Pigmentary dysplasias in long survivors with mosaic trisomy 18: report of two cases

We describe two patients, a 19-year-old girl and a 19-year-old boy, with mosaic trisomy 18 and pigmentary dysplasias. Both patients had profound growth and mental retardation, marked kyphoscoliosis, bushy eyebrows, bulbous nose, simple ears, and joint contractures - clinical manifestations of long survivors with mosaic or non-mosaic trisomy 18. In addition, the boy showed total asymmetry. Pigmentary dysplasias of the skin with hypopigmented whorls and streaks, initially absent or overlooked at the ages 2 and 15 years, were detected on close examination. It is advisable to check closely every long survivor with mosaic or purportedly non-mosaic trisomy 18 for pigmentary dysplasias.     

Hypomelanosis of Ito—a nonspecific marker of somatic mosaicism: Report of case with trisomy 18 mosaicism

We report on a patient with hypomelanosis of Ito (HI), developmental delay, recurrent pneumonia, and facial asymmetry. Chromosome analysis done on blood and on one of three skin biopsies showed trisomy 18 mosaicism. This is the first report of HI associated with trisomy 18 mosaicism. This neuroectodermal disorder appears to be a nonspecific manifestation of chromosome mosaicism.     

UV exposure modulates hemidesmosome plasticity,contributing to long‐term pigmentation in human skin

Human skin colour, ie pigmentation, differs widely among individuals, as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals, UV‐induced pigmentation persists for months to years in a phenomenon termed long‐lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, eg solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV‐induced molecular changes may persist in individuals with LLP, clinical specimens from non‐sunburn‐inducing repeated UV exposures (UVA, UVB or UVA + UVB) at 4 months post‐exposure (short‐term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from six healthy individuals (three LLP+ and three LLP?) followed for more than 9 months (long‐term LLP) who initially received a single sunburn‐inducing UVA + UVB exposure. The results support a UV‐induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighbouring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin α6β4 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal–dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long‐term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin colour. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

观察不同模式的Q-开关红宝石激光对UVB诱导的色素沉着斑的影响

目的：观察不同模式的Q-开关红宝石激光对中波紫外线(UVB)诱导的豚鼠皮肤色素沉着斑的影响。方法：10只豚鼠分为4组,即对照组(不行激光治疗)、低剂量组、高剂量组和点阵组。用UVB照射豚鼠背部皮肤诱导色素沉着后,使用低、高剂量及点阵模式的Q-开关红宝石激光分别照射色素沉着区,能量分别为1.5,6.0,3.0 J/cm2,分别照射4,1,2次,每次间隔1周。治疗前及治疗后即刻、2周,采用拍照、Fontana-Masson组织染色、电镜等方法观察色斑的颜色及色斑皮肤组织中的黑素颗粒、黑素小体的变化。结果：低剂量组、点阵组治疗后2周色素完全消退,观察8周未见复发,色度值(L*值)较治疗前增加,黑素颗粒及黑素小体明显减少,与对照组相比差异有统计学意义(P<0.05)。高剂量组皮肤色素沉着出现不同程度地复发。结论：Q-开关红宝石激光可以有效治疗豚鼠皮肤色素沉着,点阵模式治疗的疗效较好。     

X-linked short stature with skin pigmentation: evidence for heterogeneity of the Russell-Silver syndrome

A family is described with a syndrome of short stature, abnormal pigmentation of the skin and mild facial dysmorphism. The short stature and pigmentary anomalies were more marked in the males than the females. The pattern of inheritance appeared X-linked. In 2 young brothers the clinical picture mimicked that of the Russell-Silver syndrome. It is suggested that the Russell-Silver syndrome is heterogeneous and that the criteria for its diagnosis need re-evaluation.     

Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes

In the past 15 years, insights in clinical and genetic characteristics of Parkinson disease (PD) have increased substantially. Sequence or copy number variants in at least six genes (SNCA, LRRK2, PARK2, PINK1, DJ-1 and ATP13A2) have been identified to cause monogenic forms of PD. Routine clinical testing for mutations in these genes is feasible and available, but overlapping phenotypes in monogenic and sporadic PD complicate straightforward diagnostic screening. Primarily, a positive familial history and an early onset age should prompt clinicians to consider genetic testing. Based on a literature review on clinical and neuropathological features of PD patients carrying a pathogenic mutation we propose guidelines for genetic diagnostic testing in clinical practice. However, the absence of disease-modifying therapies and the variable penetrance of most known mutations currently limit the usefulness of genetic diagnostic testing for PD in clinical practice.     

Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis

X-linked reticulate pigmentary disorder (PDR), previously reported as X-linked cutaneous amyloidosis (MIM#301220), is characterized by brown pigmentation of the skin which follows the lines of Blaschko in females but appears as reticulate sheets in males. Males may suffer severe gastrointestinal disorders in infancy with failure to thrive and early death. Nowadays symptomatic treatment allows survival and other manifestations may appear such as corneal dystrophy with severe photophobia or chronic respiratory disease. Amyloid deposition in the skin may be no more than an age-dependent secondary manifestation. The PDR gene was localised by linkage analysis to Xp21-p22. The background genetic map is Xpter-DXS996-22.5-DXS207-3.3-DXS999-3.3-DXS365-14.2-DXS989-4.1-3′DMD-3.5-DXS997-1.0-STR44-9.3-DYSI-2.3-DXS1068-11.0-DXS228 with distances between markers given in cM. Recombinants detected with DXS999 distally and DXS228 proximally, define the limits to the localisation. Linkage was found with several markers within this interval. Peak lod scores of 3.21 at θ = 0.0 were obtained between PDR and DXS989 and between PDR and 5′DYSI within the dystrophin locus. © 1994 Wiley-Liss, Inc.     

The role of Self-Defined Race/Ethnicity in Population Structure Control

Population-based association studies are powerful tools for the genetic mapping of complex diseases. However, this method is sensitive to potential confounding by population structure. While statistical methods that use genetic markers to detect and control for population structure have been the focus of current literature, the utility of self-defined race/ethnicity in controlling for population structure has been controversial. In this study of 1334 individuals, who self-identified as either African American, European American or Hispanic, we demonstrated that when the true underlying genetic structure and the self-defined racial/ethnic groups were roughly in agreement with each other, the self-defined race/ethnicity information was useful in the control of population structure.     

Diagnosis of Fanconi anemia in patients without congenital malformations: An international Fanconi anemia registry study

Data were analyzed from 419 Fanconi anemia (FA) patients enrolled in the American Registry of the International Fanconi Anemia Registry (IFAR) to determine whether Fanconi anemia (FA) patients without major congenital malformations (CM) have distinguishing characteristics that can lead to an earlier diagnosis. These included 377 patients reported by physicians to the IFAR and 42 patients examined by us. The number of FA patients in each group without CM was 128 and 16, respectively; one third of all patients lacked CM. We found that height, weight, and head circumference were ≥5th centile in 26.6%, 18.0%, and 8.6% of FA patients without CM referred to the IFAR, and in 43.8%, 25.0%, and 43.8% of FA patients without CM examined by us. Minor anomalies were reported in 9.4% of FA patients without CM referred to the IFAR and 100% of FA patients without CM examined by us. Most FA patients without CM have alterations in growth parameters, skin pigmentation abnormalities, or microphthalmia. Increased awareness of the complete spectrum of FA by clinicians will enable an earlier diagnosis to be made. Am. J. Med. Genet. 68:58–61, 1997 © 1997 Wiley-Liss, Inc.     

Parkinson's disease involves autophagy and abnormal distribution of cathepsin L

Intrinsic brain activity in a resting state incorporates components of the task negative network called default mode network (DMN) and task-positive networks called attentional networks. In the present study, the reciprocal neuronal networks in the elder group were compared with the young group to investigate the differences of the intrinsic brain activity using a method of temporal correlation analysis based on seed regions of posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC). We found significant decreased positive correlations and negative correlations with the seeds of PCC and vmPFC in the old group. The decreased coactivations in the DMN network components and their negative networks in the old group may reflect age-related alterations in various brain functions such as attention, motor control and inhibition modulation in cognitive processing. These alterations in the resting state anti-correlative networks could provide neuronal substrates for the aging brain.     

Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Background

Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance‐associated protein 6).

Objective

To investigate the mutation spectrum of ABCC6 and possible genotype–phenotype correlations.

Methods

Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high‐performance liquid chromatography‐based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype–phenotype correlations were assessed.

Results

In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide‐binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23–29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype–phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.

Conclusions

This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.     

Signatures of Positive Selection in Genes Associated with Human Skin Pigmentation as Revealed from Analyses of Single Nucleotide Polymorphisms

Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level. A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour, but only limited genetic evidence for positive selection has been presented. To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset, studying single nucleotide polymorphisms (SNPs), and analyzed 55 genes in detail. We identified eight genes that are associated with the melanin pathway ( SLC45A2, OCA2, TYRP1, DCT, KITLG, EGFR, DRD2 and PPARD ) and presented significant differences in genetic variation between Europeans, Africans and Asians. In six of these genes we detected, by means of the EHH test, variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( OCA2, TYRP1 and KITLG ) and in Asians ( OCA2, DCT, KITLG, EGFR and DRD2 ), whereas signals were scarce in Africans ( DCT, EGFR and DRD2 ). Furthermore, a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed. Overall, our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians, whereas dark skin color seems of unique origin, reflecting the ancestral state in humans.     

Hamartomatous dental cusps in hypomelanosis of Ito

Multiple dental cusps, protruding from the crowns of both deciduous and permanent incisors, were observed in a 4-year-old girl affected with hypomelanosis of Ito. This unusual dental anomaly has been described in one previous report of this neurocutaneous syndrome. In contrast to ordinary talon cusps, the dental outgrowths observed in hypomelanosis of Ito appear to be of hamartomatous origin. Apparently, these dental deformities are characteristic of hypomelanosis of Ito and may help to identify the syndrome in cases where other findings are minimal or atypical.     

对皮肤疾病动物模型的哲学思考

皮肤病动物模型的发展过程经历两大阶段,人们利用动物模型对疾病有了进一步的认识,虽然基础实验与临床应用还有差距,但它将会为人类的皮肤病的研究做出重要的贡献。     

Constructing immunoprofiles to deconstruct disease complexity in pemphigus

The complex etiology of multifactorial diseases such as pemphigus vulgaris complicates mechanistic investigations and confounds current therapeutic approaches. Two major sources contribute to the overall complexity of disease. Biological complexity involves the disruption of multiple immune pathways that underlie autoimmune destruction in the skin. Overlaying this altered immunobiology is clinical complexity that is manifest as heterogeneous presentations of disease. Merging cumulative data on immune dysfunction with the detailed clinical information can be expected to allow the deconstruction of the processes that lead to specific disease presentations. Our group has undertaken comprehensive analyses in stratified patient populations to assign T cell, cytokine, and autoantibody immunoprofiles linked to defined constant and variable clinical parameters. We propose the concept of a “disease array” that is based on a matrix of supporting biological and clinical information that can be used to guide the development of next-generational tools that enhance our ability to diagnose, prognose, and individually treat disease.     

Behavioral treatment of Raynaud's disease

In order to assess the efficacy of a behavioral intervention in the treatment of idiopathic Raynaud's disease, 30 female patients were trained to control their digital skin temperature using autogenic training or a combination of autogenic training and skin temperature feedback either in the laboratory or at home. All trained subjects demonstrated a significant ability to maintain digital skin temperature in the presence of a cold stress challenge and reported significant reductions in both frequency and intensity of vasospastic attacks. The addition of skin temperature feedback to autogenic training did not provide additional clinical benefit.This research was supported by National Institute of Mental Health Research Grant MH-25104 to Richard S. Surwit.