Divergent growth of the transient brain compartments in fetuses with nonsyndromic isolated clefts involving the primary and secondary palate.

Cleft lip/palate is a common orofacial malformation that often leads to speech/language difficulties as well as developmental delays in affected children, despite surgical repair. Our understanding of brain development in these children is limited. This study aimed to analyze prenatal brain development in fetuses with cleft lip/palate and controls. We examined in utero MRIs of 30 controls and 42 cleft lip/palate fetal cases and measured regional brain volumes. Cleft lip/palate was categorized into groups A (cleft lip or alveolus) and B (any combination of clefts involving the primary and secondary palates). Using a repeated-measures regression model with relative brain hemisphere volumes (%), and after adjusting for multiple comparisons, we did not identify significant differences in regional brain growth between group A and controls. Group B clefts had significantly slower weekly cerebellar growth compared with controls. We also observed divergent brain growth in transient brain structures (cortical plate, subplate, ganglionic eminence) within group B clefts, depending on severity (unilateral or bilateral) and defect location (hemisphere ipsilateral or contralateral to the defect). Further research is needed to explore the association between regional fetal brain growth and cleft lip/palate severity, with the potential to inform early neurodevelopmental biomarkers and personalized diagnostics.

Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. METHODS: BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. RESULTS: Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. CONCLUSION: Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.

Elastic Chain Premaxillary Retraction Appliance Does Not Increase Inter-Canthal Dimension in Patients with Bilateral Cleft Lip and Palate.

OBJECTIVE: To determine if the elastic chain premaxillary retraction (ECPR) appliance increases inter-medial and inter-lateral canthal dimension in patients with bilateral complete cleft lip and palate (BCLP). DESIGN: Retrospective cohort study. SETTING: Specialized tertiary care facility. PATIENTS, PARTICIPANTS: 126 patients with BCLP; 75 had ECPR, 51 had no pre-surgical manipulation. INTERVENTIONS: Three-dimensional facial photographs were obtained prior to insertion of appliance (T0), post-appliance therapy prior to appliance removal/labial repair (T1), and several months after labial repair (T2) for a longitudinal ECPR group, and were obtained after age 4 years (T3) for a non-longitudinal ECPR group and for the non-ECPR group. MAIN OUTCOME MEASURES: Inter-medial and inter-lateral canthal dimension (en-en, ex-ex) was determined for all groups/time-points. Measurements were compared between groups and to norms. RESULTS: The mean en-en and ex-ex was 32.6 ± 3.2 mm and 84.4 ± 6.3 mm for the ECPR group and 33.5 ± 3.1 mm and 86.7 ± 7.2 mm for the non-ECPR group at T3. Inter-medial and inter-lateral canthal dimensions were significantly greater than normal (P < .05) in both groups; there was no significant difference between groups (P > .05). The mean en-en and ex-ex for the Longitudinal ECPR group was 27.5 ± 2.4 mm and 66.7 ± 3.7 mm at T0, 29.6 ± 2.4 mm and 70.4 ± 2.9 mm at T1, and 29.2 ± 2.3 mm and 72.3 ± 3.8 mm at T2. en-en and ex-ex increased significantly from T0-T1 (P < .05), decreased at T2 (P > .05) and was significantly larger than normal at all time-points (P < .05). CONCLUSIONS: Inter-medial and inter-lateral canthal dimension increased after ECPR but returned to baseline growth trajectory. These dimensions were above normal at all time-points. There was no difference between those that did and did not have dentofacial orthopedic manipulation.

Infantile hemangioma: the common and enigmatic vascular tumor.

Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of newborns. The tumor follows a life cycle of rapid proliferation in infancy, followed by slow involution in childhood. This unique life cycle has attracted the interest of basic and clinical scientists alike as a paradigm for vasculogenesis, angiogenesis, and vascular regression. Unanswered questions persist about the genetic and molecular drivers of the proliferating and involuting phases. The beta blocker propranolol usually accelerates regression of problematic IHs, yet its mechanism of action on vascular proliferation and differentiation is unclear. Some IHs fail to respond to beta blockers and regrow after discontinuation. Side effects occur and long-term sequelae of propranolol treatment are unknown. This poses clinical challenges and raises novel questions about the mechanisms of vascular overgrowth in IH.

R(+) Propranolol decreases lipid accumulation in hemangioma-derived stem cells.

Background: Infantile hemangioma (IH) is a benign vascular tumor that undergoes an initial rapid growth phase followed by spontaneous involution. A fibrofatty residuum remains in many tumors and often necessitates resection. We recently discovered that R(+) propranolol, the non-ß blocker enantiomer, inhibits blood vessel formation of IH patient-derived hemangioma stem cells (HemSC) xenografted in mice. HemSC are multipotent cells with the ability to differentiate into endothelial cells, pericytes, and adipocytes. Objectives: We investigated how R(+) propranolol affects HemSC adipogenic differentiation and lipid accumulation, in vitro and in a preclinical murine model for IH. Methods: We conducted a 10-day adipogenesis assay on 4 IH patient-derived HemSCs. Oil Red O (ORO) staining was used to identify the onset and level of lipid accumulation in HemSC while quantitative real-time polymerase chain reaction was conducted to determine the temporal expression of key factors implicated in adipogenesis. 5-20µM R(+) propranolol treatment was added to HemSC induced to undergo adiogenesis for 4 and 8 days, followed by quantification of lipid-stained areas and transcript levels of key adipogenic factors. We immunostained for lipid droplet-associated protein Perilipin 1 (PLIN1) in HemSC-xenograft sections from mice treated with R(+) propranolol and quantified the area using ImageJ. Results: We found that different patient-derived HemSC exhibit a robust and heterogenous adipogenic capacity when induced for adipogenic differentiation in vitro. Consistently across four IH patient-derived HemSC isolates, R(+) propranolol reduced ORO-stained areas and lipoprotein lipase (LPL) transcript levels in HemSC after 4 and 8 days of adipogenic induction. In contrast, R(+) propranolol had no significant inhibitory effect on transcript levels encoding adipogenic transcription factors. In a pre-clinical HemSC xenograft model, PLIN1-positive area was significantly reduced in xenograft sections from mice treated with R(+) propranolol, signifying reduced lipid accumulation. Conclusions: Our findings suggest a novel regulatory role for the R(+) enantiomer of propranolol in modulating lipid accumulation in HemSC. This highlights a novel role of R(+) propranolol in the involuting phase of IH and a strategy to reduce fibrofatty residua in IH. What is already known about this topic?: Propranolol is the mainstay treatment for infantile hemangioma (IH), the most common tumor of infancy, but its use can be associated with concerning ß-blocker side effects.R(+) propranolol, the enantiomer largely devoid of ß-blocker activity, was recently shown to inhibit endothelial differentiation of hemangioma-derived stem cells (HemSC) in vitro and reduce blood vessel formation in a HemSC-derived xenograft murine model of IH. What does this study add?: R(+) propranolol inhibits lipid accumulation in HemSC in vitro.R(+) propranolol does not affect mRNA transcript levels of key adipogenic transcription factors in differentiating HemSC in vitro.R(+) propranolol reduces lipid accumulation in a pre-clinical xenograft murine model of IH. What is the translational message?: The R(+) enantiomer of propranolol could be advantageous in terms of reduction in ß-adrenergic side effects and fibrofatty tissue formation in the involuting phase of IH.Less fibrofatty residua might reduce the need for surgical resection.Disfigurement and associated psychosocial impacts might be improved in this young patient cohort.

Infantile Hemangioma of the Breast: Long-Term Assessment of Outcomes.

Background: The literature is meager regarding the natural history and outcomes of infantile hemangiomas (IHs) in the breast. Treatment in childhood may be considered due to psychosocial and physical concerns with breast development. Early surgical intervention may cause iatrogenic breast asymmetry and possibly impair lactation later in life. This study characterizes the clinical presentation, management, and long-term outcomes of IHs arising in the breast. Methods: Female patients aged 11 years or older at presentation were included in a retrospective review of the Vascular Anomalies Center database for patients with IHs of the breast seen at our institution between 1980 and 2020. Breast development was ascertained by a structured telephone interview, physical examination, or photographs. Results: A total of 10 patients met criteria for inclusion in this study. The median age at enrollment was 14 years (11-36 years). Breast asymmetry was noted in 60% of patients (n = 6). Of the four patients who underwent subtotal excision of breast IH, three developed ipsilateral breast hypoplasia. Breast asymmetry was also noted in three of five patients who did not receive medical treatment: two with hypoplasia and one with hyperplasia. No asymmetry was noted in the single patient who received corticosteroid. Conclusions: IHs involving the nipple-areola complex can be associated with breast asymmetry. Hypoplasia was noted in patients not treated with corticosteroid or resection in childhood. These findings suggest that systemic treatment should be considered. Longitudinal follow-up on patients treated with propranolol will elucidate its possible benefits in minimizing breast asymmetry.

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma.

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a ß-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis.