Current clinical evidence is insufficient to support HMME-PDT as the first choice of treatment for young children with port wine birthmarks.

BACKGROUND: Port wine birthmark (PWB) is a congenital vascular malformation of the skin. Pulsed dye laser (PDL) is the "gold standard" for the treatment of PWB globally. Hematoporphyrin monomethyl ether (HMME or hemoporfin)-mediated photodynamic therapy (HMME-PDT) has emerged as the first choice for PWB treatment, particularly for young children, in many major hospitals in China during the past several decades. AIM: To evaluate whether HMME-PDT is superior to PDL by comparing the clinical efficacies of both modalities. METHOD: PubMed records were searched for all relevant studies of PWB treatment using PDL (1988-2023) or HMME-PDT (2007-2023). Patient characteristics and clinical efficacies were extracted. Studies with a quartile percentage clearance or similar scale were included. A mean color clearance index (CI) per study was calculated and compared among groups. An overall CI (C0), with data weighted by cohort size, was used to evaluate the final efficacy for each modality. RESULT: A total of 18 HMME-PDT studies with 3910 patients in China were eligible for inclusion in this analysis. Similarly, 40 PDL studies with 5094 patients from nine different countries were eligible for inclusion in this analysis. Over 58% of patients in the HMME-PDT studies were minors (<18 years old). A significant portion (21.3%) were young children (<3 years old). Similarly, 33.2% of patients in the PDL studies were minors. A small proportion (9.3%) was young children. The overall clearance rates for PDL were slightly, but not significantly, higher than those for HMME-PDT in cohorts with patients of all ages (C0, 0.54 vs. 0.48, p = 0.733), subpopulations with only minors (C0, 0.54 vs. 0.46, p = 0.714), and young children (C0, 0.67 vs. 0.50, p = 0.081). Regrettably, there was a lack of long-term data on follow-up evaluations for efficacy and impact of HMME-PDT on young children in general, and central nervous system development in particular, because their blood-brain barriers have a greater permeability as compared to adults. CONCLUSION: PDL shows overall albeit insignificantly higher clearance rates than HMME-PDT in patients of all ages; particularly statistical significance is nearly achieved in young children. Collectively, current evidence is insufficient to support HMME-PDT as the first choice of treatment of PWBs in young children given: (1) overall inferior efficacy as compared to PDL; (2) risk of off-target exposure to meningeal vasculature during the procedure; (3) administration of steriods for mitigation of side effects; -and (4) lack of long-term data on the potential impact of HMME on central nervous system development in young children.

Supporting materials: Endothelial cells differentiated from patient dermal fibroblast-derived induced pluripotent stem cells resemble vascular malformations of Port Wine Birthmark.

Background: Port wine birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models for PWB studies is currently an unmet need. Objective: Our study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and iPSC-derived ECs that preserve disease-related phenotypes. Methods: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and differentiated into ECs. RNA-seq was performed to identify differentially expressed genes (DEGs) and enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized by capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo . Results: Human PWB and control iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the "Yamanaka factors" (Oct3/4, Sox2, Klf4, c-Myc) into them; the iPSCs were successfully differentiated into ECs. These iPSCs and their derived ECs were validated by expression of a series of stem cell and EC biomarkers, respectively. PWB iPSC-derived ECs showed impaired CLS in vitro with larger perimeters and thicker branches as compared to control iPSC-derived ECs. In the plug-in assay, perfused human vasculature formed by PWB iPSC- derived ECs showed bigger perimeters and greater densities than those formed by control iPSC- derived ECs in severe combined immune deficient (SCID) mice. The transcriptome analysis showed that dysregulated pathways of stem cell differentiation, Hippo, Wnt, and focal adhesion persisted through differentiation of PWB iPSCs to ECs. Functional enrichment analysis showed that Hippo and Wnt pathway-related PWB DEGs are enriched for vasculature development, tube morphology, endothelium development, and EC differentiation. Further, members of the zinc finger (ZNF) gene family were overrepresented among the DEGs in PWB iPSCs. ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinoic acid receptor signaling. Furthermore, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were dysregulated in PWB ECs as readouts of impaired differentiation. Conclusions: PWB iPSC-derived ECs render a novel and clinically-relevant disease model by retaining pathological phenotypes. Our data demonstrate multiple pathways, such as Hippo and Wnt, NF-kappa B, TNF, MAPK, and cholesterol metabolism, are dysregulated, which may contribute to the development of differentiation-defective ECs in PWB. Bulleted statements: What is already known about this topic?: Port Wine Birthmark (PWB) is a congenital vascular malformation with an incidence rate of 0.1 - 0.3 % per live births.PWB results from developmental defects in the dermal vasculature; PWB endothelial cells (ECs) have differentiational impairments.Pulse dye laser (PDL) is currently the preferred treatment for PWB; unfortunately, the efficacy of PDL treatment of PWB has not improved over the past three decades.What does this study add?: Induced pluripotent stem cells (iPSCs) were generated from PWB skin fibroblasts and differentiated into ECs.PWB ECs recapitulated their pathological phenotypes such as forming enlarged blood vessels in vitro and in vivo.Hippo and Wnt pathways were dysregulated in PWB iPSCs and ECs.Zinc-finger family genes were overrepresented among the differentially expressed genes in PWB iPSCs.Dysregulated NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were enriched in PWB ECs.What is the translational message?: Targeting Hippo and Wnt pathways and Zinc-finger family genes could restore the physiological differentiation of ECs.Targeting NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways could mitigate the pathological progression of PWB.These mechanisms may lead to the development of paradigm-shifting therapeutic interventions for PWB.

Tongue dysmorphology in craniofacial microsomia.

BACKGROUND: Craniofacial microsomia is one of the most common and well-characterized craniofacial anomalies. Tongue dysmorphism, however, has been neither thoroughly investigated nor reported in the context of this disease. This review focuses on the true prevalence of tongue dysmorphology in craniofacial microsomia and its relation to the deformities seen in this condition. METHODS: A 20-year retrospective study was performed to determine the number of patients who had a documented tongue anomaly and any relation to the development of abnormal speech. In recognition of the limitations of this approach, a 1-year prospective study was also performed to see the true prevalence of tongue dysmorphology in these patients. RESULTS: Eight of 167 patients (4.8 percent) in the retrospective study were found to have tongue dysmorphologies, as opposed to 24 of 55 (43.6 percent) in the prospective study. The majority of tongue anomalies were mild. Of the eight retrospective patients, seven currently have intelligible speech with a combination of intensive speech therapy and/or surgical correction. The eighth patient is without intelligible speech. Tongue dysmorphology was positively correlated with the degree of hard- and soft-tissue deformity. CONCLUSIONS: Tongue dysmorphologies in craniofacial microsomia, although usually mild, are frequently overlooked. The correlation of the tongue, soft tissue, and mandible anomalies may point to a common error early in gestation or an interdependence of adjacent growth centers.

Evaluation of the safety of posterior cranial vault reconstruction.

BACKGROUND: Posterior vault reconstruction involves exposure, craniotomy, and reconstruction of the occipital cranium. Although it is commonly performed, the safety and complications associated with posterior vault reconstruction have not been specifically or thoroughly examined. METHODS: A retrospective chart review was performed for all patients undergoing posterior vault reconstruction at the Children's Hospital of Philadelphia between 1996 and 2006. Diagnosis, operative indication, age and weight at time of surgery, procedure type, intraoperative and postoperative complications, estimated blood loss, blood transfusion volume, and length of surgery and admission were recorded. RESULTS: Fifty posterior vault reconstruction cases were included in the study (17 syndromic and 33 nonsyndromic). Mean estimated blood loss was 53.6 percent (range, 15.9 to 142.9 percent) of total blood volume and was statistically greater in syndromic patients (60.6 percent versus 50.0 percent; p = 0.038). Transfusion volume averaged 66.1 percent of total blood volume but was not statistically significant. Length of surgery and number of intraoperative complications were significantly elevated in the syndromic cohort (p = 0.007 and p = 0.037, respectively), whereas length of admission and number of postoperative complications were not. Complications were intraoperative in seven patients (14 percent) and postoperative in seven (14 percent), for an overall complication rate of 28 percent. CONCLUSIONS: This is the largest series to date addressing the safety and complications of posterior vault reconstruction. In the authors' experience, posterior vault reconstruction carries a higher risk of intraoperative complications and blood loss compared with that reported in the literature for other types of cranial vault reconstruction. In addition, syndromic patients were more likely than nonsyndromic patients to encounter intraoperative problems.