Non‐random maternal X‐chromosome inactivation associated with PHACES

Abstract

The acronym PHACES is used to describe the association of posterior fossa malformations, hemangiomas, arterial anomalies (cardiovascular or cerebrovascular), coarctation of the aorta and cardiac defects, eye abnormalities, and sternal or ventral defects. We report a female patient with an uncommon variant of this neurocutaneous disorder who manifested a sternal cleft; supraumbilical raphe; hemangiomas of the face, chest, and extremities; micrognathia and cerebrovascular anomalies. A literature review of PHACES patients with both sternal cleft and supraumbilical raphe showed a marked female predilection. Taken together with cases of sternal cleft, supraumbilical raphe and facial hemangiomas tabulated by Gorlin et al. (1994), 91% (40/44) of patients are female. One affected male died shortly after birth. We hypothesized that the gender bias in PHACES results from mutation in an X-linked dominant gene often lethal in males, and performed X-inactivation analysis of the polymorphic androgen receptor locus in this family. We documented consistently skewed X-inactivation (80%/20% in two independent analyses) in the unaffected mother and consistently random X-inactivation (47:53 and 61:39 in independent analyses) in the proband. These findings are consistent with favorably skewed X-inactivation producing a normal maternal phenotype, a phenomenon documented in X-linked dominant Rett syndrome.

X Chromosome-Inactivation Patterns in 31 Individuals with PHACE Syndrome

“…No specific environmental influences have been identified, and to date, all reports of PHACE syndrome have been sporadic. One prior case report demonstrating skewed X-inactivation in the mother of a female with PHACE syndrome raised the question of whether skewed XCI may play a protective role in the mothers of children with PHACE [Levin and Kaler, 2007]. In this study, we follow-up on that report by performing XCI studies on a group of 31 females with PHACE syndrome and their mothers.…”

“…X chromosome-inactivation (XCI) studies showed a random XCI pattern in the affected child and a skewed pattern in the mother, suggesting that the skewed XCI in the mother may have been protective [Levin and Kaler, 2007]. Given the female predominance and the previous case report of skewed XCI in PHACE syndrome, the question of whether XCI could have a broader role in the pathogenesis of PHACE has been raised [Levin and Kaler, 2007]. In general, XCI is expected to be random.…”

“…More recently, larger studies on individuals with PHACE, as well as data from the PHACE Syndrome Clinical Registry and DNA Repository with 150 subjects enrolled, have reported a slightly lower female to male ratio at 5.6: 1 [Haggstrom et al, 2010]. Levin et al [2007] reported a case of a female infant with a diagnosis of PHACE syndrome based on perioral hemangiomas as well as hemangiomas on the chest and extremities, cerebrovascular anomalies, sternal scar and supraumbilical raphe. X chromosome-inactivation (XCI) studies showed a random XCI pattern in the affected child and a skewed pattern in the mother, suggesting that the skewed XCI in the mother may have been protective [Levin and Kaler, 2007].…”

“…Levin et al [2007] reported a case of a female infant with a diagnosis of PHACE syndrome based on perioral hemangiomas as well as hemangiomas on the chest and extremities, cerebrovascular anomalies, sternal scar and supraumbilical raphe. X chromosome-inactivation (XCI) studies showed a random XCI pattern in the affected child and a skewed pattern in the mother, suggesting that the skewed XCI in the mother may have been protective [Levin and Kaler, 2007]. Given the female predominance and the previous case report of skewed XCI in PHACE syndrome, the question of whether XCI could have a broader role in the pathogenesis of PHACE has been raised [Levin and Kaler, 2007].…”

Posterior Fossa Neoplasm and PHACES Syndrome

“…It has been proposed that an X-linked dominant gene may be responsible for PHACES that would be lethal in males and explain the female sex bias. 14 Cytogenetic studies in the tumors of future patients would be of interest.…”