We report a 2-year old boy with central hypothyroidism accompanied by delayed myelination, born to a mother with untreated Graves’ disease. His mother was diagnosed as having Graves’ disease 6 days after delivery. At 3 months of age he was diagnosed as having central hypothyroidism, and L-thyroxine replacement therapy was started. His psychomotor development was delayed and magnetic resonance imaging of the brain showed severely delayed myelination. At 2 years of age serum thyrotropin responses to thyrotropin-releasing hormone were still blunted. Whether his central hypothyroidism is permanent or ultimately reversible remains to be determined, but it is possible that hypothyroxinemia in the neonatal period may interrupt the myelination of the brain.

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We reported a tall Japanese girl who was treated with a somatostatin analog (SA: octreotide acetate). The patient was an 11 years and 10 months old girl who was 171.0 cm tall (+3.58 standard deviations: SD), and whose father and mother were 176.0 cm and 171.0 cm tall, respectively. Although menarche had not occurred on admission, her pubertal development had reached Tanner stage II (breast II, pubic hair II) and the bone age was 11.5 years. The serum levels of estradiol and insulin-like growth factor I (IGF-I) and the early morning urinary growth hormone (U-GH) level were 33 pg/ml, 480 ng/ml, and 58 pg/mg creatinine, respectively. The peak GH responses to insulin, glucagon-propranolol, and GH-releasing hormone were 22.5, 54.2, and 21.9 ng/ml, respectively. There were no abnormal findings in the pituitary gland on magnetic resonance imaging. We diagnosed her as being of familial tall stature and started treatment with SA at a dose of 250 μg per day (100 μg in the morning and bedtime plus 50 μg in the evening) after informed consent was obtained from her and her parents. This treatment resulted in suppressing the serum level of IGF-I and the U-GH level to 180 ng/ml and 18 pg/mg creatinine, respectively, after 10 days. Bone maturation was accelerated by 42 months during 26 months of treatment. Her final height was suppressed to 173.8 cm after treatment, while her predicted final height was above 180 cm. No side effects such as impaired glucose tolerance, hypothyroidism and physical discomfort were observed. Although a slight decrease in spinal bone mineral density was observed during the treatment period, an increase in bone mineralization was observed 6 mon after the cessation of treatment. In conclusion, SA was effective and safe for reducing the increase in height in this present case.

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We investigated the etiology of hirsutism in 117 hirsute females (HF) comprised of 5 racial/ethnic groups, and the effect of 3 menstrual cycle phases and dexamethasone (Dex) pre-treatment on the hormonal response to ACTH stimulation in 19 normal females (NF). All HF and control NF (n=33) had an ACTH stimulation test, and 35 HF and 19 NF had an adrenal and/or ovarian suppression test. No significant differences were found in the ACTH stimulated hormonal levels between no-Dex and Dex pre-treatment states, and between the phases of the menstrual cycle in NF. The hirsute etiology findings in all HF revealed no apparent cause (idiopathic) in 48%, polycystic ovary syndrome (PCOS) in 26%, increased adrenal androgen secretion in 12%, mild defect in adrenal 3β-HSD activity in 7.7%, increased adrenal and ovarian androgen secretion in 5%, and 21-hydroxylase deficiency in 1.7%. In each of the Caucasian and African-American HF groups, and in a small number of HF of Ashkenazi Jewish, Hispanic, and Middle Eastern decent, idiopathic or PCOS was the most common etiology, while other etiologies were uncommon or rare.

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We identified a patient with a nonclassical (NC) form of 21-hydroxylase deficiency (21-OHD). A 6-month-old boy was referred to the Shinshu University Hospital because of increased concentration of serum 17-OH progesterone (17-OHP). The high 17-OHP concentration was detected in mass screening program for CAH. He did not manifest any signs or symptoms of adrenal insufficiency or androgen excess at birth. Molecular analysis of the CYP21 gene revealed that he carried a compound heterozygote with the I172N mutation in one allele and the V281L mutation in the other allele. This suggests that the newborn mass screening can detect some NC 21-OHD cases in which both alleles contain only NC-associated mutations. He is the first patient with the NC phenotype which shares the same mutation as caucasian NC patients.

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We report a case of inherited isolated GH deficiency (IGHD) type IA. The patient (S.A.) is a 15-year-old boy with a chief complaint of short stature. His parents were second cousins. He was delivered of normal size without asphyxia or fetal distress. His growth retardation became prominent 3 months after birth. When he was admitted to Tohoku University Hospital at the age of 3 years and 1 month, his height was 68.3 cm (-7.1 SD), his body wt was 7.5 kg, and his bone age was 10 months. His plasma GH level measured with a high sensitivity GH immunoradiometric assay (IRMA) kit was below the detection level (6 pg/ml) either after sequential 3 day administrations of GH releasing hormone (GHRH) followed by arginine infusion, or after GH releasing peptide (GHRP) administration. His other endocrine functions remained normal. No abnormalities were observed in his hypothalamo-pituitary region by magnetic resonance imaging. Among 5 patients with IGHD whose GH levels were undetectable even after the stimulation with GHRH plus arginine, 2 patients (including the above case) still did not show any response to GHRP. Genetic analyses of the GH-1 gene were undergone in these 5 patients, and revealed that only the patient S.A. had a homozygous 6.7-kb GH-1 gene deletion. His parents, sisters, and paternal grandfather were heterozygotes. The patient was therefore diagnosed as IGHD type IA. We consider that the measurement of plasma GH with the high sensitivity GH IRMA kit after strong GH provocation tests may be useful for the screening of IGHD type IA.

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Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) are intermolecular crosslinking compounds in mature collagen and have been utilized as biomedical markers of bone resorption. We determined the reference ranges of urinary Pyr and D-Pyr in 358 normal children aged 6-14 years, and investigated urinary secretion of these pyridinolines in 16 patients with various growth disorders (7 with precocious puberty, 6 with Turner syndrome, and 3 with GH deficiency). The Pyr and D-Pyr levels in first morning void urine samples were measured by a high performance liquid chromatography (HPLC) assay. The age related changes in urinary pyridinolines were similar to growth velocity curves, reached peak levels at 11-12 years and decreased thereafter. Significant positive correlations were observed between growth velocities and urinary Pyr levels in both normal children and patients with growth disorders. These findings suggest that urinary pyridinolines are good markers of bone remodeling and might be useful in estimating and predicting growth in both normal children and patients with growth disorders.

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We report a boy with infant-onset (2 months) IDDM who has been in a good glycemic state until the present 3 years of age and describe how we have managed diabetes on the basis of his diabetes diary, which contains results of home-monitoring blood glucose (HMBG), calories and kinds of foods, symptoms of hypoglycemia, and his attitude toward blood sampling and insulin injection. He has well tolerated painful procedures, such as HMBG and insulin injection, and started to help his mother to prepare the HMBG kit at the age of 2 years and 4 months. Symptoms of hypoglycemia varied with age, and the pallor of his face and sudden unusual crying during sleep were common signs of hypoglycemia throughout the course. Since he sometimes has remained asymptomatic even with hypoglycemia under 50 mg/dl, frequent HMBG and carbohydrate-rich meals were necessary to maintain a good glycemic state. Blood glucose levels were largely influenced by physical activity, which depended on his neurological development. The diabetes diary was very useful not only to detect minor signs of hypoglycemia and control the blood glucose level, but also to establish a good parent-physician relationship.

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A nine-year-old girl was first found to have microscopic hematuria and proteinuria when she was diagnosed with growth hormone deficiency. As the results of urinalysis had not changed for three months, growth hormone treatment was started. At the age of nine-years and eight-months, a kidney biopsy was performed because the hematuria had gradually increased. The pathologic diagnosis was IgA nephropathy group I. After 2.5 years of GH treatment, glycosuria developed. She was diagnosed with IDDM and the GH treatment was discontinued. The second renal biopsy showed IgA nephropathy group II. She was treated with azathioprine for two years. The microhematuria and proteinuria decreased. Currently at 15.6 years of age, her height is 148 cm (-3.1 SD) and IDDM has been well controlled.

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Neonatal thyrotoxicosis is thought to be induced by transplacental transfer of maternal TSH receptor antibodies (TRAb). We analyzed the relationship between the serum TRAb levels at birth and the development of thyrotoxicosis in neonates born to mothers with Graves disease. Thirty-three neonates born to mothers with Graves disease were eligible for the study. The thyroid function tests were performed with neonatal serum within 24 h after birth. The subjects were divided in two groups: neonates developed to thyrotoxicosis (Group A) and those not to thyrotoxicosis (Group B). Five neonates developed to thyrotoxicosis. There were no significant differences in free T₃, free T₄ and TSH concentrations in the blood of neonates within 24 h after birth between Group A and Group B. TRAb values were 75.0 ± 9.9% and 19.3 ± 2.6% in Group A and Group B, respectively (p<0.01). All 4 neonates with serum TRAb levels above 50% had developed to thyrotoxicosis. Serum TRAb of the other one neonate who developed to thyrotoxicosis was 26.0% on the 30th day after birth. Neonatal thyrotoxicosis can be predicted in neonates with high TRAb values. These results suggest that the screening of TRAb is useful for predicting thyrotoxicosis in neonates born to mothers with Graves disease.

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