Analysis of Whole Genome Sequencing in a Cohort of Individuals with PHACE Syndrome Suggests Dysregulation of RAS/PI3K Signaling

The acronym PHACE stands for the co-occurrence of posterior brain fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and eye abnormalities. The majority of patients have a segmental hemangioma and at least one developmental structural anomaly. The etiology and pathogenesis are unknown. Here we discuss the candidate causative genes identified in a de novo analysis of whole genome sequencing of germline samples from 98 unrelated trios in which the probands had PHACE, all sequenced as part of the Gabriella Miller Kids First Pediatric Research Program. A g:Profiler pathway analysis of the genes with rare, de novo variants suggested dysregulation of the RAS/MAPK and PI3K/AKT pathways that regulate cell growth, migration, and angiogenesis. These findings, along with the developmental anomalies and the vascular birthmark, support including PHACE within the RASopathy family of syndromes.

The Role of Lung Function Testing in Newborn Infants With Congenital Thoracic Arterial Anomalies

Introduction: Congenital thoracic arterial anomalies (CTAAs), such as complete or incomplete vascular rings, pulmonary artery sling, and innominate artery compression syndrome, may cause severe tracheomalacia and upper airway obstruction. An obstructive ventilatory pattern at lung function testing (LFT) has been suggested in the presence of CTAA. The severity of obstruction may be evaluated by LFT. Little is known about the use of LFT in newborn infants with CTAA. The aim of our study is to evaluate the role of LFT in CTAA diagnosis.Methods: This is a retrospective study, conducted between February 2016 and July 2020. All CTAA cases for whom LFT was performed preoperatively were considered for inclusion. Tidal volume (Vt), respiratory rate, and the ratio of time to reach the peak tidal expiratory flow over total expiratory time (tPTEF/tE) were assessed and compared to existing normative data. Demographics and CTAA characteristics were also collected.Results: Thirty cases were included. All infants with CTAA showed a significantly reduced Vt and tPTEF/tE, compared to existing normative data suggesting an obstructive pattern.No significant differences were found for LFT between cases with a tracheal obstruction <50% compared to those with tracheal obstruction ≥50%, or between cases with and without symptoms. Sixteen infants (53.3%) had respiratory symptoms related to CTAA. Of these, only two cases had also dysphagia.Conclusion: LFT values were significantly reduced in cases with CTAA before surgery. LFT represents a potential feasible and non-invasive useful tool to guide diagnosis in the suspect of CTAA.

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

Background. Oculofaciocardiodental (OFCD) syndrome is due to mutations in BCOR (BCL-6 corepressor). OFCD has phenotypic overlaps with PHACE syndrome (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac defects, Eye anomalies). Infantile hemangiomas are a key diagnostic criterion for PHACE, but not for OFCD. A previous study reported two cases of infantile hemangiomas in OFCD, but the authors could not exclude chance association. Case Presentation. We describe two novel cases of female patients (one initially diagnosed with PHACE syndrome), both of whom had infantile hemangiomas. Ophthalmological findings were consistent with oculofaciocardiodental (OFCD) syndrome. Upon genetic testing, these two females were determined to have X-linked BCOR mutations confirming OFCD syndrome diagnoses. Conclusion. These case reports add support to the hypothesis that infantile hemangiomas may be a feature of OFCD. BCOR may potentially be within a pathway of genes involved in PHACE syndrome and/or in infantile hemangioma formation.

A case of PHACE syndrome with growth hormone deficiency and abnormal thyroid functions

Background PHACE syndrome is a rare vascular neurocutaneous disorder characterized by posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies and eye anomalies. Growth hormone deficiency (GHD) has been infrequently described. Case presentation We report a girl with PHACE syndrome. Endocrine abnormalities including abnormal thyroid functions and GHD have recently been described in similar cases. Conclusions This case suggests the necessity to screen pituitary functions in all patients with PHACE syndrome with abnormal hypothalamus and pituitary (HP) anatomy. Likewise, growth parameters and thyroid function test (TFT) should be monitored in all patients with PHACE syndrome at regular intervals.

Endocrine manifestations of PHACE syndrome

PHACE syndrome is an uncommon disorder of posterior fossa anomalies, cervicofacial infantile hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects. Endocrine abnormalities including hypopituitarism and ectopic thyroid were rarely described. In this article we review occurrence, onset, presenting symptoms, hormonal treatments and outcomes of all endocrine abnormalities in PHACE syndrome. Eleven of 20 (55%) had hypothalamic-pituitary dysfunction and 10 of 20 (50%) had thyroid dysgenesis. A thorough understanding of the endocrine manifestations is important for clinicians to early identify endocrine involvement in PHACE and develop plans for monitoring and treatment of its complications.