A novel homozygous mutation p.E88K in maternal SLC30A2 gene as a cause of transient neonatal zinc deficiency

The SLC30A2 gene encodes zinc transporter ZnT2, which is indispensable for the transport of zinc into the breast milk in the mammary gland. Transient neonatal zinc deficiency (TNZD) is caused by a mutation in the maternal SLC30A2 gene and has a clinical presentation similar to that of acrodermatitis enteropathica (AE). We described the case of a Chinese infant who presented with AE-like lesions 10 days after birth. Sanger sequencing of the AE-causing gene SLC39A4 revealed no mutations in genomic DNA from the infant, excluding the possibility of AE. Detection of the mother's breast milk showed a significantly lower zinc level. Thus, SLC30A2 sequencing was performed on her genomic DNA and a previously unreported homozygous c.262G > A (p.E88K) mutation was disclosed. Functional analysis suggested the novel mutation could lead to a strong disruption of zinc secretion, which indicated a complete loss of function in the ZnT2 protein. We finally diagnosed the infant with TNZD. To the best of our knowledge, this is the first case of TNZD caused by a homozygous mutation in the maternal SLC30A2 gene. Compared to the heterozygous condition, a homozygous mutation seems to result in a more significant decrease in zinc secretion and a more rapid onset of TNZD.     

Transient Neonatal Zinc Deficiency Caused by a Novel Mutation in the SLC30A2 Gene

This is a case report of a 4‐month‐old full‐term, fully breastfed boy who presented with a persistent periorificial and groin rash associated with poor weight gain and irritability. His serum zinc level was low. The mother's breast milk zinc level was found to be low despite her serum zinc levels being normal, confirming the diagnosis of transient neonatal zinc deficiency. Mutational analysis revealed a novel mutation in the mother's SLC30A2 gene, which encodes a zinc transporter expressed in mammary gland epithelial cells.     

Novel ERCC2 mutation in two siblings with trichothiodystrophy

Trichothiodystrophy describes a group of recessively inherited multisystem neuroectodermal disorders that takes its name from the characteristic feature of brittle, sulfur‐deficient hair. We describe two siblings with trichothiodystrophy due to a novel genotype. The maternal mutation (p.Arg722Trp) is a previously described pathogenic mutation in ERCC2 that has been shown to result in a severe phenotype, while the paternal mutation (c.1480‐1G > C) has not been previously reported. Our cases confirm the severe phenotype associated with the p.Arg722Trp mutation and expand the known genetic mutations associated with trichothiodystrophy by demonstrating a novel pathogenic mutation in ERCC2.     

A randomized,double‐blind,placebo‐controlled trial to determine the efficacy and safety of lactoferrin with vitamin E and zinc as an oral therapy for mild to moderate acne vulgaris

Lactoferrin is an iron‐binding milk‐derived protein that has shown antibacterial and anti‐inflammatory effects in vitro and in vivo. The objective of this study was to determine the efficacy and safety of lactoferrin, combined with vitamin E and zinc, for mild to moderate acne vulgaris. In this randomized, double‐blind, placebo‐controlled trial, 168 subjects aged 13–40 years old were randomly assigned to take either a capsule formulation containing lactoferrin with vitamin E and zinc or placebo twice a day for 3 months. The primary outcome measure was a reduction in the number of acne lesions compared to placebo. A total of 164 subjects completed the study per protocol. The lactoferrin group (n = 82) showed a significant median percent reduction in total lesions as early as 2 weeks (14.5%, P = 0.0120), with the maximum reduction occurring at week 10 (28.5%, P < 0.0001) compared to placebo group (n = 82). Maximum reduction in comedones (32.5%, P < 0.0001) and inflammatory lesions (44%, P < 0.0001) was also seen at week 10 compared to placebo. Sebum scores were improved by week 12. No adverse events were observed during the trial. A twice daily regimen of lactoferrin with vitamin E and zinc significantly reduced acne lesions in people with mild to moderate acne vulgaris.     

Deodorant effects of a supercritical hops extract: antibacterial activity against Corynebacterium xerosis and Staphylococcus epidermidis and efficacy testing of a hops/zinc ricinoleate stick in humans through the sensory evaluation of axillary deodorancy

Background There is little scientific evidence to support the efficacy of natural deodorants and therefore, such products may be perceived as inefficacious. The evaluation of the in vitro antibacterial activity of a hop extract and the evaluation of the odor‐reducing capacity of a hops/zinc ricinoleate‐containing product by a sensory evaluation panel is employed to verify deodorant performance. Aims The goal of this study was to evaluate the in vitro antibacterial activity of a hop extract against Corynebacterium xerosis and Staphylococcus epidermidis and to verify in vivo deodorant performance of a hops/zinc ricinoleate‐containing product. Methods The hops extract was evaluated on a culture of an armpit swab from six volunteers. Furthermore, the extract was submitted to a zone of inhibition test and an agar‐dilution assay against two major odor‐causing bacteria. The clinical evaluation of the finished product was carried out according to a standard method for substantiating deodorant efficacy using trained odor judges for the assessment of axillary malodor (ASTM method E 1207‐87 Standard Practice for the Sensory Evaluation of Axillary Deodorancy). Results The supercritical hops extract showed good antibacterial activities in all three tests. Minimum inhibitory concentration values of 6.25 and 25 μg/mL against C. xerosis and S. aureus, respectively, were obtained in the agar‐dilution assay. In the clinical underarm odor‐reduction evaluation, the mean malodor score dropped from 6.28 (±0.70) to 1.80 (±0.71) after 8 h of application. There was still a noticeable effect at both 12 and 24 h after the application, with a score of 1.82 (±0.74) and 2.24 (±0.77), respectively. Conclusion The hops extract has good in vitro antibacterial properties and, in combination with zinc ricinoleate in an appropriate base, delivers in vivo odor reduction. The clinical efficacy is likely due to a combination of the base ingredients and the antibacterial actives.     

Zinc and atopic dermatitis: a systematic review and meta‐analysis

Zinc plays a central role in skin integrity via barrier and immune mechanisms and may also be relevant in the pathogenesis of atopic dermatitis (AD). However, little is known about the relationship between zinc and AD. We performed a systematic review to determine (i) the association between zinc levels or zinc deficiency and AD and (ii) the efficacy of oral zinc supplementation in the treatment of AD. We searched PubMed, Scopus, Web of Science and article references for observational studies on zinc levels or zinc deficiency in participants with AD vs. controls and for randomized control trials (RCTs) on zinc supplementation in AD. For observational studies, we calculated pooled standardized mean differences (SMDs) or odds ratios (ORs) along with 95% confidence intervals (CIs) using a random effects model. We included 14 observational studies and two RCTs. The pooled SMD demonstrated significantly lower serum (SMD 0.66, 95% CI 0.21–1.10, P = 0.004), hair (SMD 0.95, 95% CI 0.38–1.52, P = 0.001) and erythrocyte (SMD 0.95, 95% CI 0.38–1.52, P = 0.001) zinc levels in participants with AD compared to controls. Pooled unadjusted data from three studies showed a non‐significant increased odds of AD in those with zinc deficiency compared with those without zinc deficiency (OR = 1.50, 95% CI 0.71–3.16, P = 0.28). One RCT of oral zinc supplementation among AD patients with zinc deficiency showed improvement in extent and severity of AD, while another RCT among all AD patients showed no significant improvement. All the studies were of low or moderate quality. We conclude that low serum, hair and erythrocyte zinc levels are associated with AD. However, the poor quality of included studies makes interpretation of these results problematic. High‐quality observational studies are needed to confirm the association between low zinc levels and AD, and RCTs are required to evaluate the merit of zinc supplementation for the treatment or prevention of AD.     

Serum zinc and copper status in Iranian patients with pemphigus vulgaris

Background The role of nutritional factors including trace elements has been reported in the pathogenesis of many autoimmune diseases. Objective Regarding the relatively high prevalence of pemphigus vulgaris in Iran, we investigated the serum levels of zinc and copper as two important trace elements, together with the oxidative stress status in patients with pemphigus vulgaris. Materials and methods This case‐control study was performed on 25 patients with newly diagnosed pemphigus vulgaris and 25 age‐ and sex‐matched healthy control subjects. Serum concentrations of zinc, copper, ceruloplasmin as well as copper/zinc ratio were determined for each subject. Oxidative stress was also measured using a novel assay of peroxidant‐antioxidant balance (PAB). Results Mean serum concentrations of zinc and copper as well as copper/zinc ratio were significantly lower in patients (mean age: 47.2 ± 16.2 years; male/female: 14/11) compared with the controls (mean age: 47.3 ± 12.8 years; male/female: 14/11; P < 0.001). In contrast, PAB values were significantly elevated in patients compared with controls (P < 0.01). No significant difference in serum ceruloplasmin concentrations was observed between the groups (P > 0.05). Conclusion Our findings indicate that low serum zinc and copper and increased oxidative stress may be associated with pemphigus vulgaris.     

An observational study of methionine‐bound zinc with antioxidants for mild to moderate acne vulgaris

APC is a novel methionine‐based zinc complex with antioxidants that has been used in acne as a nutritional supplement. This is based on the proven role of zinc and antioxidants in improving acne, specially the inflammatory lesions. The objectives of this study are to explore the efficacy, safety, and tolerability of APC in acne patients with mild to moderate facial acne vulgaris. In this exploratory trial, 48 patients were treated with oral APC thrice a day for 3 months followed by a 4‐week treatment‐free period. At the end of treatment (Week 12), there was a statistically significant improvement in the global acne count (p < 0.05), which began after 8 weeks (p < 0.05). Almost 79% (38/48) of the patients had 80–100% improvement. There was a significant reduction in pustules (8 weeks (p < 0.05) and 12 weeks (p < 0.001)), and papules and closed comedones (8 weeks (p < 0.05) and 12 weeks (p < 0.001)). Only two patients had side effects. The current data indicate that treatment with oral APC thrice daily for 12 weeks in patients with mild to moderate facial acne vulgaris is efficacious and well tolerated. As the onset of action is late, concomitant topical therapy can enhance the results.     

Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity

Acne is a chronic inflammatory illness of the pilosebaceous follicle where innate immunity plays a central role. In acne, the density of Propionibacterium acnes is increased in the pilosebaceous unit. We hypothesized that the severity of acne is not only dependent on the proliferation of P. acnes but also dependent on the pro‐inflammatory potential of P. acnes strains and consequently constitutes potential triggering factor for acne scarring. We investigated pro‐inflammatory potential of five different strains of P. acnes and P. avidum in skin explants and the preventive effect of zinc gluconate. The expression of immune markers was studied by immunohistochemistry, RT‐qPCR and ELISA. P. acnes strains modulate differently the expression of immune markers both at gene and at protein levels. P. acnes type III had the highest pro‐inflammatory potential by up‐regulating the expression of PAR‐2, TNF‐alpha, MMP‐13 and TIMP‐2, whereas P. avidum had the weakest by up‐regulating only MMP‐13 and TIMP‐2. Preincubation of zinc gluconate, which is a modulator of innate immunity, down‐regulates the expression of most immune markers induced by P. acnes, PAR‐2, TIMP‐2, up‐regulates MMP‐1, TIMP‐1. Our results demonstrate that different P. acnes strains have different inflammatory potential targeting markers of cutaneous innate immunity, and that inflammatory potential can be down‐regulated by zinc gluconate. As such, the inflammatory potential of P. acnes strains on acne skin may influence the severity of inflammatory acne lesions and scars.     

Evaluation of zinc level in skin of patients with necrolytic acral erythema

Summary Background Necrolytic acral erythema (NAE) is considered a cutaneous sign of hepatitis C virus infection. Its exact pathogenesis is still not fully understood, with some reports about decreased serum zinc levels but none about its level in the skin. Objectives To assess skin (lesional and perilesional) and serum zinc levels in patients with NAE and compare them with levels in control subjects. Methods Fifteen patients with NAE and 10 healthy controls were included in this study. Assessment of zinc level, in serum by graphite furnace atomic absorption spectrophotometry and in lesional and perilesional skin biopsies by flame atomic absorption spectrometry, was done in all subjects. Re‐evaluation of serum and lesional skin zinc level was done after oral zinc treatment. Results Mean ± SD zinc levels were significantly lower in patients (serum 0·44 ± 0·13 mg L^?1; lesional skin 42·6 ± 18·9 mg L^?1; perilesional skin 32·5 ± 17·2 mg L^?1) than controls (serum 1·17 ± 0·29 mg L^?1; skin 100·1 ± 2·77 mg L^?1), with a positive correlation between lesional and perilesional skin zinc (r = 0·91, P < 0·01). Oral zinc supplementation significantly increased serum and skin zinc levels (by 159% and 4%, respectively; P < 0·05). Conclusions NAE is associated with decreased serum and skin zinc levels. Oral zinc supplementation corrects decreased levels of plasma and skin zinc much earlier than the desired clinical benefits appear.     

A Prospective Two‐Year Assessment of Miconazole Resistance in Candida Spp. with Repeated Treatment with 0.25% Miconazole Nitrate Ointment in Neonates and Infants with Moderate to Severe Diaper Dermatitis Complicated by Cutaneous Candidiasis

A petrolatum and zinc oxide–based ointment containing 0.25% miconazole nitrate is reported to be effective and well tolerated in the treatment of diaper dermatitis complicated by cutaneous candidiasis (DDCC). This prospective, multicenter, open‐label, long‐term, phase IV study investigated the potential resistance of Candida spp. to repeated topical use of 0.25% miconazole nitrate in infants age 15 months and younger with moderate to severe DDCC. For initial and recurring episodes of DDCC over the 2‐year study period, subjects were treated with a 7‐day course of 0.25% miconazole nitrate ointment (active components: miconazole nitrate 0.25%, zinc oxide 15%, and white petrolatum 81.35%) with a 7‐day follow‐up. Clinical and mycologic evaluations were conducted before treatment (day 0) and 7 days after treatment (day 14). Potential resistance to miconazole was defined using an arbitrary breakpoint of minimum inhibitory concentration of 2 μg/mL. There was no evidence of resistance to miconazole in Candida spp. after single or repeated treatment courses of 0.25% miconazole nitrate ointment. For the initial episode of DDCC, 83 of 168 subjects (49.4%) achieved a clinical cure, 77 (45.8%) achieved a mycologic cure, and 49 (29.2%) achieved an overall cure (clinical and mycologic). The overall cure rate for recurrent episodes of DDCC was similar to or numerically greater than rates observed for the initial episode. Treatment of DDCC with 0.25% miconazole nitrate ointment was effective and generally well tolerated. No evidence of the development of resistance to miconazole in Candida spp. was observed.     

A Diagnostic Challenge: A Case of Acrodermatitis Enteropathica without Hypozincemia and with Maternal Milk of Low Zinc Level

Abstract: Acrodermatitis enteropathica is a rare and distinct form of zinc deficiency with a requirement of life‐long zinc supplementation and inherited in a recessive manner. Transient nutritional zinc deficiency is also a well known condition mimicking acrodermatitis enteropathica like skin changes in preterm and term infants who are generally breastfed with a low level of zinc containing milk. Here, a 4‐month‐old male, term and fully breastfed acrodermatitis enteropathica case without hypozincemia and with maternal milk of low zinc level is presented.     

Acrodermatitis enteropathica: an uncommon differential diagnosis in childhood – first description of a new sequence variant

An 11‐month‐old boy was brought to our clinic with superinfected, sharply‐defined, symmetrical, erythematous macules and vesicles, some with yellowish‐brownish crusts, on the cheeks, fingers, and in the diaper region. The suspected impetigo contagiosa had failed to respond to both topical antiseptic therapy and systemic antibiotics. Because of the unusual clinical picture and course, we measured the serum zinc level. A significantly reduced level of 2 μmol/l (normal range 9.2–18.4 μmol/l) was identified. Initial skin lesions had appeared one week after weaning (5th week after birth). Since the age of 8 months the infant had also had recurrent diarrhea. Two weeks after zinc‐histidine substitution, the diarrhea ceased and skin lesions slowly disappeared. Molecular genetic testing for the SLC39A4 (zinc transporter) gene revealed compound heterozygosity for the previously unidentified mutations c.1465_1474+4del (p.?) and c.295G>A (p.Ala99Thr). The parents are healthy heterozygous gene carriers. The same compound heterozygosity was later detected in the newborn brother of our patient shortly after birth. A zinc deficiency could therefore be identified and treated before symptoms occurred. The inherited autosomal recessive zinc transporter deficiency is termed acrodermatitis enteropathica. Lifelong zinc substitution is recommended. A differential diagnosis can be difficult because bacterial and fungal superinfection is common in zinc deficiency. Precise diagnosis requires testing family members for the gene.     

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Generalized pustular psoriasis (GPP) is now known to be caused by biallelic variants in IL36RN and monoallelic variants in CARD14 and AP1S3. The presence of a modifier locus or oligogenic inheritance have been hypothesized. We report on a patient with a unique coinheritance of pathogenic variants in IL36RN (c.115+6T>C) and TNFAIP3 (c.547C>T, p.R183 * ) causing the genetic entities GPP and familial Behçet‐like autoinflammatory syndrome (AISBL). The heterozygous variant in IL36RN identified by Sanger sequencing was inherited from his unaffected father, while the heterozygous variant in TNFAIP3 was detected by whole‐exome sequencing and was also identified in the patient's AISBL‐affected maternal relatives. Further functional studies are required to research whether the variant of TNFAIP3 plays a part in the development of GPP or simply causes the Behçet's disease phenotype. However, our data suggest that whole‐exome sequencing for the heterozygous carrier of the IL36RN gene in GPP be used to find the potential second genetic locus.     

Novel compound heterozygous mutation in LAMC2 genes (c.79G>A and 382insT) in Herlitz junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is a heritable blistering skin disease characterized by separation within the lamina lucida. It is caused by mutations in the LAMA3, LAMB3 and LAMC2 genes encoding the α3‐, β3‐ and γ2‐chains, respectively, of laminin‐332. JEB Herlitz type (JEB‐H) is a lethal blistering disease with severe cutaneous and extracutaneous involvements caused by null mutations in the gene encoding laminin‐332. Here, we report a proband with JEB‐H who is a compound heterozygote for two novel mutations in LAMC2; a missense mutation (c.79G>A) and an insertion mutation (382insT) leading to a premature termination codon.     

DNA-based prenatal diagnosis of plectin-deficient epidermolysis bullosa simplex associated with pyloric atresia

Background Mutations in the plectin gene (PLEC) generally lead to epidermolysis bullosa simplex (EBS) associated with muscular dystrophy. It has been recently demonstrated that PLEC mutations can also cause a different clinical subtype, EBS associated with pyloric atresia (EBS‐PA), which shows early lethality. Prenatal diagnosis (PND) of EBS‐PA using mutation screening of PLEC has not been described. Objective This study aimed to perform DNA‐based PND for an EBS‐PA family. Materials and methods The EBS‐PA proband was compound‐heterozygous for a paternal c.1350G>A splice‐site mutation and a maternal p.Q305X nonsense mutation. Genomic DNA was obtained from amniocytes taken from an at‐risk fetus of the proband’s family. Direct sequencing and restriction enzyme digestion of polymerase chain reaction products from the genomic DNA were performed. Results Mutational analysis showed that the fetus harbored both pathogenic mutations, suggesting that the fetus was a compound‐heterozygote and therefore affected with EBS‐PA. The skin sample obtained by autopsy from the abortus confirmed the absence of plectin expression at the dermal–epidermal junction. Conclusions This is the first successful DNA‐based PND for an EBA‐PA family.     

Unique presentation of transient zinc deficiency from low maternal breast milk zinc levels

We report full‐term siblings with a unique clinical presentation of polycyclic papulosquamous plaques secondary to transient zinc deficiency due to low maternal breast milk zinc levels. We present this case to highlight this unique presentation of zinc deficiency in breastfed infants.     

Photodamaging effects of porphyrins and chitosan on primary human keratinocytes and carcinoma cell cultures

Background Photodynamic therapy (PDT) is a non‐surgical method for treating non‐melanoma skin cancer and precancerous lesions which involves the activation of a photosensitizer by visible light to produce activated oxygen species within target cells, resulting in the destruction of the latter. The present study evaluates the effect of PDT on primary normal and basal cell carcinoma cultures in vitro. Methods Primary human keratinocytes and carcinoma cell cultures were exposed to various concentrations of 5,10,15,20‐tetra‐(para‐methoxyphenyl) porphyrin (TMP) and its zinc compound (Zn‐TMP) for 24 hours, with or without chitosan, and then irradiated using a PDT lamp (630 nm, 6 J/cm²). The effects of PDT were assessed using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium inner salt (MTS) assay and an immunocytochemical method with Annexin V‐FITC for detecting apoptosis. Results Both tested substances, TMP and Zn‐TMP, had a phototoxic effect on primary human carcinoma cell cultures in concentrations of 1–100 μg/ml, which positively correlated with the concentration of the photosensitizer. There was no phototoxic effect on primary keratinocytes, probably because of the preferential accumulation of photosensitizing substances in tumoral cells. Administration of chitosan in association with photosensitizing substances increased cell viability compared with photosensitizers alone, exerting a cytoprotective effect. Conclusions The study demonstrates that the photodynamic activity of TMP and its metalloporphyrin derivative is limited to primary human carcinoma cells and suggests that these porphyrins could be efficiently used in PDT in vivo.     

Sexually transmitted infections in pregnant adolescents: prevalence and association with maternal and foetal morbidity

Background Pregnant adolescents have a high incidence of sexually transmitted infections and higher risk of adverse birth outcome. Objectives To assess the prevalence of sexually transmitted infections in pregnant adolescents and the associations between these infections and adverse birth outcome. Methods  A prospective study with a face‐to‐face interview to pregnant adolescents was followed by first‐void urine and cervical swabs collection for polymerase chain reaction testing for Chlamydia trachomatis and Neisseria gonorrhoeae. After child delivery, clinical files were also reviewed for serological and microbiological results for other infections and data concerning maternal–foetal morbidity. A 5% level of significance was used. Results The inclusion criteria were fulfilled by 204 pregnant adolescents, and the prevalence of C. trachomatis was 11.8% and of N. gonorrhoeae was 4.9%, with the majority being asymptomatic. No antibodies for syphilis or human immunodeficiency virus were found. Maternal morbidity occurred in 3.4%, prematurity was observed in 11.8% of the newborns and low birth weight in 9.8%. Statistically significant associations were observed between maternal morbidity and the presence of gonorrhoea, younger adolescents and severe prematurity and between infection with C. trachomatis and/or N. gonorrhoea and low birth weight. Conclusions Sexually transmitted infections are frequently asymptomatic and cause maternal–foetal morbidity. The opportunity that pregnancy offers for screening and counselling should not therefore be missed, especially in adolescents.