Etiology-associated definitions for blistering severe cutaneous adverse reactions in children were recently proposed to replace the existing terms Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and others (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/7mj555m5vr/1; Table I).1Ramien M.L. Bahubeshi A. Lara-Corrales I. et al.Blistering severe cutaneous adverse reactions in children: proposal for paediatric-focused clinical criteria.Br J Dermatol. 2021; 185: 447-449https://doi.org/10.1111/bjd.20063Crossref PubMed Scopus (13) Google Scholar In this multicenter retrospective cohort study, patients previously diagnosed with conditions on the Stevens-Johnson syndrome–toxic epidermal necrolysis spectrum were reclassified using the new definitions.2Canavan T.N. Mathes E.F. Frieden I. Shinkai K. Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review.J Am Acad Dermatol. 2015; 72: 239-245https://doi.org/10.1016/j.jaad.2014.06.026Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar,3Bastuji-Garin S. Rzany B. Stern R.S. Shear N.H. Naldi L. Roujeau J.C. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.Arch Dermatol. 1993; 129: 92-96https://doi.org/10.1001/archderm.1993.01680220104023Crossref PubMed Scopus (1393) Google Scholar In this report, we summarize the cohort features and reclassification results.Table ICase reclassification with the proposed pediatric-specific criteria for reactive infectious mucocutaneous eruption and drug-induced epidermal necrolysisCase identification diagnosisTotal cases, n (%)Reclassified as DEN, n (% of total cases)Reclassified as RIME, n (% of total cases)SJS136 (43.0)53 (49.0)83 (39.9)MIRM65 (20.6)0 (0)65 (31.2)TEN43 (13.6)40 (37.0)3 (1.4)EMM24 (7.6)0 (0)24 (11.5)MPAM18 (5.7)0 (0)18 (8.6)SJS-TEN overlap15 (4.7)12 (11.1)3 (1.4)Mucosal respiratory syndrome2 (0.6)0 (0)2 (0.96)Incomplete SJS7 (2.2)1 (0.9)6 (2.9)Fuchs' syndrome1 (0.3)0 (0)1 (0.5)Ectodermosis pluriorificialis1 (0.3)0 (0)1 (0.5)Three hundred sixteen patients were included from 1192 identified; most cases were excluded at collaborating sites due to incomplete information that prevented confirmation of the diagnosis.EMM, erythema multiforme major; MIRM, Mycoplasma pneumoniae–induced rash and mucositis; MPAM, Mycoplasma pneumoniae–associated rash and mucositis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Open table in a new tab Three hundred sixteen patients were included from 1192 identified; most cases were excluded at collaborating sites due to incomplete information that prevented confirmation of the diagnosis. EMM, erythema multiforme major; MIRM, Mycoplasma pneumoniae–induced rash and mucositis; MPAM, Mycoplasma pneumoniae–associated rash and mucositis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Institutional review board approval was obtained at 13 participating North American sites. The Research Electronic Data Capture (REDCap) database (http://project-redcap.org) was used for data collection from September 2019 to December 2020. Inclusion criteria were age <18 years at diagnosis, met reactive infectious mucocutaneous eruption (RIME) or drug-induced epidermal necrolysis (DEN) criteria, and hospitalized between January 2019 and 2000. Cases were identified by International Classification of Diseases (ICD) 9/10 coding or clinical diagnosis (Table I). Cases with unclear body surface area involved or length of hospitalization <1 day or where another diagnosis was possible were excluded. Cases were reclassified as RIME or DEN by site principal investigators (J.C., S.H., I.L.C., H.B.B., A.Y.K., L.C.S., L.A., C.L.W., M.R., J.S., S.A.G., S.S., and M.L.R.) and confirmed by 2 central independent reviewers (M.L.R. and I.L.C.). Three hundred sixteen of 1192 identified cases were eligible: 208 (66%) RIME and 108 (34%) DEN (Table II). Case identification diagnoses are compared to reclassified diagnoses in Table I, showing that Stevens-Johnson syndrome was the most heterogeneous diagnosis, made up of 60% RIME (83/136) and 40% DEN (53/136). Both RIME and DEN showed a male predominance that was more marked for RIME (70% male). Between-group differences were significant (Fisher exact test) for age, microbiological tests performed, and treatments given other than immunosuppressive therapies.Table IIPatient characteristicsDemographicsOverall, n (%)DEN, n (%)RIME, n (%)Patients316108 (34.2)208 (65.8)Age (y) <642 (13.3)25 (23.2)17 (8.2) 6-12182 (57.6)55 (50.9)127 (61.1) >12 to <1892 (29.1)25 (23.2)64 (30.8)Sex Male210 (66.5)64 (59.3)146 (70.2) Female106 (33.5)44 (40.7)62 (29.8)Microbiological tests HSV workup∗HSV workup included serology, polymerase chain reaction, and culture: "not performed" only if none of the 3 tests were performed, "negative" if the only result was negative, and "positive" if any of the 3 come back as positive (eg, patients with 1 negative HSV test result but 1 positive HSV test result are classified as positive).Positive results18 (5.7)4 (3.7)14 (6.7)Negative results211 (66.8)59 (54.6)152 (73.1)Not performed87 (27.5)45 (41.7)42 (20.2) MP workup†MP workup included culture, polymerase chain reaction of a lesion, polymerase chain reaction of the oropharynx/nasopharynx, and immunoglobulin G and immunoglobulin M serology: "not performed" only if none of the 4 tests were performed, "negative" if the only result was negative, and "positive" if any of the 4 come back as positive (eg, patients with 1 negative test result for MP and 1 positive test result for MP are classified as positive).Positive results159 (50.3)8 (7.4)151 (72.6)Negative results108 (34.2)64 (59.3)44 (21.2)Not performed49 (15.5)36 (33.3)13 (6.2)Treatment Antibiotics23256 (51.9)176 (84.6) Supportive‡Supportive care included wound care, barrier protection, nutrition, fluid and electrolyte replacement, and infection monitoring.21290 (83.3)123 (59.1) CS17773 (67.6)104 (50) IVIG11561 (56.5)54 (25.9) Antivirals8215 (13.9)67 (32.2) Immunosuppressive therapy§Immunosuppressive therapy included the conventional immunosuppressive therapies systemic cyclosporine (majority of cases) and methotrexate.3314 (12.9)12 (5.7) Anti-TNF88 (7.4)0CS, corticosteroids; DEN: drug-induced epidermal necrolysis; HSV, herpes simplex virus; IVIG, intravenous immunoglobulins; MP, Mycoplasma pneumoniae; RIME, reactive infectious mucocutaneous eruption; TNF, tumor necrosis factor.∗ HSV workup included serology, polymerase chain reaction, and culture: "not performed" only if none of the 3 tests were performed, "negative" if the only result was negative, and "positive" if any of the 3 come back as positive (eg, patients with 1 negative HSV test result but 1 positive HSV test result are classified as positive).† MP workup included culture, polymerase chain reaction of a lesion, polymerase chain reaction of the oropharynx/nasopharynx, and immunoglobulin G and immunoglobulin M serology: "not performed" only if none of the 4 tests were performed, "negative" if the only result was negative, and "positive" if any of the 4 come back as positive (eg, patients with 1 negative test result for MP and 1 positive test result for MP are classified as positive).‡ Supportive care included wound care, barrier protection, nutrition, fluid and electrolyte replacement, and infection monitoring.§ Immunosuppressive therapy included the conventional immunosuppressive therapies systemic cyclosporine (majority of cases) and methotrexate. Open table in a new tab CS, corticosteroids; DEN: drug-induced epidermal necrolysis; HSV, herpes simplex virus; IVIG, intravenous immunoglobulins; MP, Mycoplasma pneumoniae; RIME, reactive infectious mucocutaneous eruption; TNF, tumor necrosis factor. In RIME cases, Mycoplasma pneumoniae (MP) was isolated in 35% (51/146) by culture or polymerase chain reaction, and MP serology was positive in 83% (127/153). In DEN cases, anticonvulsants were the most common class of medications (44%, 47/108), and neurologic or psychiatric disorders were the most common underlying conditions. Trimethoprim/sulfamethoxazole was the single most common culprit drug (27%, 29/108), followed by lamotrigine (19%, 20/108). No deaths were reported with RIME (0/185), while the mortality rate with DEN was 4% (4/93). Treatment was reported for 97% (202/208) of RIME cases and 99% (107/108) of DEN cases. RIME cases most often received antibiotics (85%, 176/208), while DEN cases most often received supportive care (83%, 90/108). This dichotomy reflects the association of RIME with infection, leading to early initiation of antibiotics for presumed MP infection, and its relatively lesser severity compared to that of DEN, thus not requiring supportive care. A greater proportion of DEN cases compared to RIME cases received corticosteroids, intravenous immunoglobulins, and immunosuppressive therapies (primarily cyclosporine), again likely related to severity. Eight DEN cases and no RIME cases received anti–tumor necrosis factor therapy. The pediatric-specific definitions regrouped cases previously described with 10 different diagnoses into RIME and DEN to create 2 groups with more homogeneous causes, management, and outcomes. RIME and DEN are rare, necessitating a multicenter retrospective study with stringent inclusion criteria and central review to obtain a representative sample. The limitations include missing data, multiple persons involved in data entry, and possible misclassification of cases. Our study highlights the importance of standardized case definitions and data collection instruments to facilitate more complete prospective data collection. Analysis of treatment outcomes, recurrences, and complications are ongoing. Dr Lara-Corrales has received honoraria from Pierre Fabre, Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme and grants from AbbVie, Janssen, Clementia, Eli Lilly, Mayne Pharma, and Sanofi Genzyme. Dr Liy-Wong is advisor for Sanofi, Bayer, and Pfizer. Dr McKenzie is advisor for AbbVie, Amgen, Bausch, Bristol-Myers, Celgene, Galderma, Janssen, Leo Pharma, Lilly, Novartis, Pfizer, Sandoz, Sanofi, Sun Pharma, and UCB. Dr Rieder is advisor/consultant for, has received grants/honoraria from, and/or has served as a speaker for LEO Pharma, Pfizer, and Sanofi Genzyme. Drs Martinez-Cabriales, Coulombe, Aaron, Hussain, Linggonegoro, Barootes, Brandling-Bennett, Covelli, Kirkorian, Shah, Castelo-Soccio, Arkin, Heinze, Travis, Del Pozzo-Magana, Schoch, Monir, Glick, Uwakwe, Skillman, Hekman, Lethebe, and Ramien have no conflicts of interest to declare.

Stevens–Johnson syndrome and toxic epidermal necrolysis are especially challenging to diagnose and manage in paediatric populations given their rarity, more frequent infectious triggers and lack of randomized controlled trials to guide management. This retrospective case series of 59 paediatric blistering severe cutaneous adverse reactions uses the new diagnostic classification and British Association of Dermatologists’ guidelines, and confirms their value in a real-life clinical setting.

A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. This study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors that might lead to personalized prophylactic or therapeutic strategies.

A 66-year-old woman presented to the hospital with cutaneous necrosis of her right ankle and foot. Her symptoms began immediately after an intra-articular injection of hyaluronic acid for ankle osteoarthritis, which was performed 6 days before. Histopathology showed an intra-vascular hyaluronic acid embolus. The initial treatment approach was conservative, but the patient's clinical state degraded. She was thus treated with sub-cutaneous hyaluronidase, the enzyme that degrades hyaluronic acid, which yielded a moderate improvement even though it was administered 22 days after the initial hyaluronic acid injection. Although hyaluronic acid embolism and subsequent cutaneous necrosis are well-known complications of dermal fillers, there are few reported cases of embolism following intra-articular injection. To our knowledge, this is the first time hyaluronidase has been used in this setting.

Aim: To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). Patients & methods: To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. Results: The minor allele of rs1944294 in CDH2 gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). Conclusion: The variant in CDH2 gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.

Background: Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Purpose: Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers. Patients and methods: We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models. Results: Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616DUOX2,P=0.0002 (Pmax) and rs41270041ADAMTS4, P=0.02 (Fmax)) and two rare ones located in the ALOX15 gene (P=0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (P≤0.02). Conclusion: Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the DUOX2, ADAMTS4 and ALOX15 genes, which could lead to personalized prevention strategies in childhood ALL survivors.

1Department of Medicine, University of Montreal, Montreal, QC, Canada; 2Sainte-Justine University Hospital Research Centre, Montreal, QC, Canada; 3Division of paediatrics, Montreal Shriners Hospital for Children, Montreal, QC, Canada; 4Division of HematoOncology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada; 5Division of Endocrinology, Sainte-Justine University Hospital Centre, Montreal, QC, Canada