DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Verrulyse Methionine® as Monotherapy in Children and Adolescents With Common Warts.

BACKGROUND: Common cutaneous non-genital viral warts are a common skin infection with significant morbidity in the pediatric population. Although various therapeutics are available, many of them necessitate recurrent patient visits and may be associated with significant irritation and pain. Verrulyse Methionine® (VM), a nutritional supplement, was previously suggested as a non-invasive treatment option for the disease. OBJECTIVE: To assess the response to oral VM supplement as a monotherapy in a cohort of children and adolescents with multiple, non-genital viral warts after failing previous treatments. METHODS: We reviewed medical records of pediatric patients (<18 y/o) with viral warts treated with VM between 2010 and 2021. RESULTS: Among 25 patients with multiple verrucae vulgaris lesions who failed previous treatments, 14 (56%) had complete or almost-complete response to VM within 4 months, after an average of 18 months of active disease prior to VM treatment initiation. None of the 4 patients with verruca plana had response to VM treatment. Favourable cosmetic results were found in responders, and no adverse events were recorded. CONCLUSION: Response rates in our cohort are comparable to those reported in the literature for destructive local therapeutics for viral warts. Thus, our data suggest that VM may be considered for children with multiple verrucae vulgaris, providing a painless and non-invasive therapeutic option for this common disease.

Mycosis Fungoides in Solid-Organ Transplant Recipients: A Multicenter Retrospective Cohort Study.

BACKGROUND: Mycosis fungoides (MF) in solid-organ transplant recipients (SOTRs) is rare, with limited data on disease characteristics. OBJECTIVE: The aim was to study the characteristics of MF in SOTRs with an emphasis on the immunosuppressive therapy. METHODS: A retrospective cohort of patients diagnosed with MF, who were also SOTRs, were followed at 3 cutaneous lymphoma outpatient clinics, between January 2010 and February 2022. RESULTS: Ten patients were included (7 male; median ages at transplantation and at diagnosis of MF were 33 and 48 years, respectively; 40% were diagnosed before the age of 18 years). Median time from transplantation to diagnosis of MF was 8 years (range 0.5-22). Transplanted organs and immunosuppressive treatments included: liver (n = 5; 4 treated with tacrolimus, 1 with tacrolimus and prednisone), kidney (n = 3), liver and kidney (n = 1), and heart (n = 1), all treated with mycophenolic acid, tacrolimus, and prednisone. Nine had early-stage MF (IA - 4, IB - 5; 40% with early folliculotropic MF), treated with skin-directed therapies, in 2 combined with acitretin, achieving partial/complete response. One patient had advanced-stage MF (IIIA) with folliculotropic erythroderma, treated with ultraviolet A and narrow-band ultraviolet B with acitretin, achieving partial response. Immunosuppression was modified in 3. At last follow-up (median 4 years, range 1-8), no stage progression was observed; 5 had no evidence of disease, 5 had active disease (IA/IB - 4, III - 1). CONCLUSIONS: MF in SOTRs is usually diagnosed at an early stage, with overrepresentation of folliculotropic MF, and of children. Immunosuppressive therapy alterations, not conducted in most patients, should be balanced against the risk of organ compromise/rejection. Disease course was similar to MF in immunocompetent patients, during the limited time of follow-up.

Treating pediatric cutaneous Leishmania tropica with systemic liposomal amphotericin B: A retrospective, single-center study.

Leishmania tropica (L. tropica) cutaneous leishmaniasis (CL) is associated with high morbidity and low response rate to therapy, especially in pediatric patients. Intravenous (IV) liposomal amphotericin B (LAmB) has been used off-label as a treatment for L. tropica CL for many years. However, data regarding its efficacy and safety in children is lacking. In order to evaluate the efficacy and safety of IV LAmB for treating pediatric patients with L. tropica, we retrospectively reviewed electronic medical records of 24 children who were diagnosed with L. tropica CL and treated with IV LAmB during 2014-2020, at a tertiary medical center in Israel. Fourteen (58%) completed the treatment protocol and 10 (42%) experienced an infusion-related adverse event (IRAE) leading to treatment termination. Complete response was noted in 6/14 (43%) patients, while 8/14 (57%) failed to respond. Lower response rate was noted in lesions involving the mid-facial area. The relatively low response rate is speculated to result from a low dose of LAmB, short follow-up period, and difficult to treat anatomic locations. The observation of a lower response rate for mid-facial lesions should be validated in larger cohorts. The highrisk of IRAE should be considered in physician decisions regarding this treatment.

Psoriasis and Renal Disorders: A Large-Scale Population-Based Study in Children and Adults.

BACKGROUND: Psoriasis is a systemic disease with associated comorbidities. An association between renal diseases and psoriasis has previously been reported in adult patients, but little is known about renal diseases in pediatric patients. OBJECTIVE: To determine whether there is an association between psoriasis and renal comorbidities in adult and pediatric patients. METHODS: This cross-sectional study analyzed the database of the largest health care maintenance organization in Israel. Logistic regression was used to calculate odds ratios to compare 68,836 psoriatic patients and 68,836 controls with respect to renal comorbidities. RESULTS: In adults, an inverse association emerged between psoriasis and dialysis (OR, 0.69; 95% CI, 0.58-0.83) and kidney transplantation (OR, 0.60; 95% CI, 0.43-0.83), a positive association with other kidney diseases (OR, 1.09; 95% CI, 1.05-1.13), and no association between psoriasis and chronic kidney disease (OR, 1.03; 95% CI, 0.98-1.09). Comparing 9,127 pediatric patients and 9,478 controls, no association was found between psoriasis and renal comorbidities, chronic kidney disease (OR, 0.90; 95% CI, 0.33-2.48), dialysis (OR, 2.06; 95% CI, 0.19-22.69), kidney transplantation (OR, 0.34; 95% CI, 0.04-3.29), or other kidney diseases (OR, 0.98; 95% CI, 0.79-1.23), even after a multivariate analysis adjusting for putative confounders. CONCLUSION: As opposed to adult patients, pediatric patients with psoriasis were not shown at risk of kidney diseases.

Segmental Pigmentation Disorder: Clinical Manifestations and Epidemiological Features in 144 patients, a Retrospective Case-control Study.

Segmental pigmentation disorder (SPD) is characterized by hypo- or hyper-pigmented patches segmentally distributed, present in infancy, more prominently in darker-skinned children. The aim of this study was to define the demographic and clinical characteristics of SPD in a large series of patients. This was a retrospective case-control study at 2 paediatric dermatology centres in Israel. Data were collected through a telephone questionnaire and medical records. The study group consisted of 144 individuals with SPD and 144 individuals visiting the same institutions matched for age and sex. Median age of onset of SPD was near birth; 51% of patients were Sephardic Jews, and patients were followed up for a median period of 27 years. The patches were located on the torso (43%), mostly hypopigmented (52%), and remained of the same intensity and size in 55% and 41% of cases, accordingly. No differences in extracutaneous morbidities were found between SPD and control patients. This study delineates the demographic and clinical characteristics of SPD, confirms that cutaneous findings in SPD are more prominent in darker skin, tends not to expand in size or accentuate throughout the years, nor to be associated with extracutaneous morbidities.

Epidemiologic features and risk of scarring in pediatric patients with kerion celsi.

BACKGROUND: Kerion celsi represents the inflammatory extreme of tinea capitis, as a delayed hypersensitivity reaction to the causative dermatophyte. Data regarding prevalence, trends in pathogens, and risk factors for scarring are limited. OBJECTIVE: The main objective of the study is to assess clinical and epidemiologic features of children with kerion celsi and risk factors for scarring. METHODS: We reviewed medical records of pediatric patients with kerion celsi treated between January 2006 and July 2020. RESULTS: Among 80 patients, the prevalence of permanent alopecia was 27.5%. Patients with remaining alopecia presented to our clinic at a mean 1.3 months earlier than those with complete response to treatment (2.2 ± 2.1 and 3.4 ± 4.8, respectively; p < .05). Patients of Ethiopian ethnicity were more represented than in the general population; however, scarring was observed in only 11% (p = 0.08). Outcomes did not differ by pathogen, antifungal treatment prescribed, duration of treatment, or the use of prednisone or antibiotics. CONCLUSIONS: Scarring alopecia is a common complication of kerion celsi. Host innate immune response, pathogen virulence, and treatment timeline should be considered as possible variables affecting risk of scarring in the future studies.

[TRENDS IN HOSPITALIZATION OF CHILDREN WITH HENOCH -SCHONLEIN PURPURA].

BACKGROUND: Traditionally, most children diagnosed with Henoch-Schonlein Purpura (HSP) were hospitalized. This policy gradually changed towards selective hospitalization, yet there are still no criteria for admitting pediatric patients with HSP. OBJECTIVES: To examine the clinical features and criteria for hospitalization of pediatric patients with HSP. METHODS: A retrospective analysis was conducted of medical records of pediatric patients with HSP examined in the emergency department (ED) of Schneider Children's Medical Center, during 2005-2015. We compared children who were admitted with those not admitted to the hospital. RESULTS: During the study period, 116 children diagnosed with HSP were examined in the ED of Schneider Children's Medical Center: 14(12%) were admitted at first referral, and 22 (19%) of the children were hospitalized subsequently. The average age of all the children with HSP was 7.4 years, 57% were boys, and approximately 10% of the children had additional diseases, most of them auto-inflammatory. The main indications for hospitalization were gastrointestinal involvement (abdominal pain or bleeding), renal involvement (hematuria or proteinuria), and inability to walk. Most of these symptoms were also present in the children who were not admitted. CONCLUSIONS: Approximately 30% of the children were admitted to the hospital, most of them not at first referral. No clear criteria for admission were found, except for gastrointestinal bleeding.

Cutaneous Leishmaniasis Treated with Miltefosine: A Case Series of 10 Paediatric Patients.

Cutaneous leishmaniasis poses a therapeutic challenge in the paediatric population. The aim of this study was to assess the efficacy and safety of miltefosine treatment for Old World cutaneous leishmaniasis in paediatric patients. A multicentre retrospective review of 10 children (≤ 18 years of age) with cutaneous leishmaniasis treated with miltefosine in Israel was performed. Mean ± standard deviation age at diagnosis was 9.1 ± 5.0 years. The Leishmania species diagnosed was L. tropica in 8 cases and Leishmania major in 2 cases. Mean ± standard deviation duration of treatment was 44.8 ± 20.6 days, with a mean follow-up period of 12.1 ± 17.1 months. Complete response was noted in 8 (80%) patients. Treatment failure was noted in 2 (20%) cases. Side-effects related to the medication were minimal. In conclusion, oral miltefosine may be an effective and safe treatment for Old World cutaneous leishmaniasis caused by Leishmania tropica or Leishmania major in children. However, further studies are warranted to draw a definite conclusion.

Cutaneous Leishmaniasis Treated with Miltefosine: A Case Series of 10 Paediatric Patients.

Cutaneous leishmaniasis poses a therapeutic challenge in the paediatric population. The aim of this study was to assess the efficacy and safety of miltefosine treatment for Old World cutaneous leishmaniasis in paediatric patients. A multicentre retrospective review of 10 children (≤ 18 years of age) with cutaneous leishmaniasis treated with miltefosine in Israel was performed. Mean ± standard deviation age at diagnosis was 9.1 ± 5.0 years. The Leishmania species diagnosed was L. tropica in 8 cases and Leishmania major in 2 cases. Mean ± standard deviation duration of treatment was 44.8 ± 20.6 days, with a mean follow-up period of 12.1 ± 17.1 months. Complete response was noted in 8 (80%) patients. Treatment failure was noted in 2 (20%) cases. Side-effects related to the medication were minimal. In conclusion, oral miltefosine may be an effective and safe treatment for Old World cutaneous leishmaniasis caused by Leishmania tropica or Leishmania major in children. However, further studies are warranted to draw a definite conclusion.

Vascular lesions in genital lichen sclerosus in pediatric patients.

BACKGROUND/OBJECTIVES: Lichen sclerosus is a rare, pruritic, mucocutaneous disease affecting mostly the anogenital area. Reports have occasionally associated lichen sclerosus with overlapping vascular lesions. This study explores this association in children. METHODS: A retrospective study was conducted in the dermatology unit of a pediatric tertiary care medical center. Electronic medical records were searched for patients diagnosed with lichen sclerosus from 2006 to 2019. Review of the cases was performed to identify overlapping vascular lesions and review the clinical course of overlap cases. RESULTS: Of 74 children diagnosed with lichen sclerosus during the study period, five (6.75%) had overlapping vascular lesions and genital lichen sclerosus. Four patients presented with reticular telangiectatic macules and patches (n = 4, 5.4%) that appeared at or shortly after disease onset; resolution occurred a few months after treatment initiation. The fifth patient presented with telangiectases that appeared more than 2 years after the onset of the first symptoms of lichen sclerosus (n = 1, 1.3%). CONCLUSION: Vascular lesions in children with genital lichen sclerosus are common and have variable clinical manifestations. Early appearance of reticular macules, patches, and papules is a variant of the disease and is followed by prompt resolution of these lesions. Pathogenesis is attributed to structural changes and repositioning of the papillary vascular plexus. These changes may be alarming to parents and therefore must be recognized by physicians to prevent unnecessary concern and investigations.

Cutaneous presentations of omphalomesenteric duct remnant: A systematic review of the literature.

BACKGROUND: Disorders of the umbilicus are commonly seen in infancy, including hernias, infections, anomalies, granulomas, and malignancies. Meticulous inspection of the umbilicus at birth might reveal a persisting embryonic remnant, such as an omphalomesenteric duct (OMD), manifested by a variety of cutaneous signs, such as an umbilical mass, granulation tissue, or discharge. OBJECTIVE: To systematically review the available data regarding the presence and management of OMD remnant with cutaneous involvement to suggest a practical approach for diagnosis and treatment. METHODS: A systematic review of the literature evaluating OMD anomalies presenting with cutaneous symptoms was performed. In addition, an index case of an 11-month-old patient is presented. RESULTS: We included 59 publications reporting 536 cases; 97% of the patients whose age was noted were infants (mean age 11 months). In 7.5% of the cases, diagnosis was established only after treatment failure. In 6.4% of patients, nonlethal complications were reported, and in 10.3%, the outcome was death, partly due to delayed diagnosis or mismanagement. LIMITATIONS: Limited quality of the collected data, reporting bias. CONCLUSION: OMD is relatively rare; however, the clinician must consider this remnant while examining patients with umbilical abnormalities because mismanagement could cause severe morbidity and mortality.

Patch testing in Israeli children with suspected allergic contact dermatitis: A retrospective study and literature review.

BACKGROUND/OBJECTIVES: Childhood allergic contact dermatitis is recognized as a significant clinical problem. The objective was to evaluate the rate of positive patch tests in Israeli children with clinically suspected allergic contact dermatitis, identify possible sex and age differences, compare results with those in Israeli adults, and review pediatric studies in the literature. METHODS: The study sample included 343 children and adolescents (197 female, 146 male; 1-18 years of age, mean age 11.8 years) with clinically suspected allergic contact dermatitis who underwent patch testing with a standard pediatric series of 23 allergens at a tertiary medical center from 1999 to 2012. Data on clinical characteristics and test results were collected retrospectively from the medical files. RESULTS: Ninety-eight subjects (28.6%) (75 girls [38.1%], 23 boys [15.8%]) had at least one positive reaction. The most frequent reactions were to nickel sulfate, followed by potassium dichromate and cobalt chloride. Nickel sulfate sensitivity was more common in girls, especially those younger than 3 years and older than 12 years. The prevalence of contact sensitization was similar in subjects with and without atopic dermatitis (50% and 51%, respectively). CONCLUSION: Nickel is the most common allergen in Israeli children, especially girls. Patch testing should be performed in children with clinically suspected allergic contact dermatitis regardless of atopic background.

Screening for Brain Involvement in Infants with Multifocal Cutaneous Infantile Hemangiomas.

BACKGROUND: Multifocal (≥5) infantile hemangiomas (IHs) are known as a risk factor for extracutaneous involvement. Liver is the most commonly involved organ, but involvement of other systems has also been reported. This study aims to describe the characteristic findings in a group of infants with multiple cutaneous hemangiomas, with emphasis on intracranial involvement. METHODS: A retrospective case series study was carried out in a pediatric dermatology unit of a tertiary pediatric medical center. Patients diagnosed with multiple cutaneous IHs from 2006 to 2015 were identified by a computerized search. Clinical data were retrieved from the medical charts. RESULTS: A total of 60 infants (37 females and 23 males) were identified for analysis. Forty-four brain ultrasounds were recorded and reported as normal. One patient out of the 44 was later diagnosed with a small asymptomatic hemangioma seen on a brain MRI/MRA done for another indication. CONCLUSION: Brain hemangiomas may present as an asymptomatic incidental finding in infants presenting with multifocal cutaneous and liver IHs. The single case reported in our study emphasizes the low prevalence and the benign course expected. Therefore, routine ultrasound screening for brain involvement is probably unnecessary for this population.

Intra-familial Variation in Clinical Phenotype of CARD14-related Psoriasis.

Psoriasis is a multifactorial chronic inflammatory disease. Monogenic psoriasis has been described recently, including dominantly inherited plaque and generalized pustular types, related to activating mutations in the CARD14 gene. We describe here a family with CARD14-related psoriasis, exhibiting an extreme variability of clinical presentation (from mild plaque-type to generalized pustular psoriasis) and early disease onset. The affected family members harboured the c.349G>A [p.Gly117Ser] mutation in CARD14, which has not previously been linked to pustular psoriatic phenotype. Furthermore, most severely affected individuals carried 3 additional CARD14 coding region polymorphisms (rs2066964, rs34367357 and rs11652075), suggesting their possible effect on disease expression. Early-onset psoriasis co-segregated with the HLA-C*0602, indicating that HLA-C*0602 could potentially modulate the time of disease onset. In summary, this paper describes a family with CARD14-related psoriasis and discusses the possible influence of the specific haplotypes on intra-familial variation in the clinical phenotype of the disease.

Juvenile mycosis fungoides: cutaneous T-cell lymphoma with frequent follicular involvement.

BACKGROUND: The literature on mycosis fungoides (MF) in children/adolescents is sparse. OBJECTIVE: We sought to evaluate the characteristics of juvenile MF in a large cohort. METHODS: Data were collected on all patients with MF, aged 18 years or younger at the time of clinicopathologic diagnosis, who attended the Rabin Medical Center Dermatology Department, Petach Tikva, Israel, between 1994 and 2012 and were followed up prospectively. RESULTS: There were 50 patients (30 male; mean age 11.4 years at diagnosis); 18 (36%) had Fitzpatrick skin type IV or higher. All were given a diagnosis of early-stage disease (IA-IIA) except 1 (tumor stage, IIB). Eight had classic MF lesions only and 42 had other variants, alone or in combination; these were mainly hypopigmented MF (n = 29) and cases with subtle but clear clinicopathologic features of folliculotropic MF (FMF) (n = 18). Among the various skin-targeted therapies, psoralen plus ultraviolet A (systemic/bath) proved beneficial for FMF. During a follow-up period of 0.25 to 15 years (mean 4.5), 2 patients progressed from stage IA to IB or IIA. LIMITATIONS: Relatively short follow-up is a limitation. CONCLUSIONS: This case series shows that FMF is not uncommon in children and adolescents. It is characterized by more superficial clinical features and less heavy perifollicular lymphocytic infiltrates than adult FMF, and responds well to psoralen plus ultraviolet A. The prognosis of childhood FMF remains unclear.

Efficacy and safety of propranolol for the treatment of infantile hemangioma: a presentation of ninety-nine cases.

BACKGROUND: Propranolol is highly effective in the treatment of infantile hemangioma (IH), but important clinical and pharmacological data are lacking. OBJECTIVE: The aims of the present study were to evaluate the efficacy of propranolol for the treatment of IH, to identify favorable prognostic factors in propranolol-treated IH, and to evaluate the safety of propranolol for the treatment of IH. METHODS: Clinical data were recorded from the electronic files and digital photographs of 99 patients with IH attending a tertiary pediatric medical center (2008-2011). Findings were evaluated by regression in volume and color changes. RESULTS: The male-to-female ratio was 1:4. Age at treatment initiation was 9.4 ± 10.1 months; 15% of the treated hemangiomas were beyond the proliferative phase (17-54 months). The propranolol starting dose was 2 mg/kg/day. Duration of the treatment was 8.5 ± 3.2 months. All but 1 patient responded to treatment. A longer treatment course was required for segmental and deep hemangiomas. Mild side effects occurred in 32% of patients. Recurrence occurred in 13% of patients. CONCLUSION: Lesions located on the face are better responders when treatment is started early. Treatment should continue up to age 12-15 months, with a longer course for segmental or deep hemangiomas.

Treatment of the skin manifestations of hereditary hemorrhagic telangiectasia with pulsed dye laser.

Hereditary hemorrhagic telangiectasia (HHT) is a familial disorder, in which variably sized arteriovenous malformations develop in the skin, respiratory tract, central nervous system, and gastrointestinal and urogenital tracts. Bleeding is a major problem in the abnormal vessels, primarily in the nose and internal lesions. Skin lesions, in contrast, do not generally bleed spontaneously but pose a significant cosmetic concern. The lesions are characteristically small caliber vessels located in the dermis. As such, they are ideal targets for vascular lesions. Eight patients with cutaneous facial lesions of HHT were treated by pulsed dye laser. All patients exhibited excellent (75-100%) clearance after a mean of 2.6 treatments (range 1-8). In comparison, a control group of patients with non-HHT facial telangiectasia required a mean of 1.9 (range 1-5; p < 0.05) treatments. No adverse events were reported in either group. The study confirms the safety and efficacy of PDL in the management of the cutaneous lesions of HHT.

Diagnosis, treatment, and long-term outcomes of pediatric pemphigus: a retrospective study at tertiary medical centers.

BACKGROUND: Pediatric pemphigus is a rare bullous disease that represents a diagnostic and therapeutic challenge;  evidence on patients' response to various treatments and long-term surveillance data are lacking. We aimed to investigate pediatric pemphigus patients' characteristics, diagnosis, therapeutics, response, and long-term follow-up. METHODS: This is a retrospective study of all pemphigus patients aged <18 years, diagnosed between 2000 and 2023, from three tertiary medical centers in Israel. The diagnosis was confirmed by positive immunofluorescence. RESULTS: Twelve pediatric pemphigus patients were included (mean age 10.7 ± 4.3 years, male:female ratio 1:1). Mean diagnostic delay was 11.1 ± 12.6 months (range 1.8-36 months). Most patients had pemphigus vulgaris with mucosal involvement (58.3%). First-line treatment for all patients included systemic corticosteroids (sCS), with a treatment duration (including tapering down) of 28 ± 18.4 months. Hospitalization did not yield better outcomes. Only three patients achieved sustained complete response with sCS treatment (25.0%), and the rest required additional therapeutics, most commonly rituximab. Rituximab showed a good safety profile and therapeutic response. Follow-up was recorded up to 18.1 years after diagnosis (mean: 5.6 years). Three of five patients with information available more than 5 years after the pemphigus diagnosis still exhibited disease symptoms. CONCLUSIONS: Pediatric pemphigus is associated with a significant diagnostic delay. While sCS can induce remission in most patients as a first-line treatment, long-term disease control requires additional immunomodulators. Long-term follow-up reveals a chronic yet mostly benign disease course in this population and advocates for the use of rituximab in pediatric pemphigus patients.