Anakinra-Associated Systemic Amyloidosis.

OBJECTIVE: To describe a 41-year-old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin-1 receptor antagonist (IL-1Ra) protein, anakinra, since the age of 28, who presented with golf-ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation. METHODS: Clinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo-red staining and proteomic evaluation of microdissected Congo red-positive amyloid deposits by liquid chromatography-tandem mass spectrometry. RESULTS: The skin, stomach, and kidney biopsies all showed the presence of Congo red-positive amyloid deposits. Mass spectrometry-based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL-1Ra protein)-type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P-component) and the amyloidogenic IL-1Ra protein, which were present in Congo red-positive areas and absent in Congo red-negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL-1Ra (anakinra) and not endogenous wild-type IL-1Ra. CONCLUSION: This is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra).

Association of Demographic Factors and Infantile Hemangioma Characteristics With Risk of PHACE Syndrome.

Importance: A 2010 prospective study of 108 infants estimated the incidence of PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome to be 31% in children with facial infantile hemangiomas (IHs) of at least 22 cm2. There is little evidence regarding the associations among IH characteristics, demographic characteristics, and risk of PHACE syndrome. Objectives: To evaluate demographic characteristics and comorbidities in a large cohort of patients at risk for PHACE syndrome and assess the clinical features of large head and neck IH that may be associated with a greater risk of a diagnosis of PHACE syndrome. Design, Setting, and Participants: This multicenter, retrospective cohort study assessed all patients with a facial, head, and/or neck IH who were evaluated for PHACE syndrome from August 1, 2009, to December 31, 2014, at 13 pediatric dermatology referral centers across North America. Data analysis was performed from June 15, 2017, to February 29, 2020. Main Outcomes and Measures: The main outcome was presence or absence of PHACE syndrome. Data included age at diagnosis, sex, patterns of IH presentation (including size, segment location, and depth), diagnostic procedures and results, and type and number of associated anomalies. Results: A total of 238 patients (mean [SD] age, 2.96 [4.71] months; 184 [77.3%] female) were included in the analysis; 106 (44.5%) met the criteria for definite (n = 98) or possible (n = 8) PHACE syndrome. A stepwise linear regression model found that a surface area of 25 cm2 or greater (odds ratio [OR] 2.99; 95% CI, 1.49-6.02) and involvement of 3 or more locations (OR, 17.96; 95% CI, 6.10-52.85) to be statistically significant risk factors for PHACE syndrome. Involvement of the parotid gland (OR, 0.39; 95% CI, 0.18-0.85) and segment S2 (OR, 0.38; 95% CI, 0.16-0.91) was associated with a lower risk. Race and ethnicity may also be associated with PHACE syndrome risk, although more studies are needed. Conclusions and Relevance: This cohort study further described factors associated with both a higher and lower risk of PHACE syndrome. The presence of multiple anatomical sites and large surface area were associated with greater risk, whereas S2 or parotid IHs were associated with lower, but still potential, risk. These findings can help in counseling families and decision-making regarding evaluation of infants with large head and neck IHs.

Holmes heart and tetralogy of Fallot in association with PHACE.

PHACE is an association between large infantile hemangiomas and brain, arterial, cardiac, and/or ocular abnormalities. Aortic or subclavian aberrations are the most common cardiovascular anomalies in PHACE, whereas complex congenital heart disease is rare. We report a case of Holmes heart and three cases of tetralogy of Fallot in PHACE association.

Diagnostic Accuracy of Pediatric Teledermatology Using Parent-Submitted Photographs: A Randomized Clinical Trial.

Importance: Advances in smartphone photography (both quality and image transmission) may improve access to care via direct parent-to-clinician telemedicine. However, the accuracy of diagnoses that are reliant on parent-provided photographs has not been formally compared with diagnoses made in person. Objective: To assess whether smartphone photographs of pediatric skin conditions taken by parents are of sufficient quality to permit accurate diagnosis. Design, Setting, and Participants: A prospective study was conducted among 40 patient-parent dyads at a pediatric dermatology clinic at the Children's Hospital of Philadelphia from March 1 to September 30, 2016, to assess concordance between diagnoses made by an independent pediatric dermatologist based on in-person examination and those based on parental photographs. Half of the patient-parent dyads were randomized for a secondary analysis to receive instructions on how best to take photographs with smartphones. Clinicians were blinded to whether parents had received photography instructions. Exposures: Half of the patient-parent dyads received a simple, 3-step instruction sheet on how best to take photographs using a smartphone (intervention group); the other half did not (control group). Main Outcomes and Measures: Concordance between photograph-based vs in-person diagnosis in the intervention vs control groups, as quantified using Cohen κ, a measure of interrater agreement that takes into account the possibility of agreement occurring by chance. Results: Among the 40 patient-parent dyads (22 female children and 18 male children; mean [SD] age, 6.96 [5.23] years), overall concordance between photograph-based vs in-person diagnosis was 83% (95% CI, 71%-94%; κ = 0.81). Diagnostic concordance was 89% (95% CI, 75%-97%; κ = 0.88) in a subgroup of 37 participants with photographs considered of high enough quality to make a diagnosis. No statistically significant effect of photography instructions on concordance was detected (group that received instructions, 85%; group that did not receive instructions, 80%; P = .68). In cases of diagnostic disagreement, appropriate follow-up was suggested. Conclusions and Relevance: Parent-operated smartphone photography can accurately be used as a method to provide pediatric dermatologic care. Trial Registration: clinicaltrials.gov Identifier: NCT03246945.

Alopecia: Kids are not just little people.

Alopecia is a disorder that affects all patients, young and old. Many diagnoses, particularly the scarring alopecias, are more common in adults; however, others, such as tinea capitis, are more common in children, and some, such as alopecia areata, often affect both age groups. The approach to, and evaluation of, an alopecia patient is thus highly dependent on his or her age. In adults with diffuse, non-scarring hair loss, a part-width examination can help detect pattern hair loss, the most common cause of diffuse loss in this age group. In children this is much less likely, and a careful evaluation for tinea capitis is in order. The same holds true for patchy alopecia in children, as well as scarring alopecia-tinea needs to always be considered. In adults, patchy alopecia is often due to alopecia areata and sometimes to one of the primary scarring alopecias. A laboratory evaluation, and especially a biopsy, would be a more appropriate undertaking for an adult than a child, and an adult would be more likely to tolerate certain therapeutic regimens such as intralesional injections. In a conversational manner, the authors discuss their individual approaches to the alopecia patient, highlighting the differences in diagnosis, workup, and management that depend on whether the affected individual is an adult or a child.

Wnt proteins induce dishevelled phosphorylation via an LRP5/6- independent mechanism, irrespective of their ability to stabilize beta-catenin.

Wnt glycoproteins play essential roles in the development of metazoan organisms. Many Wnt proteins, such as Wnt1, activate the well-conserved canonical Wnt signaling pathway, which results in accumulation of beta-catenin in the cytosol and nucleus. Other Wnts, such as Wnt5a, activate signaling mechanisms which do not involve beta-catenin and are less well characterized. Dishevelled (Dvl) is a key component of Wnt/beta-catenin signaling and becomes phosphorylated upon activation of this pathway. In addition to Wnt1, we show that several Wnt proteins, including Wnt5a, trigger phosphorylation of mammalian Dvl proteins and that this occurs within 20 to 30 min. Unlike the effects of Wnt1, phosphorylation of Dvl in response to Wnt5a is not concomitant with beta-catenin stabilization, indicating that Dvl phosphorylation is not sufficient to activate canonical Wnt/beta-catenin signaling. Moreover, neither Dickkopf1, which inhibits Wnt/beta-catenin signaling by binding the Wnt coreceptors LRP5 and -6, nor dominant-negative LRP5/6 constructs could block Wnt-mediated Dvl phosphorylation. We conclude that Wnt-induced phosphorylation of Dvl is independent of LRP5/6 receptors and that canonical Wnts can elicit both LRP-dependent (to beta-catenin) and LRP-independent (to Dvl) signals. Our data also present Dvl phosphorylation as a general biochemical assay for Wnt protein function, including those Wnts that do not activate the Wnt/beta-catenin pathway.

Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins.

Secreted signaling proteins of the Wnt family are known to regulate a diverse range of developmental processes, and their signaling pathway through beta-catenin is frequently activated in cancer. The identification of both Frizzled and LRP5/6 (LRP: low-density lipoprotein receptor-related protein) proteins as components of cell-surface receptors for Wnt proteins has raised questions about their individual functions. We have investigated this issue through a structure-function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling. Consistent with other reports, we find that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/beta-catenin signaling pathway. Importantly, our results demonstrate that this signaling from LRP6/Arrow derivatives can occur in a Frizzled- and ligand-independent manner. Furthermore, we show that the PPSP motifs within the intracellular domain of LRP6 are required for signaling. In contrast to results with LRP6, overexpression of Frizzled proteins did not activate the pathway. Based on evidence of ligand binding to both Frizzled and LRP6, current models suggest that both proteins are components of a Wnt receptor complex that signals to beta-catenin. In light of these models, our data imply that LRP5/6/Arrow proteins constitute the distal signal-initiating component of these receptors. The results also support the notion that LRP5/6 are candidate oncogenes.