The effect of growth hormone (GH) treatment was evaluated in non-growth hormone deficient (GHD) short children with intrauterine growth retardation (IUGR). The 104 short children with IUGR enrolled in the study were divided into three groups. Group A received recombinant human growth hormone (rhGH, Genotropin) 0.5 IU/kg/week 6 or 7 times a week in the first year and 1.0 IU/kg/week in the second year. Group B received rhGH 1.0 IU/kg/week for two years and Group C received rhGH 2.0 IU/kg/week for two years. Mean growth velocity increased from 5.6 cm/year before treatment to 7.2 cm/year in the first year and to 7.4 cm/year in the second year in Group A, from 5.3 cm/year to 8.4 cm/year in the first year and to 7.1 cm/year in the second year in Group B, and from 5.3 cm/year to 10.0 cm/year in the first year and to 7.2 cm/year in the second year in Group C. Mean serum IGF-I was 194.5 ng/ml, 281.7 ng/ml, and 339.0 ng/ml after 12 months of treatment, and 246.9 ng/ml, 305.0 ng/ml, and 318.9 ng/ml after 24 months of treatment in Groups A, B, and C, respectively. Bone age advanced 1.52 years, 1.39 years, and 1.48 years in the first year, and 1.18 years, 1.20 years, and 1.30 years in the second year, respectively. Mean increments in height standard deviation score (SDS) during the two years were 0.89 standard deviation in Group A, 1.09 SD in Group B, and 1.40 SD in Group C. Although a diabetic blood curve on oral glucose tolerance test (oGTT) was observed in a few children, neither increased HbA1c level nor clinical diabetic symptoms were observed. There were no other serious adverse events during GH treatment. This study showed clearly that GH treatment improved such psychosocial problems caused by the patients’ short stature such as self-consciousness about their height, mocking and bullying. High-dose GH administration for 2 years significantly improves height velocity, height SDS, and quality of life in IUGR short children.

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We report a case of partial GH insensitivity syndrome. A 10-year-old boy was referred to the National Iwakuni Hospital with the chief complaint of short stature. His height was 116.7 cm (-3.65 SD), body weight 17.2 kg, and recent growth velocity (GV) 3.1 cm/year (-2.61 SD). After two provocation tests (L-dopa and clonidine), the basal and peak GH levels were 0.29 ng/ml and 12.26 ng/ml, and 0.48 ng/ml and 12.27 ng/ml, respectively. His 24-h urinary GH concentration was 41.9 pg/mgCr. These data indicate normal GH secretion. In contrast, both his serum IGF-I level and IGF-binding protein 3 (IGFBP-3) level were low at 46 ng/ml and 1.80 μg/ml, respectively. His serum GH-binding protein (GHBP) level was also low at 62.0 pmol/l. These findings may imply partial GH insensitivity due to a defect at the level of the GH receptors (GHR). GH therapy led to an increase in GV from 3.1 to 6.4 cm/year, of the serum IGF-I level from 46 to 110 ng/ml and of serum IGFBP-3 from 1.80 to 2.23 μg/ml after 1 year. On the other hand, the serum GHBP level decreased from 62.0 to 39.6 pmol/l, and the second-year GV did not decrease. Although the reason why the GHBP level decreased is unclear, the constant GV during the second-year treatment may be due to the relatively optimal serum GH level maintained by the reduction in GHR and the administration of exogenous GH.

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We report the first case with 21-hydroxylase deficiency (21-OHD) not detected by the newborn mass screening program in Kagoshima prefecture. A one year and four months old girl was referred to the Kagoshima University Hospital because of her ambiguous genitalia. Her plasma level of ACTH and serum level of 17α-hydroxyprogesterone (17-OHP) were extremely high at her initial consultation, although at the time of newborn mass screening her paper disk blood 17-OHP was 5.8 ng/ml which was less than the cut-off point (7 ng/ml) used in the mass screening. The diagnosis of 21-OHD was confirmed by gene analysis of the steroid 21-hydroxylase gene (CYP21B). The patient had I172N (exon4) and R356W (exon8) heterozygous variations. We reviewed the screening program in Kagoshima prefecture because of this false negative case. Although the incidence of false negative cases is rare, this case informs that normal results at screening cannot exclude the possibility of congenital adrenal hyperplasia.

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Recently it has been reported that Mt5178A (a C-to-A transversion at nucleotide position 5178 within the NADH dehydrogenase subunit 2 gene) is related to longevity, and the individuals with Mt5178C are more susceptible to adult-onset diseases than those with Mt5178A. Oxidative stress plays an essential role in the destruction of pancreatic islet cells in type 1 diabetes mellitus. To evaluate the effect of mitochondrial DNA variations on the occurrence of type 1 and type 2 diabetes, we analyzed the incidence of Mt5178A/Mt5178C by PCR-RFLP with Alu I in 385 type 1 diabetic patients, 687 type 2 diabetic patients, and 469 healthy controls. The frequency of Mt5178A was significantly lower in type 1 diabetic patients (121/385, 31.4%) than in healthy controls (184/469, 39.2%) (p=0.018). There were no associations of the Mt5178A/Mt5178C ratio with HLA-DR4, DR9, DQ3 and DQ4 as representative HLA class II in type 1 diabetic patients. On the other hand, the frequency of Mt5178A in type 2 diabetic patients (281/689, 40.9%) was similar to that in healthy controls. These findings suggest that the individual with Mt5178C is susceptible to type 1 diabetes.

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The etiology of thyroid dysgenesis is still unknown. One of the thyroid specific transcription factors, thyroid transcription factor-2 (TTF-2), performs a crucial role in the development of thyroid gland as shown by TTF-2 knock out mice. In the present study, we analyzed the TTF-2 gene in patients with congenital hypothyroidism due to thyroid malformation: three patients with thyroid agenesis, two with hypoplasia, and five with ectopy. Genomic DNA was isolated from peripheral leukocytes, and the TTF-2 gene, consisting of a single exon with extremely high GC content, was amplified by polymerase chain reaction (PCR) with 2 pairs of primers. The PCR products were directly sequenced. One of the patients with ectopic thyroid showed the deletion of 9 bases (GCCGCCGCC), which corresponded to 3 alanine repeats, at the region of 1, 226-1, 234 bp in one chromosome. Also in the patient’s mother the same 9 bases deletion was noted at the same position. However, the mother had normal thyroid function and ^99mTc thyroid scintigraphy revealed no abnormalities of thyroid morphology. Whether this heterozygous deletion of 9 bases corresponding 3 alanine repeats from TTF-2 gene observed in the patient with ectopy was involved in the development of thyroid abnormalities is unclear in the present study and further studies are required.

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Twenty-four patients with Turner syndrome were treated with human growth hormone (GH) and reached their final height. Mean age was 11.7 years and mean height SDS was 0.28 SD for Japanese Turner standard at the start of GH treatment. Mean duration of GH treatment was 6.6 years and mean age at discontinuation of GH treatment was 18.6 years. Final height of all the patients was 146.9 ± 4.2 cm (140.5∼153.9 cm). Since predicted adult height (PAH) was 139.4 ± 5.8 cm (131.8∼155.0 cm), the benefit from growth-promoting therapy (final height - PAH) was 7.5 ± 4.6 cm (-1.4∼+15.2 cm). The final height in 10 patients (42%) exceeded the -2.0 SD value (147.9 cm) for normal girls. It can be concluded that the adult height in Turner syndrome was improved by GH treatment. However, final height was improved by starting pubertal induction later in addition to GH treatment in Japan. Early diagnosis and initiation of treatment with a higher dose of GH is important for adequate pubertal induction and final height.

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