Pediatric Neutrophilic Dermatoses.

The term neutrophilic dermatosis encompasses a heterogeneous group of diseases, often associated with an underlying internal noninfectious disease, with an overlapping histopathologic background characterized by perivascular and diffuse neutrophilic infiltrates in one or more layers of the skin; extracutaneous neutrophilic infiltrates may be associated. Neutrophilic dermatoses are not frequent in children and, when they appear in this age group, represent a diagnostic and therapeutic challenge. Apart from the classic neutrophilic dermatoses such as pyoderma gangrenosum, Sweet syndrome, and Behçet disease, a neutrophilic dermatosis can be the presentation of rare genetic diseases of the innate immune system, such as autoinflammatory diseases.

Frequency of the prominent transverse nasal root vein in children.

BACKGROUND: The presence of a vascular, blue linear discoloration on the nasal root of infants and young children is a frequent incidental feature, rarely reported in the medical literature. It is related to the trajectory of the transverse nasal root vein (TNRV). OBJECTIVE: To study the frequency and clinical characteristics of the vascular discoloration of the nasal root in children. METHODS: A prospective study was performed to address the presence or absence of vascular discoloration of the nasal root in all children under 6 years of age attending a pediatric dermatology clinic from November 2022 to November 2023. Data on age and skin phototype (Fitzpatrick classification I-VI) were also collected. RESULTS: Of 701 patients examined, 345 (49.2%) presented with a vascular discoloration of the nasal root. This was present in 97 of 193 (50.3%), 127 of 261 (48.7%), and 121 of 247 (49.0%) patients for the age groups 0-1, 1-3, and 3-6 years, respectively. The presence of vascular discoloration of the nasal root was more frequent in patients with lighter Fitzpatrick skin phototypes: 49 of 69 (71.0%) phototype II, 157 of 290 (54.1%) phototype III, and 137 of 337 (40.7%) phototype IV. CONCLUSIONS: A vascular discoloration of the nasal root is a frequent skin feature in infants and children, persisting at least until the age of 6. It does not constitute any medical problem aside from cosmetic concern and parents can be reassured of its benign nature. We propose the medical term "prominent TNRV" to describe this condition.

Transient infantile lingual leukoplakia: An underrecognized cause of white tongues in infancy.

We have observed a distinct phenomenon of transient oral lingual leukoplakia in infancy and report 22 healthy infants with gray-white plaques on the dorsal tongue with sparing of the tip from four medical centers in three countries. The onset of the eruption ranged from 1 week to 7 months of life and resolved in 19 patients (86%, with 3 patients lost to follow-up). None of the eight patients examined at 1 year of age had residual findings. We believe this is a common entity that can be distinguished from oral candidiasis on clinical and/or laboratory examination and name this entity "transient infantile lingual leukoplakia."

NLRP1-associated autoinflammatory disease with epithelial dyskeratosis.

Several gain-of-function variants in NLRP1 cause a distinctive autoinflammatory disease reported under different names featuring mainly skin and mucosal involvement and variable systemic signs. Here, we report a new case of NLRP1-associated autoinflammatory disease in a 6-year-old Peruvian girl, who presented with confluent hyperkeratotic plaques that drained purulent material with subsequent scarring. A c.3641C > G (p. Pro1214Arg) variant that has been previously been reported was found in NLRP1 and was not present in either parent. The term NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) is proposed to encompass all reported cases, which have received different nomenclature so far.

Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications.

Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis, type V pityriasis rubra pilaris), IL36RN (generalized pustular psoriasis without concomitant psoriasis vulgaris, impetigo herpetiformis, acrodermatitis continua of Hallopeau), NLRP1 (familial forms of keratosis lichenoides chronica), and genes of the mevalonate pathway, i.e., MVK, PMVK, MVD, and FDPS (porokeratosis). Since then, endotypes underlying novel entities matching the concept of autoinflammatory keratinization diseases have been discovered (mutations of JAK1, POMP, and EGFR). This review describes the concept and pathophysiology of autoinflammatory keratinization diseases and outlines the characteristic clinical features of the associated entities. Furthermore, a novel term for NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) describing the spectrum of autoinflammatory keratinization diseases secondary to NLRP1 mutations is proposed.

Idiopathic calcinosis cutis in an infant: The importance of a wait-and-see approach.

A healthy 2-year-old girl presented with multiple asymptomatic subcutaneous nodules on both legs. Histologically demonstrated calcium deposition within the dermis and subcutaneous tissue consistent with calcinosis cutis. Laboratory abnormalities, underlying genetic conditions, and potential triggering factors were ruled out. The lesions resolved over an 18-month period without treatment, emphasizing the importance of the wait-and-see approach in idiopathic cases of calcinosis cutis.

Algorithm to attenuate atopic dermatitis and for promoting a healthy skin barrier using skincare in newborns and infants.

The human skin barrier is structurally and functionally immature at birth, with elevated skin surface pH, lower lipid content, and lower resistance to chemicals and pathogens. Infants at risk for atopic dermatitis (AD) may present with xerosis almost immediately after birth. The current algorithm on skincare for newborns and infants aims to promote a healthy skin barrier and potential mitigation of AD. The project used a modified Delphi hybrid process comprising face-to-face discussions followed by an online follow-up replacing a questionnaire. During the meeting, a panel of eight clinicians who treat newborns and infants discussed the systematic literature review results and a draft algorithm addressing non-prescription skincare for neonates and infants. Online the panel reviewed and adopted the algorithm using evidence coupled with the panel's expert opinion and clinical experience. The algorithm provides clinical information for pediatric dermatologists, dermatologists, and pediatric healthcare providers treating neonates and infants. The advisors adopted a scale based on clinical signs for the algorithm: 1) scaling/xerosis; 2) erythema; and 3) erosion/oozing. Skincare for newborns and infants includes: aim for a cool environment and soft cotton clothing, give lukewarm baths (~5 min, 2-3 x week) with consideration of a gentle cleanser (pH 4-6) and the application of a full-body moisturizing after bath, while avoiding products with toxic and irritating ingredients. A growing body of evidence recognizes the benefits of ongoing daily use of non-alkaline cleansers and moisturizers. Gentle cleansers and moisturizers containing barrier lipids help maintain the protective skin barrier when applied from birth onwards.

Efficacy and safety of baricitinib in combination with topical corticosteroids in paediatric patients with moderate-to-severe atopic dermatitis with an inadequate response to topical corticosteroids: results from a phase III, randomized, double-blind, placebo-controlled study (BREEZE-AD PEDS).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in many countries for moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. OBJECTIVES: To evaluate the efficacy and safety of three doses of baricitinib in combination with low-to-moderate potency topical corticosteroids in paediatric patients with moderate-to-severe AD. METHODS: Patients (aged 2 to < 18 years) were randomized (1 : 1 : 1 : 1) to once-daily baricitinib low dose (1 mg equivalent), medium dose (2 mg equivalent), high dose (4 mg equivalent) or placebo for 16 weeks. The primary endpoint was the proportion of patients achieving a validated Investigator Global Assessment® (vIGA-AD) of 0/1 with a ≥ 2-point improvement at week 16. Key secondary endpoints included the proportions of patients achieving ≥ 75% and ≥ 90% improvement in the Eczema Area and Severity Index (EASI-75 and EASI-90, respectively), ≥ 75% improvement in the SCORing Atopic Dermatitis (SCORAD 75), mean change from baseline in EASI score and proportion of patients achieving a 4-point improvement in the Itch Numeric Rating scale (NRS) for patients aged ≥ 10 years. Primary and key secondary efficacy analyses were conducted on the intent-to-treat population and adjusted for multiplicity. Safety analyses included all randomized patients who received ≥ 1 dose of study treatment. RESULTS: A total of 483 patients were randomized (mean age 12 years). The baricitinib 4 mg equivalent achieved a statistically significant (P < 0.05) improvement vs. placebo on all 16-week endpoints (vIGA 0/1 with ≥ 2-point improvement, EASI-75, EASI-90, SCORAD 75, mean change in EASI score and Itch NRS 4-point improvement for patients aged ≥ 10 years). Improvement (P < 0.05, non-multiplicity adjusted) was also observed for baricitinib 4 mg equivalent vs. placebo in the ability to fall asleep and in reduction of topical corticosteroid use. Few patients discontinued due to adverse events (1.6% for placebo and 0.6% for those treated with baricitinib). There were no deaths, venous thromboembolic events, arterial thrombotic events, major adverse cardiovascular events, malignancies, gastrointestinal perforations or opportunistic infections seen. CONCLUSIONS: The results indicate that baricitinib offers a potential therapeutic option with a favourable benefit-risk profile for paediatric patients with moderate-to-severe AD who are candidates for systemic therapies.

Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 years and up to 3.9 years of treatment: an updated integrated analysis of eight clinical trials.

BACKGROUND: Baricitinib, a selective Janus kinase (JAK)1/JAK2 inhibitor, is approved for treatment of moderate-to-severe atopic dermatitis (AD) in adults. OBJECTIVES: We report integrated baricitinib safety data in patients with up to 3.9-years exposure. METHODS: Three datasets from the integrated AD clinical trial program were analyzed: placebo-controlled, 2-mg-4-mg extended, and All-bari. Data cutoffs were up to 21-December-2021 for long-term extension studies. Proportions of patients with events and incidence rates (IR)/100 patient years (PY) at risk were calculated. RESULTS: 2636 patients received baricitinib for 4628.4 PY. Discontinuation due to adverse events was low (IR = 3.4). IRs in All-bari were: serious adverse events, 5.2; infection, 67.2 (any infection), 6.7 (herpes simplex), 2.8 (herpes zoster), and 0.3 (opportunistic infections). Adverse events of special interest in All-bari included seven patients with positively adjudicated major adverse cardiovascular events (MACE) (IR = 0.15), three pulmonary emboli (PE) (IR = 0.06), 14 malignancies excluding nonmelanoma skin cancer (IR = 0.3), one gastrointestinal perforation (IR = 0.02), and four deaths (IR = 0.1). No deep vein thromboses (DVT) or tuberculosis were reported. CONCLUSION: In this analysis, baricitinib maintained a similar safety profile to earlier analyses with no new safety signals. Rates of MACE, DVT/PE, malignancies, and serious infections were within ranges of background rates in patients with AD. CLINICALTRIALS.GOV: NCT02576938 (JAHG), NCT03334396 (JAHL; BREEZE-AD1), NCT03334422 (JAHM; BREEZE-AD2), NCT03334435 (JAHN; BREEZE-AD3), NCT03428100 (JAIN; BREEZE-AD4), NCT03435081 (JAIW; BREEZE-AD5), NCT03559270 (JAIX; BREEZE-AD6), NCT03733301 (JAIY; BREEZE-AD7).

Erythema nodosum after COVID-19 vaccine: Report of two pediatric cases.

With the introduction of large-scale COVID-19 vaccination programs, a variety of cutaneous manifestations have been described. We present two girls (ages 12 and 5 years) who developed erythema nodosum (EN) 3 and 14 days after Pfizer-BioNTech COVID-19 vaccination, respectively. While EN after COVID-19 vaccination has been reported in adults, it is can also occur in children.

Cutaneous lesions and mitochondrial hearing loss: A case report.

Pathogenic sequence changes in mitochondrial DNA (mtDNA) are one of the most common causes of genetic hearing loss. We report an infant with palmoplantar hyperkeratosis, extrapalmoplantar cutaneous features and mitochondrial sensorineural hearing loss caused by the previously reported pathogenic NC_012920:m.7445A > G sequence change in the mitochondrial gene COX1 (COX1, MT-CO1). Next generation sequencing- based technology was key for the diagnosis and management of this patient.

Monkeypox disease in a breastfeeding infant.

A previously healthy breastfed 7-month-old infant presented with several papulovesicular lesions, a hyperemic pharynx and a petechial enanthema. His mother had confirmed monkeypox infection with similar skin lesions on the chest wall. Skin-to-skin contact is the most likely mode of transmission of monkeypox. Precautions to limit skin contact during activities such as breastfeeding are recommended if suspected skin lesions are present.

Germline intergenic duplications at Xq26.1 underlie Bazex-Dupré-Christol basal cell carcinoma susceptibility syndrome.

BACKGROUND: Bazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. OBJECTIVES: To investigate the genetic aetiology and molecular mechanisms underlying BDCS. METHODS: We ascertained multiple individuals from eight unrelated families affected with BDCS (F1-F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head-tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. RESULTS: In eight families with BDCS, we identified overlapping 18-135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. CONCLUSIONS: Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex-Dupré-Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1. Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1. The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene. ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management. ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

Inter- and intra-observer variability in the selection of therapy for infantile hemangiomas among pediatric dermatologists in Spain.

BACKGROUND: Guidelines and expert recommendations on infantile hemangiomas (IH) are aimed at increasing homogeneity in clinical decisions based on the risk of sequelae. OBJECTIVE: The objective was to analyze the inter- and intra-observer agreement among pediatric dermatologists in the choice of treatment for IH. METHODS: We performed a cross-sectional inter-rater and intra-rater agreement study within the Spanish infantile hemangioma registry. Twenty-seven pediatric dermatologists were invited to participate in a survey with 50 clinical vignettes randomly selected within the registry. Each vignette contained a picture of an infantile hemangioma with a clinical description. Raters chose therapy among observation, topical timolol, or oral propranolol. The same survey reordered was completed 1 month later to assess intra-rater agreement. Vignettes were stratified into hemangioma risk categories following the Spanish consensus on IH. The agreement was measured using kappa statistics appropriate for the type of data (Gwet's AC1 coefficient and Gwet's paired t test). RESULTS: Twenty-four dermatologists completed the survey. Vignettes represented 7.8% of the Spanish hemangioma registry. The inter-rater agreement on the treatment decision was fair (AC1  = 0.39, 95% confidence interval [CI]: 0.30-0.47). When stratified by risk category, good agreement was reached for high-risk hemangiomas (AC1  = 0.77, 95% CI: 0.51-1.00), whereas for intermediate- and low-risk categories, the agreement was only fair (AC1 0.31, 95% CI: 0.16-0.46 and AC1  = 0.38, 95% CI: 0.27-0.48, respectively). Propranolol was the main option for high-risk hemangiomas (86.4%), timolol for intermediate-risk (36.8%), and observation for low-risk ones (55.9%). The intra-rater agreement was good. The inter-rater agreement between pediatric dermatologists on the treatment of IH is only fair. Variability was most significant with intermediate- and low-risk hemangiomas.

Transient breast livedo reticularis-like exanthem in an adolescent with COVID-19.

Livedo reticularis-like eruptions have been described in different viral infections. In patients with COVID-19, livedo reticularis-like rashes are usually mild, typically present in a symmetric distribution and mostly involve the lower limbs. A case of livedo reticularis located exclusively on the breasts of a girl with mild systemic symptoms of COVID-19 is presented. Coagulation studies were normal and findings disappeared within 1 week.