FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish.

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.

Combination of tissue expansion and porcine mesh for secondary abdominal wall closure after pediatric liver transplantation.

We report the case of a two and a half yr boy hospitalized in our Pediatric Transplantation Unit for portal vein thrombosis following liver transplantation. After performing a meso-Rex shunt, abdominal wall closure was impossible without compressing the portal flow. A combination of two techniques was used to perform the reconstruction of the muscular fasciae and skin layers. The association of tissue expanders and porcine mesh (Surgisis(®)) allowed complete abdominal wall closure with good functional and esthetic results. Use of both techniques is a useful alternative for difficult abdominal closure after liver pediatric transplantation.

Congenital erosive and vesicular dermatosis with reticulated scarring in a newborn: an innovative treatment using a silicone dressing.

Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. We report the case of a premature baby 31 weeks old. Diagnosis was confirmed by skin biopsies, and the clinical improvement was excellent, with complete healing observed within 7 weeks. This report highlights clinical and histopathologic features, and a new successful treatment approach using a silicone dressing.

Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population.

Cleft lip with or without cleft palate is the most frequent craniofacial malformation in humans ( approximately 1/700). Its etiology is multifactorial; some are a result of a genetic mutation, while others may be due to environmental factors, with genetic predisposition playing an important role. The prevalence varies widely between populations and the mode of inheritance remains controversial. The interferon regulatory factor-6 (IRF6) gene has been shown to harbor mutations in patients with van der Woude syndrome, a dominant form of clefts associated with small pits of the lower lip. Moreover IRF6 has been associated with nonsyndromic cleft of the palate (CL/P) in two separate studies. We investigated the role of IRF6 in a set of 195 trios from Belgium. Cleft occurred as an isolated feature. We studied association of the IRF6 locus using two variants: one in the IRF6 gene and the other 100 kpb 3' of the gene. Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate. This result, with previous studies performed in the United States and Italy, shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. It is likely that association to this locus can be identified in various populations and that the IRF6 locus thus represents an important genetic modifier for this multifactorial malformation.

Autologous Adipose Stromal Cells Seeded onto a Human Collagen Matrix for Dermal Regeneration in Chronic Wounds: Clinical Proof of Concept.

BACKGROUND: Nonhealing wounds are unable to integrate skin autografts by avascular and fibrotic dermal tissue. Adipose-derived stromal cells can improve the local environment of the wound bed by angiogenesis and immunomodulation. This work aimed to develop a biological dressing made of adipose-derived stromal cells onto a human acellular collagen matrix. METHODS: Adipose-derived stromal cells were isolated from human adipose tissue (n = 8). In vitro, the genetic stability during early and late passages (1, 4, 10, and 16) and vascular endothelial growth factor (VEGF) secretion were assessed. Adipose-derived stromal cell adhesion and spreading on collagen matrix were preliminarily studied. In vivo tumorigenicity, angiogenesis, and tissue oxygenation were assessed after implantation of the construct in nude rats (n = 10). The biological dressing was manufactured and implanted in three patients with chronic wounds. RESULTS: In vitro, aneuploidies, but no clonal transformation, were detected up to late cellular passages. VEGF was secreted more during hypoxia (0.1% oxygen) than during normoxia (21% oxygen). Adipose-derived stromal cells can adhere and spread on the scaffold within 18 to 20 days. No tumor development occurred 3 months after implantation in immunocompromised rats. Vessel counts and tissue oxygenation were higher after adipose-derived stromal cell implantation. In patients, granulation tissue was found (276 percent of vessel density), followed by epithelialization or split-thickness skin engraftment up to 22 months after implantation. CONCLUSIONS: Implantation of adipose-derived stromal cells seeded onto human acellular collagen matrix (biological dressing) represents a promising therapy for nonhealing wounds, offering improvement in dermal angiogenesis and remodeling. This therapy using autologous stromal cells is safe, without significant genetic alterations after in vitro expansion.

The "collerette" technique for skin excision and biopsy: an efficient method for managing lentigo maligna of the head and neck.

BACKGROUND: Melanoma is responsible for 75% of all skin cancer-related deaths. Lentigo maligna (LM), the most prevalent melanoma in situ (MIS), accounts for 79-83% of all MIS. Its location in the head and neck area requires that tissue be spared in the course of clearing the tumor. METHODS: We conducted a therapeutic study based on our practice experience with the so-called "collarette" skin biopsy technique used in the management of LM. RESULTS: Thirty-one patients were diagnosed with LM in the head and neck area. These included 16 women and 15 men with a mean ± standard deviation (SD) age of 64.4 ± 13.6 years (range: 33-88 years). The majority (36%) of lesions were located on the cheek. To clear the tumor, surgery was performed using margins of >10 mm in 71% of cases. The average surface area of the surgical defect was 5.8 cm(2) (range: 1.1-15.5 cm(2) ). Reconstructive skin grafts were performed in the majority (68%) of cases. After the removal of the central tumor, 16 cases of MIS and 15 cases of invasive melanoma were identified. Only one patient experienced recurrence over a mean ± SD follow-up of 31 ± 16 months. CONCLUSIONS: The so-called "collarette" or "spaghetti" skin excision and biopsy technique is an advantageous and efficient way to achieve tumor clearance and represents an equally effective alternative to Mohs micrographic surgery in the treatment of LM in the head and neck area.

Association of localized intravascular coagulopathy with venous malformations.

OBJECTIVE: To determine which venous malformations (VMs) are at risk for coagulopathy. Venous malformations are slow-flow vascular malformations present at birth, and localized intravascular coagulopathy (LIC) causes pain and thrombosis within a lesion and severe bleeding during surgical procedures. DESIGN: Prospective convenience sample accrued from 2 multidisciplinary sites in Brussels, Belgium, and Caen, France. PARTICIPANTS: The study population comprised 140 patients with clinical data and coagulation parameters. Magnetic resonance imaging was performed for 110 patients. MAIN OUTCOME MEASURE: Measurement of D-dimer levels. RESULTS: Of the 140 participants, 59 (42%) showed high D-dimer levels, 36 (61%) of whom had levels higher than 1.0 microg/mL. Six of the participants had low fibrinogen levels. In univariate analysis, large surface, presence of palpable phleboliths, and truncal localization were associated with high D-dimer levels. In the multivariate analysis, only large surface area and presence of phleboliths remained independently associated with high D-dimer levels. Severe LIC, characterized by concomitant low fibrinogen level, was associated with extensive venous malformations of the extremities. CONCLUSIONS: Localized intravascular coagulopathy is statistically significantly associated with large and/or deep venous malformations that affect any location, which can have a palpable phlebolith. These patients are at risk of local pain due to thrombosis. Lesions with elevated D-dimer levels associated with low fibrinogen levels (severe LIC) commonly affect an extremity and have a high risk of hemorrhage. Low-molecular-weight heparin can be used both to treat the pain caused by LIC and to prevent decompensation of severe LIC to disseminated intravascular coagulopathy.

Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations.

Capillary malformation (CM), or "port-wine stain," is a common cutaneous vascular anomaly that initially appears as a red macular stain that darkens over years. CM also occurs in several combined vascular anomalies that exhibit hypertrophy, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and Parkes Weber syndrome. Occasional familial segregation of CM suggests that there is genetic susceptibility, underscored by the identification of a large locus, CMC1, on chromosome 5q. We used genetic fine mapping with polymorphic markers to reduce the size of the CMC1 locus. A positional candidate gene, RASA1, encoding p120-RasGAP, was screened for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in six families manifesting atypical CMs that were multiple, small, round to oval in shape, and pinkish red in color. In addition to CM, either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome was documented in all the families with a mutation. We named this newly identified association caused by RASA1 mutations "CM-AVM," for capillary malformation-arteriovenous malformation. The phenotypic variability can be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.