A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

Triple pass laser therapy for recalcitrant facial port wine stains.

Patients with recalcitrant facial port wine stains (rfPWS) can be challenging to manage, often leaving the clinician with difficult decisions for treatment options. 'Triple therapy' consists of using three different laser wavelengths at each treatment setting. The evidence on outcomes is limited as this treatment approach has not been previously reported to the best of our knowledge. Children who received triple therapy at least once for rfPWS, and for whom SIAscopy readings had been taken, were retrospectively identified. SIAscope readings were compared before the first triple therapy treatment and at final the most recent clinical follow-up. The clinical appearance was also assessed using a Visual Analogue Scale comparing clinical photographs taken before triple therapy to those taken at the most recent clinical follow-up. A total of 47 children were identified and included in our review. The SIAscope readings showed an overall significant (p < 0.001) lightening with 39 (83%) showing lightening and 8 (17%) patients showing a darkening. Scores using the VAS also showed improvement with 55% experiencing an improvement in their clinical appearance, 38% showing no visible change and 6% appearing to have worsened. Triple therapy can offer improvement of rfPWS which have failed to respond to single wavelength laser therapy. SIAscopy and VAS scores correlate well in assessing clinical response; however, the added clinical benefit of SIAscopy in vascular laser clinics remains uncertain.

Surveillance of pediatric parapneumonic effusion/empyema in New Zealand.

AIM: The incidence of childhood empyema has been increasing in some developed countries despite the introduction of pneumococcal vaccination. This study aimed to document the incidence, bacterial pathogens, and morbidity/mortality of parapneumonic effusion/empyema in New Zealand. METHODS: A prospective study of 102 children <15 years of age requiring hospitalization with parapneumonic effusion/empyema between May 1, 2014 and May 31, 2016 notified via the New Zealand Paediatric Surveillance Unit. Parapneumonic effusion/empyema was defined as pneumonia and pleural effusion persisting ≥7 days, and/or any pneumonia, and pleural effusion necessitating drainage. Notifying pediatricians completed standardized questionnaires. RESULTS: Annual pediatric parapneumonic effusion/empyema incidence was 5.6/100,000 (95% confidence interval [CI]: 4.7-6.9). Most children (80%) required surgical intervention and 31% required intensive care. A causative organism was identified in 71/102 (70%) cases. Although Staphylococcus aureus (25%) and Streptococcus pneumoniae (25%) infection rates were equal, prolonged hospitalization and intensive care admission were more common in children with S. aureus PPE/E. Maori and Pasifika children were over-represented at 2.2 and 3.5 times, their representation in the New Zealand pediatric population. Pneumococcal vaccination was incomplete, with only 61% fully immunized and 30% unimmunized. Haemophilus influenzae type b vaccine uptake was near complete at 89/94 (95%), with influenza immunization only 3/78 (4%). CONCLUSIONS: New Zealand has a high incidence of pediatric complicated parapneumonic effusion/empyema with significant morbidity. S. aureus was a significant cause of severe empyema in New Zealand, particularly for Maori and Pasifika children. Improvements in vaccine coverage are needed along with strategies to reduce S. aureus disease morbidity.

A baseline patch test series for New Zealand.

BACKGROUND: Patch testing is the gold standard diagnostic test for allergic contact dermatitis and needs to be relevant to the region and the population being tested. The aim of this study was to develop a specific New Zealand baseline series (NZBS). METHOD: We performed a retrospective case note review of patients attending four regional patch test centres between 2008 and 2020. Demographic and diagnostic information was collected for each patient along with results of patch testing. Using the results of this review, a group of 11 dermatologists with an interest in contact dermatitis agreed on a core group of allergens for inclusion in an NZBS, based on the frequency of positive reactions and allergens of interest. The remaining potential allergens were ranked by each dermatologist using an online questionnaire, with inclusion in the final NZBS by consensus. RESULTS: Results from 2402 patients (67% female, mean age 44 years) from Auckland, Wellington, Palmerston North and Christchurch were collated. The 10 most frequent positive (relevant and non-relevant) allergens were nickel sulfate (22.0%), fragrance mix I (8.6%), cobalt chloride (7.3%), Myroxylon pereirae (5.6%), colophonium (5.1%), p-phenylenediamine (4.9%), methylisothiazolinone/methylchloroisothiazolinone (4.1%), fragrance mix II (3.9%), potassium dichromate (3.5%) and methylisothiazolinone (3.4%). Based on these results, a core series of 30 allergens was developed, with an additional 30 allergens added to form the extended series (total 60 allergens). CONCLUSION: The baseline series of patch test allergens for routine use in New Zealand (NZBS) is based on national patch test data and expert consensus.

Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families.

BACKGROUND: Amyloidosis cutis dyschromica (ACD) is a rare variant of cutaneous amyloidosis. This disorder often clusters in families, and it has been suggested that genetic factors might be involved in its development. OBJECTIVE: To identify the genetic causes of ACD, we recruited a consanguineous Pakistani family with multiple cases of ACD that display a recessive mode of inheritance. METHODS: We performed whole-exome sequencing of samples from 7 members of this family, followed by bioinformatic and in silico analyses to identify the causative variant. For the replication study, we recruited a British family with Pakistani ancestry, and sequenced all exons of glycoprotein non-metastatic melanoma protein b (GPNMB) to identify mutations. We also investigated effects of the mutations on the stability of the GPNMB protein using the I-TASSER three-dimensional modeling tool. RESULTS: We found a novel homozygous mutation, p.Gly363Val (c.1088 G>T), in GPNMB in all affected cases. In a replication study, another homozygous missense mutation in GPNMB, pIle174Met (c.522 C>G), was carried by the affected son. The two mutations were not observed in our in-house data set comprising 217 healthy Pakistani individuals or in The Genome Aggregation Database. Our structural modeling of GPNMB suggested that p.Gly363Val enhanced its stability, whereas p.Ile174Met caused instability. CONCLUSIONS: This study reports two novel missense mutations in two Pakistani families that cause ACD. The mutations appear to influence GPNMB stability, as revealed by protein modeling.

Panniculitis in a 3-year-old child with Fanconi anemia-associated bone marrow hypoplasia heralds transformation to acute myeloid leukemia.

Fanconi anemia is a rare, autosomal recessive genomic instability disorder characterized by congenital limb anomalies, panmyelopathy and a high risk of malignancy, principally acute myeloid leukemia. Hematologic malignancy presenting with acute febrile neutrophilic dermatosis (Sweet syndrome), both deep and superficial forms, is well described in Fanconi anemia patients but is a rare phenomenon in otherwise healthy children. We present a case of panniculitis (presumptive subcutaneous Sweet syndrome) heralding transformation to acute myeloid leukemia in a 3-year-old boy with a severe Fanconi anemia phenotype.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Incidence, aetiology and outcome of pleural empyema and parapneumonic effusion from 1998 to 2012 in a population of New Zealand children.

AIM: To document rising incidence rates of childhood empyema and parapneumonic effusion (PPE) in South Auckland, New Zealand between 1998 and 2012; to compare epidemiology, pathogens and outcomes of children with empyema and PPE; and to ascertain whether primary care antibiotic prescribing, delayed presentation, or bacterial epidemiology might account for the rising incident rates. METHODS: Children aged 0 to14 years hospitalised with pleural empyema or PPE were retrospectively identified. Empyema was defined by ultrasound and pleural tap criteria. PPE was defined as the presence of pleural fluid on chest xray not fulfilling empyema criteria. Epidemiology, clinical features, microbiology and outcomes of empyema and PPE were compared and incidence rates analysed. RESULTS: Of 184 cases identified, 104 met the criteria for empyema. Empyema incidence increased from 1 per 100 000 children aged 0 to 14 years in 1998 to 10 per 100 000 in 2012, with a peak incidence of 13 per 100 000 in 2009. Staphylococcus aureus was most frequently detected (n=38), followed by Streptococcus pneumoniae (n=31). Cases of S. aureus empyema increased 4 fold over the 15 years. Dominant S. pneumoniae serotypes were 1 and 14. Thirty-five percent of empyema and 53% of PPE cases received pre-hospital antibiotics. Children who received pre-hospital antibiotics were more than 40% less likely to require surgical intervention than those not pre-treated. CONCLUSIONS: Childhood empyema incidence has increased markedly in South Auckland. Paediatric S. aureus empyema is becoming increasingly common in South Auckland. Pre-hospital antibiotic prescribing may mitigate the need for surgical intervention in our population.

Amyloidosis cutis dyschromica in two siblings and review of the epidemiology, clinical features and management in 48 cases.

Amyloidosis cutis dyschromica (ACD) is a rare form of primary cutaneous amyloidosis (PCA). There is a paucity of information in the dermatology literature to guide its diagnosis, investigation and treatment. We present two siblings with ACD and summarise the epidemiology, clinical features, natural history and treatments in 48 cases of ACD from the literature. Familial cases were more common (37) than sporadic cases. ACD is predominantly reported in those of East and South-East Asian ethnicity (63%). The mean age of onset was 6 years in familial cases, and 23 years in sporadic cases. The clinical features of familial and sporadic ACD do not differ substantially. Pruritus was the only symptom, and was reported in 19% of all cases. There were no reported ACD cases with systemic amyloidosis. Acitretin was reported to result in improvement in seven of 10 patients treated. Routine investigation for systemic involvement is not necessary. Acitretin may be helpful.

Imatinib mesylate-induced pseudoporphyria in two children.

Imatinib mesylate was the first of several tyrosine kinase inhibitors approved for use in the treatment of a number of human cancers. Adverse cutaneous reactions to imatinib are common. Pseudoporphyria has been infrequently reported in adults undergoing imatinib therapy for chronic myeloid leukemia. We present two children with pseudoporphyria induced by imatinib therapy for hematologic malignancies. In view of the burgeoning use of imatinib in children, physicians should be aware that pseudoporphyria may develop as a consequence of imatinib therapy.

Congestion bleeding of the head and neck following myocardial infarction.

We present an unusual case of congestion bleeding of the head and neck following myocardial infarction. A 51-year-old man presented with widespread facial petechiae and subconjunctival haemorrhages following a collapse associated with evolving electrocardiographic changes. Emergency coronary artery stent placement was undertaken. No cardiopulmonary resuscitation (CPR) was performed. We hypothesise that the presence of facial petechiae in our case following transient loss of consciousness due to a presumed ventricular arrhythmia in the setting of acute myocardial ischaemia, may have been precipitated by a Valsalva manoeuvre on regaining consciousness with sudden acute increase in venous pressure and consequent venous congestion of the head and neck, and that congestion bleeding of the face may occur in acute cardiac events without a history of CPR.