Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

BACKGROUND: Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. OBJECTIVES: To investigate the genetic aetiology and molecular mechanisms underlying BDCS. METHODS: We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. RESULTS: In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. CONCLUSIONS: Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

Pilot study: optical coherence tomography as a non-invasive diagnostic perspective for real time visualisation of onychomycosis.

The objective of this study was to compare optical coherence tomography (OCT) with conventional techniques such as KOH-preparation, culture and histology in the identification of the fungal elements in the nail. A total of 18 patients were examined; 10 with clinically evident onychomycosis in toe nails, two with psoriatic nail lesions, one with nail affection caused by lichen planus and five healthy controls. Serial in vivo OCT analyses of onychomycosis was performed prior to KOH-preparation, culture and punch biopsy of the nail plate for consecutive histology. Fungal elements were detected non-invasively in vivo using OCT in all 10 patients with histologically proven onychomycosis. Fungal elements were detectable as highly scattering elongated structures inside the nail plate, in the middle of the areas of homogeneous decrease in signal intensity. KOH-preparations and culture did reveal a positive result in 5/6 out of 10 patients. In patients with psoriasis, lichen planus as well as in the healthy controls, no fungal infection could be detected by either method used. OCT is a reliable, easy to use, non-invasive and non-destructive method to visualise fungal elements in vivo in onychomycosis, even in cases of false negative KOH-preparation and culture. Furthermore, OCT offers the opportunity to screen several areas of the same nail plate and to detect fungal elements during local or systemic therapy.

Effects of photodynamic therapy evaluated in a novel three-dimensional squamous cell carcinoma organ construct of the skin.

Squamous cell carcinoma (SCC) of the skin is a malignant neoplasm that occurs in all ethnic groups primarily due to chronic sun exposure and constitutes a major health problem worldwide. Novel therapies for SCC are in development but as yet no in vitro models capable of screening these therapies and their mechanism of action before proceeding to clinical trials in human subjects have emerged. For this reason we have developed and characterized a novel three-dimensional human SCC construct and validated it using photodynamic therapy (PDT), a well-established modality for treating in situ SCCs. Histologic and immunohistochemical characterization of these SCC constructs revealed epidermal and dermal de-differentiation, increased cell proliferation and expression of immunohistochemical markers specific for cutaneous SCC. Application of PDT to these constructs led to tumor regression with widespread apoptosis and necrosis within 5 days. This in vitro model consistently reproduces the tumor development and dynamics of growing SCCs in vivo and provides a useful approach for screening new treatment modalities for this form of cutaneous cancer.