Showing papers by "John A. McGrath published in 2016"

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.

Abstract: This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.

Frontal fibrosing alopecia: reflections and hypotheses on aetiology and pathogenesis.

Abstract: Since first described by Kossard in 1994, frontal fibrosing alopecia (FFA) has been something of an enigma. The clinical heterogeneity of FFA, its apparent rarity and investigators' suboptimal access to phenotypically consistent patient cohorts may all have had a negative impact on delineating disease pathogenesis. Moreover, there is a relative paucity of epidemiological, interventional and basic research studies, and there have been no advances in translational therapeutics, unlike for other inflammatory dermatoses, such as alopecia areata (AA). Dermatologists anecdotally describe an increasing incidence in FFA over the last decade, which has led to the notion that the disorder may be induced by unknown environmental triggers. On the other hand, segregation of FFA in some families lends support to an unexplored genetic element implicated in disease pathogenesis. We herein review what is known about the pathobiology of FFA and formulate working hypotheses to advance insight into this intriguing hair disorder.

Suppression of TGFβ and Angiogenesis by Type VII Collagen in Cutaneous SCC

Abstract: Background: Individuals with severe generalized recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disorder caused by mutations in the COL7A1 gene, develop unexplained aggressive squamous cell carcinomas (SCC). Here we report that loss of type VII collagen (Col7) in SCC results in increased TGF β signaling and angiogenesis in vitro and in vivo. Methods: Stable knockdown (KD) of Col7 was established using shRNA, and cells were used in a mouse xenograft model. Angiogenesis was assessed by immunohistochemistry, endothelial tube-forming assays, and proteome arrays. Mouse and zebrafish models were used to examine the effect of recombinant Col7 on angiogenesis. Findings were confirmed in anonymized, archival human tissue: RDEB SCC tumors, non-EB SCC tumors, RDEB skin, normal skin; and two human RDEB SCC cell lines. The TGF β pathway was examined using immunoblotting, immunohistochemistry, biochemical inhibition, and siRNA. All statistical tests were two-sided. Results: Increased numbers of cross-cut blood vessels were observed in Col7 KD compared with control xenografts (n = 4 to 7 per group) and in RDEB tumors (n = 21) compared with sporadic SCC (n = 24, P < .001). Recombinant human Col7 reversed the increased SCC angiogenesis in Col7 KD xenografts in vivo (n = 7 per group, P = .04). Blocking the interaction between α2β1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p-Smad2 levels two-fold. Increased TGF β signaling and VEGF expression were observed in Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGF β markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGF β markers, n = 6; VEGF, n = 21). Inhibition of TGF β receptor signaling using siRNA resulted in decreased endothelial cell tube formation (n = 9 per group, mean tubes per well siC = 63.6, SD = 17.1; mean tubes per well siT βRII = 29.7, SD = 6.1, P = .02). Conclusions: Type VII collagen suppresses TGF β signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

Frontal fibrosing alopecia: there is no statistically significant association with leave-on facial skin care products and sunscreens.

Abstract: We were interested to read the article Frontal Fibrosing Alopecia - Possible Association with Leave-on Facial Skin Care Products and Sunscreens; A Questionnaire Study by Aldoori et al1. The authors sought to identify possible causative environmental factors associated with frontal fibrosing alopecia (FFA). One conclusion was that the use of facial products containing sunscreens might be implicated. This article is protected by copyright. All rights reserved.

Olmsted syndrome in an Indian male with a new de novo mutation in TRPV3

Abstract: DEAR EDITOR, Olmsted syndrome (OS; MIM #614594), is a rare genetic skin disorder, with ~50 cases reported in the literature. Most cases are sporadic although familial cases with varying modes of inheritance have also been described. Recently, the gene responsible for most cases of OS has been identified as TRPV3 (transient receptor potential vanilloid 3), and a number of de novo autosomal dominant mutations and one autosomal recessive mutation have been published. In addition, an X-linked variety of OS-like syndrome has been shown to result from mutations in MBTPS2 (membrane-bound transcription factor protease site 2). Olmsted syndrome is characterized by extensive mutilating palmoplantar keratoderma, periorificial plaques, alopecia and pruritus. The first two clinical features are considered as diagnostic hallmarks and may help rule out other similar clinical entities. Other signs, which are seen with variable frequency, include leukoplakia, pseudoainhum, onychodystrophy, follicular keratosis and erythromelalgia. There is also an increased risk for squamous cell carcinoma within the hyperkeratotic plaques. OS has features overlapping with other palmoplantar keratodermas (PPK), but the modern-day discriminator is mutational analysis. We present a case of OS in a 28-year-old Indian male in whom a new and atypical de novo mutation in TRPV3 was identified. The proband is the first child born to unrelated, healthy parents. He had no skin problems at birth but on the third day of life scaly lesions were noted on his scalp. Thickening of palmar and plantar skin was noted by 3 years of age, which progressively became more diffuse. During the patient’s teens, progressive hyperkeratotic thickening of perioral skin appeared. He had difficulty in walking and developed fixed contractures of the hands that significantly impacted on his quality of life. His left fifth toe was surgically amputated because of painful pseudoainhum. There was no family history of OS, although his sister developed an acquired PPK at 20 years of age. Examination of her skin revealed a diffuse pattern with accentuation of the hyperkeratosis on weightbearing areas but no other potential clinical manifestations of OS were evident. On examination, the proband had thick diffuse PPK with sharply marginated, thick fissured plaques with a verrucous appearance and evident malodour (Fig. 1). He had flexion deformities of the left wrist and fingers of both hands. Constriction bands were present on the toes. Verrucous plaques were prominent around the mouth, ears and anus. In addi-

Cardiomyopathy diagnosed in the eldest child harbouring p.S24X mutation in JUP.

Abstract: 1 Kardaun SH, Sidoroff A, Valeyrie-Allanore L et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007; 156:609–11. 2 Yu MK, Yu MC, Lee F. Association of DRESS syndrome with chylous ascites. Nephrol Dial Transplant 2006; 21:3301–3. 3 Brown RJ, Rother KI, Artman H et al. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol 2009; 145:63–6. 4 Kano Y, Tohyama M, Aihara M et al. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol 2015; 42:276–82.

Finasteride is of uncertain utility in treating frontal fibrosing alopecia.

Abstract: To the Editor: We were interested to read the report by Danesh and Murase on the potential of finasteride as ‘‘a safe and alternative’’ treatment option for frontal fibrosing alopecia in the Journal’s Therapeutic Pearls section. We note that their conclusions were based on 2 reports by Va~ n o-Galv an et al and Moreno-Ram ırez et al and we wish to highlight the following: Danesh and Murase state that ‘‘2.5 to 5 mg/d in a study involving 102 patients showed improvement in 48 (47%) and stabilization in 54 (53%) patients.’’ However, Danesh and Murase have omitted the detail that 74.8% of the 111 people treated with antiandrogens (dutasteride and finasteride) in this retrospective study were treated concurrently with topical minoxidil. Of the 28 of 111 subjects who only received a 5 -reductase inhibitor, 9 reportedly improved and 19 stabilized. Va~ n o-Galv an et al have clarified that ‘‘in cases of improvement the regrowth of hair was minimal and always located at the hairline.’’ Also, these authors have stated that ‘‘response to antiandrogens was more frequent if androgenetic alopecia was present.’’ Moreover, Va~ n o-Galv an et al accepted that spontaneous stabilization could be possible, although the reported frequency was low in their case series (6% of the 79 untreated cases). To this end, it is worth emphasizing that the mean follow-up time in this study was 2.1 years (ranging from 0.4-19 years). Reference is made to a report by MorenoRam ırez et al according to which ‘‘a combination strategy using finasteride (2.5 mg/d) and minoxidil (2% twice daily) in 8 patients halted progression of disease in 4 (50%) patients after 12 to 18 months.’’ Danesh and Murase omitted reference to an additional statement made by Moreno-Ram ırez et al: ‘‘the improvement obtained was related to the improvement in the level of the associated androgenetic alopecia.’’ Danesh and Murase correctly highlight the side effects associated with finasteride but we would like to add that in a report from the United Kingdom Medicines and Healthcare Products Regulatory Agency on the risk of male breast cancer with finasteride, the data mentioned 4 cases of female breast cancer associated with off-license use of finasteride. Although there is lack of documentation on the doses of finasteride, 3 cases were treated with the 1 mg of Propecia brand (1 with 5 mg of Proscar brand [Proscar and Propecia are manufactured by Merck, Kenilworth, NJ]).

Ichthyosis Prematurity Syndrome: From Fetus to Adulthood

Abstract: Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.

Induced Pluripotent Stem Cell Differentiation and Three-Dimensional Tissue Formation Attenuate Clonal Epigenetic Differences in Trichohyalin

Abstract: The epigenetic background of pluripotent stem cells can influence transcriptional and functional behavior. Most of these data have been obtained in standard monolayer cell culture systems. In this study, we used exome sequencing, array comparative genomic hybridization (CGH), miRNA array, DNA methylation array, three-dimensional (3D) tissue engineering, and immunostaining to conduct a comparative analysis of two induced pluripotent stem cell (iPSC) lines used in engineering of 3D human epidermal equivalent (HEE), which more closely approximates epidermis. Exome sequencing and array CGH suggested that their genome was stable following 3 months of feeder-free culture. While the miRNAome was also not affected, ≈7% of CpG sites were differently methylated between the two lines. Analysis of the epidermal differentiation complex, a region on chromosome 1 that contains multiple genes involved in skin barrier maturation (including trichohyalin, TCHH), found that in one of the iPSC clones (iKCL004), TCHH retained a DNA methylation signature characteristic of the original somatic cells, whereas in other iPSC line (iKCL011), the TCHH methylation signature matched that of the human embryonic stem cell line KCL034. The difference between the two iPSC clones in TCHH methylation did not have an obvious effect on its expression in 3D HEE, suggesting that differentiation and tissue formation may mitigate variations in the iPSC methylome.

Autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma due to a recurrent mutation in aquaporin-5.

Abstract: DEAR EDITOR, Autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma (NEPPK; MIM 600231) is a clinically and genetically heterogeneous disorder, one form of which is associated with a whitish spongy appearance upon immersion in water. Using linkage data in combination with whole-exome sequencing in families with NEPPK, heterozygosity for five different missense mutations in AQP5 (encoding aquaporin-5) was identified recently in affected members of seven Swedish families, three British families and a Scottish family. All the mutations segregated with disease in the respective families and were not found in the dbSNP or 1000 Genomes Project databases. A further gain-of-function mutation in AQP5 was subsequently reported in a large NEPPK pedigree of Chinese Han descent. Aquaporins are cell membrane channels that conduct water or sugar alcohol molecules (aquaglyceroporins). The protein family member aquaporin-5 is predominantly expressed in epithelial cells, such as in the lung and cornea, and helps

Rare inherited skin diseases and the Genomics England 100 000 Genome Project.

Abstract: Back in April 2003 an important milestone in human genetics was announced – the complete sequencing of the human genome. Sequencing 3 1 billion nucleotides of human DNA had taken thousands of dedicated scientists across the world 13 years to complete at a cost exceeding £2 billion. From that platform, technology progressed rapidly and it has become possible to sequence an entire human genome in a few days for less than £1000. With these advances, the emphasis has now moved on to wondering how we can best harness the potential of genomic medicine for patients and society. Enter the Genomics England 100 000 Genome Project. The underlying concept of the project relates to the internationally unique nature of the U.K.’s National Health Service (NHS). In principle, the NHS is able to capture a whole lifetime of medical records, which, if added to a person’s genome data, could provide a rich resource with which to understand disease and decipher complex interactions between genes, the environment, health and illness. Why 100 000 genomes? In truth, the number is an arbitrary one, given that previous human DNA sequencing projects had looked at 10, then 100, then 1000 and then 10 000 human genomes, and thus 100 000 seemed a natural scale-up. With political backing, the 100 000 Genomes Project was therefore heralded in late 2012. To launch the project, the Department of Health established and funded a company, Genomics England, charged with completing genome sequencing on 100 000 people before the end of 2017. Genomics England has four main aims: (i) to create an ethical and transparent programme based on consent, (ii) to bring benefit to patients and set up a genomic medicine service for the NHS, (iii) to enable new scientific discovery and medical insights, and (iv) to kick start the development of a U.K. genomics industry. For patients, the big promise is one of better diagnosis and better treatments. The focus of the project is on patients with rare diseases (and their families), as well as patients with cancer. Rare diseases are individually very uncommon, but because there are close to 8000 rare diseases, up to one in 17 of the U.K. population has such a condition. So how are the 100 000 individuals for genome sequencing going to be determined? For cancer, there will be ~50 000 genomes, which equates to ~25 000 patients (patients will contribute two genomes for comparison, i.e. cancer/noncancer tissue). For rare diseases, ~50 000 genomes will involve ~15 000 patients and ~35 000 relatives (mainly parents, in order to generate trios for analysis). Thus, the 100 000 genomes can be broken down to involve ~75 000 people in total, of whom ~40 000 will be patients. Currently, all 100 000 genomes will be committed to people in England, although capacity for an additional 15 000 genomes has already been created for those in Scotland, Wales and Northern Ireland, with the likelihood of further expansion. Genomics England (and the NHS) has a vision that the project will also enable new medical research. Research goals may vary but the unifying theme will be how best to use genomics in healthcare and to interpret the data to help patients, identifying the cause(s) of particular diseases, creating new diagnostic tests and introducing new treatments. But to make genomics a reality for the NHS it has to be of high quality, fast and affordable, with results that are readily understood. The big challenge is how to make this work. For the DNA sequencing, Genomics England is working with Illumina and the Wellcome Trust to provide sequencing capacity at the Sanger Institute near Cambridge; that new infrastructure is now operational. Genomics England has also partnered with NHS England to create 11 Genome Medicine Centres (GMCs) around England, which will serve as the entry points for participants (identifying, enrolling and registering suitable patients/family members), taking informed consent, capturing clinical information and feeding back results to participants. Clinicians and the GMCs are also key partners of the project through other groupings called Genomics England Clinical Interpretation Partnerships (GeCIPs), with the remit of helping determine diseases for inclusion in the project, initiating genomics research, leading on education, interpreting genomic data in a clinical context and embedding learning about genomics within the NHS. So, where does dermatology, as a relatively small specialty, sit within this new initiative? The answer is right at the top table. Rare skin diseases have been approved as one of the major categories for recruitment. Nevertheless, it is likely that only ~1000 of the total genomes will be apportioned to dermatology, which equates to just ~400 patients. This means we probably have the capacity to investigate no more than 15–20 particular conditions, with no individual disease meriting more than 50 genomes (some much less). This is not a huge amount of sequencing, perhaps, but certainly there is an opportunity for discovery, research and helping some patients and families. For skin cancer, recruitment will be via oncology rather than dermatology. There is also a single GeCIP for rare skin diseases – signed up to by ~70 U.K. dermatologists, scientists and researchers.

Incontinentia pigmenti in a father and daughter

Abstract: DEAR EDITOR, Incontinentia pigmenti (IP) is a rare multisystem X-linked dominant genetic disorder caused by mutations in IKBKG, encoding inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-c). Functionally, the encoded IKK-c protein participates in nuclear factor (NF)-jB signalling to regulate inflammatory and immune responses and prevent apoptosis. Loss-of-function mutations in IKBKG, such as those that occur in IP, leave mutant cells vulnerable to apoptosis when exposed to tumour necrosis factor-a. Female patients with IP who inherit germline mutations in IKBKG usually survive because of skewed X-inactivation favouring expression of the wild-type allele, whereas most male patients with IP die in utero. However, possible explanations for rare examples of the survival of male patients with IP include Klinefelter syndrome (47XXY), hypomorphic IKBKG mutations and postzygotic mutations in IKBKG leading to somatic mosaicism. Here, we describe a male adult with IP, with survival being attributed to tissue mosaicism, who then fathered a female child with IP affecting her germline. A 29-year-old Kuwaiti man was born with severe linear blistering followed by hyperpigmentation and hyperkeratotic plaques in a Blaschkoid distribution on the head, trunk, upper and lower limbs (Fig. 1a, b). He had linear facial asymmetry and blindness of the left eye. His dentition was abnormal, necessitating dentures. The rest of his neurological examination was unremarkable. His 1-year-old daughter was born at term via normal vaginal delivery. There was no history of consanguinity in the family. Soon after birth she had linear, streaky erythema and vesicles, with subsequent hyperpigmentation and hyperkeratotic plaques; lesions were noted on the upper and lower limbs along lines of Blaschko (Fig. 1c). Other systemic abnormalities were excluded on clinical examination and developmental parameters were normal. No neurological abnormalities have been noted during her first 12 months. Following informed consent, a three-primer polymerase chain reaction (PCR) protocol was used to screen for the most common recurrent pathogenic mutation in IKBKG that underlies ~80% of IP cases worldwide. This mutation is an intragenic deletion from within intron 3 to within intron 10 that removes all of exons 4–10. Such a PCR protocol is necessary because of a nonfunctional copy of IKBKG running in the opposite direction. We used a recently reported method that

Mutations in EXPH5 underlie a rare subtype of autosomal recessive epidermolysis bullosa simplex.

Abstract: DEAR EDITOR, Epidermolysis bullosa simplex (EBS) is a heterogeneous disorder with mutations in at least nine different genes underlying various autosomal dominant and recessive subtypes thereof. Making an accurate clinical and laboratory diagnosis in some of the less common forms of EBS can be challenging. A 9-year-old boy with first-cousin Pakistani parents presented with skin fragility from birth. He had scattered vesicles and bullae up to 1–2 cm in size on the limbs and trunk (Fig. 1a, b). Blistering was made worse by hot weather. Individual blisters healed within 1–2 weeks, leaving postinflammatory hypopigmentation. His blistering tendency persisted but ameliorated with age. Hair, teeth, nails and mucosae were normal. His 2-year-old brother had similar symptoms and signs from birth. Of note, the father of both children, whose parents were also first cousins, had similar skin fragility as a child that resolved completely by 10 years of age. The pattern of inheritance was consistent with autosomal recessive transmission, with possible pseudodominant inheritance, given the father’s history of blistering. Unfortunately, the father declined to participate in the study and was not available for further evaluation. To date, eight of the nine EBS genes have been implicated in the pathophysiology of autosomal recessive subtypes: KRT14, PLEC, DST-e, PKP1, DSP, JUP, TGM5 and EXPH5. With

Intrafamilial phenotypic heterogeneity of epidermolytic ichthyosis associated with a new missense mutation in keratin 10.

Abstract: Mutations in the keratin 10 gene (KRT10) have been shown to underlie several forms of epidermolytic ichthyosis (EI), including generalized, annular and naevoid variants. We investigated an autosomal dominant pedigree with ichthyosis in which there was intrafamilial clinical heterogeneity, with the affected individual family members presenting with features of either erythrokeratoderma progressiva, annular EI, localized or superficial EI, or more generalized EI. Sanger sequencing identified a new heterozygous missense mutation (c.457C>A; p.Leu153Met) in KRT10 in all affected individuals. No additional mutations were identified in the genes for keratin 1 (KRT1) keratin 2 (KRT2), connexin 31 (GJB3) or connexin 30.3 (GJB4) that might account for the clinical heterogeneity seen in this family. Our findings illustrate the intrafamilial variability in phenotype and diverse clinical presentations that can occur in EI resulting from a single mutation in KRT10.

Novel missense mutation in a patient with recessive pretibial epidermolysis bullosa and a mild phenotype

Abstract: Editor A 44-year-old man presented with a greater than 20-year history of persistent red patches on his shins. He described occasional blistering in the area but was otherwise asymptomatic. He had no relevant medical or family history. On examination, he had large violaceous plaques on his anterior shins with surface atrophy. (Fig. 1a) A bulla was evident at the peripheral edge of the involved skin on the left shin. (Fig. 1b) No milia were observed. He was also noted to have dystrophic toenails. (Fig. 2) Full skin examination was otherwise unremarkable. Skin biopsy showed subepidermal bulla formation with minimal inflammation. (Fig. 3) Direct immunofluorescence was negative. Given these findings and clinical localization to the shins, the presumptive diagnosis was pretibial epidermolysis bullosa (EB). To confirm the diagnosis, Sanger sequencing of COL7A1, encoding type VII collagen was preformed. Two heterozygous mutations were identified: c.3840delC (p.Gly1281Valfs*44) and c.8780G>A (p.Arg2927His) in exon 31 and exon 117 of this 118 exon gene respectively. The first mutation is a recurrent lossof-function mutation identified previously in other unrelated individuals with recessive dystrophic EB. The second mutation is a new missense mutation occurring within the NC-2 domain of type VII collagen and appears to be the most distal amino acid substitution discovered to date. Pretibial EB is a rare variant of the inherited immunobullous disorder, dystrophic EB. Dystrophic EB includes all subtypes where blistering occurs just beneath the lamina densa of the basement membrane zone and results from mutations in COL7A1. Type VII collagen is composed of three identical a chains, each with a central collagenous triple-helical segment with a large NC-1 domain at one end and a smaller NC-2 domain at the other. Individual molecules form anti-parallel dimers which then aggregate to form anchoring fibrils (AFs). It has been postulated that the NC-2 domain within one a chain may bind to an appropriate site on the triple-helical domain of a second molecule and align cysteine residues, which subsequently become stabilized by intermolecular disulphide bonds. Mutations in the NC-2 domain have been shown to affect dimer formation (NC2 is normally cleaved during this process converting the procollagen collagen). The sites for cleavage and disulphide bonding are proposed to be localized within a 57amino acid segment between residues 2780 and 2837. Christiano et al. reported on a family with recessive DEB where two affected siblings had homozygous methionine to lysine mutations. This substitution was localized to position 2789 within the NC2 domain and these patients had a complete lack of AFs. Another patient with localized DEB had a deletion mutation leading to in-frame skipping of exon 115 (encoding amino acids 2814-2843) resulted in a lack of peptide processing. Anchoring fibrils were reduced with diffuse cross-banding but no other gross morphological alterations suggesting defective lateral aggregation of type VII collagen dimers. Our patient’s mutations, located outside this region (including at the terminus), likely have a diminished impact on the structure and function of type VII collagen and AFs, thus explaining his mild clinical phenotype. Pretibial EB is characterized by blisters, milia and atrophic scarring localized to the pretibial skin associated with

Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function.

Abstract: © 2016 The Authors. doi: 10.2340/00015555-2307 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 Most cases of erythrokeratoderma variabilis (EKV, OMIM#133200) are inherited in an autosomal dominant manner, although autosomal recessive cases can occur. EKV is caused by mutations in GJB3 or GJB4, which encode connexin (Cx) 31 and Cx30.3, respectively. Clinically, there are 2 characteristic skin manifestations of EKV: localized, sharply circumscribed hyperkeratotic plaques; and migratory erythematous lesions (1, 2). Cxs are components of gap junctions, intercellular junctions that are expressed in several organs, including the skin and the cochlea. Individual Cxs are assembled in groups of 6 to form hemichannels in the plasma membrane, and then 2 hemichannels between adjacent cells combine to form a gap junction (2). To date, 21 Cx genes have been discovered that have essential roles in cell communication and free transfer of small molecules in many organs. In this report, we describe a recurrent mutation in GJB3, p.Gly45Glu, in a Japanese female with EKV. In addition, we review the literature and focus on genotype-phenotype correlations, notably for Cx mutations affecting the first glycine within the first extracellular domain of the protein.

Improved molecular diagnosis of the common recurrent intragenic deletion mutation in IKBKG in a Filipino family with incontinentia pigmenti.

Abstract: Incontinentia pigmenti is a rare, multisystem X-linked dominant genetic disorder caused by mutations in IKBKG, the encoding inhibitor of kappa light polypeptide gene enhancer in B-cells. Almost 80% of all cases result from a recurrent intragenic deletion mutation that removes exon 4-10. At present, this mutation can be detected by a multi-primer polymerase chain reaction (PCR) technique although current protocols may preferentially amplify the wild-type allele and miss the deletion. Here, we report a female infant with incontinentia pigmenti that also affected her mother and sister, and two spontaneously aborted male siblings. We developed a modified PCR amplification method that provides more robust detection of the exon 4-10 deletion mutation, which was demonstrated in all affected females in this pedigree.

Mesenchymal stem cell therapy for recessive dystrophic epidermolysis bullosa: prospects and clinical progress

Abstract: Epidermolysis bullosa (EB) is a group of inherited disorders characterized by trauma-induced fragility of skin and mucosal surfaces. EB affects approximately 1 in 17,000 live births and is classifi...