Nicolas Ortonne

Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment

BACKGROUND The mammalian hair represents an unparalleled model system to understand both developmental processes and stem cell biology. The hair follicle consists of several concentric epithelial sheaths with the outer root sheath (ORS) forming the outermost layer. Functionally, the ORS has been implicated in the migration of hair stem cells from the stem cell niche toward the hair bulb. However, factors required for the differentiation of this critical cell lineage remain to be identified. Here, we describe an unexpected role of the HMG-box-containing gene Sox9 in hair development. RESULTS Sox9 expression can be first detected in the epithelial component of the hair placode but then becomes restricted to the outer root sheath (ORS) and the hair stem cell compartment (bulge). Using tissue-specific inactivation of Sox9, we demonstrate that this gene serves a crucial role in hair differentiation and that skin deleted for Sox9 lacks external hair. Strikingly, the ORS acquires epidermal characteristics with ectopic expression of GATA3. Moreover, Sox9 knock hair show severe proliferative defects and the stem cell niche never forms. Finally, we show that Sox9 expression depends on sonic hedgehog (Shh) signaling and demonstrate overexpression in skin tumors in mouse and man. CONCLUSIONS We conclude that although Sox9 is dispensable for hair induction, it directs differentiation of the ORS and is required for the formation of the hair stem cell compartment. Our genetic analysis places Sox9 in a molecular cascade downstream of sonic hedgehog and suggests that this gene is involved in basal cell carcinoma.

Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study

BACKGROUND The risk to benefit ratio of face transplantation with a composite tissue allograft remains debatable, although this procedure is technically feasible. We report here a 1-year follow-up of a patient who underwent face transplantation with a composite tissue allograft. METHODS On Jan 21, 2007, a 29-year-old man with neurofibromatosis type 1 underwent resection of a massive plexiform neurofibroma diffusely infiltrating the middle and lower part of his face. The main goal was to restore both the cutaneous appearance and function of the face, including, in particular, control of orbicularis oculi and oris muscle contraction. The issues of immunosuppressive therapy, psychological outcome, and social reintergration were addressed, together with the monitoring of graft rejection by biopsies of the skin and mucosa. FINDINGS The initial postoperative course was uncomplicated. Two episodes of clinical rejection occurred on days 28 and 64. The second episode was associated with cytomegalovirus infection. Both episodes resolved favourably, with no further clinical signs of rejection, making the reduction of immunosuppressive treatment possible. A year after surgery, the functional outcome was very good, with successful sensory and motor reinnervation in the transplanted territory. Psychological recovery was excellent, with complete social reintegration. INTERPRETATION This case demonstrates the feasibility of surgically removing a large part of the face and replacing it with a composite tissue allograft. This facial repair procedure, which seems to have a satisfactory risk to benefit ratio, could be offered in rare and selected cases.

PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.

Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes.

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain‐dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal‐photopheresis. Four patients were transplanted with 7‐ to 38‐month follow‐up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life.

Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis.

Background  Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute mucocutaneous reactions associated with poor prognosis. The treatment is mainly symptomatic, based on supportive care. Until now, several curative treatments have been proposed without evidence of effectiveness.

Role of Noncoding RNA ANRIL in Genesis of Plexiform Neurofibromas in Neurofibromatosis Type 1

BACKGROUND Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome with a worldwide birth incidence of one in 2500. Genetic factors unrelated to the NF1 locus are thought to influence the number of plexiform neurofibromas (PNFs) in patients with NF1, but no factors have been identified to date. METHODS We used high-resolution array comparative genomic hybridization of tissue from 22 PNFs obtained from 18 NF1 patients to identify modifier genes involved in PNF development. We used a family-based association test for five previously identified cancer-susceptibility tag single-nucleotide polymorphisms (rs1063192, rs2151280, rs2218220, rs10757257, and rs7023329) located in chromosomal region 9p21.3 in 1105 subjects (740 NF1 patients and 365 non-affected relatives) from 306 families. To confirm the functional role of rs2151280, we used real-time quantitative reverse transcription-polymerase chain reaction to analyze the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), CDKN2B, alternate reading frame (ARF), and antisense noncoding RNA in the INK4 locus (ANRIL) in the peripheral blood of 124 NF1 patients. Relationships between CDKN2A, CDKN2B, ARF, and ANRIL expression and the rs2151280 genotype were tested by the Kruskal-Wallis test. All statistical tests were two-sided. RESULTS In NF1-associated PNFs, 9p21.3 deletions (including the CDKN2A/B-ANRIL locus) were found as the only recurrent somatic alterations. Single-nucleotide polymorphism rs2151280 (located in ANRIL) was statistically significantly associated with the number of PNFs (P < .001) in NF1 patients. In addition, allele T of rs2151280 was statistically significantly associated with reduced ANRIL transcript levels (P < .001), suggesting that modulation of ANRIL expression mediates PNF susceptibility. CONCLUSION Identification of ANRIL as a modifier gene in NF1 may offer clues to the molecular pathogenesis of PNFs, particularly neurofibroma formation, and emphasizes the unanticipated role of large noncoding RNA in activation of critical regulators of tumor development.

Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by rash with sterile pustules, high fever and elevated circulating neutrophil counts.

SOX9 expression is a general marker of basal cell carcinoma and adnexal‐related neoplasms

Background:  SOX9 is a transcription factor that fulfills multiple functions during development. In the hair follicle SOX9 is expressed in the outer layer of the epithelial sheath, and the hair stem cell compartment. Recent data suggest that Sox9 acts as a downstream target of the Sonic hedgehog (Shh) pathway. Activation of the Shh pathway is a major cause of cutaneous basal cell carcinoma (BCC). Here we test whether activation of SOX9 is a general feature of BCC, or whether it could be used as a biomarker to better define subtypes of these skin tumors. In addition we investigated SOX9 expression in other skin epidermal tumors.

Cutaneous Destombes–Rosai–Dorfman disease: absence of detection of HHV‐6 and HHV‐8 in skin

Background:  We report three new cases of cutaneous Destombes–Rosai–Dorfman disease (DRDD). Two were skin‐limited, and one was associated with systemic involvement. In all cases typical large S100 positive macrophages with emperipolesis were present, but different patterns were seen. A viral etiology has long been suspected in DRDD.

Toxic epidermal necrolysis, DRESS, AGEP: Do overlap cases exist?

BackgroundSevere cutaneous adverse reactions to drugs (SCARs) include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and epidermal necrolysis (Stevens-Johnson syndrome–toxic epidermal necrolysis [SJS-TEN]). Because of the varied initial presentation of such adverse drug reactions, diagnosis may be difficult and suggests overlap among SCARs. Overlapping SCARs are defined as cases fulfilling the criteria for definite or probable diagnosis of at least 2 ADRs according to scoring systems for AGEP, DRESS and SJS-TEN. We aimed to evaluate the prevalence of overlap among SCARs among cases in the referral hospital in France.MethodsWe retrospectively analyzed data for 216 patients hospitalized in the referral centre over 7 years with a discharge diagnosis of AGEP (n = 45), DRESS (n = 47), SJS-TEN (n = 80) or “drug rash” (n = 44). Each case with detailed clinical data and a skin biopsy specimen was scored for AGEP, DRESS and SJS-TEN by use of diagnostic scores elaborated by the RegiSCAR group.ResultsIn total, 45 of 216 cases (21%) had at least 2 possible diagnoses: 35 had a single predominant diagnosis (definite or probable), 7 had several possible diagnoses and 3 (2.1% of 145 confirmed SCARs) were overlap SCARs.ConclusionsDespite ambiguities among SCARs, confirmed overlap cases are rare. This study did not avoid pitfalls linked to its retrospective nature and selection bias. In the acute stage of disease, early identification of severe ADRs can be difficult because of clinical or biologic overlapping features and missing data on histology, biology and evolution. Retrospectively analyzing cases by use of diagnostic algorithms can lead to reliable discrimination among AGEP, DRESS and SJS-TEN.