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Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.

Dental management of patients with epi-dermolysis bullosa (EB) is challenging because of the severe soft tissue lesions associated with this disease. A case history is presented where two immediate endosseous implants were placed in the mandible of a patient with recessive dystrophic EB using computer-aided technology to plan the surgery and prosthetic rehabilitation. After a 24-month follow-up, the prosthesis was stable with healthy asymptomatic soft tissue around the implants. The stereolithographic model provides a precise and noninvasive copy of the mandibular and maxillary arches of patients with EB for rehabilitation of the dentition with immediate endosseous implants and a prosthesis.

Our study demonstrated higher pAKT and pmTOR expression during carcinogenesis of oral mucosa, differing considerably among OED and OSCC specimens when compared to NDOT. These proteins can be considered potential diagnostic markers for early detection of cancer.

A previously unreported case of Barber-Say syndrome is described with special attention to dental manifestations. A 7-year-old female with multiple congenital anomalies such mammary gland hypoplasia, hypertrichosis, ectropion, and redundant skin was seen at the School of Dentistry of the University of São Paulo. Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion. Dental treatment included gingivoplasty and orthodontic treatment.

Pigmented squamous cell carcinoma in situ (PSCCIS) is very rare, being clinically described as a pigmented lesion with histological characteristics of an in-situ carcinoma presenting pigmentation within neoplastic cells. A 50-year-old Afro-descendant man came for clinical evaluation of a painful black and red lesion located on the right aspect of the oropharyngeal isthmus. After incisional biopsy, the resulting sample was described as a pigmented squamous cell carcinoma in situ, a diagnosis further confirmed by immunohistochemical analysis. Treatment consisted in total excision of the lesion, and no recurrence was observed after a 30-month follow-up. Clinicians and pathologists should be aware of PSCCIS as a differential diagnosis of melanoma, a lesion which significantly increases the morbidity and mortality rates among these patients. Key words:Pigmented squamous cell carcinoma in situ; oropharyngeal mucosa; immunohistochemistry.

Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous cell carcinoma highly express the neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up-regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells.