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Background The stimulatory G-protein α -subunit encoded by GNAS exons 1–13 ( GNAS -Gs α ) mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS -Gs α variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS -Gs α variants have been detected in McCune–Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. Methods We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. Results Whole-exome sequencing revealed two GNAS -Gs α candidate variants for NSIAD: GNAS -Gs α p.(F68_G70del) in one family and GNAS -Gs α p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS -Gs α alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function–compatible conformational property for p.M255V-Gs α , although such assessment was not possible for p.F68_G70del-Gs α . Both variants had gain-of-function effects that were significantly milder than those of McCune–Albright syndrome–specific somatic Gs α variants. Model mice for p.F68_G70del-Gs α showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs α exhibited severe failure to thrive. Conclusions This study shows that germline-derived gain-of-function rare variants of GNAS -Gs α exist and cause NSIAD as a novel Gs α -mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS -Gs α ’s gain-of-function effects.

Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5β-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.

Context Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings. Objective To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients. Methods We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics. Results We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency. Conclusions Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.

Aims The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. Methods We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. Results Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15–14.47) and 1.64 (corrected P value 5.3 × 10-5; 95% CI 1.34–2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. Conclusions The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

BackgroundTreatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients.MethodsThe registration data including hemoglobin A1c(HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort).ResultsThe proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p1cvalues between the two cohorts.ConclusionsThe popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.

Background/Aim: To evaluate the accuracy of the human chorionic gonadotropin (hCG) stimulation test in children with micropenis in predicting later Leydig cell function. Methods: We conducted a retrospective investigation of testosterone response to a 3-day hCG test (3,000 IU/m2/day) in prepuberty to indicate the need for hormone replacement therapy (HRT) in adolescence. Results: Fifty Japanese boys (range, 0.8-15.4 years of age; median, 8.9) with micropenis were enrolled. Thirty-four spontaneously developed puberty and preserved the ability of testosterone production (group 1), while 16 did not develop any pubertal signs without HRT (group 2). Serum testosterone levels after the hCG test (post-hCG T) in group 2 (range, Conclusions: The hCG test in prepubertal children with micropenis can be useful for predicting Leydig cell function in pubertal or postpubertal adolescents. The post-hCG T cut-off level of 1.1 ng/ml is recommended to screen for those who will likely require HRT for pubertal development.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

Sugihara S, Ogata T, Kawamura T, Urakami T, Takemoto K, Kikuchi N, Takubo N, Tsubouchi K, Horikawa R, Kobayashi K, Kasahara Y, Kikuchi T, Koike A, Mochizuki T, Minamitani K, Takaya R, Mochizuki H, Nishii A, Yokota I, Kizaki Z, Mori T, Shimura N, Mukai T, Matsuura N, Fujisawa T, Ihara K, Kosaka K, Kizu R, Takahashi T, Matsuo S, Hanaki K, Igarashi Y, Sasaki G, Soneda S, Teno S, Kanzaki S, Saji H, Tokunaga K, Amemiya S, and The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). HLA-class II and class I genotypes among Japanese children with Type 1A diabetes and their families. Objective: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. Methods: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent–child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. Results: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1∗09:01-DQB1∗03:03 and heterozygosity for DRB1∗04:05-DQB1∗04:01 and DRB1∗08:02-DQB1∗03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1∗09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. Conclusions: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.

We report a de novo heterozygous 5,013,940 bp terminal deletion of chromosome 15q26 in a 13 9/12 -year-old Japanese girl with short stature (-3.9 SD), mild mental retardation, and ventricular septal defect (VSD). This terminal deletion involved IGF1R but not NR2F2, and was associated with an addition of telomere repeat sequences (TTAGGG) at the end of the truncated chromosome. The results provide further support for the notion that terminal deletions are healed by de novo addition of telomere sequences essential for chromosome stability and DNA replication. Furthermore, while growth failure and mental retardation are primarily explained by loss of IGF1R, the occurrence of VSD might suggest the existence of a cardiac anomaly gene, other than the candidate cardiac anomaly gene NR2F2, in the deleted region.

Steroidogenic factor-1 (SF-1) regulates multiple genes involved in the adrenal and gonadal development and in the biosynthesis of a variety of hormones, including adrenal and gonadal steroids, anti-Mullerian hormone (AMH), and gonadotropins. We identified a novel SF-1 mutation in a 27-yr-old Japanese patient with a 46,XY karyotype. Sequence analysis was performed for all the seven exons of SF-1, revealing a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth codon and resultant termination at the 74th codon. Functional studies showed that the mutation produced no demonstrable protein and had no transcription activity or dominant negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, clitoromegaly, and psychosexual disturbance. Endocrine studies showed normal adrenal function (cortisol response to ACTH stimulation, 13.4→25.3 μg/dl) and primary hypogonadism (testosterone response to hCG stimulation, 0.57→0.76 ng/ml; gonadotropin responses to GnRH stimulation: LH, 10→59 mIU/ml; FSH, 36→69 mIU/ml), and urinary steroid hormone profile analysis indicated grossly normal steroidogenic enzyme activities. The results suggest that SF-1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes.

Pump sources for optical fiber amplifiers, e.g., Erbium-doped fiber amplifiers or Raman amplifiers, are reviewed. Higher optical power is required for the optical fiber amplifiers in DWDM transmission. Recently published results regarding improvements of the optical power are introduced.

In most patients with hypoparathyroidism (HP), the etiology is not defined clinically. Eight genes (AIRE, CASR, CLDN16, GATA3, GCM2, PTH, TBCE, and TRPM6) are known to be responsible genes associated with HP; however, no previous study has screened the eight responsible genes comprehensively in HP patients.This study was conducted to determine the genetic defect in HP patients. We also described clinical and molecular findings of two HP patients with novel GCM2 mutations.We enrolled 20 nonconsanguineous Japanese patients with child-onset permanent HP without 22q11 deletion. Mutations and genomic rearrangements involving the eight genes were screened by targeted next-generation sequencing (NGS). We also screened genetic rearrangements by array comparative genomic hybridization (aCGH) in the mutation-negative patients. A putative deletion, which was suspected by NGS, was additionally analyzed by droplet digital PCR (ddPCR) and junction PCR. Identified novel nucleotide-level GCM2 mutants were characterized in vitro.We identified seven patients with a single gene disorder, including a CASR mutation, GATA3 mutations, and novel GCM2 mutations (R367Tfs*15, T370M, and the deletion encompassing exon 1). This submicroscopic deletion, which had been suspected by NGS, could not be detected by aCGH and was confirmed by ddPCR and junction PCR. Functional studies of R367Tfs*- and T370M-GCM2 demonstrated a reduction of target gene transactivation in both.Using comprehensive NGS analyses, we identified the genetic defect in 35% of HP patients in our cohort and discovered novel GCM2 mutations including submicroscopic deletion that was undetectable by aCGH.

The steroidogenic acute regulatory protein (StAR) facilitates the delivery of cholesterol to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme catalyzes the initial step of steroid hormone biosynthesis. StAR was initially identified in adrenocortical cells as a phosphoprotein, the expression and phosphorylation of which were stimulated by corticotropin. A number of in vitro studies have implicated cAMP-dependent phosphorylation at serine 194 (S194, S195 in human StAR) as an important residue for StAR activity. To explore the importance of S194 phosphorylation in StAR function in vivo, we developed a transgenic model using a bacterial artificial chromosome expressing either wild-type (WT) StAR or StAR mutation S194A to rescue StAR knockout (KO) mice. Despite StAR protein expression comparable to or higher than amounts seen with control animals or rescue with WT StAR, S194A StAR did not rescue the neonatal lethality and only partially rescued the sex reversal in male mice observed uniformly in StAR KO mice. Like the StAR KO mice, the adrenal cortex and testicular Leydig cells contained abundant lipid deposits when stained with oil red O. Adrenal StAR from S194A rescue animals lacks an acidic species, which appears upon corticotropin stimulation in animals rescued with WT StAR, consistent with defective StAR phosphorylation. These findings demonstrate that S194 is an essential residue for normal StAR function in the adrenal cortex and testes of mice.

The autonomic nervous system is affected in a wide variety of neurological disorders. Its dysfunction may play an important role in the clinical course and may result in serious complications, such as cardiac arrest. We report a case of tetanus who presented with severe autonomic nervous system dysfunction which was detected by spectral analysis of heart rate variability monitored over 24 h. This is a semi-quantitative method for evaluation of the status of the autonomic nervous system. In the present case, the analysis revealed profoundly decreased activity of both sympathetic and parasympathetic nervous system modulation of cardiac rhythm. The parasympathetic nervous system activity was more severely impaired than that of the sympathetic nervous system. The relative predominance of the sympathetic nervous system in the present case may have resulted in unopposed sympathetic nervous system hyperactivity manifested in this patient by tachycardia and excessive sweating. We further infer that the documented diminished buffering capacity of the autonomic nervous system may have lead to a sudden cardiac arrest in our case. Thus, spectral analysis of heart rate variability is a non-invasive and sensitive method for evaluating the status of the autonomic nervous system of critically ill patients in the hospital setting.

We report a 30-year-old female with adrenal unresponsiveness to ACTH. Her clinical features included no adrenal crisis despite poor drug compliance, poor pubic hair development (Tanner stage 2), well-developed breasts (Tanner stage 5), and regular menstrual cycles. Endocrinological data included blood ACTH 1500 pmol/l, cortisol 18 nmol/l, dehydroepiandrosterone sulphate below 0.26 μmol/l, activated renin 0.37 pmol/l, and aldosterone 3.4 nmol/l. Direct sequencing and allele-specific amplification revealed two novel mutations in the ACTH receptor gene. One was transition from guanine to adenine at nucleotide position 1002, resulting in substitution of aspartate for asparagine at codon 103, and the other was transition from cytosine to thymine at nucleotide 1104, leading to substitution of arginine for tryptophan at codon 137. The present findings lend additional credence to the notions that adrenal androgens play an important role in female pubic hair development and that ovarian development takes place independently of adrenarche.

We present high spatial resolution images of the gravitational-lens system PG 1115+080 taken with the near-infrared camera (CISCO) on the Subaru telescope. The FWHM of the combined image is $0.''32$ in the $K'$-band, yielding spatial resolution of $0.''14$ after a deconvolution procedure. This is a first detection of an extended emission adjacent to the A1/A2 components, indicating the presence of a fairly bright emission region with a characteristic angular radius of $\sim$ 5 mas (40 pc). The near-infrared image of the Einstein ring was extracted in both the $J$ and $K'$ bands. The $J-K'$ color is found to be significantly redder than that of a synthetic model galaxy with an age of 3 Gyr, the age of the universe at the quasar redshift., 11 pages, 6 figures. Accepted for publication in PASJ(2000)

We describe a case of photosensitivity due to pyridoxine hydrochloride (vitamin B6) in a heterozygote of hypophosphatasia. Photopatch tests using pyridoxine hydrochloride and pyridoxal 5′-phosphate, compounds referred to as vitamin B6, with ultraviolet light A irradiation were positive. Laboratory examination showed low serum alkaline phosphatase. Tissue-nonspecific alkaline phosphatase exon amplification from DNA of the patient’s lymphocytes detected deletion 1154–1156 hypophosphatasia mutation, indicating that this patient was diagnosed to be a heterozygote of hypophosphatasia. The seric pyridoxal 5′-phosphate level of this patient with hypophosphatasia was higher than in normals. Furthermore, after oral administration of vitamin B6 this level increased greatly and long-lastingly, and this might be related to the low level of alkaline phosphatase in this patient. Photosensitivity in this patient may have been caused by abnormal metabolism of vitamin B6 under the hypophosphatic condition.

This paper describes the use of wafer fusion technique between submicrometer-order patterned wafers to realize novel optoelectronic devices. First, to demonstrate the feasibility of applying the technique to optoelectronic devices, we demonstrate a continuous wave oscillation of a one-dimensional distributed feedback laser with air/semiconductor gratings embedded by the wafer fusion technique. Next, we fabricate a device with two-dimensional triangular-lattice structure and obtain a very unique hexagonal symmetric surface-emitting pattern. From the calculated photonic band diagram of the device, the surface-emitting pattern is considered to reflect the photonic band nature of triangular-lattice structure. The room temperature lasing oscillation of the device with two-dimensional triangular-lattice structure is also achieved. These results indicate that the air/semiconductor gratings formed by wafer fusion technique can be applied to develop various optoelectronic devices, and the realization of novel devices is expected.

Wafer fusion between patterned or structured wafers is very useful in the construction of new optical materials and/or devices that have submicrometer-order structures inside semiconductors. In order to investigate the feasibility of wafer fusion for this purpose, a distributed feedback (DFB) laser wafer developed which has air/semiconductor gratings that are embedded using the wafer fusion technique. In this paper, the characteristics of the newly developed DFB laser and the coupling coefficient are investigated. Single-longitudinal-mode oscillation at 1.28 /spl mu/m is achieved under pulsed conditions at room temperature with a low threshold current density of 1.3 kA/cm/sup 2/, and the coupling coefficient is estimated to he approximately 100 cm/sup -1/. In addition, high-power surface emission (over 6 mW) is demonstrated due to the large difference between the refractive index of air and that of InP. These results indicate the feasibility of applying wafer fusion techniques to form submicrometer structures in semiconductors, and several other applications are expected.

A 1-year-old boy developed autoimmune hemolytic anemia after a negative direct anti-globulin test. The concentration of erythrocyte membrane-associated immunoglobulin G, determined using an immunoradiometric assay, correlated with disease activity. He was positive for cytomegalovirus (CMV) both serologically and by quantitative real-time polymerase chain reaction, indicating that his autoimmune hemolytic anemia was directly caused by CMV infection. Since anti-CMV immunoglobulin G was not absorbed by the patient's erythrocytes, cross-reaction between erythrocyte antigens and CMV was not likely a causative factor for hemolysis.

We identified 2.0 Mb of a novel deletion on chromosome 14q12, involving 8 genes and putative regulatory elements of FOXG1 by array CGH in a patient with severe growth and psychomotor retardation, hypotonia, microcephaly, dysmorphic face, and hypoplasia of the corpus callosum. Case of a submicroscopic 14q12 deletion, involving regulatory elements of FOXG1 , with the coding region of FOXG1 being unaffected, is extremely rare. Using fibroblast cell line established from the patient, we showed that the expression level of FOXG1 in our patient was decreased. Our finding provides additional evidence that not only over-dosage of FOXG1 as previously mentioned, under-dosage of FOXG1 is also associated with phenotype, overlapping between congenital variant of Rett syndrome with FOXG1 mutations and 14q12 microdeletion, not including the coding region of FOXG1 . Though the gene dosage of FOXG1 appears to be critical for the normal development of brain, the complex mechanism of its regulation of gene expression remains to be elucidated.

Receiver optoelectronic integrated circuits (OEICs) have been successfully designed on a three-inch diameter InP substrate. Epitaxial layers grown by OMVPE on three-inch diameter InP substrates showed good uniformity of electrical and optical properties. By using the epitaxial layers, transimpedance-type receiver OEICs were fabricated. the receiver OEICs over a three-inch diameter InP substrate showed an average bandwidth of 2.78 GHz with a standard deviation of 280 MHz. the receiver also exhibited a transimpedance of 61.1 dB and a sensitivity of -24.9 dBm for 2.4 Gb/s input signals. These results indicate that the receiver OEICs designed on a three-inch diameter InP substrate are ready for practical use in Gb/s lightwave systems.

We report on a pair of male monozygotic twins, one unaffected and the other affected with gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, and discuss the role of treatment with a GnRH analog in the attainment of full height potential in GnRH-dependent precocious puberty. At 1.6 years of age, the affected twin was studied for tall stature (+3.8 SD), and was diagnosed as having GnRH-dependent precocious puberty due to a hypothalamic hamartoma of the tuber cinereum. He was treated with oral cyproterone acetate (110-170 mg/m(2) daily) from 1.8 through 5. 0 years of age, with oral cyproterone acetate and intranasal buserelin acetate (700-900 microg/m(2) daily) from 5.0 through 7.5 years, and with intranasal buserelin acetate alone (1100- 1400 microg/m(2) daily) from 7.5 through 12.6 years. He attained a final height of 171.0 cm at 14.9 years of age (+0.10 SD) and his twin 170. 0 cm at 15.3 years of age (-0.10 SD), with their target height being 174.5 +/- 9.0 cm.This study indicates that GnRH analog treatment may preserve near full height potential in some patients with GnRH-dependent precocious puberty.

Lasing action of a surface-emitting laser with a two-dimensional photonic crystal structure is investigated. The photonic crystal has a triangular-lattice structure composed of InP and air holes, which is integrated with an InGaAsP/InP multiple-quantum-well active layer by a wafer fusion technique. Uniform two-dimensional lasing oscillation based on the coupling of light propagating in six equivalent Γ−X directions is successfully observed, where the wavelength of the active layer is designed to match the folded (second-order) Γ point of the Γ−X direction. The very narrow divergence angle of far field pattern and/or the lasing spectrum, which is considered to reflect the two-dimensional stop band, also indicate that the lasing oscillation occurs coherently.

The steroidogenic acute regulatory protein (StAR) stimulates the regulated production of steroid hormones in the adrenal cortex and gonads by facilitating the delivery of cholesterol to the inner mitochondrial membrane. To explore key aspects of StAR function within bona fide steroidogenic cells, we used a transgenic mouse model to explore the function of StAR proteins in vivo. We first validated this transgenic bacterial artificial chromosome reconstitution system by targeting enhanced green fluorescent protein to steroidogenic cells of the adrenal cortex and gonads. Thereafter, we targeted expression of either wild-type StAR (WT-StAR) or a mutated StAR protein lacking the mitochondrial targeting signal (N47-StAR). In the context of mice homozygous for a StAR knockout allele (StAR−/−), all StAR activity derived from the StAR transgenes, allowing us to examine the function of the proteins that they encode. The WT-StAR transgene consistently restored viability and steroidogenic function to StAR−/− mice. Although the N47-StAR protein was reportedly active in transfected COS cells and mitochondrial reconstitution experiments, the N47-StAR transgene rescued viability in only 40% of StAR−/− mice. Analysis of lipid deposits in the primary steroidogenic tissues revealed a hierarchy of StAR function provided by N47-StAR: florid lipid deposits were seen in the adrenal cortex and ovarian theca region, with milder deposits in the Leydig cells. Our results confirm the ability of StAR lacking its mitochondrial targeting signal to perform some essential functions in vivo but also demonstrate important functional defects that differ from in vitro studies obtained in nonsteroidogenic cells.

An equalizer, which is essential in order to improve the sensitivity of receiver optoelectronic integrated circuits (OEICs) at a gigabit-per-second data rate, has been monolithically integrated on an InP substrate with a p-i-n photodiode and a high-impedance high-electron-mobility-transistor (HEMT) amplifier. The receiver operated up to 1.6 Gb/s and showed low noise current characteristics. The minimum noise current is less than 4 pA/ square root Hz. The sensitivity calculated from the noise current characteristics is -28.4 dBm for 1.6-Gb/s signals. The receiver chip, which was assembled on a ceramic mount, exhibited a sensitivity of -30.4 dBm at 1.2 Gb/s and 1.3- mu m wavelength. The performance is as good as those of receiver OEICs with an external equalizer and sufficient for practical use in gigabit-per-second optical communication system. >

Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder characterized by renal tubular insensitivity to antidiuretic hormone, resulting in an inability to concentrate urine. We report on an infant boy with CNDI who showed growth failure during treatment with sodium restriction. At the age of 4 mo, he was diagnosed as having CNDI, judging from fever with hypernatremia (serum Na 153 mEq/L), diluted urine (urine osmolarity 193 mOsm/kg), high antidiuretic hormone (plasma antidiuretic hormone 53 pg/mL), and normal renal function (serum creatinine 0.3 mg/dL). His length and weight were mean +0.4 and -1.1 SD, respectively, at that time. He was treated with sodium restriction (sodium intake; 0.53 mEq/kg/day) using low sodium formula in addition to trichlormethiazide, spironolactone, and mefenamic acid. Growth failure developed: his length and weight were mean -2.4 and -3.3 SD, respectively, at the age of 10 mo. After withdrawal of sodium restriction to 1.5 mEq/kg/day of sodium intake without any change of caloric intake and medication, catch-up growth was observed. At the age of 39 mo, the patient's height and weight were mean -0.8 and -0.6 SD, respectively. We conclude that excessive sodium restriction can cause growth failure in infants with CNDI.

We have observed precise astrometric positions of the faint outer satellites of Jupiter J6–J12 with the Kiso 1.05 m Schmidt telescope. The observational period is from 1990 November through 1992 March. We discuss the postfit residuals after orbital improvement for our 1986–1990 observations and thereby emphasize the superiority of the intersatellite measures available only from wide-field Schmidt observations, which can cover all the satellites in a single plate.

We report penile length (PL) responses to testosterone enanthate (TE) therapy for micropenis, and the relevance of the V89L polymorphism of SRD5A2 encoding the 5alpha-reductase type 2 and CAG repeat length polymorphism of AR encoding the androgen receptor.A total of 53 Japanese boys with micropenis (less than -2.0 SD) 0 to 13 years old who had no SRD5A2 or AR mutation were examined. TE was given at a dosage of 25 mg intramuscularly, and PL was measured at least 4 weeks after the injection. The 2 polymorphisms were determined by direct sequencing.PLs became -2.0 SD or greater in all the boys after TE therapy (1 injection in 4 boys, 2 in 28, 3 in 19 and 4 in 2), with a significant increase in the medians of PLs (from 2.5 to 3.5 cm, p0.0001) and SD score, (from -2.6 to -0.7, p0.0001). The increment in actual PL at the first injection ranged from 0.2 to 1.5 cm (median 0.6) and was independent of age (r = 0.22, p = 0.12) and body surface area (r = 0.11, p = 0.43), while that in PL SD score at the first injection ranged from 0.3 to 2.5 (1.0) and was inversely correlated with age (r = -0.33, p = 0.02) and body surface area (r = -0.37, p = 0.008). The actual PL increment at the first injection was also unrelated to initial PL (r = -0.03, p = 0.81). The median of actual PL increments at the first injection was similar among boys with V/V, V/L and L/L genotypes of SRD5A2 (0.6 cm in 18, 0.7 cm in 30 and 0.5 cm in 5, respectively, p = 0.77), and between boys with and without long CAG repeats (26 or greater) of AR (0.65 cm in 6 and 0.6 cm in 47, respectively, p = 0.77). In addition, there was no significant correlation between actual PL increment at the first injection and CAG repeat length (r = 0.06, p = 0.67).Our results suggest that administration of 25 mg TE is effective for micropenis in prepubertal boys with no SRD5A2 or AR mutation, with variable but significant PL increments, and that the penile responsiveness to TE therapy is independent of the V89L and the CAG repeat length polymorphisms.

The 5alpha-reductase-2 encoded by the SRD5A2 gene plays a critical role in male sex differentiation by converting testosterone into 5alpha dihydrotestosterone in the peripheral target tissues. In this study, we examined the SRD5A2 gene in 81 Japanese patients with micropenis (age, 0-14 yr; median, 7 yr) whose stretched penile lengths were between -2.5 SD and -2.0 SD in 39 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD in 42 patients (age, 0-14 yr; median, 6 yr), together with 100 control males (50 boys and 50 fertile adult males). Mutation analysis was performed for exons 1-5 and their flanking introns by denaturing HPLC and direct sequencing, revealing Y26X/R227Q in an 11-yr-old boy with a penile length of -2.6 SD, G34R/R227Q in a 9-yr-old boy with a penile length of -3.6 SD, and R227Q/R227Q in a 3-yr-old boy with a penile length of -2.4 SD, together with heterozygous R227Q in a control boy and a fertile adult male. Polymorphism analysis was carried out for the most frequent V89L known to reduce the enzyme activity by approximately 30% in 78 patients, except for the three patients with SRD5A2 mutations, and in the 100 control males by direct sequencing, showing that allele and genotype frequencies were similar between 78 patients with micropenis below -2.0 SD or 40 patients with micropenis below -2.5 SD and the 100 control males, the 50 boys, or the 50 fertile adult males, with no statistically significant differences. The results suggest that, in Japanese patients, micropenis can be caused by SRD5A2 gene mutations, especially by R227Q which has been shown to retain approximately 3.2% of normal enzyme activity and appears relatively frequent in Asian populations, and that V89L polymorphism is unlikely to raise the susceptibility to the development of micropenis.

A 49-year-old Japanese phenotypic female was referred for a giant inguinal mass. The parents and maternal half brother were reported to be phenotypically normal, and there was no family history of male pseudohermaphroditism or consanguinity. The parents were divorced shortly after the patient was born, and the patient was reared by her mother. However, at presentation the mother had been deceased for 30 years and, thus, detailed familial information, such as place of parental birth, was not available. Physical examination revealed a giant mass in the left inguinal region and a small testis-like mass in the right inguinal region. The patient had a masculine habitus with no breast development, moderate pubic hair (Tanner stage 3), an enlarged clitoris (5 cm. in stretched length) and a blind ending vagina. The karyotype was 46 XY in all 30 lymphocytes analyzed. Endocrine data were consistent with 5 reductase type 2 deficiency. Basal serum luteinizing hormone was 16.5 IU/l. (adult male normal 1.0 to 8.4), folliclestimulating hormone 56.5 IU/l. (1.0 to 10.5), testosterone 14.7 nmol./l. (11.2 to 50.0), 5 -dihydrotestosterone 0.38 nmol./l. (0.87 to 2.60) and testosterone-to-5 -dihydrotestosterone ratio 39 (12 to 20). She also appeared to manifest abnormal gender role behavior, as has often been reported with this condition.2 Although the patient was raised as a female and recognized herself as a female, she had never sought medical evaluation despite the absence of pubertal development and menarche, and had remained single and was living with another woman. After obtaining informed consent, mutational analysis was performed for the SRD5A2 gene encoding steroid 5 reductase type 2. In brief leukocyte genomic DNA was amplified with the primers for all 5 exons and their flanking introns of SRD5A2 by polymerase chain reaction, and the products were subjected to direct sequencing from both directions.2 Consequently a homozygous C16T transversion resulting in a substitution of the sixth glutamine codon by stop codon (Q6X) was identified. This transversion was absent in a total of 100 normal individuals. The patient underwent surgical exploration for the bilateral masses. Macroscopically the large left mass was an 11 10 8 cm. solid tumor with extensive necrosis and focal hemorrhage, and the small right mass was an atrophic testis 2 to 3 ml. in volume. There was no discernible invasion of adjacent tissues or metastasis to the retroperitoneal lymph nodes. Wolffian structures were well developed, and mullerian structures were absent. Microscopically the solid tumor showed typical findings of seminoma, and the right testis displayed dysgenetic features, such as hyalinized seminiferous tubules, Leydig cell hyperplasia and defective spermatogenesis without carcinoma in situ (see figure). Subsequently the patient received local irradiation therapy. Estrogen supplementation therapy was not started because of her advanced age and refusal. She was healthy at 12-month followup.

Summary form only given. The photonic band structure (PBS) has been drawing much attention to control light emission and/or propagation. To realize the PBS in the optical wavelength region, we have proposed utilizing a wafer fusion technique between submicron-order patterned wafers. Furthermore, by this technique, the integration of PBS with a light-emitting layer is also possible, and the realization of novel opto-electronic devices is expected. Recently, we have developed a light-emitting device with two-dimensional (2D) triangular-lattice structure (TLS) embedded by the wafer fusion technique and have shown the very unique surface-emission pattern, which reflects the 2D photonic band nature of TLS. In the work, we demonstrate for the first time a room temperature (RT) lasing oscillation of the surface-emitting laser with 2D PBS embedded by the wafer fusion technique.

A long-wavelength receiver OEIC (optoelectronic integrated circuit) comprising an InAlAs-InGaAs MSM (metal-semiconductor-metal) detector and a InAlAs-InGaAs HEMT (high-electron mobility transistor) high-impedance preamplifier has been demonstrated. The layer structure was grown by LP-OMCVD (low-pressure organometallic chemical vapor deposition) on patterned InP substrates, which allowed independent optimization of the MSM detector and the HEMT preamplifier. The MSM detector showed the lowest leakage current (1 nA) ever reported with a 0.42 A/W responsivity, and the HEMT exhibited an external transconductance of 260 mS/mm. The bandwidth of the MSM-HEMT receiver was about 2 GHz. An excellent receiver response to 1.7 Gb/s NRZ random input signals has been obtained. The results reported strongly suggest that MSM-HEMT receivers have great potential for high-bit-rate optical-fiber communication systems. >

An 8-channel optical interconnection laser diode (LD) array module, which is a receptacle type with an multi-fibre push-on (MPO) adapter, was successfully fabricated. In consequence of adapting a receptacle type, mounting of this module on a board was facilitated. Furthermore reliability of this LD array module is guaranteed because the LD array is hermetically sealed. A variation of optical output power in each channel was obtained within 0.3 dB, and a fluctuation of coupling losses caused by reconnecting was obtained at less than 0.5 dB, respectively. Digital output at 300 Mbit/s/ch was demonstrated.

In conclusion, we have developed 1.3-/spl mu/m uncooled coaxial analog DFB MQW laser modules. They operate over the wide temperature range from -40-85/spl deg/C with low distortion and low noise, which are quite suitable for light sources of a return path in bidirectional optical CATV network systems.

In summary, a pin photodiode, a transimpedance-type preamplifier, and a comparator have been monolithically integrated on an InP substrate with pin/HBT integration technology. The receiver OEIC with a comparator showed a sensitivity of -36.0 dBm at a bit error rate of 1/spl times/10/sup -9/ for 125 Mb/s optical signals. The successful integration of digital circuits with analog circuits and optical components promises a realization of high-performance parallel optical interconnections in the near future.

We report on a Japanese family (two brothers and their mother) with ulnar-mammary syndrome (UMS). Clinical features included hypoplasia or aplasia of upper limbs on the ulnar side in the three affected individuals, micropenis with or without cryptorchidism, and hypoplastic nipples in the brothers; and hypoplastic mammary glands and nipples, poor perspiration, and bicornuate uterus in the mother. Endocrine studies performed for the underdeveloped external genitalia when the brothers were 11 6/12 and 7 2/12 years old, respectively, indicated low to low-normal responses of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to gonadotropin releasing hormone stimulation tests (elder brother: LH =0.2 --2.2 IU/L, FSH = 0.6 --2.2 IU/L; younger brother: LH =0.2 --3.3 IU/L, FSH = 0.7 --4.4 IU/L) and normal testosterone responses to human gonadotropin stimulation tests (elder brother:0.5 --8.8 nmol/L; younger brother:0.5 --6.3 nmol/L). Testosterone enanthate therapy (25 mg/dose IM twice) was effective in the brothers, with penile length increase being similar between the brothers (approximately 5 mm/dose) and 23 age-matched boys with idiopathic micropenis (mean 4.4 mm/dose, range 2.5-7.5 mm/dose). Sequence analysis of the TBX3 gene showed a novel heterozygous nonsense mutation (A817T, K273X) in exon 4 of the three patients. The results are consistent with the previous finding that UMS is caused by haploinsufficiency of TBX3, and imply that mild gonadotropin deficiency may be the primary cause for underdeveloped external genitalia in males with UMS.

We report on clinical and molecular findings in a Japanese family consisting of a male infant with SHOX nullizygosity and his four family members with SHOX haploinsufficiency. The male infant had Langer mesomelic dysplasia, the prepubertal sister had idiopathic short stature phenotype with no discernible skeletal features, the father had mild Leri-Weill dyschondrosteosis (LWDC), and the mother and the maternal grandmother had moderate LWDC. The five subjects lacked clinically recognizable short metacarpals, cubitus valgus, high arched palate, short neck, and micrognathia, as well as recurrent otitis media and hearing loss. Fluorescence in situ hybridization and sequence analyses showed that the proband had a pseudoautosomal microdeletion involving SHOX and a C502T missense mutation in the homeobox domain at exon 4, and that the father was heterozygous for the SHOX deletion, and the sister, the mother, and the grandmother were heterozygous for the C502T mutation. The results, in conjunction with the previous findings, suggest that mesomelic skeletal features such as Langer mesomelic dysplasia and LWDC, which are absent or rare in Turner syndrome, are primarily caused by the SHOX dosage effect and the bone maturing effect of gonadal estrogens, whereas other skeletal features such as short metacarpals, cubitus valgus, and various craniofacial and cervical skeletal stigmata, which are common in Turner syndrome, are largely contributed by a compressive effect of distended lymphatics and lymphedema on the developing skeletal tissues.

Distributed Raman amplification in the transmission fiber is an attractive technique to increase the transmission capacity and to extend the reach of long-haul WDM optical system [1]. The next generation WDM system is expected to offer transmission in the wide range of S, C, and L band. A single Raman pump wavelength provides flat gain in the limited wavelength range of approximately 15nm. However, multi-wavelength pumping at 12 different pump wavelengths allows to offer high gain and very good gain flatness over the wavelength range of up to 100nm [2].

Various mutations of the AR gene and expanded CAG repeats at exon 1 of that gene have been reported in patients with hypospadias or genital ambiguity. However, the role of the AR gene has not been systemically studied in those with isolated micropenis lacking hypospadias or genital ambiguity. We studied 64 Japanese boys with isolated micropenis (age, 0-14 yr; median, 7 yr), whose stretched penile lengths were between -2.5 and -2.0 SD (borderline micropenis) in 31 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD (definite micropenis) in 33 patients (age, 0-14 yr; median, 6 yr). Mutation analysis of the AR gene was performed for exons 1-8 and their flanking introns, except for the CAG and GGC repeat regions at exon 1, by denaturing HPLC and direct sequencing, identifying a substitution of cytosine to thymine at a position -3 in the 3' splice site of intron 1 in a patient with definite micropenis. CAG repeat length at exon 1 was determined by electrophoresis with internal size markers and direct sequencing, revealing no statistically significant difference in the distribution of CAG repeat lengths [median (range) and mean +/- SE: total patients with isolated micropenis, 24 (14-34) and 23.5 +/- 0.38; patients with borderline micropenis, 24 (15-29) and 23.5 +/- 0.53; patients with definite micropenis, 23 (14-34) and 23.5 +/- 0.56; and 100 control males, 23 (16-32) and 23.5 +/- 0.29] or in the frequency of long CAG repeats (percentage of CAG repeats > or =26 and > or =28: total patients with isolated micropenis, 17.2 and 4.7%; patients with borderline micropenis, 19.4 and 6.5%; patients with definite micropenis, 15.2 and 3.0%; and 100 control males, 21.0 and 10.0%). These results suggest that an AR gene mutation is rare and that CAG repeat length is not expanded in children with isolated micropenis.