Skin Eruptions in Acute Hemorrhagic Edema of Young Children: Systematic Review of the Literature.

BACKGROUND: Acute hemorrhagic edema is a skin-limited small-vessel leukocytoclastic vasculitis, which affects infants 4 weeks to 2 years of age and remits within 3 weeks. The diagnosis is made clinically in not-ill appearing children with acute onset of raised annular or nummular eruptions and edema. In this vasculitis, type, distribution, and evolution of the rash have never been systemically investigated. To address this issue, we employed the data contained in the Acute Hemorrhagic Edema Bibliographic Database, which incorporates all reports on acute hemorrhagic edema. SUMMARY: Key features of rash were documented in 383 children. Annular eruptions in a strict sense, usually targetoid, were reported in 375 (98%) cases (many children also presented polycyclic or arciform eruptions). Nummular eruptions were also very common (n = 358; 93%). Purpuric eruptions and ecchymoses were reported in the vast majority of cases. Macules and wheals were described in a minority of cases. Edema, detected in all cases, was mostly painful, indurated and nonpitting. The following regions were affected, in decreasing order, by annular or nummular eruptions: legs, feet, face, arms, ears, trunk, and genitals. With the exception of feet, which were very often affected, the same distribution was reported for edema. The initial eruption was often a wheal or a macule that evolved into a nummular or an annular eruption. Nummular eruptions successively evolved into annular ones. KEY MESSAGE: This study carefully characterizes type, distribution, and evolution of skin eruption in acute hemorrhagic edema. The data help physicians to rapidly and noninvasively make the clinical diagnosis of this vasculitis.

Atypical Bacterial Pathogens and Small-Vessel Leukocytoclastic Vasculitis of the Skin in Children: Systematic Literature Review.

Leukocytoclastic small-vessel vasculitis of the skin (with or without systemic involvement) is often preceded by infections such as common cold, tonsillopharyngitis, or otitis media. Our purpose was to document pediatric (≤18 years) cases preceded by a symptomatic disease caused by an atypical bacterial pathogen. We performed a literature search following the Preferred Reporting of Systematic Reviews and Meta-Analyses guidelines. We retained 19 reports including 22 cases (13 females and 9 males, 1.0 to 17, median 6.3 years of age) associated with a Mycoplasma pneumoniae infection. We did not find any case linked to Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Francisella tularensis, or Legionella pneumophila. Patients with a systemic vasculitis (N = 14) and with a skin-limited (N = 8) vasculitis did not significantly differ with respect to gender and age. The time to recovery was ≤12 weeks in all patients with this information. In conclusion, a cutaneous small-vessel vasculitis with or without systemic involvement may occur in childhood after an infection caused by the atypical bacterial pathogen Mycoplasma pneumoniae. The clinical picture and the course of cases preceded by recognized triggers and by this atypical pathogen are indistinguishable.

IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?

IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation.

De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Immune deposits in skin vessels of patients with acute hemorrhagic edema of young children: A systematic literature review.

BACKGROUND: Acute hemorrhagic edema of young children is a benign skin-limited vasculitis mainly affecting children 2 to 24 months of age, which is often considered the infantile variant of immunoglobulin A vasculitis (Henoch-Schönlein purpura). In most cases, the diagnosis is made on a clinical basis without a skin biopsy. METHODS: A systematic review of the literature was performed to examine the reported prevalence of vascular immune deposits in skin biopsies of patients with acute hemorrhagic edema of young children. RESULTS: Testing for vascular immune deposits was performed in 75 cases (64 boys and 11 girls aged from 3.5 to 72, median 11 months) published between 1970 and 2018. Vessel wall deposition of complement C3 was seen in 40 cases. Immunoglobulin M (N = 24), immunoglobulin A (N = 21), immunoglobulin G (N = 13), and immunoglobulin E (N = 3) were less frequently detected. Gender, age, clinical features, and disease duration were not statistically different in cases with and without vessel wall deposition of immunoglobulin A. CONCLUSION: Immune deposits in skin vessels, most frequently complement C3, are common in subjects with acute hemorrhagic edema of young children, providing furhter evidence that acute hemorrhagic edema, immunoglobulin A vasculitis, and pauci-immune vasculitides are different entities.

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Effects of multiwalled carbon nanotubes and carbofuran on metabolism in Astyanax ribeirae, a native species.

The study of the toxic effect of carbofuran and multiwalled carbon nanotubes (MWCNTs) on Astyanax ribeirae metabolism is of paramount importance due to the increasing use of this pesticide in agriculture and in the production of nanotubes within the material industry. This study aimed to evaluate the effects of carbofuran, MWCNT, and the combination of these compounds on specific oxygen consumption and excretion of ammonia in A. ribeirae. Therefore, 65 fish were divided into three groups of treatments at varying concentrations: carbofuran (0.01, 0.05, 0.1, and 0.5 mg/L), MWCNT (0.1, 0.25, 0.5, and 1.0 mg/L), and 0.5 mg/L of MWCNT added to carbofuran concentrations (0.01, 0.05, 0.1, and 0.5 mg/L). The average specific oxygen consumption in the groups exposed to carbofuran, compared to the control, increased 73.49% at the 0.01 mg/L concentration and decreased 63.86% and 91.57% with treatments of 0.1 and 0.5 mg/L, respectively. For groups exposed to the MWCNT, there was an 83.91% drop with the 1.0 mg/L treatment, and the carbofuran + MWCNT groups recorded a decrease of 71.09%, 92.77%, and 93.98% at concentrations of 0.05, 0.1, and 0.5 mg/L, respectively. In relation to specific ammonia excretion, in groups exposed to carbofuran compared to the control, there was an increase of 134.37% and 200% with the 0.1 and 0.5 mg/L treatments, respectively. The group exposed to carbofuran + MWCNT experienced a decrease of 60% and 80% with treatments of 0.1 mg/L carbofuran + 0.5 mg/L MWCNT and 0.5 mg/L carbofuran + 0.5 mg/L MWCNT, respectively. Therefore, it was concluded that carbofuran + MWCNT interact, increasing the effects in Astyanax sp.

Sporadic acute benign calf myositis: Systematic literature review.

Acute benign calf myositis is a rare infection-associated syndrome presenting with calf pain that occurs in epidemics or sporadically. Epidemic cases are usually associated with influenza virus type B. Sporadic cases, however, might be associated with a large number of microorganisms. Furthermore, during an outbreak there is a great alertness that promotes earlier diagnosis. In contrast, there is likely a lower awareness regarding the sporadic form, compromising early and correct diagnosis. In order to characterize the sporadic form of acute calf myositis and increase the knowledge of this condition, we systematically reviewed the literature reporting sporadic cases. We identified 72 reports, including 451 patients, 325 males and 126 females. Sporadic acute benign calf myositis affected subjects ≤18 years of age (N = 450; 99%), who followed a prodromal flu-like illness (N = 411; 91%), presented with pain and tenderness affecting only the calves for ≤1½ weeks (N = 441; 99%) and was never complicated by kidney involvement. The creatine kinase ratio was ≥10 in 310 (70%) out of 444 cases. Microbiological studies identified an infectious trigger in 181 cases, mostly influenza virus (type B more frequently than type A), Dengue, Ebstein-Barr or Parainfluenza virus and Mycoplasma pneumoniae. Sporadic acute benign calf myositis is a self-limited condition that can usually be diagnosed on a clinical basis. Unlike the epidemic form, many cases are due to microorganisms other than influenza virus B or A.

Familial Henoch-Schönlein Syndrome.

Little attention has been so far paid to familial cases of Henoch-Schönlein syndrome. We performed a search of the Medical Subject Headings terms (Henoch or Schönlein OR anaphylactoid purpura OR IgA nephropathy OR Berger nephropathy) AND (family OR familial). We identified no more than 19 reports including 47 families with a total of 100 affected cases: their ages ranged from 1.3 to 51 years (median, 11 years), with a male-to-female ratio of 1.4. Familial cases developed simultaneously in 45% and nonsimultaneously in 55% of the families. Age, male-to-female ratio, and clinical findings were not statistically different in cases with simultaneous and nonsimultaneous familial occurrence of Henoch-Schönlein syndrome. Henoch-Schönlein syndrome occurs almost always sporadically. Age at presentation, male-to-female ratio, and findings are similar in familial (both simultaneously and nonsimultaneously occurring) and sporadic Henoch-Schönlein cases.

Acute hemorrhagic edema of young children: a prospective case series.

UNLABELLED: Acute hemorrhagic edema of young children is a rare leukocytoclastic vasculitis that has been reported exclusively in small retrospective cases series, case reports, or quizzes. Considering that retrospective experience deserves confirmation in at least one observational prospective study, we present our experience with 16 children (12 boys and 4 girls, 5-28 months of age) affected by acute hemorrhagic edema. The patients were in good general conditions and with a low-grade or even absent fever. They presented with non-itching red to purpuric targetoid lesions not changing location within hours, with non-pitting and sometimes tender indurative swelling, and without mucous membrane involvement or scratch marks. Signs for articular, abdominal, or kidney involvement were absent. Antinuclear or antineutrophil cytoplasmic autoantibodies were never detected. The cases were managed symptomatically as outpatients and fully resolved within 4 weeks or less. No recurrence or familiarity was noted. CONCLUSION: This is the first prospective evaluation of hemorrhagic edema. Our findings emphasize its distinctive tetrad: a well-appearing child; targetoid lesions that do not change location within hours; non-pitting, sometimes tender edema; complete resolution without recurrence. What is known • Acute hemorrhagic edema of young children is considered a benign vasculitis. • There have been ≈100 cases reported in small retrospective case series. What is new • The first prospective evaluation of this condition emphasizes its features: febrile prodrome; well-appearing child; targetoid lesions not changing location within hours; non-pitting, sometimes tender indurative edema; absent extracutaneous involvement; resolution within 3 weeks. • Antineutrophil cytoplasmic autoantibodies do not play a pathogenic role.

Taste acceptability of pulverized brand-name and generic drugs containing amlodipine or candesartan.

Trials with pulverized brand-name antihypertensive drugs suggest that, from the perspective of taste acceptability, crushed candesartan, chlortalidon, hydrochlorothiazide, lercanidipine and lisinopril should be preferred to pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan. Brand-name antihypertensive drugs and the corresponding generic medicines have never been compared with respect to their taste acceptability. We therefore investigated among healthy health care workers the taste acceptability of a pulverized 1 mg-test dose of the brand-name and two generics containing either the dihydropyridine calcium-channel blocker amlodipine (Norvasc(®), Amlodipin-Mepha(®) and Amlodipin Pfizer(®)) or the angiotensin receptor antagonist candesartan (Atacand(®), Cansartan-Mepha(®) and Pemzek(®)). For this purpose, a smiley-face scale depicting four degrees of pleasure was used. Between November and December 2013, the taste test was performed among 19 nurses (15 female and 4 male subjects) and 12 physicians (5 female and 7 male subjects) aged between 25 and 49 years. Pulverized brand-names and generics containing either amlodipine or candesartan did not differ with respect to their taste acceptability.

Influenzavirus B-associated acute benign myalgia cruris: an outbreak report and review of the literature.

Acute benign myalgia cruris is characterized by transient bilateral calf pain that leads to difficulty walking. A regional outbreak of influenza virus B-associated myalgia cruris was observed during the seasonal influenza outbreak observed in Switzerland from week 1 to 13 of 2013. We performed a prospective case finding among the Swiss-Italian pediatric emergency units and pediatricians. A review of the literature was also performed. The diagnosis of myalgia cruris was made in 49 Swiss-Italian children aged 3.0-14 years (♂:♀=1.7). Flu-like symptoms were resolving when bilateral calf pain began that remitted over ⩽ 7days. The creatine kinase-level, assessed in 28 patients, was elevated in 25. Nose swabs were positive for influenza virus B in 13 out of 14 cases. The blood cell count, measured in 41 cases, disclosed leucopenia in 12 and thrombocytopenia in 3. The review of the literature found 10 outbreaks of ⩾ 10 cases of influenza virus B-associated myalgia cruris, which included a total of 203 patients with a mean age of 7.3 years and a ♂:♀ ratio of 2.0. In conclusion influenza virus B caused a large Swiss-Italian outbreak of myalgia cruris. Our outbreak and the literature indicate that influenza virus B-associated myalgia cruris affects preschool- and school-aged children, primarily boys.

Ureteral or vesical involvement in Henoch-Schönlein syndrome: a systematic review of the literature.

BACKGROUND: Little information is available on ureteral or vesical involvement in Henoch-Schönlein syndrome. To determine the features of this condition we performed a formal analysis of peer-reviewed scientific literature on this topic. METHODS: The US National Library of Medicine database was used as the data source. All articles published as full-length articles or letters were collected. Reports published in languages other than English, French, German, Italian or Spanish were not considered. RESULTS: We analyzed 32 reports describing 35 cases (24 male and 11 female subjects aged between 3.5 and 63, median 7.0 years) with ureteral (n = 30), vesical (n = 4), or both ureteral and vesical involvement (n = 1). The presentation included colicky abdominal pain, macroscopic hematuria (sometimes containing blood clots), urinary tract infection or urinary retention. The diagnosis of ureteral involvement was often fortuitous. Patients with vesical involvement were managed conservatively. However, the majority of those with ureteral involvement were managed surgically. CONCLUSIONS: Ureteral or vesical involvement is unusual and likely underappreciated in Henoch-Schönlein syndrome. Improved recognition and wider appreciation of this involvement can help to avoid associated morbidity. Management must be individualized for each patient. A multidisciplinary approach may be of value in planning medical treatment, surgical intervention, and follow-up.

Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.

Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless-like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki-Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene.