[Recurrent systemic sporadic rash for 10 years in a girl aged 11 years]. / 11å²å¥³å­©åå¤å ¨èº«æ•£åœ¨çš®ç–¹10å¹´.

A girl, aged 11 years, was admitted due to recurrent rash on the whole body and mucosa for 10 years, and typical rash was erythema at the perioral region, hand-foot joints, vulva, and perianal region, with blisters, erosions, and ulcers on the erythema. The girl was improved after zinc supplementation. Her younger brother had similar rash and medical history. The histopathological examination showed epidermal parakeratosis with mild hyperkeratosis, severe spongiform edema of the stratum corneum, significant proliferation of acanthocytes, and vacuolation of keratinocytes. The genetic testing revealed that both the girl and her younger brother had a homozygous mutation of c.1456(exon9)delG in the SLC39A4 gene, and thus the girl was diagnosed with acrodermatitis enteropathica. It is concluded that for children with recurrent rash on the limbs and at the perioral region, genetic testing should be performed as early as possible to make a confirmed diagnosis, and a sufficient dose of zinc supplementation should be given, while the levels of trace elements such as blood zinc should be regularly monitored.

Genomics-based treatment in a patient with two overlapping heritable skin disorders: Epidermolysis bullosa and acrodermatitis enteropathica.

Next-generation sequencing (NGS) is helpful in diagnosing complex genetic disorders and phenotypes, particularly when more than one overlapping condition is present. From a large cohort of 362 families with clinical manifestations of skin and mucosal fragility, referred by several major medical centers, one patient was found by NGS to have two overlapping heritable skin diseases, recessive dystrophic epidermolysis bullosa (RDEB; COL7A1 mutations) and acrodermatitis enteropathica (AE; SLC39A4 mutations). The pathogenicity of the variants was studied at gene expression as well as ultrastructural and tissue levels. Although there is no specific treatment for RDEB except avoiding trauma, supplementation with oral zinc (3 mg·kg-1 ·day-1 ) for the AE resulted in rapid amelioration of the skin findings. This case demonstrates the power of NGS in identifying two genetically unlinked diseases that led to effective treatment with major clinical benefits as an example of genomics-guided treatment.

Overview of Inherited Zinc Deficiency in Infants and Children.

Zinc nutrition is of special practical importance in infants and children. Poor zinc absorption causes zinc deficiency, which leads to a broad range of consequences such as alopecia, diarrhea, skin lesions, taste disorders, loss of appetite, impaired immune function and neuropsychiatric changes and growth retardation, thus potentially threatening life in infants and children. In addition to dietary zinc deficiency, inherited zinc deficiency, which rarely occurs, is found during the infant stage and early childhood. Recent molecular genetic studies have identified responsible genes for two inherited zinc deficiency disorders, acrodermatitis enteropathica (AE) and transient neonatal zinc deficiency (TNZD), clarifying the pathological mechanisms. Both of these zinc deficiencies are caused by mutations of zinc transporters, although the mechanisms are completely different. AE is an autosomal recessive disorder caused by mutations of the ZIP4 gene, consequently resulting in defective absorption of zinc in the small intestine. In contrast, TNZD is a disorder caused by mutations of the ZnT2 gene, which results in low zinc breast milk in the mother, consequently causing zinc deficiency in the breast-fed infant. In both cases, zinc deficiency symptoms are ameliorated by a daily oral zinc supplementation for the patients. Zinc is definitely one of the key factors for the healthy growth of infants and children, and thus zinc nutrition should receive much attention.

SLC39A4 mutation in zinc deficiency patients.

OBJECTIVE: To analyze the clinical presentation and SLC39A4 mutations in zinc deficiency patients. MATERIAL AND METHOD: The authors conducted a cross-sectional study on all cases of zinc deficiency treated at Queen Sirikit National Institute of Child Health between January 2004 and December 2012. Demographic data, clinical manifestations, laboratory results, treatment and outcome were analyzed. Genetic, SLC39A4 for acrodermatitis enteropathic (AE), mutation analysis was performed in all cases. RESULTS: There were 15 cases, 10 males and 5 females. The age of onset was between 2 and 10 months (median 3 months). Duration of the disease ranged between 3 days and 17 months (median 2 months). Acral and periorificial dermatitis, diarrhea and alopecia were present in 15 cases (100%), 12 cases (80%) and 8 cases (53%) respectively. The characteristic triad of acral and periorificial dermatitis, diarrhea and alopecia was observed in only 6 patients (40%). Serum zinc level ranged between 10 and 111 mcg/dl (mean 49.69 ± 33.87 mcg/100 ml). Low serum zinc level was observed in 10 cases (67%). All of the patients were treated with zinc sulfate 5 mg/kg/day. All cutaneous lesions and diarrhea had resolved within 7 days of starting therapy. A genetic study of SLC39A4 gene in our 15 patients revealed that 3 patients had homozygous c.1878_1879ins21 (p.G627_T633dup) in exonl2. These three patients have to receive lifelong zinc supplementation to prevent recurrence of the disease. The other twelve patients, who did not carry the gene mutation, did not have symptoms after discontinuance of oral zinc therapy. This is the first report of genetically confirmed acrodermatitis enteropathic in Thailand. CONCLUSION: Acrodermatitis enteropathica is a rare disease, which needs lifelong zinc supplementation. A genetic study of SLC39A4 gene will confirm the diagnosis. Most of patients presenting with characteristic triad of acral and periorificial dermatitis, diarrhea and alopecia in Thailand were acquired zinc deficiency. Early recognition and treatment of the disease will decrease morbidity and mortality.

Clioquinol synergistically augments rescue by zinc supplementation in a mouse model of acrodermatitis enteropathica.

BACKGROUND: Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. METHODS/PRINCIPAL FINDINGS: Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 (intest KO) phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. CONCLUSIONS: These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

Update on zinc deficiency and excess in clinical pediatric practice.

The critical importance of adequate zinc status to human health, including normal growth and development, is indisputable. The high prevalence of zinc deficiency on a global basis and its importance to public health have been well documented through large-scale randomized controlled zinc supplementation trials. Similar evidence in the clinical setting, however, is much less widely available due to the nonspecific features of zinc deficiency and to the lack of sensitive biomarkers to detect zinc deficiency, especially that of a mild degree of severity. The current understanding of zinc homeostasis indicates that the primary determinants of zinc absorption are the amount of zinc ingested and dietary phytate, the latter having a major effect on zinc bioavailability. In normal as well as in many pathologic conditions, the gastrointestinal tract is the major site of zinc losses resulting from secretion of endogenous zinc into the lumen and subsequent excretion in the feces. The amount excreted is dependent on host status, the amount reabsorbed, and sometimes the presence of pathophysiologic conditions, including diarrhea and steatorrhea. Assessment in the clinical setting dictates that the clinician obtain a careful medical and diet history, recognize clinical presentations in which zinc adequacy may be compromised, and link this risk with nonspecific but plausible manifestations of deficiency. Examples discussed in this article include primary zinc deficiency due to dietary inadequacy (older breastfed infants or toddlers without zinc-rich complementary foods); genetically based deficiency (acrodermatitis enteropathica, acquired zinc deficiency of lactogenic origin), and acquired secondary deficiency in low birth weight and prematurity, gastrointestinal and hepatic disease, and cystic fibrosis. Evidence for efficacy of zinc therapy with pharmacologic doses for two conditions, Wilson's disease and viral upper respiratory infections, is also discussed.

Novel SLC39A4 mutation in acrodermatitis enteropathica.

Acrodermatitis enteropathica (AE) is a rare autosomal-recessive disorder characterized by dermatitis, alopecia, diarrhea, and retardation of growth and development. AE maps to 8q24.3 and is associated with mutations in the intestinal zinc transporter ZIP4 encoded by the gene SLC39A4. We describe a novel homozygous mutation, 1191insC, in SLC39A4 in a patient from Sierra Leone and suggest that AE should be considered within the differential diagnosis for acrodermatitis in children from Sierra Leone. Genetic testing for this founder mutation can be easily performed for this treatable disorder.

Acrodermatitis enteropathica: a novel SLC39A4 gene mutation found in a patient with an early-onset.

We report the case of a 3-month-old full-term, breast-fed infant with clinical and laboratorial findings consistent with acrodermatitis enteropathica. In addition, the mother had low zinc levels in her breast milk. Mutation analysis revealed a novel insertion in the SLC39A4 gene.

Acrodermatitis enteropathica: a review of 29 Tunisian cases.

INTRODUCTION: Acrodermatitis enteropathica is a rare autosomal recessive disease due to an abnormality in a zinc transporting molecule. METHODS: We conducted a retrospective monocentric study on 29 Tunisian cases of Acrodermatitis enteropathica (AE) treated in our Department of Dermatology in Tunisia, between January 1981 and June 2008. RESULTS: The age of onset of disorders was between 15 d and 12 months (mean 6.86 ± 3.25 months). The delay of consultation ranged between 15 d and 8 months (mean of 2.8 ± 2.17 months) after onset. Onset of gastrointestinal and psychiatric signs depended significantly on consulting times. Plasma zinc levels ranged between 14 and 88 lg/100 ml (mean 44.86 ± 18.4 lg/100 ml). There was not a significant relation between zincemia and clinical features. Genetic analyses in 13 of our patients showed three different mutations in the SLC39A4 gene: c.1223_1227del (p.Trp411ArgfsX7) in exon 7,c.143T>G (p.Leu48X) in exon 1 and c.1784T>C (p.Gly595Val) in exon 11. No significant genotype-phenotype correlations could be established. CONCLUSION: Acrodermatitis enteropathica is a rare disease which diagnosis is easy. Its biological confirmation is made on a simple dosage of zincemia. However, the diagnosis is not always suggested, and is unfortunately made late. At present, there is a molecular test to detect SLC39A4 mutations.

Acrodermatitis enteropathica: case report and review of the literature.

Acrodermatitis enteropathica (AE) is a rare hereditary disorder caused by impaired absorption of zinc from the gastrointestinal tract. It is characterized by acral and periorificial dermatitis, alopecia, and diarrhea. Symptoms usually begin on weaning from breast or formula feeding. We report a full-term, 21-month-old boy with typical skin lesions and decreased plasma zinc level (12 micro g/dl). The patient was given zinc sulfate 40 mg/day and at the end of 1 month his condition had improved significantly. After reviewing the literature we emphasize the important role of zinc in human metabolism and the difference between AE and acquired zinc deficiencies.

A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane.

Zinc is essential to a wide range of cellular processes; therefore, it is important to elucidate the molecular mechanisms of zinc homeostasis. To date, no zinc transporters expressed at the enterocyte apical membrane, and so essential to mammalian zinc homeostasis, have been discovered. We identified hZTL1 as a human expressed sequence tag with homology to the basolateral enterocyte zinc transporter ZnT1 and deduced the full-length cDNA sequence by PCR. The protein of 523 amino acids belongs to the cation diffusion facilitator family of membrane transporters. Unusually, the predicted topology comprises 12 rather than 6 transmembrane domains. ZTL1 mRNA was detected by reverse transcription-PCR in a range of mouse tissues. A Myc-tagged hZTL1 clone was expressed in transiently transfected polarized human intestinal Caco-2 cells at the apical membrane. Expression of hZTL1 mRNA in Caco-2 cells increased with zinc supplementation of the nutrient medium; however, in the placental cell line JAR hZTL1 appeared not to be regulated by zinc. Heterologous expression of hZTL1 in Xenopus laevis oocytes increased zinc uptake across the plasma membrane. The localization, regulatory properties, and function of hZTL1 indicate a role in regulating the absorption of dietary zinc across the apical enterocyte membrane.

Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3.

Acrodermatitis enteropathica (AE) is a rare autosomal recessive pediatric disease characterized by dermatitis, diarrhea, alopecia, and growth failure. The disease results from insufficient uptake of zinc by the intestine and can be fatal unless the diet is supplemented with zinc. To map the gene responsible for AE, a genomewide screen was performed on 17 individuals, including 4 affected individuals, in a consanguineous Jordanian family. Three markers-D8S373, D10S212, and D6S1021-had a pattern consistent with tight linkage to a recessive disease: one allele in the affected sibs and multiple alleles in unaffected sibs and parents. Two-point parametric linkage analysis using FASTLINK identified one region, D8S373, with a maximum LOD score >1.5 (1.94 at D8S373: recombination fraction.001). Twelve additional markers flanking D8S373 were used to genotype the extended family, to fine-map the AE gene. All five affected individuals-including one who was not genotyped in the genomewide screen-were found to be homozygous for a common haplotype, spanning approximately 3.5 cM, defined by markers D8S1713 and D8S2334 on chromosomal region 8q24.3. To support these mapping data, seven consanguineous Egyptian families with eight patients with AE were genotyped using these markers, and six patients from five families were found to be homozygous in this region. Multipoint analysis with all consanguineous families, by Mapmaker/Homoz, resulted in a maximum LOD score of 3.89 between D8S1713 and D8S373. Sliding three-point analysis resulted in a maximum LOD score of 5.16 between markers D8S1727 and D8S1744.

Differences in the cellular zinc content and 5'-nucleotidase activity of normal and acrodermatitis enteropathica (AE) fibroblasts.

The acrodermatitis enteropathica (AE) mutation affects zinc (Zn) metabolism in human fibroblasts. We hypothesize that the mutation affects the cell Zn content, which subsequently affects the activity of various zinc-dependent enzymes, such as 5'-nucleotidase. Therefore, normal and AE fibroblasts were grown in normal medium containing physiological levels of Zn (16 micromol/L) for approximately 24 h. The medium was replaced by normal medium (16 micromol/L Zn), Zn-depleted medium (1.5 micromol/L Zn), or Zn-supplemented medium (200 micromol/L Zn) for another 24 h. Regardless of the Zn concentration of the growth medium, the AE fibroblasts contained significantly less Zn than normal fibroblasts grown in comparable medium. Nevertheless, growth of the fibroblasts in 200 micromol/L Zn medium significantly increased the cell Zn content fourfold of both normal and AE fibroblasts. The activity of 5'-nucleotidase in the AE fibroblasts grown in 16 micromol/L Zn or 1.5 micromol/L Zn medium was also significantly lower than in normal fibroblasts. Changing the growth medium from 16 micromol/L Zn to 1.5 micromol/L Zn medium did not affect the activity of the enzyme in either genotype. Cells grown in 200 micromol/L Zn medium exhibited threefold greater 5'-nucleotidase activity in AE fibroblasts, but had no affect on enzyme activity in normal cells. In summary, altering the cell Zn content of normal fibroblasts did not result in a significant change in their 5'-nucleotidase activity. However, AE fibroblasts grown in 200 micromol/L Zn medium exhibited recovery of their 5'-nucleotidase activity to normal levels. These results support the hypothesis that the AE mutation affects the cellular Zn content. The lower cell Zn content subsequently affects the activity of 5'-nucleotidase.

Acrodermatitis enteropathica in Saudi Arabia.

Four patients with acrodermatitis enteropathica (AE) are presented from three Saudi families. The clinical picture in these patients is basically similar to that described elsewhere. These patients, however, showed different degrees of involvement of various body systems. In all cases, low serum zinc levels were documented, and they responded well to zinc supplementation. In the follow-up evaluation, angular cheilitis was observed as a feature that appears to herald the relapse of disease. Interestingly, when patients are treated, it was the last sign to disappear. Current information on zinc is summarized.

Self-limiting acrodermatitis enteropathica. A follow-up study of three interrelated families.

A variant of acrodermatitis enteropathica is described that has its onset before weaning and clears when the child starts its normal solid diet. A pedigree with three interrelated families is reported where 10 children were afflicted with this variant. They had symptoms of hypozincemia for a brief period during infancy. At the time of this study, they were symptom-free and their serum zinc levels were found to be within normal limits. The term "self-limiting acrodermatitis enteropathica" is proposed for the variant. In one lactating mother, the mammary zinc secretion was determined and was found to be deficient and unresponsive to oral zinc supplements. The possible mode of inheritance is also discussed.

Interrelationships between zinc and immune function.

Zinc deficiency is a common nutritional problem observed both in human and in animal populations that has profound effects on host defense mechanisms. Using the young adult mouse as a model, it has been demonstrated that a moderate period of suboptimal zinc causes thymic atrophy, lymphopenia, and alterations in the proportions of the various subsets of lymphocytes and mononuclear phagocytes. As a result, antibody-mediated responses to both T cell-dependent and T cell independent antigens are significantly reduced. Cytolytic T cell responses, natural killer (NK) cell activity, and delayed-type hypersensitivity (DTH) reactions are also depressed. Suboptimal zinc during in utero development of mice causes persistent states of immunodeficiency in the offspring that can even be transferred to subsequent generations. In regard to human immunological consequences of zinc deficiency, patients with the genetic disorder of zinc absorption, acrodermatitis enteropathica, also exhibit atrophic thymuses, lymphopenia, anergic DTH responses, and reduced NK cell activity. Patients suffering from sickle cell anemia or uremia with associated deficiencies in zinc exhibit similar immune deficiencies. An additional outcome of these studies has been shown to be an essential cofactor for thymulin, one of the thymic hormones. Furthermore, addition of zinc salts to culture can polyclonally activate lymphocytes as well as augment responses to mitogens in adjuvant-like manner.

Acquired zinc deficiency in two breast-fed mature infants.

Zinc deficiency was diagnosed in a breast-fed mature infant and her sister. In both infants the characteristic dermatitis appeared on the face and buttocks around 10 weeks of age. It responded rapidly to zinc supplements. Their mother's serum zinc level was slightly low but her milk was found to be remarkably low in zinc. Oral zinc supplementation could correct only her serum zinc level but not her low breast milk zinc level. Therefore the mother's deficiency in the transfer process of zinc from serum to breast milk was suspected as a cause of the skin changes in her children. These cases indicate that even mature infants, who feed exclusively on mother's milk, run a risk to develop zinc deficiency, if the concentration of zinc in the breast milk is very low.

Serum and hair zinc as predictors of clinical symptoms in acrodermatitis enteropathica.

Hair- and serum-zinc concentrations were measured in six patients with acrodermatitis enteropathica before and sequentially after cessation of zinc supplementation; supplementation was restarted when symptoms appeared. Serum zinc correlated accurately with zinc dosage and was lowest when symptoms of deficiency appeared. Hair zinc was initially age- and body size-related and was minimally influenced by the supplementation break. Adult patients had continuously normal concentrations. In paediatric patients hair zinc was low. Their serum concentrations should probably be maintained slightly above or at the upper limit of reference values for prolonged periods for normalization of hair and perhaps tissue zinc contents.