Cutaneous histiocytoses in children

Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of macrophages or dendritic cells. The clinical spectrum ranges from self-resolving, skin-limited conditions to severe, multiorgan disease with a high morbidity rate. Until recently, cutaneous histiocytoses were classified according to the immunophenotype of the pathological cells, with differentiation between Langerhans cell histiocytosis (LCH) [CD1a+, CD207 (langerin)+] and non-Langerhans cell histiocytosis (CD68+, CD163+, CD1a?, CD207?). Over the last 12 years, a number of new pathophysiological findings (in particular, molecular pathology results) regarding histiocytoses have contributed to a new classification based on molecular alterations, as well as on clinical and imaging characteristics and the phenotype. The most frequent entities in children are juvenile xanthogranuloma and LCH.     

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups ‐ revisiting this controversial concept after 16 years of additional evidence

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi‐level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S′) and diastole (E′), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty‐eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional‐hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end‐organ failure. On Cox proportional‐hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S′ results in a 91% increase, and 1 cm/s decrease in E′ results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.     

Hemangioma with dabskoid features: a rare histopathologic variant of acquired hemangioma

Dabska tumor, also known as papillary intralymphatic angioendothelioma (PILA), is a locally aggressive hemangiendothelioma characterized by intravascular papillary proliferations of atypical endothelial cells. Besides PILA, papillary tufts lined by hobnail endothelial cells have been rarely described in vascular proliferations. We report two cases of acquired hemangiomas, which focally showed this finding. We present a 15‐year‐old male and a 7‐year‐old girl with erythematous nodules. Both lesions were composed of capillary lobules intermingled with large sinusoidal spaces lined with a single layer of flat endothelial cells, which focally developed intravascular papillary proliferations lined by plump hyperchromatic endothelial cells and a central connective tissue core. Both types of cells were positive with CD31 and ERG and negative for Lyve‐1, Prox‐1 and podoplanin. Wilm's tumor 1 marker was strongly positive in the capillary hemangioma areas while negative in the intravascular tufts. Both lesions recurred after the first excision but we did not observe further recurrence or evidence of metastasis in the follow‐up. In summary, our cases expand the histopathologic findings that may be seen in conventional acquired capillary hemangiomas. The focal presence of dabskoid tufts within an otherwise conventional capillary hemangioma should be not misinterpreted as evidence of malignancy.     

Varying proliferative and clonogenic potential in NRAS‐mutated congenital melanocytic nevi according to size

Congenital melanocytic nevi (CMN) are benign proliferations that may be associated with various consequences depending on their size. They are characterized by a specific molecular signature, namely a postzygotic somatic NRAS or BRAF mutation. We have recently reported that large CMN (lCMN), which are classically associated with an increased melanoma risk, harbour cell subpopulations with specific clonogenic and tumorigenic potential. We wished to ascertain whether cells displaying similar properties persisted postnatally in medium CMN (mCMN). Eighteen medium M1, nine large and one giant NRAS‐mutated CMN were prospectively included in the study. Subpopulations of mCMN cells expressed stem cell/progenitor lineage markers such as Sox10, nestin and Oct4, as was the case in lCMN. Nevertheless, conversely to lCMN, mCMN cells with clonogenic properties were rarer. In vitro, approximatively one in 1500 cells isolated from fresh mCMN formed colonies that could be passaged. In vivo, mCMN seemed to harbour cells with less proliferative potential than the larger lesions as lCMN biopsies displayed a threefold expansion compared to mCMN when xenografted in Rag2^?/? mice. Thus, our data revealed variations in clonogenicity and tumorigenic properties in NRAS‐mutated CMN according to size.     

Influence of physiological and supraphysiological hyperinsulinemia on skin microcirculation in healthy volunteers

AIM: To examine skin perfusion in dependency on insulinemia in healthy subjects.METHODS: All volunteers were informed in detail about the procedures and signed informed consent. The protocol of this study was approved by the ethical committee. In our study, a two stage hyperinsulinemic euglycemic clamp was performed, with insulinemia 100 and 250 mIU/mL and glycemia 5.0 mmol/L (3% standard deviation). Before the clamp and in steady states, microcirculation was measured by laser Doppler flowmetry and transcutaneous oximetry and energy expenditure was measured by indirect calorimetry. Results (average and standard deviation) were evaluated with paired t-test.RESULTS: Physiological (50 mIU/L) insulinemia led to higher perfusion in both tests; hyperemia after heating to 44%-1848% (984-2046) vs 1599% (801-1836), P < 0.05, half time of reaching peak perfusion after occlusion release 1.2 s (0.9-2.6) vs 4.9 s (1.8-11.4), P < 0.05. Supraphysiological (150 mIU/L) insulinemia led to even higher perfusion in both tests; hyperemia after heating to 44%-1937% (1177-2488) vs 1599% (801-1836), P < 0.005, half time to reach peak perfusion after occlusion release 1.0 s (0.7-1.1) vs 4.9 s (1.8-11.4), P < 0.005. A statistically significant increase occurred in tissue oxygenation in both insulinemia. The difference in perfusion and oxygenation between physiological and supraphysiological hyperinsulinemia was not statistically significant.CONCLUSION: The post occlusive hyperemia test in accordance with heating test showed significantly increasing skin perfusion in the course of artificial hyperinsulinemia. This effect rises non-linearly with increasing insulinemia. Dependency on the dose was not statistically significant.     

Familial benign chronic pemphigus and doxycycline: a review of 6 cases

Background Hailey‐Hailey disease (HHD) or familial benign chronic pemphigus is a rare autosomal dominant inherited skin disorder, characterized by flaccid vesicles and erosions on the intertriginous areas. Current treatments are not particularly effective. We report 6 cases dramatically improving with doxycycline. Case reports 6 patients, aged from 33 to 77 years old, presented with a variable 4 to 40 year history of severe treatment‐resistant HHD. All 6 patients were then treated successfully with doxycycline 100 mg per day for at least 3 months. Discussion An improvement was observed in all 6 patients from 1 week to 3 months after the beginning of treatment. Relapses were observed after various periods. Maintenance half‐dose therapy seemed to be beneficial in patients experiencing recurrence. Only one patient developed gastro‐intestinal intolerance. No other side effects were reported. Currently, 2 patients have improved and present a decreased number of exacerbations, 2 others are in complete remission after more than 5 years of follow‐up. Treatment efficiency is difficult to evaluate in HHD as it is a rare condition. No controlled studies have been published. Local treatments may improve inflammation but do not treat the underlying cause, targeted systemic therapies exist but there is little evidence supporting their use, physical treatments are cumbersome. Besides their antibiotic potential, tetracycline antibiotics also have anti‐inflammatory properties and anticollagenase activity via inhibition of matrix metalloproteinases. Conclusions Doxycycline appears to be an interesting therapeutic option in Hailey‐Hailey disease.