, is autosomal dominant (B).

Genetic Syndromes Associated with Café au Lait Spots and Axillary Freckling

The combination of café au lait spots and axillary freckling strongly points to one of several genetic conditions:

1. Neurofibromatosis Type 1 (NF1):

   • Most common cause of multiple café au lait spots with axillary freckling
   • Autosomal dominant inheritance pattern 1
   • Complete penetrance but variable expressivity
   • Nearly 50% of cases occur as de novo mutations 2

2. Constitutional Mismatch Repair Deficiency (CMMRD):

   • Can present with NF1-like features including café au lait spots and axillary freckling 3
   • Autosomal recessive inheritance 3
   • Often mistaken for NF1 due to similar cutaneous findings 3

3. Legius Syndrome:

   • Presents with café au lait spots and freckling similar to NF1
   • Autosomal dominant inheritance 4
   • Lacks the tumor risks associated with NF1

Family Pattern Analysis

The key to determining the inheritance pattern is the family history, specifically:

• Pediatric patient with café au lait spots and axillary freckling
• Affected nephew

This family pattern strongly supports autosomal dominant inheritance because:

1. The presence of an affected nephew indicates transmission through either the patient's sibling or the patient's sibling's spouse. If the condition were X-linked recessive, a maternal uncle would typically be affected rather than a nephew.

2. Autosomal recessive conditions like CMMRD would be unlikely to appear in multiple generations unless there was consanguinity or the condition was extremely common in the population 3.

3. The combination of café au lait spots with axillary freckling is a hallmark of NF1, which follows an autosomal dominant inheritance pattern 2.

Differential Diagnosis

While considering the inheritance pattern:

• Autosomal dominant (AD): NF1, Legius syndrome, and familial café au lait spots all follow this pattern 4, 1, 5

• Autosomal recessive (AR): CMMRD and MYH-associated polyposis follow this pattern 3

• X-linked patterns: Not typically associated with the classic presentation of café au lait spots and axillary freckling

Conclusion

The family history of an affected nephew, combined with the classic presentation of café au lait spots and axillary freckling, is most consistent with an autosomal dominant inheritance pattern. While some studies have reported families with isolated café au lait spots that are not linked to the NF1 gene 6, others have found linkage to NF1 5, suggesting genetic heterogeneity in these presentations.

The most likely diagnosis is NF1 or a related condition with autosomal dominant inheritance, and genetic testing would be recommended to confirm the specific genetic cause.