Seizo Suwa

The Prevalence of Islet Cell Antibodies in Japanese Insulin-dependent and Non-insulin-dependent Diabetic Patients Studied by Indirect Immunofluorescence and by a New Method

Islet cell antibodies (ICA) were measured in Japanese patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) by a standard, indirect immunofluorescence method (IF method) and by a newly established, threelayer immunofluorescence method applying a biotin-avidin system (BAS method). In addition, the relationship between ICA and HLA was studied in IDDM patients. ICA titers detected by the BAS method correlated well with those determined by the standard IF method (rs = 0.987, P < 0.01). The BAS method had about an eightfold higher sensitivity for ICA than the IF method. The overall prevalence of ICA detected by the BAS method (ICA-BAS) versus that by the IF method (ICAIF) was 41% (82/198) versus 28% (56/198) in IDDM patients and 3% (19/593) versus 2% (14/593) in patients with NIDDM. In IDDM patients, ICA-BAS was all positive <1 mo after the onset of diabetes, while the prevalence of ICA-IF was 83% (20/24) during the same period. The prevalence of ICA-IF decreased rapidly with the duration of disease, reaching a value of 6% (3/55) in the patients with a disease duration of 10 yr or more. The incidence of ICA-BAS also decreased with the duration of disease, although to a lesser degree than ICA-IF. No association was found between HLA types and persistence of ICA-BAS or -IF. These results suggest that pancreatic autoimmune processes occur in almost all Japanese IDDM patients. Although IDDM is less common in Japan than among Caucasians, the prevalence of ICA seems to be the same. The higher sensitivity of the BAS method may be of significant diagnostic value, especially in patients with a long duration of disease.

Clinical characteristics of children with hypoparathyroidism due to 22q11.2 microdeletion

Abstract The phenotypes of chromosomal 22q11.2 microdeletion are quite variable among individuals and hypoparathyroidism (HP) constitutes a definite portion of the clinical spectrum. For the correct diagnosis and pertinent follow up of the HP children due to del22q11.2, we tried to delineate the clinical characteristics of such patients. By employing fluorescence in situ hybridization (FISH) to all the patients diagnosed as HP in our clinic, ten possessed the 22q11.2 microdeletion. Among them, the incidence of cardiac defect (5/10), recurrent infection (1/10) and cleft palate (1/10) was modest. Additionally, seven of them had been diagnosed as HP during the infantile period, when their facial abnormality and intellectual problem had not become evident. Notably, two patients were complicated by Graves disease, while the association of idiopathic thrombocytopenic purpura was also observed in two girls. Conclusion HP due to del22q11.2 may be misdiagnosed as idiopathic, especially in an infant who lacks apparent complications like cardiac anomaly. They should be closely followed up for auto-immune complications.

Follow-up study of a nation-wide neonatal metabolic screening program in Japan

A nationwide neonatal sreening program for phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, histidinemia and galactosemia was started in Japan in 1977. The total number of infants screened had reached 6,311,754 by March, 1982. A follow-up study revealed the incidence of the disease in Japan: 1/108,823 for PKU; 1/450,840 for hyperphenylalaninemia (HPA); 1/1,577,939 for biopterin deficiency; 1/525,980 for MSUD; 1/1,051,959 for homocystinuria; 1/8,371 for histidinemia, and 1/788,969 for galactosemia type 1. The incidences of PKU, HPA, homocystinuria, and galactosemia (type 1) were found to be markedly low in Japan as compared with those in Caucasian countries. There was no great difference in the incidence of MSUD between both. On the other hand, the incidence of histidinemia was higher in Japan.It was found that most of the patients with PKU, HPA, MSUD, homocystinuria, or galactosemia are developing normally due to the early initiation of dietary treatment. These results clearly indicate that the neonatal mass screening program plays a great role in preventing the occurrence of handicapped children.

Testicular Juvenile Granulosa Cell Tumor in an Infant with X/XY Mosaicism Clinically Diagnosed as True Hermaphroditism

We report a testicular juvenile granulosa cell tumor (T-JGCT) with characteristic clinical and histopathological features. The tumor was present in the left abdominal testis of a 7-month-old infant with a 45,X/46,XY karyotype and ambiguous genitalia. Preoperatively, the infant was diagnosed as having functional testicular and ovarian elements based on elevated levels of serum testosterone and estradiol following human chorionic gonadotropin and human menopausal gonadotropin administration, respectively. Histologically, the left gonad contained a tumorous lesion composed of an admixture of cellular areas and multiple cystic follicles that had some continuity with the adjacent testicular tubules. Some tumor cells showed immunoreactivity for estradiol. The right gonad was a streak gonad containing small irregular nests of sex cord-type cells. No maturing ovarian follicle was present in either gonad. To our knowledge, this is the fifth reported case of T-JGCT with abnormal sex chromosomes, and the first case of T-JGCT confirmed to have not only the morphological but also the functional characteristics of granulosa cells.

Three Novel PHEX Gene Mutations in Japanese Patients with X-Linked Hypophosphatemic Rickets

X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disorder characterized by renal phosphate wasting, abnormal vitamin D metabolism, and defects of bone mineralization. The phosphate-regulating gene on the X-chromosome (PHEX) that is defective in XLH has been cloned, and its location identified at Xp22.1. It has been recognized to be homologous to certain endopeptidases. So far, a variety of PHEX mutations have been identified mainly in European and North American patients with XLH. To analyze the molecular basis of four unrelated Japanese families with XLH, we determined the nucleotide sequence of the PHEX gene of affected members. We detected a new nonsense mutation (R198X) in exon 5, a new 3 nucleotides insertion mutation in exon 12 and a new missense mutation (L160R) in exon 5 as well as a previously reported nonsense mutation in exon 8 (R291X). These results suggest that:1) PHEX gene mutations are responsible for XLH in Japanese patients, and 2) PHEX gene mutations are heterogeneous in the Japanese population similarly to other ethnic populations.

Immunoreactive Somatomedin C/Insulin-Like Growth Factor I in Urine from Normal Subjects, Pituitary Dwarfs, and Acromegalics

ABSTRACT: Using antibodies to somatomedin C/insulin-like growth factor I (SmC) produced in rabbits using the recombinant hormone, we have developed a radioimmuno-assay for SmC. Gel-chromatography of urine revealed that the vast majority of immunoreactive SmC was eluted coincident with 125I-SmC and a small portion eluted with fractions having a mol. wt. range of 30,000–40,000. The SmC concentration in urine was determined by radioimmuno-assay after ammonium sulfate extraction. Values did not ordinarily exceed 1 ng/ml. When the values from normal subjects were expressed as ng/mg creatinine, high levels were observed in the neonatal period. These values fell rapidly in infancy, declined more gradually in childhood, were slightly elevated at early puberty, and were lowest in adulthood. Urine SmC concentrations in 15 pituitary dwarfs were lower than the averages obtained from age-matched control subjects, and six of them showed abnormally low values. Three patients with active acromegaly had high SmC values in urine. In conclusion, 1) SmC, mainly of monomeric form, was immunologically detected in urine. 2) Radioimmunoassay for urine SmC revealed that values varied considerably with age in normal subjects and were partially dependent on the human growth hormone status. However, the full meaning of the findings remains to be elucidated.

Monthly Urinary LH and FSH Secretory Patterns in Normal Children and Patients with Sexual Disorders

ABSTRACT: Urinary gonadotropin concentrations were determined by polyclonal double antibody RIA after ammonium sulfate extraction. Good correlation was observed between urinary gonadotropin/creatinine ratios in first morning voided and full 24-h urine collections. Using consecutive 30-d first morning voided urine specimens from normal children and from patients with sexual disorders, we have studied the monthly patterns of nighttime gonad-otropin secretion. In normal prepubertal girls, the levels of urinary LH were low with few variations and those of urinary FSH were higher with episodic fluctuations. In early puberal girls, the levels of urinary LH increased with striking, rhythmic fluctuations. The same changes were seen in urinary FSH. A single big surge of urinary gonadotropins was observed in postmenarcheal girls, In normal boys, the secretory patterns of urinary gonadotropins were similar to those of normal girls, but varied less. In patients with idiopathic precocious puberty, the patterns of urinary gonadotropins were similar to those of normal subjects matched for sexual stage. The measurement of 30-d first morning voided urinary gonadotropins can provide a simple and physiologic test of gonadotropin function in children.

Prolonged Activation of Hypothalamo-Pituitary-Ovarian Axis during Early Infancy in Female Patients with Salt-Losing 21-Hydroxylase Deficiency

ABSTRACT: We observed prolonged genital bleeding during the first 2–3 months after treatment in five of 13 female patients with salt-losing 21-hydroxylase deficiency. Their relatively low concentrations of serum follicle-stimulating hormone and luteinizing hormone before therapy increased rapidly to high levels which were maintained for 1–3 wk and then decreased. The duration of these relatively high levels after therapy was longer in the patients with genital bleeding than those without. Before therapy, there was no release of serum follicle-stimulating hormone and luteinizing hormone following the administration of synthetic luteinizing hormone-releasing hormone in two patients; 1 month after therapy, the response to luteinizing hormone releasing hormone increased significantly. Serum estradiol increased above 300 pg/ml in four patients with genital bleeding but was less than 175 pg/ml in three patients without bleeding. The etiology of genital bleeding in these female patients may be more prolonged activation of the hypothalamo-pituitary-ovarian axis and a greater increase in the responsiveness of internal genitalia to gonadotropins and sex hormones, perhaps induced by prolonged exposure to excessive adrenal steroids starting before birth.

Quantitation of Urinary Gonadotropins in Normal Children

ABSTRACT: A simple and improved method for the quantification of urinary LH and FSH was developed. Urinary gonadotropin concentrations were determined by polyclonal double antibody RIA after ammonium sulfate extraction. Urinary LH and FSH concentrated by ammonium sulfate were coeluted with an iodinated LH and FSH tracer. Gel chromatography of the urine revealed that the majority of immunoreactive LH and FSH were eluted coincident with 125I-LH and 125I-FSH. Good correlation was observed between urinary gonadotropin/creatinine ratios in first morning voided and full 24-h urine collections. Age-de-pendent changes in urinary LH excretion were significant in normal boys and girls 6–17 y of age. Urinary FSH excretion in these children did not change in an age-dependent fashion.

Hunter's syndrome. An ultrastructural study of an autopsy case.

An autopsy case of a 10‐year, 8‐month‐old boy with Hunters syndrome Is reported with emphasis on the ultrastructural findings of almost all the organs, except the brain. Intracytoplasmic inclusion bodies were observed in various organs as follows: nerve cells and glia in the spinal cord, hepatocytes and Kupffer cells in the liver, sinusoidal endothelium of the spleen, proximal tubules, podocytes and epithelium of Bowmans capsule of the kidney, interstitial fibroblast‐like cells among cardiac muscle bundles, cardiac valves and aorta, exocrine and endocrine cells of the pancreas, adrenocortical cells, follicular epithelial cells of the thyroid, Leydig cells of the testis, chondrocytes, fibroblasts and endothelium of capillaries throughout the body. Three types of inclusion bodies were morphologically distinguishable. Type 1: clear vacuole, Type 2: zebra body, Type 3 : clear vacuole with a lipid‐like lamellar structure. The clear vacuole (Type 1) was thought to represent an accumulation of glycosaminoglycans, and the zebra body (Type 2), probably ganglioside. The type 3 inclusion body might be an intermediate and mixed form of the type 1 and type 2 inclusions. Histochemical study also suggested that the type 3 inclusion body contained glycosaminoglycan and a type of lipid. ACTA PATHOL JPN 38: 1175 ∼ 1190, 1988.