Assuntos
Epidermólise Bolhosa Simples , Queratina-14 , Humanos , Epidermólise Bolhosa Simples/genética , Epidermólise Bolhosa Simples/patologia , Epidermólise Bolhosa Simples/diagnóstico , Queratina-14/genética , Masculino , Pele/patologia , Feminino , Domínios Proteicos , Análise Mutacional de DNA , Mutação de Sentido IncorretoRESUMO
Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a "congenital" phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.
Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Pitiríase Rubra Pilar , Humanos , Pitiríase Rubra Pilar/genética , Ictiose Lamelar/genética , Eritrodermia Ictiosiforme Congênita/genética , Eritrodermia Ictiosiforme Congênita/patologia , Fenótipo , Mutação , Transportadores de Cassetes de Ligação de ATP/genéticaAssuntos
ATPases Transportadoras de Cálcio , Pênfigo Familiar Benigno , Humanos , Pênfigo Familiar Benigno/genética , Pênfigo Familiar Benigno/patologia , Pênfigo Familiar Benigno/diagnóstico , ATPases Transportadoras de Cálcio/genética , Feminino , Masculino , Estudos de Associação Genética , Pessoa de Meia-Idade , Adulto , MutaçãoAssuntos
Ictiose Lamelar , Ictiose , Neoplasias Cutâneas , Humanos , Ictiose/genética , Ictiose Lamelar/genética , TroncoRESUMO
Self-healing collodion baby (SHCB), also called "self-improving collodion baby", is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.
Assuntos
Ceramidas , Ictiose Lamelar , Lactente , Recém-Nascido , Humanos , Colódio , Ceramidas/metabolismo , Ictiose Lamelar/diagnóstico , Ictiose Lamelar/genética , Testes GenéticosRESUMO
BACKGROUND: Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. OBJECTIVES: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. METHODS: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. RESULTS: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. CONCLUSION: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.
Assuntos
Ictiose Lamelar , Ictiose , Síndrome de Sjogren-Larsson , Ceramidas/análise , Epiderme/patologia , Ácidos Graxos , Feminino , Humanos , Ictiose/genética , Ictiose/patologia , Ictiose Lamelar/patologia , Síndrome de Sjogren-Larsson/genética , Síndrome de Sjogren-Larsson/patologiaAssuntos
Ictiose Lamelar , Ictiose , Melanoma , Humanos , Ictiose/diagnóstico , Ictiose/genética , Ictiose/patologia , Queratina-10/genética , Melanoma/diagnóstico , Melanoma/genética , MutaçãoRESUMO
PURPOSE: Ascorbic acid is a strong antioxidant and has potent radioprotective effects on radiation injuries. Ascorbic acid 2-glucoside (AA2G) is a stabilized derivative of ascorbic acid and rapidly hydrolyzed into ascorbic acid and glucose. Since there is the possibility that AA2G treatment interferes with the antitumor activity of radiotherapy, we investigated the effect of AA2G treatment during radiotherapy on acute radiation enteritis and antitumor activity of radiotherapy in rats. MATERIALS AND METHODS: AY-27 rat bladder tumor cells were used to induce bladder tumors in rats. Two weeks after inoculation rats received fractionated pelvic radiotherapy in eight fractions for 4 weeks totaling 40 Gy. During radiotherapy, one group of rats received per os AA2G (ascorbic acid: 250 mg/kg/day) and its bolus engulfment (ascorbic acid: 250 mg/kg) 8 h before each X-irradiation fraction. Seven days after the last X-irradiation, we studied histology, DNA double strand break (DSB) damage (by 53BP1 foci staining), and the M1/M2 macrophage response by immunohistochemistry of paraffin-fixed bladder and intestinal tissues. RESULTS: AA2G treatment reduced the intestinal damage (shortening of villi) but did not reduce antitumor effectiveness of radiotherapy against bladder tumors. Like the controls, AA2G-treated rats showed no residual tumor lesions in the bladder after X-irradiation. Both AA2G-treated and control groups showed similar persistent DSB damage (53BP1 foci) both in bladders and ilea seven days after radiotherapy. Radiotherapy tended to reduce CD163+ M2 macrophages, which are considered as an anti-inflammatory subtype favoring tissue repair, in the bladders. X-irradiation also reduced the occurrence of M2 macrophages in the ilea. AA2G treatment significantly increased CD163+/CD68+ macrophage ratio in the ilea of rats after pelvic irradiation in comparison to the sham irradiated control rats. AA2G treatment increased, albeit not significantly, the CD163+/CD68+ macrophage ratio in the irradiated bladders relative to the control irradiated rats. On the other hand, bladders and ilea of the irradiated rats with and without AA2G treatment showed similar frequencies of CD68+ macrophages. CONCLUSIONS: AA2G treatment mitigated radiation-induced intestinal damage without reducing antitumor activity after fractionated pelvic radiotherapy against bladder tumors in rats. The beneficial effect of AA2G treatment seems to promote a restoration of the M2 answer as well as tissue remodeling and wound healing. Similar residual DNA damage in bladders and ilea seven days post-irradiation is consistent with tumor control in both groups.
Assuntos
Neoplasias da Bexiga Urinária , Animais , Antioxidantes , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Feminino , Glucosídeos , Humanos , Masculino , Ratos , Neoplasias da Bexiga Urinária/radioterapiaAssuntos
Ceratodermia Palmar e Plantar/genética , Serpinas/genética , Adolescente , Adulto , Idoso , Povo Asiático/genética , Criança , Pré-Escolar , Feminino , Efeito Fundador , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Adulto JovemRESUMO
Basal cell nevus syndrome (BCNS) is an autosomal dominant skin disorder characterized by multiple basal cell nevi. Patients with BCNS tend to develop basal cell carcinoma (BCC) and frequently show skeletal abnormalities. Most cases of BCNS are caused by mutations in patched 1 (PTCH1). PTCH1 encodes a transmembrane receptor protein for the secreted molecule sonic hedgehog, which plays a key role in the development of animals ranging from insects to mammals. We analyzed two Japanese BCNS patients from two independent families. Both of our patients had multiple jaw keratocysts. In one patient, these were the key to noticing his BCNS, as he had no skin tumors. The early detection of PTCH1 mutations would enable BCNS patients to be carefully followed up for the occurrence of BCC. The diagnosis of BCC at the early stage leads to prompt surgical treatments, resulting in a good prognosis. The present cases suggest that keratocysts of the jaw might be an important clue for diagnosing BCNS.
Assuntos
Síndrome do Nevo Basocelular , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/genética , Carcinoma Basocelular , Proteínas Hedgehog , Humanos , Masculino , Cistos Odontogênicos/diagnóstico , Cistos Odontogênicos/genética , Receptor Patched-1/genéticaAssuntos
Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Melanoma , Neoplasias Cutâneas , Idoso , Epidermólise Bolhosa Juncional/complicações , Epidermólise Bolhosa Juncional/diagnóstico , Epidermólise Bolhosa Juncional/genética , Humanos , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnósticoAssuntos
Queratina-1/genética , Ceratodermia Palmar e Plantar/genética , Adulto , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Sequenciamento do ExomaAssuntos
Hepatomegalia/diagnóstico , Esplenomegalia/diagnóstico , Doença de Still de Início Tardio/diagnóstico , Adulto , Antirreumáticos/uso terapêutico , Biópsia , Feminino , Hepatomegalia/tratamento farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Fígado/diagnóstico por imagem , Pele/patologia , Baço/diagnóstico por imagem , Esplenomegalia/tratamento farmacológico , Doença de Still de Início Tardio/tratamento farmacológico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
The development of an effective therapy for radiation-induced gastrointestinal damage is important, because it is currently a major complication of treatment and there are few effective therapies available. Although we have recently demonstrated that pretreatment with ascorbic acid attenuates lethal gastrointestinal damage in irradiated mice, more than half of mice eventually died, thus indicating that better approach was needed. We then investigated a more effective therapy for radiation-induced gastrointestinal damage. Mice receiving abdominal radiation at 13 Gy were orally administered ascorbic acid (250 mg/kg/day) for three days before radiation (pretreatment), one shot of engulfment (250 mg/kg) at 8 h before radiation, or were administered the agent for seven days after radiation (post-treatment). None of the control mice survived the abdominal radiation at 13 Gy due to severe gastrointestinal damage (without bone marrow damage). Neither pretreatment with ascorbic acid (20% survival), engulfment (20%), nor post-treatment (0%) was effective in irradiated mice. However, combination therapy using ascorbic acid, including pretreatment, engulfment and post-treatment, rescued all of the mice from lethal abdominal radiation, and was accompanied by remarkable improvements in the gastrointestinal damage (100% survival). Omitting post-treatment from the combination therapy with ascorbic acid markedly reduced the mouse survival (20% survival), suggesting the importance of post-treatment with ascorbic acid. Combination therapy with ascorbic acid may be a potent therapeutic tool for radiation-induced gastrointestinal damage.