Analysis of similarities and differences between transient symptomatic zinc deficiency and acrodermatitis enteropathica in children: a case report of a Chinese Yi-ethnic infant.

BACKGROUND: Transient symptomatic zinc deficiency (TSZD), an acquired type of zinc deficiency, is a rare, but probably underrecognized disease, extremely in breastfed premature with low birthweight infants. Its clinical manefestations are similar to Acrodermatitis enteropathica (AE), which is a genetic zinc absorption disorder caused by SLC39A4 gene mutations. This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. TSZD is often misdiagnosed as AE because of their extremely similar manefestations, characterized by a typical rash. Therefore, the differention between them is still a clinical challenging. CASE PRESENTATION: Here, we present a case of TSZD in a 4 month and 23 days female Chinese Yi-ethnic premature with AE-like skin lesions, mainly presenting periorificial, perianal and perineal crusted, eroded, erythemato-squamous eruption. Laboratory examination showed the patient's blood zinc level was significantly decreased. Further sequencing of the SLC39A4 gene showed no mutation in the infant and her parents. Skin lesions significantly improved after 6 days of initial zinc supplementation (3 mg/kg/d), and maintenance treatment with 1 mg/kg/day of zinc was discontinued after 8 months without recurrence. CONCLUSIONS: The clinical manifestations of TSZD and AE are extremely similar, leading to a high rate of clinical misdiagnosis. While genetic analysis of the SLC39A4 gene is a reliable method for differentiating TSZD from AE. It is recommended that SLC39A4 gene test should be performed as far as possible in children with AE-like rash.

Genetic analysis of different subtypes of aseptic pustulosis in the Chinese population.

Aseptic pustulosis involves inflammatory skin conditions with nonbacterial pustules on erythema, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the interleukin (IL)-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN, CARD14, AP1S3, MPO, SERPINA3 and BTN3A3 have been identified in generalized pustular psoriasis (GPP) in the past. Some patients with acrodermatitis continua of Hallopeau (ACH), palmoplantar pustulosis and acute generalized exanthematous pustulosis (AGEP) also exhibit mutations in IL36RN, CARD14 and AP1S3, albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among those with aseptic pustulosis. We performed Sanger sequencing on six genes in 126 patients with aseptic pustulosis. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP and subcorneal pustular dermatosis (SPD). Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP and SPD, emphasizing the IL-1/IL-36-chemokine-neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions for aseptic pustulosis.

Acrodermatitis continua of Hallopeau and generalised pustular psoriasis: Should they be the same or different entities?

Pustular psoriasis is characterised by eruptions of neutrophilic sterile pustules. The European Rare and Severe Psoriasis Expert Network consensus defines pustular psoriasis into three subtypes; generalised pustular psoriasis (GPP), palmoplantar pustulosis and acrodermatitis continua of Hallopeau (ACH). Mixed forms are categorised according to their predominant features. However, the Japanese Dermatological Association includes ACH under the diagnosis of GPP. This article aims to review the similarities and differences between ACH and GPP. Based on our review, interleukin (IL)-36RN mutations, the most frequent genetic findings in pustular psoriasis are found most commonly in GPP, followed by ACH. Genotypes of IL-36RN mutations among GPP patients and ACH patients are different between European and Asian ethnicities. IL-36 signalling pathway is the main mechanism. Metabolic diseases are common comorbidities and joint involvement can occur in 20.5%-36.4% of both conditions. Associated plaque psoriasis is more common in GPP than in ACH. Generally, ACH, even the generalised type, does not have systemic inflammation whereas GPP can occur with or without systemic inflammation. ACH can occur before, simultaneously, or after the development of GPP. However, response to treatment for GPP and ACH even in the same patients appear to be different. ACH seemed to be more recalcitrant to treatment than GPP but severe flare of GPP can lead to morbidity and mortality. Although GPP and ACH share genotypes and pathogenesis, we believe that ACH should be classified separately from GPP, and not under diagnosis of GPP. Future research is warranted to satisfactorily distinguish the two conditions.

Enterokinase deficiency with novel TMPRSS15 gene mutation masquerading as acrodermatitis enteropathica.

Enterokinase deficiency (EKD) is a rare autosomal recessive inherited disorder caused by loss-of-function mutations of the transmembrane protease serine 15 (TMPRSS15) gene. To date, only 12 cases of EKD have been described in the literature and skin involvement has seldom been described. We identified a novel homozygous nonsense mutation in the TMPRSS15 gene (c.1216C>T, p.R406*) in a female infant, who manifested with acrodermatitis enteropathica (AE)-like lesions that were dramatically relieved within 11 days after initiation of a protein-rich hydrolyzed formula. Our case shows that AE-like rashes can be a manifestation of EKD and expands the spectrum of causative mutations in the TMPRSS15 gene.

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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.

Secondary acrodermatitis enteropathica-like skin findings in a case of methylmalonic acidemia.

Methylmalonic acidemia (MMA) is an autosomal recessive genetic disorder caused by decreased activity of methylmalonyl-CoA mutase or metabolic disturbance of its coenzyme cobalamin, cutaneous manifestations are rare clinical signs in this disease. Herein, we describe a Chinese boy with MMA fed with a formula lacking branched-chain amino acids presenting with erythroderma and acrodermatitis enteropathica-like rash, a homozygous nonsense mutation c.742C>T (p.Gln248*) was identified in the MMAA gene. The pedigree exhibited a non-Mendelian inheritance pattern which was attributed to maternal uniparental disomy on chromosome 4q26-q34.1 of the proband, confirmed by chromosomal microarray analysis. Our case highlights the association between skin changes and nutritional deficiency due to therapeutic amino acid restrictions in MMA.

A Missense Variant in SLC39A4 in a Litter of Turkish Van Cats with Acrodermatitis Enteropathica.

In a litter of Turkish Van cats, three out of six kittens developed severe signs of skin disease, diarrhea, and systemic signs of stunted growth at 6 weeks of age. Massive secondary infections of the skin lesions evolved. Histopathological examinations showed a mild to moderate hyperplastic epidermis, covered by a thick layer of laminar to compact, mostly parakeratotic keratin. The dermis was infiltrated with moderate amounts of lymphocytes and plasma cells. Due to the severity of the clinical signs, one affected kitten died and the other two had to be euthanized. We sequenced the genome of one affected kitten and compared the data to 54 control genomes. A search for private variants in the two candidate genes for the observed phenotype, MKLN1 and SLC39A4, revealed a single protein-changing variant, SLC39A4:c.1057G>C or p.Gly353Arg. The solute carrier family 39 member 4 gene (SLC39A4) encodes an intestinal zinc transporter required for the uptake of dietary zinc. The variant is predicted to change a highly conserved glycine residue within the first transmembrane domain, which most likely leads to a loss of function. The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 173 unrelated control cats. Together with the knowledge on the effects of SLC39A4 variants in other species, these data suggest SLC39A4:c.1057G>C as candidate causative genetic variant for the phenotype in the investigated kittens. In line with the human phenotype, we propose to designate this disease acrodermatitis enteropathica (AE).

Zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking.

ZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, acrodermatitis enteropathica (AE). These mutations occur not only in the conserved transmembrane zinc transport machinery, but also in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. How these AE-causing ECD mutations lead to ZIP4 malfunction has not be fully clarified. In this work, we characterized all seven confirmed AE-causing missense mutations in hZIP4-ECD and found that the variants exhibited completely abolished zinc transport activity in a cell-based transport assay. Although the variants were able to be expressed in HEK293T cells, they failed to traffic to the cell surface and were largely retained in the ER with immature glycosylation. When the corresponding mutations were introduced in the ECD of ZIP4 from Pteropus Alecto, a close homolog of hZIP4, the variants exhibited structural defects or reduced thermal stability, which likely accounts for intracellular mistrafficking of the AE-associated variants and as such a total loss of zinc uptake activity. This work provides a molecular pathogenic mechanism for AE.

Analysis of the relationship between the mutation site of the SLC39A4 gene and acrodermatitis enteropathica by reporting a rare Chinese twin: a case report and review of the literature.

BACKGROUND: Acrodermatitis enteropathica (AE) is a rare autosomal recessive hereditary skin disease caused by mutations in the SLC39A4 gene and is characterized by periorificial dermatitis, alopecia and diarrhoea due to insufficient zinc absorption. Only one of the three known sets of twins with AE has genetic information. This case reports the discovery of new mutation sites in rare twin patients and draws some interesting conclusions by analysing the relationship between genetic information and clinical manifestations. CASE PRESENTATION: Here, we report a pair of 16-month-old twin boys with AE exhibiting periorificial and acral erythema, scales and blisters, while subsequent laboratory examination showed normal plasma zinc and alkaline phosphatase levels. Further Sanger sequencing demonstrated that the patients were compound heterozygous for two unreported SLC39A4 mutations: a missense mutation in exon 5 (c.926G > T), which led to a substitution of the 309th amino acid residue cysteine with phenylalanine, a splice site mutation occurring in the consensus donor site of intron 5 (c.976 + 2 T > A). A family study revealed that the boys' parents were heterozygous carriers of these two mutations. CONCLUSION: We identified a new compound heterozygous mutation in Chinese twins with AE, which consisted of two previous unreported variants in exon 5 and intron 5 of SLC39A4. We propose an up-to-date review that different mutations in SLC39A4 may exhibit different AE manifestations. In conjunction with future research, our work may shed light on genotype-phenotype correlations in AE patients and provide knowledge for genetic counselling and treatment for AE patients.

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.

The histidine-rich loop in the extracellular domain of ZIP4 binds zinc and plays a role in zinc transport.

The Zrt-/Irt-like protein (ZIP) family mediates zinc influx from extracellular space or intracellular vesicles/organelles, playing a central role in systemic and cellular zinc homeostasis. Out of the 14 family members encoded in human genome, ZIP4 is exclusively responsible for zinc uptake from dietary food and dysfunctional mutations of ZIP4 cause a life-threatening genetic disorder, Acrodermatitis Enteropathica (AE). About half of the missense AE-causing mutations occur within the large N-terminal extracellular domain (ECD), and our previous study has shown that ZIP4-ECD is crucial for optimal zinc uptake but the underlying mechanism has not been clarified. In this work, we examined zinc binding to the isolated ZIP4-ECD from Pteropus Alecto (black fruit bat) and located zinc-binding sites with a low micromolar affinity within a histidine-rich loop ubiquitously present in ZIP4 proteins. Zinc binding to this protease-susceptible loop induces a small and highly localized structural perturbation. Mutagenesis and functional study on human ZIP4 by using an improved cell-based zinc uptake assay indicated that the histidine residues within this loop are not involved in preselection of metal substrate but play a role in promoting zinc transport. The possible function of the histidine-rich loop as a metal chaperone facilitating zinc binding to the transport site and/or a zinc sensor allosterically regulating the transport machinery was discussed. This work helps to establish the structure/function relationship of ZIP4 and also sheds light on other metal transporters and metalloproteins with clustered histidine residues.

MKLN1 splicing defect in dogs with lethal acrodermatitis.

Lethal acrodermatitis (LAD) is a genodermatosis with monogenic autosomal recessive inheritance in Bull Terriers and Miniature Bull Terriers. The LAD phenotype is characterized by poor growth, immune deficiency, and skin lesions, especially at the paws. Utilizing a combination of genome wide association study and haplotype analysis, we mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14. Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame. MKLN1 encodes the widely expressed intracellular protein muskelin 1, for which diverse functions in cell adhesion, morphology, spreading, and intracellular transport processes are discussed. While the pathogenesis of LAD remains unclear, our data facilitate genetic testing of Bull Terriers and Miniature Bull Terriers to prevent the unintentional production of LAD affected dogs. This study may provide a starting point to further clarify the elusive physiological role of muskelin 1 in vivo.

Pustular psoriasis and related pustular skin diseases.

Patients with pustular psoriasis or related pustular diseases may have genetic abnormalities impairing the function of key players of the innate skin immune system. Recently, identification of these abnormalities has changed the paradigm of several of these diseases. These include generalized pustular psoriasis, palmoplantar pustular psoriasis and acrodermatitis continua of Hallopeau, and also drug-induced acute exanthematous generalized pustular eruption. Identified mutations in IL36RN, CARD14 and AP1S3 in different groups of patients lead to enhanced inflammatory cascade in several cellular subtypes including keratinocytes, and to the recruitment and activation of neutrophils and macrophages. These insights have unveiled pathophysiological features that shift the existing paradigms and emphasize the autoinflammatory nature of skin pustular disorders. They also highlight the crucial role of the innate immune system across entities belonging to the psoriasis disease spectrum, allowing identification of new appealing therapeutic targets.