A case of Incontinentia Pigmenti associated with concurrent IKBKG/NEMO and MED13L mutations

Incontinentia Pigmenti (IP; OMIM#308300) and syndromic intellectual disability (ID) (MRFACD; OMIM#616789) are two genetically dominant rare diseases. Their phenotypes are characterized by distinctive clinical signs: IP is caused by skin and neuroectodermal abnormalities with highly variable expression, while MRFACD is caused by a broad range of neurologic manifestations, including ID, hypotonia, ophthalmological abnormalities, motor delay, abnormalities in cerebral magnetic resonance, and a remarkable speech delay. The two diseases have genetically different causes: IP is an X-linked disorder caused by mutations in the IKBKG/NEMO gene, whereas MRFACD is an autosomal dominant disease caused by mutations in the MED13L gene. In this study, we describe the unique case of a female patient with a complex phenotype characterized by neuroectodermal abnormalities typical of IP and by syndromic intellectual disability. The multiple genetic approaches revealed the concurrence of postzygotic mosaicism for the genomic deletion (NEMOdelta4_10) in the IKBKG gene and of a constitutive deleterious variant in the MED13L gene (NM_015335.4: c.1708_1709del). This genetic combination, never previously reported, makes this case particularly interesting from a clinical perspective because it underscores the importance of considering multilocus genomic alterations, including postzygotic mosaicism, as possible contributors to complex clinical presentations.