弹性纤维性假黄瘤1例

报告1例颈部弹性纤维性假黄瘤,患者女,41岁,颈部多发性肤色或淡黄色扁平丘疹40余年,偶觉瘙痒。组织病理学检查示真皮网状层中部有多量波纹状,扭曲,断裂或不规则形状的深嗜碱性纤维成分,诊断为弹性纤维性假黄瘤。     

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a heritable disease characterized by dermal, ocular, and vascular lesions that result from degeneration of the elastic fibers. Recently, the ATP-binding cassette subfamily C member 6 (ABCC6) gene has been demonstrated to be responsible for PXE, and 43 mutations have been identified to date. However, it is still unknown now mutations in the ABCCC6 gene can lead to manifestations of PXE.     

Pseudoxanthoma elasticum and nephrolithiasis

We report the case of a 42-year-old man with pseudoxanthoma elasticum (PXE) and recurrent bilateral nephrolithiasis. Diagnosis of PXE was made by yellow papules on the neck and ophthalmologic angioid streaks. This diagnosis was confirmed by a skin biopsy (Von Kossa stain) and by genotyping analysis of ABCC6 (homozygous mutation R1138Q). Nephrolithiasis was recurrent and biological investigations showed hypophosphoraemia, hyperphosphaturia, hypercalciuria, normocalcaemia, normal serum parathyroid hormone value, high 1,25-dihydroxy vitamin D value and a renal calcium oxalate stone. ABCC6 encodes for MRP6, a multidrug resistant protein strongly expressed in the liver and kidney. The substrates of the MRP6 remain unknown. As PXE is characterized by calcification of elastic fibres and this patient presents important phosphocalcic anomalies, we discuss the possible implications of MRP6 in the phosphocalcic metabolism.     

Histological skin changes in heterozygote carriers of mutations in ABCC6, the gene causing pseudoxanthoma elasticum

BACKGROUND: Pseudoxanthoma elasticum (PXE) is related to mutations in the ABCC6 gene and characterized pathologically by dystrophic and mineralized elastic fibres. Heterozygote carriers of ABCC6 mutations may have a limited PXE phenotype. OBJECTIVE: To compare histological changes in the skin of genotyped siblings from two PXE pedigrees. METHODS: Mutation analysis of ABCC6 was performed. Skin biopsy samples were stained (orcein) and immunolabelled for elastin, and for vitronectin and bone sialoprotein, which are partially responsible for the mineralization within the elastorrhexic fibres. Results In all individuals mutation analysis of ABCC6 allowed definition of the genotype status, i.e. PXE (n = 2), heterozygote (n = 7) or wild type (n = 2). The study identified three histological phenotypes related to the ABCC6 genotype in siblings from both families. Heterozygote carriers had changes in dermal elastic fibre organization, morphology and labelling midway between those seen in PXE skin and normal skin. CONCLUSION: Even though the number of individuals studied here is small and precludes any hasty generalization, having a single mutation in the ABCC6 gene seems enough to modify dermal elastic fibres. The relevance of performing a skin biopsy to identify heterozygote carriers in the family of a PXE patient remains to be determined.     

Pseudoxanthoma elasticum: evaluation of diagnostic criteria based on molecular data

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disorder due to mutations in the gene encoding the transmembrane transporter protein adenosine triphosphate binding cassette (ABC)-C6, resulting in calcification of elastic fibres in the skin, eyes and cardiovascular system. OBJECTIVES: To evaluate the diagnostic criteria for PXE based on molecular data. METHODS: Of 10 families with a positive history of PXE 142 subjects were investigated for clinical symptoms, histological findings and genetic haplotype analysis. RESULTS: Of these, 25 subjects were haplotypic homozygous for PXE and 23 had typical clinical and histopathological manifestations. Two of the 25 patients showed such marked solar elastosis and macular degeneration that PXE could not be confirmed clinically. Sixty-seven subjects were haplotypic heterozygous carriers and 50 were haplotypic homozygous unaffected. Of these 117 subjects, 116 showed no cutaneous or ophthalmological signs of PXE. In one of the 50 haplotypic homozygous unaffected patients important solar elastosis and scarring of the retina mimicked PXE lesions. Only four of the 67 haplotypic heterozygous carriers had biopsies of nonlesional skin; all were histopathologically normal. CONCLUSIONS: In our patients, PXE presents as an autosomal recessive genodermatosis. Correlation of haplotype and phenotype confirmed actual major diagnostic criteria. In patients with marked solar elastosis and/or severe macular degeneration clinical diagnosis can be impossible and molecular testing is needed to confirm the presence of PXE. To the best of our knowledge our large study compares for the first time clinical findings with molecular data.     

Pseudoxanthoma elasticum: biopsy of clinically normal skin in the investigation of patients with angioid streaks

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by fragmentation and calcification of elastic fibres with resultant pathological changes in the dermis, Bruch's membrane and blood vessels. Defects in Bruch's membrane produce angioid streaks on the retina but this appearance is not pathognomonic of PXE. Biopsy of clinically normal skin or scar tissue in patients with angioid streaks may show the histological features of PXE. OBJECTIVES: To test the hypothesis that biopsy of clinically normal skin is a useful investigation in patients with angioid streaks. METHODS: This prospective study investigated 18 consecutive patients with angioid streaks. Each patient underwent a full dermatological examination and was investigated for diseases known to be associated with angioid streaks. Axillary skin biopsies were taken from 14 consenting patients. RESULTS: Typical PXE was found in 11 patients. No other diseases associated with angioid streaks were identified. Five patients had angioid streaks in the absence of systemic disease. Two patients had nondiagnostic dermatological features which were not clarified by histology. Two of the 11 patients with PXE showed histological evidence of PXE from clinically normal axillary skin. However, in both cases flexural skin elsewhere showed the typical clinical and histological features of PXE. CONCLUSIONS: This study demonstrates the association between angioid streaks and PXE. However, it does not support the hypothesis that biopsy of normal-looking skin is helpful in the investigation of adult patients with angioid streaks.     

Pseudoxanthoma elasticum (PXE)-like calcification in adult dermatomyositis

A case of pseudoxanthoma elasticum (PXE)-like calcification in adult dermatomyositis (DM) is described. The patient was a 38-year-old woman with a history of dermatomyositis for 3 months. Yellowish, hard, papulo-plaque lesions, which looked like those of pseudoxanthoma elasticum, were noted on her left axilla. Calcium deposition was confirmed by X-ray, histopathological, and electron microscopic examinations. Histopathological and histochemical examinations showed acicular calcium deposition in the middle and deep dermis surrounded by mucin. Electron microscopic examination revealed that the calcium deposition was not on collagen fibers. These morphological features were distinct from those of PXE. We proposed the possibility that degenerated mucin or degenerated elastic fiber might result in subsequent calcium deposition in reticular calcinosis in adult DM. The calcification clinically disappeared without any specific treatment except for prednisolone and cyclophosphamide.     

Pseudoxanthoma elasticum: report of two cases

Pseudoxanthoma elasticum is a rare inherited multisystem disorder that ischaracterized by a pathological mineralization of the elastic connective tissue,which involves predominantly the skin, eyes and cardiovascular system. Its cause lieson mutations in the ABCC6 gene, which lead to reduction or absence of thetransmembrane transport ADP dependent protein (MRP6), causing an accumulation ofextracellular material and subsequent deposition of calcium and other minerals in theelastic tissue. The authors report two cases of pseudoxanthoma elasticum, emphasizingits major clinical features and the importance of early diagnosis of the disorder,aiming for adequate therapeutic management of associated complications.     

弹性纤维假黄瘤一例

<正>临床资料患者,女,9岁。腹部、颈部、腋下淡黄色丘疹2年。患者2年前无明显诱因出现腹部淡黄色斑丘疹,无瘙痒、疼痛不适症状,未予治疗,后颈部、腋下出现类似皮疹,逐渐增多,遂于2018年4月来我科就诊。患者足月顺产,平素体健,否认心血管及胃肠道疾病病史,否认家族中有类似病史,心肺腹     

Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE ) is a hereditary disease, causing calcification and degeneration of elastic fibers, which affects the skin, eye, cardiovascular systems and gastrointestinal tract. PXE is caused by mutations in the ABCC 6 gene. Neither detailed nor large‐scale analyses have been accomplished in Japanese patients with PXE . We, therefore, investigated clinical symptoms and ABCC 6 gene mutations in 76 Japanese patients. Japanese PXE patients (n = 76) had a significantly lower incidence of vascular lesions than 505 PXE patients in the Leiden Open Variation Database (LOVD ) (38.7% vs 65.1%, respectively; P = 1.34E‐06); however, the incidences of the skin, eye, cardiac and gastrointestinal lesion symptoms were not significantly different. Symptom severity scores for skin, eye and vascular lesions, calculated using the Phenodex? system, were significantly lower in Japanese PXE patients than in LOVD PXE patients. Genetic analysis revealed three nonsense, four frame‐shift, one exon deletion and 13 missense mutations in ABCC 6 in 73 patients; however, we were unable to detect pathogenic mutations in three patients. Frequent mutations differed between Japanese and LOVD PXE patients. In Japanese PXE patients, the top five mutations accounted for more than 60% of all pathogenic changes, suggesting the presence of founder effects. Consistent with previous reports, no obvious correlations between genotypes and phenotypes were identified in this study. In conclusion, we consider that the milder clinical phenotypes, observed even in older Japanese PXE patients, could be attributed to environmental factors such as dietary habits and lifestyle, as well as genetic background.     

Elastosis perforans serpiginosa-like pseudoxanthoma elasticum in a child with severe Moya Moya disease

A 2-year-old girl with Moya Moya disease who had relapsing cerebrovascular strokes presented with loose skin folds, 'chicken' skin appearance and perforating elastosis serpiginosa-like lesions in the genitocrural region. Histologically, calcified material perforating the epidermis and adjacent short curled and mineralized elastic fibres suggested a variant of pseudoxanthoma elasticum (PXE). As PXE is known to be caused by various mutations in the transmembrane transporter ABCC6 gene, we hypothesized that a novel ABCC6 mutation may underlie this unique combination of PXE and elastopathic vascular damage. Therefore, the complete ABCC6 coding region of the patient and her parents was screened for genetic alterations. No bona fide disease-causing mutation of ABCC6 could be found in the child and in her parents. However, two novel allelic amino acid substitutions (Arg1273Lys and Glu1293Lys; exon 27) were found in the girl and her father, localized in close proximity to the region that codes for the functionally critical second nucleotide-binding fold of ABCC6. Although a causal involvement of these amino acid substitutions could not be proven based on this study, both heterozygote substitutions may possibly have interacted with other undetected recessive maternal ABCC6 changes in the child. To the best of our knowledge, this is the first report of an association between early-onset PXE and severe Moya Moya syndrome possibly related to ABCC6 changes.     

Classic pseudoxanthoma elasticum in a girl with sickle cell disease

A pseudoxanthoma elasticum (PXE)–like phenotype develops in a subset of patients with inherited hemoglobinopathies. Although PXE tissue changes are thought to develop in the absence of ABCC6 mutations in patients with beta‐thalassemia, ABCC6 mutations have not been well evaluated among sickle cell disease patients with PXE‐like disease. To our knowledge, we describe the first patient with sickle cell disease, PXE skin findings, and two confirmed pathogenic ABCC6 mutations. This case suggests that ABCC6 testing is warranted for sickle cell disease patients with the PXE‐like phenotype and that the pathogenesis of PXE manifestations in beta‐thalassemia and sickle cell disease may differ.     

Heterogeneity of clinical features of pseudoxanthoma elasticum: analysis of thirteen cases in Oita Prefecture from a population of 1,240,000

Thirteen cases among 16,260 patients seen at our department during the nine years from 1981 were diagnosed as pseudoxanthoma elasticum (PXE). The sex and age distributions were similar to those so far reported in the literature. There were two cases of the autosomal dominant type. One patient had skin lesions typical of PXE in association with Ehlers-Danlos syndrome. In two of three patients with cutis laxa-like lesions, eruptions of elastosis perforans serpiginosa were present. In three cases, we failed to detect deposition of calcium in typical skin lesions in either an early or a late stage by histochemical staining, in spite of the presence of slightly degenerated elastic fibers.     

Manifestations of pseudoxanthoma elasticum in childhood

Background  Pseudoxanthoma elasticum (PXE) affects the skin, retina and cardiovascular system. Most cases are related to mutations in the ABCC6 gene. The diagnosis is most often made late in the second or third decade of life.
Objectives  To describe the manifestations of PXE before the age of 15 years.
Methods  Children under age 15 years with definite PXE were evaluated at a PXE referral centre, as were adult patients in whom serious manifestations of PXE had occurred before the age of 15 years.
Results  Our series included 96 patients; 15 (16%) had paediatric onset of the disease. Nine children were diagnosed at a mean age of 10 years, a mean of 2·5 years after the presenting symptoms. Cutaneous lesions were the presenting symptoms in eight. None had cardiovascular or ophthalmological symptoms. Six adult patients had had severe cutaneous and/or cardiovascular manifestations before the age of 15 years. Both adult patients with early extensive skin lesions had the PXE-like condition related to the GGCX gene. No ocular symptoms were recorded during childhood.
Conclusions  Cutaneous manifestations of PXE are the same in children as in young adults. Absence of complications is common in childhood, but severe complications are unpredictable. The frequency of complications was retrospectively estimated to be 7% in the adults of our series, although this figure was probably an overestimate because of the recruitment bias in a referral centre. It is, however, important to consider PXE in the paediatric setting, as early diagnosis may be important to provide accurate information and discuss lifestyle adjustments in order to improve the prognosis of the disease.     

弹性假黄色瘤一例ABCC6基因突变分析

目的 报告1例弹性假黄色瘤,并检测ABCC6基因突变情况。方法 分析1例弹性假黄色瘤先证者的临床资料,并收集其父母、儿子及100例无亲缘关系的健康对照的外周血,提取基因组DNA,PCR扩增ABCC6基因编码区31个外显子,并进行DNA直接测序与ABCC6编码蛋白质功能预测。结果 先证者父母及儿子表型均正常。基因突变分析显示,先证者存在ABCC6基因c.373G > A（p.E125K）和c.3703C > T（p.R1235W）的复合杂合突变,先证者母亲为c.3703C > T（p.R1235W）杂合突变携带者,先证者父亲和儿子为c.373G > A（p.E125K）杂合突变携带者,而100例无亲缘关系的健康对照均未检测到该两种突变。物种间序列比对分析发现,ABCC6编码蛋白质第125位谷氨酸和第1235位精氨酸为进化高度保守的序列,SIFT和Polyphen?2软件预测c.373G > A（p.E125K）和c.3703C > T（p.R1235W）突变为有害变异位点。结论 ABCC6基因c.373G > A（p.E125K）和c.3703C > T（p.R1235W）的复合杂合突变可能是该例弹性假黄色瘤患者发病的原因。     

Relationship between the distribution of pseudoxanthoma elasticum skin and mucous membrane lesions and cardiovascular involvement

Pseudoxanthoma elasticum (PXE) primarily affects organs that are abundant in elastic fibers, such as the skin, eye and blood vessels, and may eventually cause loss of vision or cardiovascular disease (CVD). Because CVD is a potentially life-threatening complication, its early detection is important for improving the quality of life of PXE patients. To determine the relationship between the distribution of skin and mucous membrane lesions and the prevalence of CVD in patients with PXE, we examined 14 PXE cases who presented between 2004 and 2007. All patients had angioid streaks (AS) and positive pathological findings. The skin lesions in PXE patients are distributed discontinuously and thus the degrees of skin involvement were assessed by determining the presence or absence of PXE skin and mucous membrane lesions in six sites (oral mucosa, neck, periumbilical region, cubital fossa, axillae and inguinal regions). Each site was given a binary score (i.e. present = 1, absent = 0) irrespective of severity and the scores were summed to yield a total distribution score (potential range of 0–6). Four cases had PXE-associated CVD. Their mean distribution score was 5.7, which was significantly higher than the score of the cases without CVD (1.8) ( P  =   0.0049). There was also significant correlation between the high distribution score ( P  =   0.0053) as well as CVD ( P  =   0.029) with the maximum width of AS. A higher distribution score and the presence of oral mucosal lesions were associated with CVD. This scoring method may be useful for predicting the presence of CVD in PXE patients.     

Pseudoxanthoma elasticum with periumbilical perforation in a nullipara

Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder that primarily affects the skin and is characterized by progressive calcification and degeneration of the elastic fibers. PXE has recently been found to be caused by mutations in the ATP-binding cassette transporter C6 (ABCC6) or the multidrug resistance-associated protein 6 (MRP6) genes. Perforating PXE is a rare presentation that is usually seen in the periumbilical area in obese multiparous black women; it has distinct clinical and histopathological features and there may or may not be systemic manifestations. We report an unusual case of PXE in a nulliparous woman, with perforation in the periumbilical area and without any systemic involvement.