Genetic analysis of the ferrochelatase gene in eight Japanese patients from seven families with erythropoietic protoporphyria

A decrease in the activity of ferrochelatase (FECH; EC 4.99.1.1), the terminal enzyme of the heme biosynthetic pathway, results in erythropoietic protoporphyria (EPP; MIM 177000). We analyzed the FECHgene in eight Japanese EPP patients from seven non-consanguineous families and found two distinct genomic DNA abnormalities. In six patients from five families, there was a G-to-A point-mutation at the first position of the intron 9 donor site; it resulted in aberrant splicing and skipping of exon 9 in FECH mRNA. In one patient, we found an A-to-G point-mutation 4 bases from the 3" terminus of intron 4 that led to the in-frame insertion of 3 bases in mRNA. No allelic anomalies, except for 3 single nucleotide polymorphisms were detected in another patient. We analyzed intron polymorphism at IVS3-48, known to be associated with the phenotypic expression of EPP, in these eight patients and 152 healthy Japanese volunteers. All patients were C/C homozygous for IVS3-48. The allelic frequency of IVS3-48C polymorphism in the healthy Japanese volunteers was 67.8% (103/152).     

Case of late‐onset erythropoietic protoporphyria with myelodysplastic syndrome who has homozygous IVS3‐48C polymorphism in the ferrochelatase gene

We report the case of a 42‐year‐old man with a 5‐year history of myelodysplastic syndrome and photosensitivity who had developed painful erythema and blisters on sun‐exposed sites. Histological examination of a mildly lichenified lesion on the dorsal finger revealed extensive deposits of a hyaline‐like, periodic acid‐Schiff‐positive material around superficial dermal blood vessels. Laboratory tests showed elevated erythrocyte protoporphyrin and normal urinary porphyrins, suggesting a diagnosis of erythropoietic protoporphyria. Late‐onset erythropoietic protoporphyria is rare and is usually associated with an acquired somatic mutation of the ferrochelatase gene secondary to a hematological malignancy such as myelodysplastic syndrome. DNA analysis revealed that our patient has the homozygous IVS3‐48C polymorphism that is a low‐expression variant of wild‐type ferrochelatase allele.     

X连锁显性遗传性原卟啉症一家系及ALAS2基因突变分析

目的 报道中国人X连锁显性遗传性原卟啉症一家系,并对其5?氨基酮戊酸合成酶2（ALAS2）基因突变进行研究。方法 收集该家系成员资料,进行临床调查。用二代测序方法检测后再行Sanger测序,测定该家系中患病者及部分表型正常者ALAS2致病基因。用皮肤镜观察皮肤卟啉皮损,根据Fotofinder系统和甚高频皮肤超声系统评估皮肤卟啉症的光损伤严重程度,对该家系成员做肝胆B超检查,同时检测血液学改变。结果 该家系中所有患者X染色体的1706号到1709号碱基发生AGTG缺失,导致转录时移码突变,最终导致翻译得到的ALAS2酶C端19、20个残基替换或缺失,ALAS2酶活性升高。XLDPP患者皮肤光损伤显著,肝胆可出现卟啉损伤,随年龄增加而加重,可出现贫血和铁过载。结论 X染色体1706?1709碱基AGTG缺失突变可能是该ALDPP家系患者的发病原因。     

Analysis of the STS gene in 40 patients with recessive X‐linked ichthyosis: a high frequency of partial deletions in a Spanish population

Background Recessive X‐linked ichthyosis (RXLI) (OMIM 308100) is a genodermatosis characterized by polygonal, dark, adherent and mild‐to‐moderate scales that normally improve during summer. RXLI is caused by a deficiency in steroid sulphatase (STS), whose gene has been located on the X chromosome (locus Xp22.3). Up to 90% of the mutations described in this gene are complete deletions. Objectives Previous reports of partial deletion of STS gene in cases of RXLI prompted us to determine the incidence of these abnormalities in a Spanish population. Methods We have studied exons 1, 5 and 10 of the STS gene by polymerase chain reaction in 40 patients with clinical features of RXLI. Results Our results revealed that 30 patients presented complete deletions (75%) while 10 patients had partial deletions (25%) a rate higher than that reported in the previous studies. Conclusions Amplification of exons 1, 5 and 10 is reliable in screening RXLI in the population studied here. No correlation was found between phenotype and the extent of the deletions.     

Cutaneous squamous cell carcinoma,thyroid cancer and Langerhans cell histiocytosis in a patient with X‐linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor‐κB essential modifier mutation

Nuclear factor (NF)‐κB essential modifier (NEMO), also known as IκB kinase subunit‐γ (IKKγ), is a pivotal molecule in the NF‐κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X‐linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X‐linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.     

In‐transit recurrence of Merkel cell carcinoma associated with Bowen's disease: The first reported case successfully treated by avelumab

A 65‐year‐old Japanese man presented with a dome‐shaped nodule, the base of which was contiguous with a dull brown plaque, on the left leg. After local excision of the cutaneous lesion and left inguinal lymph node dissection, several dermal and subcutaneous nodules developed successively on the left lower extremity. Hematoxylin–eosin staining of the primary cutaneous lesion demonstrated uniform neoplastic cells arranged in a trabecular pattern extending from the dermis to subcutis. Mitotic figures were abundant. Although the overlying epidermis was substantially intact, the Merkel cells had invaded the epidermis, resulting in Pautrier‐like microabscesses. The hyperplastic epidermis adjacent to the nodule consisted of abnormally growing atypical keratinocytes. The enlarged left inguinal lymph node and successive secondary nodules contained Merkel cells similar to those in the primary nodule. Immunohistochemically, most tumor cells were positive for CAM5.2, synaptophysin, chromogranin A, CD56 and vimentin. The tumor cells in the left inguinal lymph node were positive for CAM5.2, synaptophysin and cytokeratin 20 but negative for CM2B4, and less than 1% of the cells expressed programmed cell death ligand 1. The patient was treated with avelumab, which showed significant efficacy against the in‐transit recurrence. Two months later, all nodules had disappeared completely. We describe a case of in‐transit recurrence of Merkel cell carcinoma that was associated histologically with Bowen's disease and was successfully treated with avelumab. Although accumulation of additional cases is needed, avelumab therapy may be a useful treatment for in‐transit recurrence of Merkel cell carcinoma.     

The efficacy of fractional CO2 laser in acne scar treatment: A meta‐analysis

Fractional CO₂ laser is a good option for treating acne scars. However, the clinical efficacy of this treatment modality requires further evidence. To perform a meta‐analysis to assess clinical improvements in acne scars with fractional CO₂ laser and non‐CO₂ laser therapies. Databases (PubMed, Embase, Cochrane Library) were searched using the search strategy to identify eligible studies. All statistical analyses were performed using the Review Manager 5.0, and a meta‐analysis was conducted to assess the effects of fractional CO₂ laser used as a treatment for acne scars. Eight studies were included for further analysis. There was no significant difference between fractional CO₂ laser and non‐CO₂ laser therapies in terms of clinical improvement, observer assessment (P = .19), patient assessment (P = .91), and incidence of post‐inflammatory hyperpigmentation (P = .69). The subgroup analyses showed that the duration of follow‐up had little effect on the evaluation of treatment effect. The efficacy of fractional CO₂ laser therapy in acne scars appeared to be equal to that of non‐CO₂ laser therapies. More well designed randomized controlled trials and more credible and standard evaluation criteria are needed, and the efficiency of combination therapy requires further analysis.