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Biomedical subjects

K Fujieda

Publications and source records attributed to K Fujieda.

At least 37 records · Page 2Linked to original sources
PubMed1999

Gene amplification as a common cause of inherited thyroxine-binding globulin excess: analysis of one familial and two sporadic cases.

T4-binding globulin (TBG) is the major thyroid hormone transport protein in humans. Inherited abnormalities in the level of serum TBG have been classified as partial deficiency, complete deficiency and excess. A single nucleotide deletion or substitution in the TBG gene, located on Xq22, has been detected in partial and complete deficiencies. As for inherited TBG excess, the gene amplification has been recognized in two Japanese families recently. In this study, an additional three Japanese families, one familial (F-I) and two sporadic TBG excess (F-II, F-III), were analyzed. Serum TBG levels in hemizygous males were 73, 47 and 42 microg/ml, three- to two-fold the normal value. The molecule had normal properties in terms of heat stability and isoelectric focussing pattern. The gene dosage of TBG was evaluated by coamplification with autosomal betaGlobin or X-chromosomal Duchenne Muscular Dystrophy (DMD) and subsequent quantitation by HPLC. The TBG/betaGlobin ratios of the affected male and female of F-I were 3.09- and 3.86-times, respectively, compared to that of the normal males. The TBG/DMD ratios were 2.93- and 2.09-times, respectively. These results are compatible with three copies of the TBG gene on the affected X-chromosome. Similarly, a twofold increase in gene dosage was demonstrated in the affected males of sporadic cases. Their mothers with normal TBG values had the same TBG gene dosage as normal females, suggesting that de novo gene duplication arose in gametes probably during meiosis. Amplification of the TBG gene was not recognized in these three families by in situ hybridization of prometaphase chromosomes. Though the mechanism remains unproved, gene amplification of TBG was considered to be a common cause for inherited TBG excess.

Female↗
PubMed1999

A Japanese case with Frasier syndrome caused by the splice junction mutation of WT1 gene.

The Wilms' tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and also subsequent normal function of this system. Recently, the splice mutations in intron 9 of WT1 gene have been detected in Frasier syndrome, which is characterized by streak gonads, pseudohermaphroditism, slowly progressive nephropathy and frequent development of gonadoblastoma. Here to elucidate the molecular basis in a Japanese patient of Frasier syndrome, WT1 gene was analyzed by polymerase-chain-reaction (PCR) and direct sequencing. We identified the splice junction mutation in intron 9 of WT1, which is recognized as a mutation hot-spot in intron 9. This finding concludes that 1) the mutation in intron 9 might be the cause of Frasier syndrome, and 2) the mutation hot-spot in Japanese and Caucasian patients is similar.

Adolescent↗
PubMed1999

21-Hydroxylase deficiency presenting as massive bilateral adrenal masses in the seventh decade of life.

A 72-year-old woman was found to have massive bilateral adrenal masses on computed tomography and was diagnosed with 21-hydroxylase deficiency (21-OHD) based on endocrinological findings. Physical examination revealed no abnormalities except markedly short stature. She was diagnosed with 21-OHD because she had an elevated serum 17alpha-hydroxyprogesterone (17-OHP) level which significantly decreased in response to dexamethasone. Percutaneous CT-guided biopsy and later autopsy confirmed that the adrenal masses were due to adrenocortical hyperplasia. Analysis of the CYP21 gene revealed that the patient was a compound heterozygote for the Ile-172-->Asn mutation in exon 4 and the 8-bp deletion in exon 3. Simple virilizing 21-OHD (SV) would be predicted from this genotype. She had few symptoms associated with 21-OHD except for markedly short stature, but the serum 17-OHP level was higher than that of typical nonclassical form of 21-OHD and near to that of typical SV. This finding was confirmed by analysis of the CYP21 gene. From these results, we report that when adrenal masses are incidentally detected, 21-OHD should be ruled out to avoid excessive examination and surgery on the suspicion of adrenal carcinoma.

Adrenal Cortex↗
PubMed1999

Height responses in complete idiopathic growth hormone deficient children less than three years of age during growth hormone therapy. Executive Committee of the International Cooperative Growth Study in Japan.

To know the effect of the age factor on growth response to growth hormone (GH) therapy in patients less than three years of age with complete idiopathic growth hormone deficiency (GHD). One hundred thirty-seven prepubertal children with complete idiopathic GHD from the database of the International Growth Cooperative Study (ICGS) of Japan for more than two years were analyzed. The patients were divided into four groups according to age at the start of GH therapy; group 1, < or = three years, group 2, three to < or = six years, group 3, six to < or = nine years, group 4, >nine years. In group 1 the mean birth weight SDS of -0.17 was not the lowest. Patients in group 1 had the lowest HSDS (-4.53) at the start of the therapy (P<0.01). During two years of the treatment, the mean HSDS improved from -4.53 to -2.15 with an increase in mean SD score of 2.12 in group 1, but in group 4 it was only 0.92 (P<0.01). In group 1, the mean HSDS declined from -0.17 at birth to -4.53 progressively. Delta height SDS during the first year of treatment in Group 1 was 1.59 SD, which is the highest. The decrease in %overweight during the first year showed that in group 1, the reduction in adiposity was the greatest among the groups (P<0.05). Our data showed that in children with complete GHD less than three years of age, there was severe growth failure, and the onset was not in the prenatal period, but in the postnatal period. Early detection of GHD and therapy with GH is important because normalization of height may be achieved earlier than in older age groups.

Age Factors↗
PubMed1999

Newborn screening for congenital adrenal hyperplasia in Sapporo City: sixteen years experience.

A screening program for congenital adrenal hyperplasia (CAH) in Sapporo began in 1982, 7 years prior to the introduction of the national program. Since its inception, testing has involved the detection of 17-hydroxyprogesterone (17-OHP) in dried blood samples, using ELISA. Up to the end of March 1998, of 298,731 newborn screened, second samples were requested in 1,723 cases (0.6%). This number included 789 newborns who weighed less than 2,000 gm at birth. A total of 14 cases were diagnosed with 21-hydroxylase deficiency (21-OHD). "Salt-wasting type (SW)" outnumbered "simple virilizing type (SV)" by 11:3. The ratio of male to female was a converse. but unrelated, 3:11. Our study from 1982-1997 revealed that the incidence of 21-OHD in Sapporo City was 1:21.338, markedly similar to the worldwide incidence of 1:15,000. In order to improve the program, other type of analysis are also currently in use and under evaluation. These include highly sensitive HPLC analysis for 17-OHP and molecular analysis to identify some mutations associated with the 21-OHD gene (CYP21). These methodologies are very useful for the confirmation of information acquired from dried blood specimens.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Occult neurohypophyseal germinomas in patients presenting with central diabetes insipidus.

Although neurohypophyseal germinoma is known be a common initial symptom in cases of diabetes insipidus (DI), its radiological detection may take months or years even by a high-resolution magnetic resonance (MR) imaging. The term "occult neurohypophyseal germinoma" denotes such cases, but its clinical picture remains obscure. Of seven patients with neurohypophyseal germinoma presenting with DI during the last 5 years, three patients showed no evidence of tumor at the onset of DI and were treated as "idiopathic" DI. Neurohypophyseal germinoma was eventually diagnosed in these three patients as the tumor became evident on sequential MR imaging studies and the patients were successfully treated with chemotherapy and radiation therapy. To delineate the clinical features of the occult neurohypophyseal germinoma, the authors analyzed endocrinological aspects and MR images in these patients and compared them with those in two patients with true idiopathic DI and four patients with overt neurohypophyseal germinoma and DI. Nine previously reported cases in the literature were reviewed. During the stage at which the germinoma gave no notable change on MR images, patients often displayed anterior pituitary dysfunction, particularly growth hormone (GH) deficiency, or an elevation of serum or cerebrospinal fluid human chorionic gonadotropin-beta. Preceding the appearance of an obvious tumor mass, a slight swelling of the pituitary stalk with loss of normal hyperintensity of the posterior pituitary lobe was a common finding on MR imaging. Central DI associated either with an enlarged stalk, decreased GH secretion, or an elevated serum human chorionic gonadotropin-beta should prompt the diagnosis of an occult germinoma.

Journal Article↗
PubMed1998

Prenatal identification of mos 45,X/46,X,+mar in a normal male baby by cytogenetic and molecular analysis.

We report a case of mos 45,X/46,X,+mar, diagnosed prenatally by amniocentesis, whose physical examination, including external and internal organs, along with serum testosterone values were normal five years after delivery. The mosaic karyotype was seen in 146 of 240 cells examined (amniotic fluid cells, 110/65; placental chorionic villi: 5/4; cord blood, 21/81; cultured skin fibroblasts, 10/90) from 386 metaphases, and the marker chromosome appeared as a small non-fluorescent acrocentric chromosome. All autosomes appeared normal, and no normal Y chromosome could be demonstrated. Analysis of 26 Y-chromosome loci by molecular techniques such as PCR, Southern analysis using multiple Y-specific DNA probes, and Hae III restriction endonuclease assessment of male-specific repeated DNA in the heterochromatic region of the Y chromosome, and fluorescence in situ hybridization (FISH), revealed the marker was derived from a Y chromosome including p terminal to q11.23, and paracentric inversion in the remaining Y long arm. The formation of testes can be considered as existence of SRY (sex-determining region of Y) as a testis-determining factor. The present report illustrates the importance of FISH and molecular techniques as a complement to cytogenetic methods for accurate identification and characterization of chromosome rearrangements in prenatal diagnosis.

Adult↗
PubMed1998

The effects of estrogen deficiency on glycosylation of odontoblasts in rats.

To investigate the effects of estrogen deficiency on odontoblast metabolism, we induced osteoporosis in rats by ovariectomy and examined the glycosylation of the matrix component in odontoblasts. Peanut agglutinin (PNA) lectin histochemistry, which detects D-galactose and N-acetylgalactosamine sugars, was conducted in incisor odontoblasts of ovariectomized (OVX) and sham-operated (sham) rats. At 5 wk after the operation, bone mineral density and serum level of estrogen in OVX rats were lower than those in sham rats. PNA binding sites were found in the odontoblasts in incisors, and the binding sites in OVX rats were much stronger than those in sham rats. Furthermore, PNA binding sites were localized at the predentin matrix in OVX rats, but the reaction in sham rats was not detected. Because D-galactose and N-acetylgalactosamine sugars bound to PNA are important constituents of proteoglycans in dentin matrix and the PNA binding sites reflect the proteoglycan production of odontoblasts, these results indicated that galactosyl glycosylation of proteoglycans in odontoblasts is influenced by estrogen deficiency in rat incisors.

Acetylgalactosamine↗
PubMed1998

Seminoma in a postmenopausal woman with a Y;15 translocation in peripheral blood lymphocytes and a t(Y;15)/45,X Turner mosaic pattern in skin fibroblasts.

We report an unusual case of a 55 year old Japanese woman with a seminoma but relatively normal menses. The patient was a phenotypic female with late onset menarche (18 years of age), who was amenorrhoeic for the first year, followed by menses of one to three days' slight flow with dysmenorrhoea, but an otherwise normal menstrual history. A typical seminoma was removed from the left adnexal region and an immature testis was identified separately as an associated right adnexal mass. Repeated karyotypic studies on peripheral blood lymphocyte cultures showed only 46,X,-Y,t(Y;15)(q12;p13). Cytogenetic examination of the patient's younger brother, who had fathered three healthy children, showed an identical karyotype. Mosaicism of 46,X,-Y,t(Y;15)(q12;p13)/45,X cell lines was found in skin samples from the patient's elbow and genital regions, although there were no clinical stigmata of Turner syndrome. An androgen receptor binding assay of cultured genital skin fibroblasts was negative. Molecular analysis using Southern blot hybridisation, PCR, and direct DNA sequencing showed that neither the patient nor her brother had a detectable deletion or other abnormalities of Y chromosome sequences, including the SRY (sex determining region of the Y chromosome) gene sequence. These findings suggest that Turner mosaicism of the 45,X cell line may have contributed to this atypical presentation in an XY female, although we cannot exclude abnormalities of other genes related to sex differentiation.

Blotting, Southern↗
PubMed1998

High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures.

A missense and loss of function mutation of the Na+/I- symporter (NIS) gene, T354P [Thr354-->Pro (ACA-->CCA)], was found in the homozygous state in two unrelated Japanese patients with iodide transport defect. In this study we have identified the homozygous T354P NIS germline mutation in seven Japanese patients, including one previously reported, from five unrelated families. No other nucleotide changes were found in the coding regions and the exon-intron boundaries of the NIS gene in these seven patients. These results suggest a common prevalence of the T354P mutation in Japanese patients. Although these seven patients have the identical NIS mutation, T354P, marked heterogeneity in clinical pictures, especially concerning goiter and hypothyroidism, were noted among them. Therefore, another factor(s), but not the nature of the NIS mutation, may account for the clinical heterogeneity among patients with the iodide transport defect. We have previously reported that the NIS messenger ribonucleic acid was markedly increased in the thyroid of a patient with the homozygous T354P mutation. In this study we demonstrated that the NIS proteins in the patients' thyroids were significantly increased (approximately 10-fold) by Western blot analysis of integral membrane proteins using an antibody against the C-terminal peptide of the human NIS. Furthermore, we showed by immunohistochemical staining that the T354P mutant NIS proteins were overexpressed in the basal and lateral plasma membranes of patients' thyrocytes.

Adult↗
PubMed1998

Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.

Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient's fibroblasts showed normal binding of IGF-I, normal phosphorylation of the beta-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous s.c. injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both s.c. injection and continuous s.c. infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-I-deficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.

Blood Glucose↗
PubMed1998

Prenatal diagnosis of steroid 21-hydroxylase deficiency by the modified polymerase chain reaction to detect splice site mutation in the CYP21 gene.

A splicing junction mutation at nucleotide 656 (A-> G substitution, I2G) in the steroid 21-hydroxylase gene (CYP21) is the most frequently detected mutation in patients with the salt-wasting and simple-virilizing forms of steroid 21-hydroxylase deficiency (approximately 60%). In this disease, prenatal diagnosis and treatment to minimize the effects of excess androgen in affected females has been advocated. Therefore, to detect the I2G mutation rapidly, accurately, and without the use of radioisotope, we developed a modified polymerase chain reaction (PCR) with a mismatched 3' nucleotide primer to introduce a new restriction site upon PCR amplification of the mutant allele. This allowed the mutant allele to be identified readily by restriction enzyme digestion of the PCR product, and subsequently this PCR product was subjected to restriction enzyme digestion for diagnosis. Chorionic villus biopsy samples (CVS) were obtained at 10 to 11 weeks gestation from two females carrying fetuses at risk for steroid 21-hydroxylase deficiency. Prenatal diagnosis was successful in both cases. One affected female was treated with dexamethasone to term. In the other case, treatment was withdrawn at an early stage when testing revealed a normal fetus. The results demonstrate the rapid and accurate detection of the I2G mutation by this method, thereby indicating the feasibility of for prenatal diagnosis of the I2G mutation.

Adrenal Hyperplasia, Congenital↗
PubMed1998

Timing for discontinuation of treatment with a long-acting gonadotropin-releasing hormone analog in girls with central precocious puberty. TAP-144SR CPP Study Group.

The optimal timing for discontinuing treatment with a long-acting gonadotropin-releasing hormone (GnRH) analog (TAP-144SR) was investigated in patients with central precocious puberty (CPP). Thirty-five girls with CPP (21 with idiopathic disease and 14 with organic disease) were treated with the analog for 3 to 5 years. No significant differences were seen between the idiopathic and the organic CPP in the suppressive effect of bone maturation. Advancement of bone maturation was noticeably suppressed during the period between bone ages (BA) of 11.0 and 11.9. The height standard deviation score (Ht-SDS) for BA was consistently improved from 10 to 11.5 years of BA, and patients reached peak Ht-SDS at a BA of 11.5 years. The deltaHt-SDS (annual change in Ht-SDS) was noticeably decreased at BA over 12 years in spite of prolongation of the treatment. In the eight patients who have reached final height, the average Ht-SDS was -0.49 at end of the treatment (BA 11.7 years) and the final Ht-SDS was - 1.1 SD, respectively. Predicted adult height at the end of the treatment was significantly higher than the actual final height (P<0.01). The results suggest that a fall in Ht-SDS for BA which usually occurs at approximately 12 years of BA, is an indication for cessation of the treatment with TAP-144SR, and residual growth potential judged solely from BA may be decreased in girls with CPP after discontinuation of the treatment.

Age Determination by Skeleton↗
PubMed1998

Registration system for growth hormone (GH) treatment with standardized immunoreactive GH values in Japan.

The Foundation for Growth Science has been controlling the use of GH by its registration system, which includes a scoring system for the eligibility for GH treatment according to the diagnostic criteria for GH deficiency (GHD) established by the Study Group for Hypothalamo-pituitary Disorder of the Ministry of Health and Welfare. Until 1995, 28,876 patients with GHD (19,432 boys and 9,444 girls) had been registered as eligible for GH treatment. The number of patients registered in a year increased gradually till 1990 due to the unlimited hGH supply by recombinant techniques and the change in the criteria for GH treatment and the number registered became stable after 1990. The frequency of GH-treated patients is calculated to be 55.2/100,000 persons (72.2/100,000 in boys and 37.1/100,000 in girls) in patients born between 1960 and 1990. The highest frequency was 148.4/100,000 persons (191.7/ 100,000 boys and 103.7/100,000 girls) in 1981, when 2,278 patients (1,508 boys and 770 girls) were born. Eligibility for GH treatment is assessed according to the scoring system which is basically dependent on peak GH values in provocation tests so that standardization of GH values measured with the various commercial GH kits is required to avoid inequality of patients' access to the treatment. In samples obtained by GRF test in 10 normal volunteers, hGH was measured with seven human GH (hGH) kits at a laboratory center. Since the RIA value has been used historically for the diagnosis of GHD, the mean of two RIA measurements was selected as the basis for the standardization procedure and the linear regression formula was used for each hGH kit. After the freely available supply of hGH obtained by recombinant DNA techniques, the role of the Foundation for Growth Science has changed to avoid hGH abuse. Even with this regulation, the frequency of registered patients may indicate a tendency to GH overuse.

Child↗
PubMed1998

Mutations of the CYP21 gene in nonclassical steroid 21-hydroxylase deficiency in Japan.

To determine whether nonclassical steroid 21-hydroxylase deficiency in Japan has the same molecular basis as in western countries, we have characterized the mutations of the CYP21 gene in 7 Japanese patients with nonclassical (NC) steroid 21-hydroxylase deficiency. In the Japanese NC cases the P30L was present in one allele in 5 of the 7 patients and on both alleles in one patient. By contrast, the V281L mutation, which was present in about 60% of NC cases in western countries, was not identified in any patient. Among our 7 cases, 4 were detected through neonatal mass screening by a mild increase in serum 17-hydroxyprogesterone (without any symptoms of CAH) at birth, but the 2 cases who were diagnosed as adults were born before nationwide neonatal screening was instituted, so that the Japanese neonatal screening program does detect some cases of NC steroid 21-hydroxylase deficiency. We suggest that P30L mutation is more frequent in Japanese NC CAH than V281L and that the frequency of the mutations causing NC steroid 21-hydroxylase deficiency in Japan might be different from that in western countries.

Adrenal Hyperplasia, Congenital↗
PubMed1998

Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma.

OBJECT: Although curative, radiation, which is conventionally administered for germinomas, causes significant neurological sequelae. This study aimed at reducing the volume and dose of radiation to a localized level of 24 Gy by pretreating the patient with chemotherapy. METHODS: Seventeen patients were divided into two risk groups based on serological findings and the extent of tumor. They were treated with chemotherapy prior to receiving localized radiation therapy. Six patients with solitary pure germinomas were treated with three or four cycles of cisplatin and etoposide (EP regimen) followed by 24-Gy local radiation therapy. Eleven patients with human chorionic gonadotropin (HCG)-secreting, multifocal, or disseminated germinomas received four to five cycles of ifosfamide, cisplatin, and etoposide (ICE regimen) followed by 24-Gy local radiation therapy. Craniospinal ports were used only in three cases of germinomas with dissemination. Gross-total resection was performed in three patients. Fourteen patients were able to be evaluated for their responses to chemotherapy. All patients achieved a complete response within three cycles. At a median follow-up duration of 24 months, 16 patients (94%) were alive without recurrence. One patient with an HCG-secreting germinoma experienced recurrence 38 months after surgery. That patient underwent successful salvage therapy using the same protocol. Thus, all 17 patients became free of disease with a 70 to 100% Karnofsky Performance Scale status. Toxicities associated with this study's chemotherapy regimen were mostly transient. No patient showed neurological or endocrinological deterioration during the follow-up period. CONCLUSIONS: The EP and ICE regimens were highly effective in treating the central nervous system germinomas and permitted dose and volume reduction of the radiotherapy. Localized 24-Gy irradiation was sufficient for disease control.

Adolescent↗
PubMed1997

Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. We report here the clinical, endocrinological, and molecular analyses of two unrelated Japanese kindreds of 46,XX subjects affected with lipoid CAH who manifested spontaneous puberty. Phenotypic female infants with 46,XX karyotypes were diagnosed with lipoid CAH as newborns based on a clinical history of failure to thrive, hyperpigmentation, hyponatremia, hyperkalemia, and low basal values of serum cortisol and urinary 17-hydroxycorticosteroid and 17-ketosteroid. These patients responded to treatment with glucocorticoid and 9alpha-fludrocortisone. Spontaneous thelarche occurred in association with increased serum estradiol levels at the age of 10 and 11 yr, respectively. Pubic hair developed at the age of 12 yr 11 mo in one subject and menarche was at the age of 12 yr in both cases. Both subjects reported periodic menstrual bleeding and subsequently developed polycystic ovaries. To investigate the molecular basis of the steroidogenic lesion in these patients, the StAR gene was characterized by PCR and direct DNA sequence analyses. DNA sequence analysis revealed that one patient is homozygous for the Gln 258 Stop mutation in exon 7 and that the other patient is a compound heterozygote with the Gln 258 Stop mutation and a single A deletion at codon 238 in the other allele causing a frame-shift, which renders the StAR protein nonfunctional. These findings demonstrate that ovarian steroidogenesis can be spared to some extent through puberty when the StAR gene product is inactive. This is in marked contrast to the early onset of severe defects in testicular and adrenocortical steroidogenesis which are characteristics of this disease.

Adolescent↗