Retrospective study provides evidence for risk stratification and timing of diagnostic work-up
With Colleen Cotton, MD
“Our retrospective study was conducted to identify predictors of a diagnosis of PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome in children with head and/or neck infantile hemangiomas (IH).
Our findings indicate that children whose IH involves three or more developmental segments and/or has a large surface area (≥25 cm2) should undergo a full and prompt work-up for PHACE, including magnetic resonance imaging (MRI) of the brain, magnetic resonance angiography (MRA) of the head and neck, echocardiogram, and eye examination,” said Colleen Cotton, MD, FAAD, FAAP.
“Although we found that involvement of the parotid gland and segment S2 were associated with a decreased risk, we can’t completely exonerate these lower-risk sites. Notably, all patients with lower risk IH involvement who turned out to have PHACE had cerebrovascular anomalies, and six of seven would have been missed if only an echocardiogram and eye exam were done. Therefore, we cannot recommend completely foregoing a PHACE evaluation for any child with a large IH of the head and/or neck.”
Dr. Cotton is Assistant Professor, Division of Pediatric Dermatology, Medical University of South Carolina, Charleston, and lead author of the published study.1 She went on to tell The Dermatology Digest that based on the study’s findings and the practice of many of the authors involved, most of the authors feel that a complete PHACE evaluation can be deferred for lower-risk patients in the absence of other signs or symptoms of PHACE (e.g., migraine headaches) or until the child reaches an age where risks of general anesthesia and gadolinium contrast are lower.
“We want to make sure patients who are high risk get their full PHACE work-up quickly. Timing of the work-up for those that are low risk can be decided through a discussion between the parents and healthcare team,” Dr. Cotton said.
Motivation and methods
The idea to conduct a study investigating demographic and IH characteristics as risk factors for PHACE originated from the clinical observation that PHACE work-ups for patients with purely deep parotid hemangiomas were almost always negative.
“Some clinicians had stopped conducting a work-up for those patients, and we wanted to know if data supported that decision. That led to the larger question of whether we could determine if patients were at high or low risk for PHACE just by looking at them,” Dr. Cotton explained.
To address these questions and with the help of the Pediatric Dermatology Research Alliance (PeDRA), the researchers identified 242 patients with a head and/or neck IH who underwent a work-up for PHACE at 13 pediatric dermatology referral centers located in the United States or Canada. The analyses included data for 238 patients who had a mean age of ~3 years at the time of data collection. The patients were predominantly female (77%), White (69%), and non-Hispanic (67%), but both race and ethnicity were unknown for a sizable proportion of patients (19% and 18%, respectively).
With strict application of the 2016 consensus criteria for PHACE diagnosis, 106 children (44.5%) met the criteria for definite (98 children) or possible (8 children) PHACE syndrome. Characteristics evaluated as predictors of PHACE included age at diagnosis and sex, as well as IH size, segment location, and depth.
Analysis using a stepwise linear regression model found that surface area ≥25 cm2 and involvement of three or more locations were the only features associated independently with an increased risk of PHACE (3-fold and 18-fold, respectively). IH involvement of the parotid gland and of segment S2 were each associated with an approximately 60% decreased risk.
“Both non-white race and Hispanic ethnicity were independently associated with an approximately 3-fold increased risk of PHACE syndrome. However, it is impossible to draw strong conclusions about their role as risk factors considering we had low numbers of patients in these subgroups and relatively high numbers of patients whose race and ethnicity were unknown,” noted Dr. Cotton. “Therefore, investigating associations with race and ethnicity is an important area for further research.”
Strengths and limitations
The researchers believe their study has several strengths. “The size of our sample is its greatest strength,” said Dr. Cotton. “In addition we were very careful about characterizing involvement of facial segments, with photographs or detailed diagrams for every patient reviewed by two hemangioma experts. Furthermore, the PHACE syndrome criteria were strictly applied in the analysis, and all patients with ‘possible PHACE’ were included as being affected so as not to underestimate PHACE prevalence.”
As with any retrospective investigation, the study has limitations. “In addition to missing data points, including for race and ethnicity, our study cannot account for patients who were perceived as low risk and therefore did not undergo a complete work-up for PHACE. Finally, because there was only access to imaging reports, not the images themselves, it was not possible to risk-stratify the anomalies in the PHACE patients,” Dr. Cotton said.
By Cheryl Guttman Krader
REFERENCE
1. Cotton CH, Ahluwalia J, Balkin DM, et al; PHACE retrospective study group. Association of demographic factors and infantile hemangioma characteristics with risk of PHACE syndrome. JAMA Dermatol. 2021;157(8):1–8. doi: 10.1001/jamadermatol.2021.1901. Erratum in: JAMA Dermatol. 2021;157(8):1008.
Figure courtesy of The Hemangioma Investigator Group.