Although the "backdoor" pathway to dihydrotestosterone has been postulated in the fetal-to-early-infantile period of patients with cytochrome P450 oxidoreductase deficiency (PORD), clinical data in support of this pathway remain limited.The objective of this study was to obtain clinical evidence for the presence of the backdoor pathway in PORD.This was a collaboration study between laboratories and hospitals.Twenty-two Japanese patients with molecularly confirmed PORD and 1763 control subjects participated in this study.Urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In five patients and 776 control subjects, urine samples were obtained before 12 months of age.The main outcome measure was identification of a urine steroid(s) indicating the backdoor pathway.In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages. Furthermore, etiocholanolone and 11-hydroxyandrosterone, which should originate almost exclusively from androstenedione in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, which can be derived not only from androstenedione and dihydrotestosterone in the conventional frontdoor pathway but also from 5alpha-pregnane-3alpha,17alpha-diol-20-one in the backdoor pathway, was increased during early infancy and remained grossly normal thereafter. Thus, the androsterone to etiocholanolone ratio was increased during early infancy and remained grossly normal thereafter. 5alpha-Pregnane-3alpha,17alpha-diol-20-one was elevated throughout the examined ages.The increased androsterone excretion during early infancy, as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the same period, suggests the presence of the backdoor pathway in PORD.
Abstract We report an 18-year-old Japanese male with a lack of secondary sex characterization and growth failure caused by a rare association between Rathke’s cyst and hypophysitis. He was referred to us because of delayed secondary sex characterization. Endocrinological examination showed panhypopituitarism, and the replacement of hydrocortisone, levothyroxine, and desmopressin acetate (DDAVP) was initiated. Brain magnetic resonance imaging (MRI) showed a suprasellar region and a swollen pituitary stalk. The mass was partially resected using the transsphenoidal approach. The pathological diagnosis was hypophysitis and Rathke’s cyst. Follow-up MRI performed 1 year after surgery showed that the size of sellar region had not changed. After surgery, in addition to pre-operative hormonal replacement, growth hormone and testosterone were initiated. Two years later, the size of sellar region remains unchanged. In conclusion, while an association between Rathke’s cyst and hypophysitis is rare, we suggest that this condition should be included in differential diagnosis of the sellar region, even in adolescents.
Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.
A 14.2-year-old prepubertal boy diagnosed with complete-type growth hormone deficiency and tertiary hypothyroidism, keeps growing in the height range between –1 and –2 SD. He has been treated with levothyroxine only. To understand the growth mechanism of this boy, we analyzed the serum growth hormone (GH) with a radioimmunoassay (RIA), serum GH bioactivity with Nb2 and erythroid progenitor cell bioassays, and growth hormone-binding protein (GHBP) with a ligand-mediated immunofunctional assay (LIFA). In addition, IGF-1 and free IGF-1 were analyzed by immunoradiometric assay (IRMA) and insulin-like growth factor-binding protein-3 (IGFBP-3) by Western immunoblot. Peak GH-RIA responses to insulin, arginine and GH-releasing factor, and nocturnal GH secretion, were low (0.5–2.3 ng/ml); bioactive GH was low (0.313 ng/ml), and GHBP was elevated (84 ng/ml). The serum levels of IGF-1 and free IGF-1 were continuously low, 17.1–39.3 and 0.17–0.26 ng/ml, respectively. Moreover, serum IGFBP-3 levels were low (1.68– 1.39 mg/l) and IGFBP-3 protease activity was negative. Prolactin and insulin were in the normal range. The result of the assay for growth-promoting activity showed that the patient’s serum stimulated normal erythroid progenitor cells twice as potently as did healthy thin adult control serum. These results suggest that GH and IGF-1 are not indispensable for maintaining physical growth in this boy. Thus, it appears that circulating GH and IGF-1 are not mandatory requirements for maintaining normal physical growth, and other, as yet uncharacterized, pathways or growth factors might be sufficiently compensatory under certain conditions.
This is a 12 year and 5 month old prepubertal boy, who was followed from the neonatal period because of tertiary hypothyroidism. Endocrinological examinations were performed on three occasions. All the data revealed growth hormone (GH) deficiency and hypothyroidism. GH responses to insulin, arginine and GH-releasing factor (GRF), and the nocturnal GH secretion test, were low and sometimes undetectable. In addition, the serum insulin-like growth factor I (IGF-I) values were always low. Thyroid-stimulating hormone (TSH) responses to the TSH-releasing hormone (TRH) provocation test showed a tertiary hypothyroidism pattern. The values of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were in the pre-pubertal stage and prolactin was in the normal range. Magnetic resonance (MR) imaging showed a small pituitary with stalk interruption, in spite of normal delivery.With the use of levothyroxine, growth has been maintained in the range between -1 standard deviation (SD) and -2 SD. In this case GH and IGF-I are not indispensable for maintaining physical growth, and the abnormal pituitary imaging is not caused by perinatal insult. Further detailed investigations, including a search for some growth-promoting bioactivity other than GH, are needed to elucidate the mechanism of this patient's growth.
We report the identification of a somatic mutation in the gene encoding the α subunit of the stimulatory G protein (Gsα) of adenylyl cyclase in an 8-year-old girl with a toxic thyroid nodule. She had symptoms and signs of thyrotwdcosis. The nodule was resected and found to be an adenoma. To clarify the molecular basis of this tumor, the presence of mutations at codon 201 and 227 in the Gsα gene was sought in deoxyribonucleic acid (DNA) extracted from the tumor and the patient's blood using polymerase chain reaction amplification (PCR). A G-to-A transition resulting in the replacement of Arg by His (Arg 201 to His) was found in exon 8 of one allele encoding Gsα. Because thyrocytes are programmed to proliferate in response to elevated 3', 5'-cyclic AMP (cAMP) levels, the activating Gsα mutation observed in this patient probably contributed to tumorgenic development. To our knowledge, this is the first case in which the activating Gsα mutation in a Japanese child with a toxic thyroid adenoma has been identified.
