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Reuven Bergman

Publications and source records attributed to Reuven Bergman.

At least 37 records · Page 2Linked to original sources
PubMed2005

Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1.

BACKGROUND: Mutations in genes coding for 2 desmosomal proteins, desmoglein 1 and desmoplakin, have been shown to cause autosomal dominant keratoderma palmoplantaris striata. OBSERVATIONS: We describe a family affected with a diffuse nonstriated form of palmoplantar keratoderma. Histopathologic examination of skin biopsy specimens disclosed cell-cell disadhesion in the suprabasal layers of the epidermis, as previously described in keratoderma palmoplantaris striata. We therefore genotyped all family members using microsatellite markers encompassing 3 keratoderma palmoplantaris striata-associated loci. Haplotype analysis suggested linkage of the disease to 18q12.1, which harbors the DSG1 gene, encoding desmoglein 1. Mutation analysis eventually led to the identification of a causative recurrent nonsense mutation in this gene. CONCLUSIONS: Mutations in DSG1 are not exclusively associated with striated palmoplantar keratoderma. The present study illustrates the efficacy of an integrative diagnostic approach to palmoplantar keratodermas involving clinical assessment, pathologic examination, microsatellite marker screening, and mutational analysis.

Arginine↗
PubMed2005

Familial mycosis fungoides: report of 6 kindreds and a study of the HLA system.

BACKGROUND: The familial occurrence of mycosis fungoides (MF) has been reported only in 8 families. Recently, the HLA class II alleles DRB1* 11 and DQB1* 03 have been found to be significantly increased for patients with sporadic MF, suggesting a possible immunogenetic basis for the pathogenesis of this malignancy. OBJECTIVE: We sought to detect familial occurrences of MF, to describe familial features, and to investigate the possible association or linkage with the HLA system in such cases. METHODS: The files of 300 patients with MF were reviewed to search for familial occurrence in at least two first-degree relatives. A group of 252 healthy unrelated individuals served as control subjects. Tissue typing for HLA class I was performed using the microlymphocytotoxicity technique. DNA-based analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction amplification. RESULTS: Six families comprising 12 Jewish patients (9 male and 3 female) were detected: in 5, two first-degree relatives had MF; and in one, one member had MF and another had parapsoriasis en plaque. There were 5 families with two affected siblings and one family with a parent-child pair. In all but one family, the age of onset, clinical features, and response to therapy were similar to those in sporadic MF. One family, however, was exceptional: both affected siblings were children and both exhibited a similar but unusual morphology in the form of a hypopigmented variant of MF in conjunction with a psoriasiform variant. The allele frequency of HLA DQB1* 03 was found to be significantly greater among the patients than in the control group (66.7% vs 33%, respectively; P = .027), supporting an association of this allele with familial MF. Analysis of the HLA typing in the affected sibling pairs, when grouped together, did not support linkage to the HLA locus because no segregation distortion could be demonstrated ( P = .76). CONCLUSIONS: Familial aggregation of MF among Israeli Jews may not be as rare as is reflected in the literature. This familial clustering, together with the detection of certain HLA class II alleles with this malignancy (sporadic and familial), suggests that genetic factors may play a role in MF.

Adolescent↗
PubMed2005

Histopathological and ultrastructural study of ectodermal dysplasia/skin fragility syndrome.

Ectodermal dysplasia/skin fragility syndrome (EDSFS) (MIM604536) is a newly described autosomal recessive disorder characterized by skin fragility and blistering, palmoplantar keratoderma, abnormal hair growth, nail dystrophy, and occasionally defective sweating. It results from mutations in the PKP1 gene encoding plakophilin 1 (PKP1), which is an important component of stratifying epithelial desmosomes and a nuclear component of many cell types. Our study was performed to further characterize the histopathology of EDSFS in different cutaneous sites with a special emphasis on the hypotrichosis and keratoderma. A total of 4 biopsies were obtained from 2 EDSFS female patients, aged 9 days to 4 years. The biopsies were taken from the blistering skin of the leg and trunk, the hyperkeratotic skin of the sole, and the hypotrichotic scalp. The observed histopathologic features included: widened intercellular spaces, suprabasal intraepidermal clefts and blisters with acantholytic keratinocytes, detachments of the upper epidermal layers due to disadhesion, varying degrees of dyskeratosis that were much more pronounced in the plantar hyperkeratotic skin, and increased number of catagen-telogen hair follicles. The electron-microscopic observations attributed the disadhesion and acantholysis to reduced numbers of small hypoplastic desmosomes, and the dyskeratosis to the detachment of intracellular keratin filaments from the desmosomes with perinuclear condensation, which might also underlie the plantar keratoderma. The hair follicle findings suggest disturbance in the hair cycle, which might be attributed to disturbed nuclear PKP1 function or result from aberrant desmosomal signaling.

Blister↗
PubMed2005

Absence of intraepidermal glycosyltransferase ppGalNac-T3 expression in familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder characterized by progressive, tumor-like calcifications in the dermis and subcutaneous tissues. The disease is associated with primary hyperphosphatemia due to increased renal tubular reabsorption of phosphate. We recently identified mutations in GALNT3 as the proximal cause of this metabolic disorder. GALNT3 encodes the glycosyltransferase UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (ppGalNAc-T3), which initiates mucin-type O-glycosylation and thus takes part in posttranslational modification and formation of mucin-type glycoproteins. A number of studies have previously described the histopathological and ultrastructural features of lesional skin in HFTC, but little is currently known about the morphology of the normal-appearing non-lesional skin. We obtained biopsies of uninvolved skin from two HFTC patients carrying a known splice site mutation in GALNT3. Light and electron microscopic examination of a biopsy of one of the two patients did not reveal abnormal findings in the epidermis or dermis. However, immunohistochemical studies of frozen skin sections of biopsies of the two patients using monoclonal antibodies directed against three ppGalNac isoforms revealed the complete absence of immunostaining for ppGalNAc-T3 while the staining pattern for ppGalNAc-T2 and -T6 was identical in skin biopsies obtained from HFTC patients and healthy control individuals. Our data provide for the first time evidence for ppGalNAc-T3 deficiency in the skin of HFTC patients and suggest that immunostaining of skin biopsy samples for ppGal-Nac-T3 might be a useful tool for the diagnosis of HFTC.

Calcinosis↗
PubMed2005

Identification of a novel locus associated with congenital recessive ichthyosis on 12p11.2-q13.

Congenital recessive ichthyoses represent a vast and markedly heterogeneous group of diseases that have been mapped to at least seven distinct chromosomal loci. In this study, we ascertained two consanguineous families presenting with congenital ichthyosis. Using homozygosity mapping, we identified a 6.5 cM homozygous region on 12p11.2-q13 shared by all affected individuals. Multipoint logarithm of odds ratio (LOD) score analysis placed the new locus between markers D12S345 and D12S390 with a maximum LOD score of 4.79 at marker CH12SSR13. This region harbors PPHLN1, encoding periphilin 1, a protein involved in the cornification process. No deleterious mutations were identified within the coding region of this gene, suggesting the existence of another gene associated with epidermal differentiation on 12p11.2-q13.

Antigens, Neoplasm↗
PubMed2005

A comparison of anti-desmoglein antibodies and indirect immunofluorescence in the serodiagnosis of pemphigus vulgaris.

BACKGROUND: Indirect immunofluorescence (IIF) is the standard method for the detection of pemphigus autoantibodies. Commercially available enzyme-linked immunosorbent assays (ELISAs) have recently become available to measure serum antibodies (Abs) against desmoglein1 (Dsg1) and desmoglein3 (Dsg3). It has been suggested that patients with mucosal-dominant pemphigus vulgaris (PV) have serum Abs against Dsg3 only, patients with mucocutaneous PV have Abs to both Dsg1 and Dsg3, and patients with pemphigus foliaceus (PF) have Abs against Dsg1 only. AIM: To compare the sensitivity and specificity of the IIF and ELISA tests in the diagnosis of pemphigus and its subsets. METHODS: Thirty-three patients with PV and five patients with PF were studied, and compared with 50 healthy individuals or patients with unrelated skin diseases. Monkey esophagus was used as a substrate for the IIF test. RESULTS: The IIF and ELISA tests were each positive in 26 of the 32 (81%) PV patients, and in none (0%) and 3 (6%) of the 50 controls, respectively. Both the IIF and ELISA results were concordant in 69% of the PV patients, and only one of these two tests was positive in the remaining 31% of patients. Forty-six per cent of the PV patients with a positive ELISA test did not have the PV phenotype (mucosal or mucocutaneous) predicted by their autoantibody profile. CONCLUSION: The IIF and ELISA tests may be used as complementary tests for the serologic diagnosis of pemphigus.

Adult↗
PubMed2004

Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.

Hyperphosphatemia-hyperostosis syndrome (HHS) is a rare autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and repeated attacks of acute, painful swellings of the long bones with radiological evidence of periosteal reaction and cortical hyperostosis. HHS shares several clinical and metabolic features with hyperphosphatemic familial tumoral calcinosis (HFTC), which is caused by mutations in GALNT3 encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whether GALNT3 is involved in the pathogenesis of HHS we screened two unrelated Arab-Israeli HHS families for pathogenic mutations in this gene. All affected individuals harbored a homozygous splice site mutation (1524+1G-->A) in GALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alter GALNT3 expression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across the GALNT3 region on 2q24-q31 revealed that the HHS and HFTC families share a common haplotype spanning approximately 0.14 Mb. Our results demonstrate that HHS and HFTC are allelic disorders despite their phenotypic differences and suggest a common origin of the 1524+1G-->A mutation in the Middle East (founder effect). The heterogeneous phenotypic expression of the identified splice site mutation implies the existence of inherited or epigenetic modifying factors of importance in the regulation of ppGalNAc-T3 activity.

Calcinosis↗
PubMed2004

Familial clustering of classic Kaposi sarcoma.

It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus (KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case.

Adult↗
PubMed2004

Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.

Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.

Base Sequence↗
PubMed2004

Histopathology of hypotrichosis with juvenile macular dystrophy.

Hypotrichosis with juvenile macular dystrophy (HJMD) (MIM 601553) is a rare disorder characterized by the paucity of hair and progressive macular degeneration leading to blindness. We have recently shown that mutations in the CDH3 gene encoding P-cadherin are the proximal cause of HJMD. The present study was performed to establish the histopathology of this disorder. 4 mm punch scalp biopsies from 6 HJMD patients aged 9 to 21 years were studied. All patients had a homozygous missense mutation resulting in a single amino acid substitution at position 503 of P-cadherin amino acid sequence (R503H). The total number of hair follicles varied between 6 and 14 per histologic section. More catagen-telogen hair follicles were observed in five cases, and an increased ratio of vellus hair follicles to terminal hair follicles was observed in two cases. There were no signs of inflammation or scarring. Thus, the most frequent histologic abnormality in HJMD resembles chronic telogen effluvium. This suggests that absence of functional P-cadherin interferes with normal hair cycle.

Adolescent↗
PubMed2004

Homozygous splice site mutations in PKP1 result in loss of epidermal plakophilin 1 expression and underlie ectodermal dysplasia/skin fragility syndrome in two consanguineous families.

During the last years, a growing number of inherited skin disorders have been recognized to be caused by abnormal function of desmosomal proteins. In the present study, we describe the first female individuals affected with the ectodermal dysplasia/skin fragility syndrome (MIM604536), a rare autosomal recessive disease due to mutations in the PKP1 gene encoding plakophilin 1, a critical component of desmosomal plaque. One patient was shown to carry a homozygous splice site mutation in intron 4. The second patient displayed a homozygous recurrent mutation affecting the acceptor splice site of intron 1. Both mutations were associated with intraepidermal separation, widening of intercellular spaces, and abnormal desmosome ultrastructure, and were found to result in the absence of immunoreactive plakophilin 1 in the epidermis of the affected individuals. These two cases emphasize the role of molecular genetics in the assessment of congenital blistering in newborns and illustrate the importance of proper desmosomal activity for normal epidermis development and function.

Child, Preschool↗
PubMed2004

Insect bite-like reaction associated with mantle cell lymphoma: a report of two cases and review of the literature.

BACKGROUND: An insect bite-like reaction and exaggerated reactions to insect bites are nonspecific phenomena described primarily in association with chronic lymphocytic leukemia (CLL), but also with other hematological malignancies. Two cases of mantle cell lymphoma (MCL), one associated with an insect bite-like reaction and the other with a true hypersensitivity to mosquito bites, have previously been reported in the English language literature. The pathogenesis of the skin eruption may be related to the release of different cytokines that also trigger an IgE elevation and dermal eosinophils. CASE REPORT: We describe two additional cases of MCL associated with an insect bite-like reaction. One patient had been diagnosed with MCL 4.5 years prior to the appearance of the skin eruption, and in the other patient the skin symptoms preceded the diagnosis of the MCL by 2 years and led to its diagnosis. CONCLUSIONS: Insect bite-like reaction may appear in patients with MCL. It is important to recognize this entity because it may be the presenting sign of MCL.

Diagnosis, Differential↗
PubMed2003

Epidermolysis bullosa simplex in Israel: clinical and genetic features.

BACKGROUND: Epidermolysis bullosa simplex (EBS) is the most common form of epidermolysis bullosa. The disease is characterized by intraepidermal blistering due in most cases to mutations in cytokeratin genes 5 (K5) or 14 (K14). Extensive studies in the United States and Europe have shown that EBS is almost always inherited in an autosomal dominant fashion. OBJECTIVE: To assess the possibility that the molecular features of EBS may differ according to the type of population studied. DESIGN: We assessed 10 Israeli families diagnosed as having EBS and compared their clinical and genetic features with previous observations. Affected individuals underwent complete clinical evaluation. DNA from all family members was assessed for mutations in K5 or K14 using polymerase chain reaction amplification, direct sequencing, and subsequent mutation verification. In addition, specific cases were genotyped using a panel of microsatellite markers spanning the K14 locus. RESULTS: Eight distinct pathogenic mutations in K5 (3 mutations) and K14 (5 mutations) were identified. Six of these mutations are novel. The mutations included 2 nonsense mutations and 6 missense mutations. A third of the affected families inherited EBS in a recessive fashion, in contrast with previous observations in Europe and the United States. In addition, we identified a unique case that resulted from compound heterozygosity for a missense and a nonsense mutation in K14. Homozygous nonsense mutations were strongly associated with a severe phenotype. CONCLUSION: The present study demonstrates a unique mutation spectrum and a strikingly different pattern of inheritance for EBS in a series of Israeli families compared with families of European or US extraction.

Codon, Nonsense↗