Age, gender, and topography influence the clinical and dermoscopic appearance of lentigo maligna.

BACKGROUND: Little is known about the frequency of clinical and dermoscopic patterns of lentigo maligna (LM) in relation to specific anatomic subsites and patients characteristics. OBJECTIVE: We sought to assess the frequency of clinical and dermoscopic features of LM and to correlate them to specific anatomic subsites, and patients' age and gender. METHODS: This was a retrospective analysis of clinical and dermoscopic images of a series of consecutive, histopathologically diagnosed, facial and extrafacial LM. RESULTS: A total of 201 cases from 200 patients (mean age 69.51 ± 12.26 years) including 120 women were collected. Most cases were located on the face (n = 192, 95.5%). In 102 cases, LM presented as clinically solitary facial macule (s/LM), whereas it was associated with multiple surrounding freckles in the remaining cases. s/LM were significantly smaller (<10 vs >10 mm; P = .020) and associated with younger age compared with LM associated with multiple surrounding freckles (mean age 67.73 ± 12.68 years vs 71.34 ± 11.59 years, respectively; P = .036). Dermoscopically, gray color irrespective of a specific pattern was the most prevalent finding seen in 178 (88.6%) cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: The knowledge about patient age, patient gender, and site-related clinical features of LM associated with gray color upon dermoscopy may enhance the clinical recognition of LM.

Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia.

Pontocerebellar hypoplasia (PCH) represents a group (PCH1-6) of neurodegenerative autosomal recessive disorders characterized by hypoplasia and/or atrophy of the cerebellum, hypoplasia of the ventral pons, progressive microcephaly and variable neocortical atrophy. The majority of PCH2 and PCH4 cases are caused by mutations in the TSEN54 gene; one of the four subunits comprising the tRNA-splicing endonuclease (TSEN) complex. We hypothesized that TSEN54 mutations act through a loss of function mechanism. At 8 weeks of gestation, human TSEN54 is expressed ubiquitously in the brain, yet strong expression is seen within the telencephalon and metencephalon. Comparable expression patterns for tsen54 are observed in zebrafish embryos. Morpholino (MO) knockdown of tsen54 in zebrafish embryos results in loss of structural definition in the brain. This phenotype was partially rescued by co-injecting the MO with human TSEN54 mRNA. A developmental patterning defect was not associated with tsen54 knockdown; however, an increase in cell death within the brain was observed, thus bearing resemblance to PCH pathophysiology. Additionally, N-methyl-N-nitrosourea mutant zebrafish homozygous for a tsen54 premature stop-codon mutation die within 9 days post-fertilization. To determine whether a common disease pathway exists between TSEN54 and other PCH-related genes, we also monitored the effects of mitochondrial arginyl-tRNA synthetase (rars2; PCH1 and PCH6) knockdown in zebrafish. Comparable brain phenotypes were observed following the inhibition of both genes. These data strongly support the hypothesis that TSEN54 mutations cause PCH through a loss of function mechanism. Also we suggest that a common disease pathway may exist between TSEN54- and RARS2-related PCH, which may involve a tRNA processing-related mechanism.

The nucleolar GTP-binding proteins Gnl2 and nucleostemin are required for retinal neurogenesis in developing zebrafish.

Nucleostemin (NS), a member of a family of nucleolar GTP-binding proteins, is highly expressed in proliferating cells such as stem and cancer cells and is involved in the control of cell cycle progression. Both depletion and overexpression of NS result in stabilization of the tumor suppressor p53 protein in vitro. Although it has been previously suggested that NS has p53-independent functions, these to date remain unknown. Here, we report two zebrafish mutants recovered from forward and reverse genetic screens that carry loss of function mutations in two members of this nucleolar protein family, Guanine nucleotide binding-protein-like 2 (Gnl2) and Gnl3/NS. We demonstrate that these proteins are required for correct timing of cell cycle exit and subsequent neural differentiation in the brain and retina. Concomitantly, we observe aberrant expression of the cell cycle regulators cyclinD1 and p57kip2. Our models demonstrate that the loss of Gnl2 or NS induces p53 stabilization and p53-mediated apoptosis. However, the retinal differentiation defects are independent of p53 activation. Furthermore, this work demonstrates that Gnl2 and NS have both non-cell autonomously and cell-autonomous function in correct timing of cell cycle exit and neural differentiation. Finally, the data suggest that Gnl2 and NS affect cell cycle exit of neural progenitors by regulating the expression of cell cycle regulators independently of p53.

The novel gene asb11: a regulator of the size of the neural progenitor compartment.

From a differential display designed to isolate genes that are down-regulated upon differentiation of the central nervous system in Danio rerio embryos, we isolated d-asb11 (ankyrin repeat and suppressor of cytokine signaling box-containing protein 11). Knockdown of the d-Asb11 protein altered the expression of neural precursor genes sox2 and sox3 and resulted in an initial relative increase in proneural cell numbers. This was reflected by neurogenin1 expansion followed by premature neuronal differentiation, as demonstrated by HuC labeling and resulting in reduced size of the definitive neuronal compartment. Forced misexpression of d-asb11 was capable of ectopically inducing sox2 while it diminished or entirely abolished neurogenesis. Overexpression of d-Asb11 in both a pluripotent and a neural-committed progenitor cell line resulted in the stimulus-induced inhibition of terminal neuronal differentiation and enhanced proliferation. We conclude that d-Asb11 is a novel regulator of the neuronal progenitor compartment size by maintaining the neural precursors in the proliferating undifferentiated state possibly through the control of SoxB1 transcription factors.

Apc1 is required for maintenance of local brain organizers and dorsal midbrain survival.

The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.

The Wnt/beta-catenin pathway regulates cardiac valve formation.

Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.

Dermoscopy of cutaneous sarcoidosis.

BACKGROUND: The clinical variability of cutaneous sarcoidosis (CS) often makes its correct diagnosis challenging. Although traditionally employed for the diagnosis of skin tumors, during the past years dermoscopy also gained increasing interest as an aid in the clinical diagnosis of inflammatory and infectious skin manifestations in general dermatology. OBJECTIVE: Our purpose was to evaluate the usefulness of dermoscopy in the differential diagnosis of CS. METHODS: This was a retrospective analysis of 7 clinical and dermoscopic images of CS that were collected at dermatology clinics in France and Italy between 2005 and 2009. RESULTS: Retrospective dermoscopic evaluation revealed small grouped, translucent orange globular structures associated with linear vessels of variable diameter in all 7 cases. In 5 cases, additional central scar-like areas were seen. CONCLUSION: Lesions showing dermoscopically translucent yellow to orange globular-like or structureless areas associated with linear vessels should raise the suspicion of a granulomatous skin disease, including CS.

Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion.

The developmentally important hedgehog (Hh) pathway is activated by binding of Hh to patched (Ptch1), releasing smoothened (Smo) and the downstream transcription factor glioma associated (Gli) from inhibition. The mechanism behind Ptch1-dependent Smo inhibition remains unresolved. We now show that by mixing Ptch1-transfected and Ptch1 small interfering RNA-transfected cells with Gli reporter cells, Ptch1 is capable of non-cell autonomous repression of Smo. The magnitude of this non-cell autonomous repression of Smo activity was comparable to the fusion of Ptch1-transfected cell lines and Gli reporter cell lines, suggesting that it is the predominant mode of action. CHOD-PAP analysis of medium conditioned by Ptch1-transfected cells showed an elevated 3beta-hydroxysteroid content, which we hypothesized to mediate the Smo inhibition. Indeed, the inhibition of 3beta-hydroxysteroid synthesis impaired Ptch1 action on Smo, whereas adding the 3beta-hydroxysteroid (pro-)vitamin D3 to the medium effectively inhibited Gli activity. Vitamin D3 bound to Smo with high affinity in a cyclopamine-sensitive manner. Treating zebrafish embryos with vitamin D3 mimicked the smo(-/-) phenotype, confirming the inhibitory action in vivo. Hh activates its signalling cascade by inhibiting Ptch1-dependent secretion of the 3beta-hydroxysteroid (pro-)vitamin D3. This action not only explains the seemingly contradictory cause of Smith-Lemli-Opitz syndrome (SLOS), but also establishes Hh as a unique morphogen, because binding of Hh on one cell is capable of activating Hh-dependent signalling cascades on other cells.

Nasal-type NK/T-cell lymphoma: a case report.

Extranodal NK/T-cell lymphoma represents less than 1% of all lymphomas, but is more common in Asia and South America. We present a 67-year-old female with a 10-month history of four reddish-blue firm and painful nodules in the parietal region of the head, ranging in size from 1 to 5 cm. Two nodules were taken for biopsy, which showed atypical lymphoid cells with angiocentric growth pattern. The immunophenotype of the tumor cells was CD45RO +, CD56 +, CD3 + (epsilon chain), CD20-, consistent with the diagnosis of NK/T-cell lymphoma. NK/T-cell lymphomas are rare and the optimal treatment has not been clearly established.

Dermoscopy of melanoma.

Early detection of malignant melanoma is one of the greatest challenges for dermatologists. Dermoscopy is an in vivo method for the early diagnosis of malignant melanoma and the differential diagnosis of pigmented lesions of the skin. We report a 85-year-old man with a pigmented skin lesion in left mandibular region. Dermoscopy revealed evident characteristics of malignant melanoma. The total score was 7 points according to the 7- point checklist. Pathohistological examination confirmed diagnosis of melanoma.

Immunophenotyping of amelanotic melanoma. A case report.

Amelanotic malignant melanoma (AMM) is a subtype of cutaneous melanoma with little or no pigment upon visual inspection. The lack of pigmentation is the reason for late diagnosis of lesions and a poor prognosis. We report a case of a 55-year-old female with an AMM diagnosed by immunophenotyping. Monoclonal antibodies S-100, HMB-45, and antibodies to cytokeratin were used. Our patient underwent a wide local excision (a 2 cm wide margin) 2 years ago. So far there are no signs of a recurrence. In doubtful cases, immunophenotyping with monoclonal antibodies HMB-45 and S-100 is important for confirming the correct diagnosis of AMM.

Twenty nevi on the arms: a simple rule to identify patients younger than 50 years of age at higher risk for melanoma.

Patients with a high total nevus count (TNC) merit a total-body examination, but a simple strategy to identify these high-risk individuals is essentially missing. The aim of this study was to investigate the correlation between the number of melanocytic nevi on both arms and the TNC, and to evaluate patient variables that may have an effect on this association. In this multicenter, cross-sectional study, 2175 patients were examined and the mean number of arm nevi in relation to TNC was calculated. A mean value of fewer than 10 arm nevi was found in patients with TNC lower than 51 and a mean value of greater than 19 arm nevi was scored in patients with TNC greater than 50. These values remained unchanged after adjustment for various patient variables. In relation to TNC greater than 50, the presence of 20 or more arm nevi had specificity and negative predictive values of 95.2 and 89.6%, respectively. The sensitivity was 65.5% in patients younger than 50 years of age and 37.5% in the older age group. The number of arm nevi was significantly higher in individuals with a history of melanoma and in those with a melanoma detected during the study period. The presence of 20 or more nevi on the arms is an independent predictor of a high TNC and risk of melanoma. This sign thus represents a simple and rapid screening tool for either the primary care physician or the dermatologist to help identify high-risk patients.

Problematic lesions in the elderly.

As the population continues to age, clinicians and dermatologists are increasingly faced with geriatric patients presenting with a range of dermatologic manifestations, including benign and malignant skin tumors. Knowledge of epidemiologic and morphologic features, including dermoscopy of common and benign melanocytic and nonmelanocytic skin tumors, provides the basis for a better understanding and management of problematic skin tumors in this age group. This article provides an overview of common and problematic skin lesions in elderly patients and addresses epidemiologic, clinical, and dermoscopic clues that aid the differential diagnosis and management of challenging skin lesions.

asb11 is a regulator of embryonic and adult regenerative myogenesis.

The specific molecular determinants that govern progenitor expansion and final compartment size in the myogenic lineage, either during gestation or during regenerative myogenesis, remain largely obscure. Recently, we retrieved d-asb11 from a zebrafish screen designed to identify gene products that are downregulated during embryogenesis upon terminal differentiation and identified it as a potential regulator of compartment size in the ectodermal lineage. A role in mesodermal derivatives remained, however, unexplored. Here we report pan-vertebrate expression of Asb11 in muscle compartments, where it highly specifically localizes to the Pax7(+) muscle satellite cell compartment. Forced expression of d-asb11 impaired terminal differentiation and caused enhanced proliferation in the myogenic progenitor compartment both in in vivo and in vitro model systems. Conversely, introduction of a germline hypomorphic mutation in the zebrafish d-asb11 gene produced premature differentiation of the muscle progenitors and delayed regenerative responses in adult injured muscle. Thus, the expression of d-asb11 is necessary for muscle progenitor expansion, whereas its downregulation marks the onset of terminal differentiation. Hence, we provide evidence that d-asb11 is a principal regulator of embryonic as well as adult regenerative myogenesis.

Essential role for the d-Asb11 cul5 Box domain for proper notch signaling and neural cell fate decisions in vivo.

ECS (Elongin BC-Cul2/Cul5-SOCS-box protein) ubiquitin ligases recruit substrates to E2 ubiquitin-conjugating enzymes through a SOCS-box protein substrate receptor, an Elongin BC adaptor and a cullin (Cul2 or Cul5) scaffold which interacts with the RING protein. In vitro studies have shown that the conserved amino acid sequence of the cullin box in SOCS-box proteins is required for complex formation and function. However, the in vivo importance of cullin boxes has not been addressed. To explore the biological functions of the cullin box domain of ankyrin repeat and SOCS-box containing protein 11 (d-Asb11), a key mediator of canonical Delta-Notch signaling, we isolated a zebrafish mutant lacking the Cul5 box (Asb11(Cul)). We found that homozygous zebrafish mutants for this allele were defective in Notch signaling as indicated by the impaired expression of Notch target genes. Importantly, asb11(Cul) fish were not capable to degrade the Notch ligand DeltaA during embryogenesis, a process essential for the initiation of Notch signaling during neurogenesis. Accordingly, proper cell fate specification within the neurogenic regions of the zebrafish embryo was impaired. In addition, Asb11(Cul) mRNA was defective in the ability to transactivate a her4::gfp reporter DNA when injected in embryos. Thus, our study reporting the generation and the characterization of a metazoan organism mutant in the conserved cullin binding domain of the SOCS-box demonstrates a hitherto unrecognized importance of the SOCS-box domain for the function of this class of cullin-RING ubiquitin ligases and establishes that the d-Asb11 cullin box is required for both canonical Notch signaling and proper neurogenesis.