X chromosome-inactivation patterns in 31 individuals with PHACE syndrome

Segmental hemangiomas of the head and neck can be associated with multiple congenital anomalies in the disorder known as PHACE syndrome (OMIM 606519) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies). All reported cases of PHACE syndrome to date have been sporadic, and the genetic basis of this disorder has not yet been established. PHACE syndrome has a striking female predominance which has raised the question of X-linked inheritance. In this study, the X chromosome-inactivation (XCI) patterns of 31 females with PHACE syndrome and their mothers were analyzed using blood-derived DNA and X-chromosome locus methylation assay. This study was performed to test the hypothesis that some cases of PHACE syndrome are due to X-linked inheritance and favorable skewing in the mothers may protect against a severe phenotype, but the clinical phenotype may be unmasked in daughters with a random pattern of X-inactivation. XCI analysis was informative in 27/31 mothers. Our results identified skewed XCI in 5 of 27 (19%) informative mothers, which is not statistically significant with a p value of 0.41. None of the mothers reported significant medical problems, although a full PHACE work-up has not been performed in these individuals. Skewed XCI in the mothers of children with PHACE was identified in only a minority of cases. Based on these results, genetic heterogeneity is likely in PHACE syndrome, although it is possible a subset of cases are caused by a mutation in an X-linked gene.