Non-random maternal X-chromosome inactivation associated with PHACES.

Area of Science:

• Genetics
• Pediatrics
• Dermatology

Background:

• PHACES (posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal or ventral defects) is a complex neurocutaneous disorder.
• This report details an uncommon variant of PHACES in a female patient with sternal cleft and supraumbilical raphe.
• Literature review reveals a significant female predilection in PHACES patients presenting with sternal cleft and supraumbilical raphe.

Purpose of the Study:

• To investigate the genetic basis for the observed gender bias in PHACES.
• To explore the role of X-linked inheritance and X-inactivation patterns in PHACES.

Main Methods:

• Case report of a female patient with an uncommon PHACES variant.
• Literature review of PHACES patients with sternal cleft and supraumbilical raphe.
• X-inactivation analysis of the androgen receptor locus in the patient and her mother.

Main Results:

• The patient presented with sternal cleft, supraumbilical raphe, facial and other hemangiomas, micrognathia, and cerebrovascular anomalies.
• A strong female predilection (91%) was observed in PHACES patients with sternal cleft and supraumbilical raphe.
• Consistently skewed X-inactivation was found in the unaffected mother, while random X-inactivation was observed in the proband.

Conclusions:

• The findings support the hypothesis of an X-linked dominant gene mutation underlying PHACES, which is often lethal in males.
• Skewed X-inactivation in the unaffected mother is consistent with a mechanism seen in X-linked dominant disorders like Rett syndrome.
• This genetic pattern helps explain the marked female predominance observed in this complex disorder.