Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study.

BACKGROUND: PHACE syndrome is a rare inborn condition characterized by large facial hemangiomas and variable malformations of the arterial system, heart, central nervous system, and eyes. According to Orphanet estimates, the prevalence is <1.0 per million. Data from Europe are limited to small case series, and there are no population-based data available. OBJECTIVES: We conducted the present study to provide population-based estimates of the disease prevalence of PHACE syndrome in children in Germany, Switzerland, and Austria. We compared these first systematic data on PHACE syndrome from Europe to published data from the PHACE Syndrome International Clinical Registry and Genetic Repository (USA). Clinical features in our cohort with PHACE syndrome were assessed in detail, including the need for early supportive measures. METHODS: We used a population-based approach by means of a previously well-established network of child neurologists from Germany, Switzerland, and Austria ("ESNEK") to identify potential patients. The patients' guardians and child neurologists were asked to fill in questionnaires developed in collaboration with the International PHACE Registry. RESULTS: We identified 19 patients with PHACE syndrome. Estimated prevalence rates were 6.5 per million in Switzerland, 0.59 per million in Germany, and 0.65 per million in Austria. A subset of 10 patients from Germany and Switzerland participated in our study, providing detailed clinical assessment (median age: 2.5 years; 9 females, 1 male). Cerebrovascular involvement was frequent (80%). Facial hemangioma extent correlated significantly with the number of organs involved (p = 0.011). In 9 out of 10 patients, facial hemangiomas were treated successfully with oral propranolol. Baseline demographic data as well as the rate of cerebrovascular and cardiovascular anomalies were in line with those from the US International PHACE Registry and other published PHACE cohorts. CONCLUSIONS: Our study provides population-based estimates for PHACE syndrome in 3 German-speaking countries. The data from Switzerland indicate that PHACE syndrome may be more prevalent than demonstrated by previous reports. Underreporting of PHACE syndrome in Germany and Austria likely accounts for the differences in prevalence rates. The clinical observation of a potential association between the size of facial hemangioma and extent of organ involvement warrants further investigation.

The epithelial mitogen keratinocyte growth factor binds to collagens via the consensus sequence glycine-proline-hydroxyproline.

The binding of certain growth factors and cytokines to components of the extracellular matrix can regulate their local availability and modulate their biological activities. We show that mesenchymal cell-derived keratinocyte growth factor (KGF), a key stimulator of epithelial cell proliferation during wound healing, preferentially binds to collagens I, III, and VI. Binding is inhibited in a dose-dependent manner by denatured single collagen chains and collagen cyanogen bromide peptides. This interaction is saturable with dissociation constants of approximately 10(-8) to 10(-9) m and estimated molar ratios of up to three molecules of KGF bound to one molecule of triple helical collagen. Furthermore, collagen-bound KGF stimulated the proliferation of transformed keratinocyte or HaCaT cells. Ligand blotting of collagen-derived peptides points to a limited set of collagenous consensus sequences that bind KGF. By using synthetic collagen peptides, we defined the consensus sequence (Gly-Pro-Hyp)(n) as the collagen binding motif. We conclude that the preferential binding of KGF to the abundant collagens leads to a spatial pattern of bioavailable KGF that is dictated by the local organization of the collagenous extracellular matrix. The defined collagenous consensus peptide or its analogue may be useful in wound healing by increasing KGF bioactivity and thus modulating local epithelial remodeling and regeneration.