The standard calcification pattern of selected bones was studied to estimate the bone age in fetuses by means of whole body radiographs taken at the postmortem examination. Ten bones were selected as a marker of bone age because their calcification occurred in the gestational period. They consisted of talus, os calcis, ishium, os pubis, sternum, vertebral bodies (coccygeal and 5th sacral), lumbar transverse processes, proximal epiphysis of tibia and distal epiphysis of the femur. The gestational week when each bone started calcification was determined, and we demonstrated the characteristic pattern of calcification of selected bones. The number of calcified bones and gestational week were significantly correlated. Furthermore, the symmetrical intrauterine growth retardation (IUGR) group had delayed bone age, but the asymmetrical IUGR group did not. Bone age was moderately delayed in thanatophoric dysplasia, but no delayed bone age was observed in osteogenesis imperfecta type II. In summary, the calcification pattern of the selected bones we reported is useful to assess the maturity of newborns, and may contribute to a better understanding of the pathophysiological state of various diseases.

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The relatively high cost of recombinant human growth hormone (rhGH) has raised the issue of whether intermittent treatment regimens might be efficacious for patients with GH deficiency. Two previous reports have suggested that interruption of GH treatment may avoid the typical waning of response associated with continuous GH therapy and may, therefore, result in an advantageous cost-benefit ratio. We have studied 2 patients with GH deficiency treated with rhGH which was interrupted for one month. The one month of interrupted therapy did not have any beneficial effect and may have caused a loss of potential growth. Although our observations are limited, the data indicate that intermittent GH treatment regimens should not be advocated in the absence of additional investigations.

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The objective of this study was to discuss the etiology of cerebral infarction in three cases of congenital adrenal hyperplasia (CAH) based on detailed individual case reports. Patients consisted of three children, two female, one male, 3y, 2y 6mon., and 3y 6mon, with CAH who developed cerebral infarction. The possibility of cerebral infarction following hypoglycemia due to adrenal insufficiency can be considered but the evidence is not conclusive. The combination of cerebral infarction, a rare condition among children, and CAH might not be accidental but suggests the possibility that CAH itself or treatment with glucocorticoid and/or mineralocorticoid or an inadequate treatment under stressful condition may be the cause of the cerebral infarction.

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Steroid 21-hydroxylase deficiency (21-OHD) is caused by the genetic alteration of the steroid 21-hydroxylase gene (CYP21B) and nearly 80% of all occurrences have been caused by 9 specific deleterious point mutations. We developed a modified polymerase chain reaction (PCR) method based on Hot-start PCR with dried blood spots (DBS) to analyze 4 frequent point mutations, namely (i) A or C to G substitution at base 656 in intron2 (In2g), (ii) Ile-172 to Asn in exon4 (E4IN), (iii) Gln-318 to non-coding mutation in exon8 (E8non), and (iv) Arg-356 to Trp in exon8 (E8RW). All of the 13 patients detected in our congenital adrenal hyperplasia (CAH) screening program exhibited some mutation or deletion on one or both of the alleles. This non-radioactive non-invasive molecular diagnostic method with DBS proved to be easy and quick, and could be a powerful tool for routine genetic diagnosis in newborn CAH screening.

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The implications of Bovine serum albumin (BSA) in cow's milk proteins in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) have been suggested, but is controversial even in Caucasians, and have been addressed in limited studies in other ethnic groups. We studied the prevalence of antibodies to BSA (BSAAb) in sera from Japanese children with IDDM, and compared it to those in children with other diseases including non insulin-dependent diabetes mellitus (NIDDM), autoimmune thyroid disease (AITD) and congenital hypothyroidism (cretinism) by using enzymelinked immunosorbent assay (ELISA). Significant levels of BSAAb were detected in sera from non-diabetic normal children, and higher levels in younger (1-3 years of age) than in older children (4-9 years of age). Only 2 of 20 (10%) recent-onset IDDM patients of age ≥ 4 years were assessed to have high titers of BSAAb compared to normal controls, and none of 8 sera from those of age <4 years were positive for BSAAb. No significant difference in the incidence of BSAAb was found among the various groups of children examined in both age groups. It appeared that BSAAb in IDDM patients bound to different sites on BSA from ABBOS (a 17-amino acid peptide, position 152 to 168 of BSA), based on the result that no significant blocking of BSAAb by the addition of ABBOS was detected by inhibition assay. Antibodies to glutamic acid decarboxylase (GADAb) in sera and human leukocyte antigen (HLA) -DR, -DQ genotypes of 28 recent-onset IDDM patients were examined. In addition, there was no significant difference between GADAb-positive and -negative IDDM patients in the titers of BSAAb. No association of BSAAb with HLA genotypes such as HLA-DR9-DQ9 and DR4-DQ4 was found in recent-onset IDDM patients. Collectively, BSAAb was not associated with IDDM in Japanese children.

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We analyzed the steroidogenic acute regulatory protein (StAR) gene in a Japanese patient with congenital lipoid adrenal hyperplasia (CLAH). The patient was revealed to be a compound heterozygote bearing a missense mutation A218V, which changed codon 218 (GCG) encoding Ala to GTG encoding Val in the StAR gene, and a nonsense mutation Q258X, which changed codon 258 (CAG) encoding Gln to the stop codon (TAG), by polymerase chain reaction amplification and direct sequencing of the StAR gene. The Q258X mutation has been demonstrated to cause CLAH in Japanese and Korean patients. The A218V mutation has been reported to cause CLAH in a Canadian white patient. These findings suggest that the amino acid residue Ala218 is important for the normal StAR function, and the codon 218 might be a hotspot for the StAR gene mutation.

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To determine the best fit model of age adjustment for overweight in children, we analyzed the anthropometric data for school children, ages ranging from 6 to 14 years. We referred to the height, body weight and age of 4196 boys and 3901 girls in elementary and junior high schools in Yamanashi Prefecture. From these data, randomized samples for 2250 boys and 2247 girls were subjected to statistical analysis. To obtain the index of overweight that was minimally affected by the ages of the subjects, body weight (Bw; kg) / Height (Ht; m) ^power (BMIP) was calculated for each subject, and the power of the height was adjusted so that the calculated value showed the least correlation with age. The BMIP was least correlated with age when the power was set to 2.6927 in boys, and to 2.8472 in girls. The optimized BMIP values in 3 different age and height groups were similar in boys, but somewhat different in girls. However, the variability of the mean values was around 2% in girls. These results suggest that BMIP optimized for age in each sex is a better alternative to the standard body weight for Japanese children than body mass index.

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In order to assess growth, growth hormone and IGF-I levels in girls treated with long-acting GnRH analogue (D-TRP-6-analogue), we evaluated 14 girls with idiopathic central precocious puberty. The age at the beginning of pubertal signs was 2.1 to 6.8 years; the diagnosis of GnRH-dependent precocious puberty was confirmed by a pubertal pattern of gonadotrophin response to an exogenous bolus of 2.5 μg/kg of synthetic gonadorelin hydrocloride. Evaluating growth velocity during 24-mon therapy with the analogue, it was possible to distinguish a group of 6 girls who grew less than 4 cm/year (group A) and a group of 8 girls whose growth velocity was greater than 4 cm/year (group B). Growth hormone secretion was assessed by clonidine (0.15 mg/m² orally) and pyridostigmine (60 mg orally) plus GHRH (after 60 min). Physiological GH secretion was evaluated by measuring GH in blood sampled every 30 min for 10 h from 2200 to 0800. No significant difference was observed in 10-h mean nocturnal secretion between group-A and group-B girls. Also stimulated GH levels did not differ between the two groups. Four girls (28.6%) had subnormal responses to stimulation tests peak <10 μg/L after clonidine and 20 μg/L after pyridostigmine plus GHRH; of these children two belonged to group A and two to group B. Height, growth rate, bone maturation rate and predicted height did not correlate with either spontaneous or stimulated GH levels. IGF-I levels were similar in the two groups; a significant reduction of IGF-I serum levels was observed in both groups after 24 mon of GnRH-analogue therapy. In conclusion, in some children with precocious puberty growth velocity significantly declines after 24 mon of therapy with long-acting GnRH agonists, but spontaneous and stimulated GH and IGF-I secretion is not related to growth velocity.

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