We report on two patients with 45,X/46,X,idic(Y) who showed different sex development. Case 1 is a 2-year-old boy. At one month of age his left retentio testis was noticed. Orchidopexy of left side was attempted when the patient was one year old, but gonadectomy was performed instead because an undifferentiated gonad was found. Pathological examination revealed ovotestis. Physical examination showed short stature (-2.6 SD), right testis (1 ml in volume), small penis (2.5 cm in length), and no signs of Turner syndrome. Chromosome analysis for peripheral lymphocytes revealed 45, X[5]/46, X, +mar[25].ish idic (Y) (q11.2) (SRY++, DYZ3++, DYZ1-). An HCG test showed a fairly good testosterone response (14→182 ng/dL). Case 2 is an 11- year-old girl. Physical examination showed short stature (-2.5 SD) and no signs of Turner syndrome. An LH-RH test showed excessive response (LH 36→400; FSH 200→480 mIU/mL). Small uterus was detected by abdominal echography. Because of the risk of gonadoblastoma, gonadectomy was performed. The bilateral gonads were streak gonads. Chromosome analysis of the resected gonad revealed 45, X[27]/46, X, idic (Y) (q12) [23]. PCR analysis of DNA from the resected gonad detected SRY. Since the rearranged Y chromosomes of both cases were positive for SRY, it is likely that the difference in the mosaic cell ratio in the gonad played an important role in their discordant sexual phenotypes.

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Idiopathic hypothalamic dysfunction is a rare disorder associated with adipsia, obesity and other symptoms such as central hypoventilation without any hypothalamic structural lesion. We report the case of a 3-year-old boy who died suddenly due to central hypoventilation. His obesity index increased from 0% to 75% during the 7 months prior to 3 yr 0 mo. During this clinical course, adipsia, hyperthermia, sudoresis, mild central hypoventilation, blepharoptosia, a change of character, hypernatremia, and hypothalamic hypopituitarism were observed. No treatment was given for hypoventilation. He died from sudden respiratory arrest because of central hypoventilation at 3 yr 8 mo. MRI examination was performed twice at 3 yr 3 mo and 3 yr 4 mo and revealed neither specific lesion nor invisible pituitary stalk. At autopsy, local inflammation and gliosis of the hypothalamus were present. So far at least 14 patients with idiopathic hypothalamic dysfunction have been reported. Eight cases including ours had central hypoventilation. Six out of the eight had poor respiratory prognosis, and central hypoventilation in hypothalamic dysfunction could be potentially fatal. In conclusion the patients with hypothalamic dysfunction should be treated intensively if they are suspected of having central hypoventilation.

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We studied gonadal function in 42 girls who underwent stem cell transplantation (SCT) between 1982 and 1997. Their median age at the time of transplantation was 11 years (range: 5 to 16 years), and that at the time of the study was 17 years (range: 13 to 27 years). Diagnoses included acute leukemia (n=25), aplastic anemia (n=12), chronic myelogenous leukemia (n=3) and lymphoma (n=2). They were assigned to one of four groups according to the preconditioning regimen used for SCT; busulfan plus melphalan (BU group; n=17), high-dose chemotherapy plus total body irradiation (TBI group; n=15), cyclophosphamide plus total lymphoid irradiation (TLI group; n=7), and all others (n=3). Gonadal function was assessed by occurrence of menstruation, serum levels of LH, FSH, and estradiol (E₂). Twenty-eight of forty-two patients (67%) had no menstruation after SCT. The percentages of patients with amenorrhea were 100%, 60% and 14% in the BU, TBI and TLI groups, respectively. These findings confirm that a busulfan plus melphalan regimen is a major risk factor for ovarian dysfunction in children after SCT.

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In order to estimate the mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) diagnosed after the introduction of a newborn screening program in Japan, a questionnaire was sent to all members of the Japanese Society for Pediatric Endocrinology. Three hundred and eighty two out of 960 questionnaires were available for the analysis. Twelve deaths were reported. Two died in an early neonatal period, and 10 patients were on maintenance therapy. This suggests that mortality is estimated to be one in 25-80 21OHD patients on maintenance therapy in childhood. It was speculated that cortisol deficiency somewhat contributed to their deaths. Of note, 4 died during a gastrointestinal infection. The need to increase hydrocortisone doses, and the importance of parenteral hydrocortisone administration during stress or illnesses should be repeatedly informed to carers and their physicians.

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To evaluate the usefulness of a high-sensitivity assay kit for E₂, we measured the serum E₂ levels in children. The value in a girl with true central precocious puberty was also evaluated before the LH-RH analogue treatment. The study subjects were 36 boys, ranging in age from 1 yr and 9 mo to 17 yr and 6 mo and 46 girls, ranging in age from 1 yr to 15 yr and 6 mo. The minimal detection limit was 1.4 pg/ml. The serum E₂ level in the boys and that in girls were 10.8 ± 3.1 pg/ml (mean ± SEM) and 20.7 ± 10.7 pg/ml, respectively. The E₂ level was correlated closely with bone age and chronological age. Even when the range of serum E₂ was limited to an undetectable level (<10 pg/ml) by the conventional assay, the logarithmic value for the E₂ concentration was correlated with bone age in boys (r=0.734, p<0.05) and in girls (r=0.404, p<0.05). The E₂ level in girls with partial and true precocious puberty ranged from 2.6 to 8.7 pg/ml. In a patient, who was originally considered as premature thelarche and later turned out to be true central precocious puberty, the serum E₂ level was 3.7 pg/ml before therapy, suggesting that high sensitivity to estrogen was the cause of the condition. With LH-RH analogue treatment, the E₂ level declined to below the detection limit and the bone age did not change for 1 yr without loss of linear growth. These results suggest that the high-sensitivity kit is useful for monitoring the pathophysiology of E₂ in children.

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We have developed a quantitative system to measure serum concentrations of the soluble form of human IGF-II receptor (IGF-IIR). The soluble form retains the ability to bind to IGF-II and proteins with M6P moieties in circulating blood. IGF-IIR does not only control the degradation of IGF-II, but also inhibits DNA synthesis by modifying the IGF-II action. The measurement of serum concentrations of the soluble form is able to clarify the growth mechanism in vivo. The system employs an enzyme immunoassay (EIA) making use of antibodies to peptides 1103~1119 amino acid (AA) of IGF-IIR. We could obtain two single bands at about 220 kDa corresponding to the soluble form and at about 290 kDa corresponding to the cell membrane-associated form by Western blotting. According a recent report, the soluble form was 220 kDa, and the measured level was 700 ± 230 ng/ml in healthy adults. In our trial data, the measured mean level was about 724 ± 134 ng/ml in five healthy adults. These data were nearly coincident. Consequently this antibody has high specificity for the soluble form in blood and the cell membrane associated form of IGF-IIR.

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Achondroplasia is the most common skeletal dysplasia and is caused by defective fibroblast growth factor receptor (FGFR) 3 in endochondral chondrocytes. Children with achondroplasia may have high cervical myelopathy due to stenosis of the craniocervical junction and an increased risk of sudden death. We report a female patient with achondroplasia who required surgical decompression at the age of 13 mo. The female patient was diagnosed with achondroplasia clinically, radiologically and genetically shortly after birth. The newborn period was uneventful. She developed head control at the age of 6 mo, but she could not sit by the age of 12 mo. At the age of 8 mo, her parents noticed her eyes did not close and a diagnosis of left peripheral nerve palsy was made. Occasional hyperextension of the trunk was observed. There was also minimal asymmetry of voluntary leg movement and bilateral ankle clonus. By these findings craniocervical junction compression was strongly suspected. MRI examination revealed compression at the craniocervical junction by the occipital bone and myleomalacia. The patient underwent suboccipital decompressive surgery at the age of 13 mo. Recovery after surgery was uneventful, and although her left facial nerve palsy did not improve, gross motor function had improved by the age of 2 yr. The patient is now cognitive and neurologically normal at the age of 3 yr. Infants with achondroplasia are at risk of lethal sequelae of craniocervical junction abnormalities, so careful neurological assessment and early MRI examination is recommended.

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Obesity is regarded as a risk factor for cardiovascular disease. However, it is still unclear how childhood obesity is related to atherogenesis. Endothelial dysfunction is thought to be the earliest event in the development of atherosclerosis. We evaluated vascular endothelial function in obese children by measuring percent flow-mediated dilatation, an arterial response to reactive hyperemia. Percent FMD was examined using high-resolution vascular ultrasound in 20 boys (10.0 ± 2.1 yr) and 17 girls (9.6 ± 1.9 yr) with simple obesity. Physical examination, laboratory tests, and carotid ultrasonography were also performed. No atherosclerotic changes were observed in the carotid artery in any of the obese subjects. In the obese children, percent FMD was lower than in non-obese controls, (boys: 8.0 ± 3.7% vs. 14.6 ± 3.8%, P<0.001; girls: 7.3 ± 1.8% vs. 16.3 ± 5.7%, P<0.001). There were significant inverse linear correlations between % FMD and GPT, uric acid (UA), HbA1c, and diastolic blood pressure in the boys. In the girls, significant inverse linear correlations were noted between % FMD and age, waist-hip ratio, percent body fat, fat content, fat-free mass, abdominal fat index, IRI, systolic blood pressure, and diastolic blood pressure. This study showed that endothelial function was impaired in children with simple obesity and that % FMD was an excellent parameter for detecting endothelial dysfunction in these children. While many factors are associated with endothelial dysfunction, the diastolic blood pressure seems to be one of the most important in obese children.

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Twenty-kilodalton human GH, a human GH (hGH) variant, has insulin-like and anti-insulin-like actions different from 22-kilodalton hGH (22K). The diabetogenic action of twenty-kilodalton hGH (20K) is reported to be weaker than that of 22K, yet it is still unclear whether secretion of 20K is influenced by factors in carbohydrate metabolism. We measured serum 20K and 22K in children with simple obesity and studied the regulation of 20K production. The subject were 124 boys (9.78 ± 1.94 yr old, body mass index (BMI) 25.88 ± 2.43 kg/m²) and 54 girls (10.29 ± 2.25 yr old, BMI 26.90 ± 3.72 kg/m²) with simple obesity. The serum samples were taken after overnight fasting. The data was compared with the data from children with non-GH deficient (GHD) short stature. The mean serum concentrations of 22K and 20K were 1.47 ± 1.63 ng/ml and 81.3 ± 80.3 pg/ml in obese boys and 1.86 ± 2.00 ng/ml and 108.9 ± 120.4 pg/ml in obese girls. The percentage of 20K in hGH was 7.4 ± 5.0% in obese boys and 6.5 ± 2.9% in obese girls, and the percentage was not significantly different from the percentage of 20K in children with non-GHD short stature. The height SD score, obesity index, body fat mass, BMI, fasting blood sugar, insulin, homeostasis model assessment-R (HOMA-R), HbA1c, total cholesterol, triglyceride, leptin and IGFBP-1 were not correlated to the percentage of 20K. We conclude that the percentage of 20K is constant not only in normal children but also in obese children, and factors that correlate with obesity such as glucose and insulin do not influence the 20K splicing mechanism.

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