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Biomedical subjects

A Zlotogorski

Publications and source records attributed to A Zlotogorski.

At least 19 recordsLinked to original sources
PubMed2003

Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix.

Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair resulting from periodic thinning of the shaft (MIM 158000). The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. Mutations of the helix-encoded region in two hair-specific keratins (hHb1 and hHb6) have been identified as responsible for this disorder. We investigated two unrelated families from Russia and Colombia with monilethrix and found two missense mutations in hHb6. In the Russian family, we found a G to A transition at the first base of codon 402, resulting in a lysine substitution (GAG to AAG), designated E402K. In the Colombian family, affected patients carried a missense mutation of codon 413, involving a transition from G to A causing a lysine substitution (GAG to AAG), designated E413K. These two mutations have been identified in other monilethrix families from Europe. Our findings extend the body of evidence implicating recurrent hHb6 and hHb1 mutations in monilethrix families from around the world.

Colombia↗
PubMed2001

Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.

Congenital atrichia with papular lesions is a rare, autosomal recessive form of total alopecia and mutations in the hairless (hir) gene have been implicated in this disorder. Published estimates of the prevalence of this disorder remain surprisingly low considering pathogenetic mutations in hir have been found in distinct ethnicities around the world. Therefore, it is likely that congenital atrichia with papular lesions is far more common than previously thought and is often mistaken for its phenocopy, the putative autoimmune form of alopecia universalis. To clarify this discrepancy, we propose criteria for the clinical diagnosis of congenital atrichia with papular lesions. Among these is the novel report of the consistent observation of hypopigmented whitish streaks on the scalp surface of affected individuals. Additionally, we report the identification of a novel missense mutation in hir from a family of Arab Palestinian origin that exhibits the pathognomonic features of atrichia with papular lesions. Collectively, we anticipate that an increased recognition of this disorder will result in more accurate diagnosis and the sparing of unnecessarily treatment to patients.

Alopecia↗
PubMed2000

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

Adolescent↗
PubMed2000

Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C.

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more "complex" autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited "identical by descent" from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-->T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.

Alleles↗
PubMed1999

Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family.

Congenital atrichia is a rare form of hereditary human hair loss, characterized by the complete shedding of hair shortly after birth, together with the formation of papular lesions on the skin. Recently, we cloned the human homolog of the mouse hairless gene and identified pathogenic mutations in several families with inherited congenital atrichia. Here, we present the genomic organization of the human hairless gene (HGMW-approved symbol HR), which spans over 14 kb on chromosome 8p12 and is organized into 19 exons. In addition, we report the identification of a 22-bp deletion mutation in exon 3 of the hairless gene in a large consanguineous Arab Palestinian family from a village near Jerusalem, Israel. These findings extend the body of evidence implicating mutations in the hairless gene as an underlying cause of congenital atrichia in humans.

Alopecia↗
PubMed1999

Bullous erysipelas: A retrospective study of 26 patients.

BACKGROUND: Erysipelas is a superficial form of cellulitis caused by a variety of microbes, and it responds to antibiotic treatment. During the past few years we treated several patients with a bullous form of erysipelas involving the lower legs. We believe their disease had a more protracted course than patients with nonbullous erysipelas. OBJECTIVE: We studied bullous erysipelas by conducting a retrospective analysis of 26 patients with bullous erysipelas of the legs treated by the authors during a 5-year period. METHODS: We conducted a retrospective review of the records of all patients with a diagnosis of bullous erysipelas who were treated at the Department of Dermatology, Hadassah Medical Center, Jerusalem, between the years 1992 and 1996. Data regarding patients with nonbullous erysipelas were obtained from the medical center's computerized data pool. RESULTS: A total of 26 cases of bullous erysipelas were found, comprising 22 women and 4 men whose ages ranged from 28 to 87 (mean, 58.8) years. The average hospital stay was 20.57 days (range, 12 to 46 days). The average hospital stay for patients with nonbullous erysipelas and cellulitis treated in the same department by the authors during the study period was 10.6 days (range, 2 to 54 days). CONCLUSION: Bulla formation is a complication of erysipelas, seen in our series in 5.2% of the patients (26 of 498 admissions for erysipelas and cellulitis). The course of the disease is protracted, requiring longer medical attention.

Adult↗
PubMed1999

Gastric-Mucocutaneous gammadelta T cell lymphoma: possible association with Epstein-Barr virus?

Gammadelta T cell lymphoma is usually either subcutaneous or hepato-splenic and involvement of other extranodal sites is rare. Here we report an unusual case of gammadelta T cell lymphoma involving the subcutaneous tissue, vocal cords, gastric mucosa and the central nervous system with a rapidly progressive clinical course and fatal outcome. Epstein-Barr virus (EBV) was shown to be present in the tumor cells, and is thought to play a role in the pathophysiology of this particular case of lymphoma.

Adult↗
PubMed1998

Congenital atrichia in five Arab Palestinian families resulting from a deletion mutation in the human hairless gene.

Congenital atrichia is a rare autosomal recessive disorder of hair development, characterized by complete loss of hair shortly after birth. Evidence of linkage to chromosome 8p12 has been established, implicating the human homolog of the mouse hairless (hr) gene as a candidate gene. We have previously identified missense mutations in families with congenital atrichia. Here, we report the first deletion mutation (2147del C) in exon 9 of the human hairless gene leading to a frameshift and downstream premature termination codon in five Palestinian families of Arab origin.

Alopecia↗
PubMed1998

Cutaneous lymphoma in Israel, 1985-1993: a population-based incidence study.

The incidence rate of cutaneous lymphomas (CL) [including mycosis fungoides (MF) and non-mycosis fungoides (non-MF)] for the period 1985-93 in Israel was determined using data from the population-based Cancer Registry supplemented by a field survey that covered approximately 80% of lymphoma cases. After the field survey, corrected rates were 49% and 24% higher for MF and non-MF respectively (37% for CL overall). The age-adjusted incidence rates per 100,000 were 1.18 and 0.63 for Jewish men and women respectively. MF rates (0.77 in men and 0.35 in women) were higher than non-MF (0.41 and 0.28 respectively). Rates of CL were significantly lower in non-Jews. There were no significant differences in incidence among Jewish ethnic subgroups. However, the lack of variability in the incidence of these neoplasms among subpopulations is in contrast with findings for cutaneous malignant melanoma; the observed high rates of CL could, nonetheless, be consistent with the sunlight exposure hypothesis, operating perhaps through a different mechanism.

Cohort Studies↗
PubMed1998

Monilethrix: a keratin hHb6 mutation is co-dominant with variable expression.

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and hyperkeratotic papules. Mutations in type-II hair specific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 heterozygous members, and severely expressed among 3 homozygous members. These 3 patients had essentially complete lack of scalp hair since the age of 2 months with no improvement over time as well as follicular keratotic involvement extensively expressed over the scalp and large body areas. The variability seen in heterozygous patients, along with seasonal and pregnancy-related improvement suggest that other genetic or environmental factors may modify keratin gene expression. This represents the first report of a co-dominant keratin hHb6 mutation resulting in severe disease.

Base Sequence↗
PubMed1998

Screening for tumour suppressor p16(CDKN2A) germline mutations in Israeli melanoma families.

Approximately ten percent of patients with malignant melanoma have family histories of the disease, suggesting a genetic predisposition. Germline mutations in tumour suppressor p16 gene have been implicated as disease causing mutations in some of the melanoma families. The frequency of families with p16 germline mutations among melanoma prone families varies from eight to fifty percent. The range of the variability is influenced apparently by the number of melanoma affected individuals within the family, as well as by other, yet unidentified factors. Ethnic background is known to determine both the frequency and the nature of germline alterations. Recently, specific mutations in tumour suppressor genes involved in breast cancer and in colon cancer were found at elevated frequency among Ashkenazi Jews. This report describes results of a screening for p16 germline alterations in a collection of Israeli melanoma families. We have analyzed genomic DNA from thirty one Ashkenazi and non-Ashkenazi Jewish melanoma families, as well as from thirty melanoma patients without an apparent family history of the disease. The entire coding region of the p16 gene was screened by single strand conformation polymorphism analysis and direct DNA sequencing. We have detected a number of carriers with the Ala148 Thr polymorphism at the end of the second exon and several instances of 500(G=>C) substitution at the 3' untranslated portion of the gene.

Female↗
PubMed1998

South American cutaneous leishmaniasis: report of ten cases in Israeli travelers.

BACKGROUND: Cutaneous South American leishmaniasis is caused by several species of leishmaniasis. Lack of appropriate treatment may lead to mucocutaneous leishmaniasis, mainly with L. b. braziliensis and L. b. panamensis. OBJECTIVE: To describe the clinical findings of Israeli travelers infected with cutaneous South American leishmaniasis and to draw attention to this problem. SUBJECTS: Ten patients were interviewed, examined and treated. RESULTS: Twenty-two lesions of cutaneous leishmaniasis were found, all in exposed areas. Patients were seen by an average three physicians (range 1-6) before the final diagnosis was confirmed by direct smear, after an average period of 125 days (range 88-270 days). Treatment with Pentostam was started after an average period of 134 days (range 94-275 days). All lesions healed completely, but with scarring. CONCLUSION: Travelers to endemic areas, as well as physicians, should be instructed about the potential risks and the clinical manifestations of cutaneous and mucocutaneous South American leishmaniasis. Such awareness will prevent undue delay in diagnosis and treatment.

Adult↗
PubMed1997

A model for quantitative measurement of sulfur mustard skin lesions in the rabbit ear.

The search for treatment and protection against the vesicant and inflammatory skin lesions induced by sulfur mustard suffers from the lack of a good in vivo reproducible model. We applied sulfur mustard (25-500 microg/cm2) to the outer surface of the ears of 10 rabbits and measured the edema formation 12, 24 and 48 h post-application with a caliper especially designed for soft matter. There was a dose-dependent linear increase in edema magnitude in the range from 25 to 150 microg/cm2. Maximal edema was observed after 12 h. There was a 12% reduction in edema size 24 h after application and a further decrease after 48 h. Skin thickness, inflammatory cell infiltrate, necrosis and vesiculation were evaluated in biopsies taken after 24 h. We found the same dose-related increase both in skin thickness and in degree of blister formation. This simple dose-response in vivo model can be used for evaluation of the dermal inflammation induced by topical application of sulfur mustard. This model has the additional advantage of a built-in control, namely the untreated contralateral ear. Consequently, this model can serve as a useful tool for future screening of potential compounds for prevention and treatment of sulfur mustard-induced skin lesions.

Animals↗
PubMed1997

A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.

Monilethrix is a rare dominant hair disease characterized by beaded or moniliform hair which results from the periodic thinning of the hair shaft and shows a high propensity to excess weathering and fracturing. Several cases of monilethrix have been linked to the type II keratin gene cluster on chromosome 12q13 and causative heterozygous mutations of a highly conserved glutamic acid residue (Glu 410 Lys and Glu 410 Asp) in the helix termination motif of the type II hair keratin hHb6 have recently been identified in monilethrix patients of two unrelated families. In the present study, we have investigated two further unrelated monilethrix families as well as a single case. Affected members of one family and the single patient exhibited the prevalent hHb6 Glu 410 Lys mutation. In the second family, we identified in affected individuals a lysine substitution of the corresponding glutamic acid residue, Glu 403, in the type II hair keratin hHb1, suggesting that this site represents a mutational hotspot in these highly related type II hair keratins. Both hHb1 and hHb6 are largely coexpressed in cortical trichocytes of the hair shaft. This indicates that monilethrix is a disease of the hair cortex.

Amino Acid Sequence↗