Selenium deficiency: report of a case.

We report an 18-month-old Japanese boy with selenium deficiency. He had dry skin with irregularly shaped, erythematous changes on the cheeks, groin, hip, and extremities, erosions on the external urethral and anal orifices, and sparse, short, thin, light-coloured hair. He had received parenteral nutrition for 5 months because of juvenile polyposis. At presentation, his serum selenium level was less than 2.0 microg/dL (normal range, 10.6-17.4 microg/dL). His skin lesions responded well to supplementary treatment with sodium selenite. His skin symptoms were similar to those attributable to a deficiency of zinc which, like selenium, is an essential trace element. According to the literature, selenium deficiency is responsible for cardiomyopathy, which was diagnosed in our patient. The clinical similarity to zinc deficiency and the literature yielded important clues for a diagnosis of selenium deficiency in this patient.

Morphological and biochemical studies of human beta-mannosidosis: identification of a novel beta-mannosidase gene mutation.

BACKGROUND: There are seven well-known lysosomal storage diseases that produce angiokeratoma corporis diffusum clinically. beta-Mannosidosis (MANB1; OMIM248510), first reported in humans in 1986, is a rare hereditary lysosomal storage disease caused by a deficiency of the enzyme beta-mannosidase. Since then, 13 cases of beta-mannosidase deficiency in ten families have been described. A human beta-mannosidase mutation has been reported only by Alkhayat et al. in 1998. OBJECTIVES: To clarify its pathogenesis we did electron microscopic, biochemical and molecular biological investigations of a Japanese patient with beta-mannosidosis. METHODS: Ultrastructural analyses, enzyme assays, cell culture and mRNA and genomic DNA were sequenced to find mutations in the beta-mannosidase gene. RESULTS: Electron microscopy of skin biopsy specimens from the patient showed cytoplasmic vacuolation of lysosomes in blood and lymph vessels, endothelial cells, fibroblasts, secretory portions of eccrine sweat glands, neural cells and basal keratinocytes in the epidermis. This vacuolation was also observed in cultured keratinocytes and fibroblasts. Assays of seven enzyme activities in plasma and cultured skin fibroblasts showed a marked decrease of beta-mannosidase activity. Sequencing the beta-mannosidase cDNA revealed a four-base (ATAA) insertion between exons 7 and 8, resulting in a frameshift at codon 321 and termination at codon 325. Analysis of the patient's genomic DNA revealed a novel homozygous A(+1)-->G splice site mutation in intron 7. CONCLUSIONS: To our knowledge, this is the first case of beta-mannosidosis reported in Japan and the second report in which a gene mutation is identified. The biological importance of beta-mannose moieties in glycoproteins in basal keratinocytes is suggested.

Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome.

BACKGROUND: Germline missense mutations in the GJB2 gene that encodes connexin-26 (Cx26) have recently been found to be the cause of the keratitis-ichthyosis-deafness (KID) syndrome. OBJECTIVES: To define the GJB2 mutations in three Japanese patients with KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used to amplify the GJB2 gene. Direct sequencing and endonuclease digestion were used for mutation analysis and DNA-based diagnosis. RESULTS: We identified two heterozygous mis-sense mutations (D50Y, D50N) in the GJB2 gene in three Japanese patients with KID syndrome. All mutations were located on the first extracellular domain of Cx26. CONCLUSIONS: These data expand the GJB2 mutation database and show that a dominant mutation of Cx26 can cause KID syndrome in Japanese patients.

A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière's syndrome and without mental retardation.

alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described. We report a further case in a 47-year-old Japanese woman, the product of a consanguineous marriage. The remarkable findings in this patient were her normal intelligence, Ménière's syndrome, disturbance of peripheral sensory nerves, hearing loss and cardiac hypertrophy. alpha-NAGA enzyme activity in her plasma was 0.77% of the normal value. Other enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-L-fucosidase, beta-mannosidase and aspartylglucosaminidase, were within normal limits. A large quantity of amino acid O-glycans was detected in her urine. Gene analysis revealed a novel point mutation (G-->A transition) at nucleotide 11018 (986 in the cDNA) resulting in an Arg-329-Gln substitution. Kanzaki disease has the same enzyme defect as Schindler disease, but the manifestations are quite different.

Analyses of the transglutaminase 1 gene mutation and ultrastructural characteristics in a Japanese patient with lamellar ichthyosis.

We described a Japanese female with lamellar ichthyosis whose transglutaminase 1 gene (TGM1 gene) was mutated. DNA sequence analysis revealed that the patient had a homozygous mutation, i.e. a point mutation from G to A at nucleotide 1494 resulting in the substitution of glycine for arginine at codon 143. Her mother was heterozygous for this mutation. In situ transglutaminase assay in the patient's skin showed loss of enzyme activity. Ultrastructural examination revealed incomplete formation of cornified cell envelopes and electron-dense materials adjacent to plasma membranes. These results suggest that defective transglutaminase activity caused by homozygous TGM1 gene mutation (G143R) results in disruption of cornified envelope assembly and the clinical phenotype of lamellar ichthyosis.

Early onset sarcoidosis masquerading as juvenile rheumatoid arthritis.

Symptoms of early onset sarcoidosis characterized by skin eruptions, arthritis, and uveitis mimic those of systemic type juvenile rheumatoid arthritis (JRA). We report 2 Japanese patients with early onset sarcoidosis, both of whom were initially diagnosed and treated as having JRA. Intermittent fever and synovial swelling may mask sarcoidosis in children less than 4 years old.

A case of symptomatic heterozygous female Fabry's disease without detectable mutation in the alpha-galactosidase gene.

We report a case of symptomatic heterozygous female Fabry's disease with low alpha-galactosidase blood activity. We could not find any mutations in the coding regions of either the signal peptide or the enzyme subunit in our case.

[Autopsy case of adenoid cystic carcinoma of the trachea: endobronchial treatment improves quality of life].

A 67-year-old man presented with dyspnea on exertion. Bronchoscopic examination revealed a tumor arising from the middle portion of the trachea and extending to the right main bronchus. The pathological diagnosis was adenoid cystic carcinoma. Radiotherapy and subsequent endobronchial electrocautery were performed, and elicited a partial response. In the clinical course. Dumon and Ultraflex stents were placed in the trachea asynchronically. Brachytherapy and esophageal stent placement were also performed for tumor control in the trachea and esophagus. Autopsy revealed that the tumor had invaded the trachea and esophagus, and bacterial mediastinitis was also demonstrated. Because the tumor was successfully controlled during the following 4 years and 9 months, we concluded that endobronchial therapy such as stent placement or electrocautery is useful for maintaining good quality of life.

A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis.

A nerve growth factor receptor encoded by the TRKA gene plays an important part in the formation of autonomic neurons and small sensory neurons in dorsal root ganglia and in signal transduction through its intracytoplasmic tyrosine kinase domain. Recently, three mutations in the tyrosine kinase domain of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterized by recurrent fever due to absence of sweating, no reaction to noxious stimuli, self-mutilating behavior, and mental retardation. We examined the TRKA gene in five generations of a large Japanese family with many consanguineous marriages who live in a small remote island of the southern part of Japan. We found a novel point mutation at nucleotide 1825 (A-->G transition) resulting in Met-581-Val in the tyrosine kinase domain. Two of the three affected patients were homozygous for this mutation; however, the third affected patient was heterozygous. Further analysis revealed that the third patient was a compound heterozygote with the Met-581-Val mutation in one allele and with a single base C deletion mutation at nucleotide 1726 in exon 14 in the other allele, resulting in a frameshift and premature termination codon.

Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse.

Adrenomedullin (AM) is a newly discovered hypotensive peptide which is believed to play an important role for blood pressure control in the adult. Although it has been well established that a major production site of AM is vascular endothelial cells, we now show that AM is most highly expressed in trophoblast giant cells, which are derived from the conceptus and are directly in contact with maternal tissues at the implantation site. Northern blot and in situ hybridization analyses show that the AM mRNA begins to be detected just after implantation and its level peaks at 9.5 days postconception (d.p.c.) in those cells. Expression then falls dramatically after 10.5 d.p.c., coincident with the completion of the mature chorioallantoic placenta. Immunohistochemical analyses show that the AM peptide is secreted from the trophoblast giant cells into the surrounding tissues, i.e., embryo, decidua, and maternal circulation. In contrast, the expression of an AM receptor was not detected by Northern blot analyses in either embryo or trophoblast giant cells at 7 d.p.c., when the AM gene is most highly expressed in the trophoblast giant cells. This suggests that the AM produced and secreted from the embryo's trophoblast giant cells acts on the maternal tissues rather than on the embryonic tissues. Based on these results, we propose that the high production of AM may be the mechanism by which the embryos survive at the early postimplantation period by pooling maternal blood in the implantation site in order to secure nutrition and oxygen before the establishment of efficient embryo-maternal circulation through the mature placenta.

Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome.

Mammalian embryos can only survive if they attach to the uterus (implantation) and establish proper maternal-fetal interactions. To understand this complex implantation pathway, we have initiated genomic analysis with a systematic study of the cohort of genes expressed in extraembryonic cells that are derived from the conceptus and play a major role in this process. A total of 2103 cDNAs from the extraembryonic portion of 7.5-day post-conception mouse embryos yielded 3186 expressed sequence tags, approximately 40% of which were novel to the sequence databases. Furthermore, when 155 of the cDNA clones with no homology to previously detected genes were genetically mapped, apparent clustering of these expressed genes was detected in subregions of chromosomes 2, 7, 9 and 17, with 6.5% of the observed genes localized in the t-complex region of chromosome 17, which represents only approximately 1.5% of the mouse genome. In contrast, X-linked genes were under-represented. Semi-quantitative RT-PCR analyses of the mapped genes demonstrated that one third of the genes were expressed solely in extraembryonic tissue and an additional one third of the genes were expressed predominantly in the extraembryonic tissues. The over-representation of extraembryonic-expressed genes in dosage-sensitive autosomal imprinted regions and under-representation on the dosage-compensated X chromosome may reflect a need for tight quantitative control of expression during development.

Staining of eccrine and apocrine neoplasms and metastatic adenocarcinoma with IKH-4, a monoclonal antibody specific for the eccrine gland.

The histogenesis of apocrine and eccrine neoplasms has always interested dermatopathologists. In addition, the histologic differential diagnosis of eccrine carcinoma from metastatic adenocarcinoma is of practical importance. We describe a novel monoclonal antibody IKH-4 which stains the eccrine secretory coil, but not the apocrine secretory segment. Positive staining was observed in eccrine hidradenoma, eccrine poroma, eccrine spiradenoma, papillary eccrine adenoma, eccrine hidrocystoma, syringoma, eccrine carcinoma, and in 1 case of syringocystadenoma papilliferum. Negative staining was observed in apocrine adenocarcinoma, hidradenoma papilliferum, erosive adenomatosis of the nipple, and primary and metastatic adenocarcinomas. IKH-4 antibody was useful in differentiating eccrine from apocrine neoplasms and in differentiating eccrine carcinoma from metastatic adenocarcinomas.

A case of chromomycosis with tumor-like growth.

A 66-year-old woman who lived on Tokunoshima Island, a small and remote southern island of the Japanese archipelago, had suffered from chromomycosis for more than 30 years and presented with a tumor-like growth on the posterior crural region of his right leg. Fonsecaea pedrosoi was identified as the pathogen from its growth pattern and micromorphological characteristics. The patient was successfully treated with 5-fluorocytosine, itoraconazole, and topical thermotherapy.

Cloning and expression analyses of mouse dystroglycan gene: specific expression in maternal decidua at the peri-implantation stage.

While constructing a catalog of mouse cDNAs which are expressed in the maternal-fetal interface during the peri-implantation period, we encountered a 1.6 kb cDNA clone showing a strong sequence similarity to the 3' untranslated region of the human dystroglycan gene. We cloned an additional 1.7 kb cDNA by reverse transcriptase-PCR (RT-PCR) and confirmed that this is a true mouse homolog of human dystroglycan cDNA by sequence analyses, Southern blotting, and genetic mapping of this gene on the distal region of mouse chromosome 9. Although it is well established that dystroglycan, a transmembrane protein, plays an important role in muscle tissues by bridging intracellular dystrophin to the laminin in the extracellular matrix, its role in non-muscle tissues remains elusive. To further investigate the role of the dystroglycan gene at the peri-implantation stage, we analyzed the expression patterns of this gene by in situ hybridization, which revealed that this gene is specifically expressed in decidual cells, especially in the cells surrounding the implantation site at 6.5, 7.5, and 8.5 day post conception (p.c.) stages, but not expressed in non-pregnant endometrial cells of uterus nor in the decidua at 12.5 day p.c. Further analyses by RT-PCR confirmed that the amount of dystroglycan mRNA in 8.5 day p.c. decidua was indeed 100-fold higher than that of non-pregnant uterus and 12.5 day p.c. mature placenta. These results suggest that dystroglycan may work as a mediator for adhesion between decidual cells themselves or between decidual cells and trophoblast cells, and provide a structural and functional support for maintaining pregnancy at its early stage.

Chronic lupoid leishmaniasis. Evaluation by polymerase chain reaction.

BACKGROUND: The cutaneous lesions in chronic lupoid leishmaniasis resemble those of lupus vulgaris, both clinically and histologically. The differential diagnosis is difficult and may depend on the detection of a few Leishmania amastigotes in the histologic sections, the growth of the promastigotes in cultures, or the identification of amastigotes by other techniques. Polymerase chain reaction was used to detect Leishmania amastigote DNA in tissue samples obtained from 65 patients with chronic lupoid leismaniasis, and the results were confirmed by Southern blot analysis. OBSERVATIONS: The histologic findings of a predominantly epithelioid cell granuloma surrounded by lymphocytic infiltrate in chronic lupoid leishmaniasis are very similar to those observed in lupus vulgaris. Extensive histologic examination of the sections in this series revealed occasional macrophages containing a few amastigotes in only 12 cases. Cultures in NNN medium yielded Leishmania promastigotes in 20 cases. Polymerase chain reaction studies using a Leishmania-specific primer identified Leishmania DNA in 30 of 63 cases, and those using a Mycobacterium tuberculosis primer were found to be negative for mycobacteria in 47 cases tested, including 11 cases with a positive tuberculin skin reaction. CONCLUSIONS: The histologic findings in chronic lupoid leishmaniasis resemble those of lupus vulgaris. Polymerase chain reaction studies were useful in identifying amastigotes in 30 (47.6%) of 63 cases. This study confirms the presence of DNA molecules of Leishmania amastigotes in samples of formalin-fixed, paraffin-embedded granulomatous tissue obtained from patients with chronic lupoid leishmaniasis.