Transient hypothyroxinemia in infants born to mothers with Graves' disease is a unique disorder first reported by us in 1988. Most mothers of these infants have had no treatment, are diagnosed as having thyrotoxicosis during the last trimester, or were not well controlled during pregnancy. These infants are believed to have transient central hypothyroidism, the mechanisms of which have not been elucidated. We measured TSH-receptor antibody activities in maternal serum and blood thyroxine (T4) (free thyroxine, FT4) and TSH levels in blood dried on filter paper at 1, 3, and 5 d of age in 114 infants born to mothers with Graves' disease. The 114 infants were retrospectively divided into three groups according to the clinical course and thyroid function data: group G, neonatal thyrotoxicosis; group T, transient hypothyroxinemia; and group E, euthyroid. In group T, the dried blood T4 (FT4) level from cord blood and/or 1 d of age blood was 6.0 +/- 2.3 microg/dL (0.92 +/- 0.52 ng/dL), a value significantly higher than that at 5 d of age (3.6 +/- 1.0 microg/dL; 0.38 +/- 0.18 ng/dL) (p = 0.025 in T4, p = 0.042 in FT4). In contrast, these levels were significantly lower at birth relative to 5 d in group G (p = 0.0001 in T4) and not significantly changed in group E. The TSH level of cord blood and/or 1-d-old blood in group T was significantly lower than that of group E (p = 0.0006). Moreover, the TSH levels in response to thyrotropin-releasing hormone were blunted in most infants in group T. Bone maturation was not delayed in group T, compared with euthyroid infants. The higher blood T4 (FT4) levels at birth, relative to 5 d in group T, suggested that the fetal T4 level was higher than that of the newborn period. The fetal T4 level might have been elevated owing to transfer of T4 from mother to fetus during the last trimester when the mother's thyroid function was elevated and consequently the fetal pituitary-thyroid axis was suppressed. Although the serum T4 (FT4) levels were decreased after birth, TSH levels were not elevated, probably because the pituitary-thyroid axis was suppressed. This may be the reason for the transient hypothyroxinemia with a normal TSH level in infants born to mothers with poorly controlled Graves' disease. Weak maternal thyroid-stimulating antibody activities and differences in sensitivity of the thyroid gland to TSH-receptor antibodies may contribute to this unique disorder.

Objective: One of the thyroid-speci®c transcription factors, thyroid transcription factor-2 (TTF-2), performs a crucial role in the development of the thyroid gland. We performed genetic analysis of the TITF2 gene (encoding TTF-2) in patients with thyroid dysgenesis. Methods: By direct sequencing of the PCR products of TITF2, we screened the genomic DNA from 46 patients with thyroid dysgenesis (®ve had agenesis, six had hypoplasia, 15 had ectopy, and 20 were undetermined). We also studied the transcriptional activities of TITF2 by co-expressing the luciferase gene directed by the human thyroglobulin gene promoter. Results: Human TITF2 consists of a forkhead domain, a polyalanine tract, and unique C-terminal residues. In one of the patients with an ectopic sublingual thyroid, we found a polyalanine tract of 11 alanine residues on one chromosome instead of the 14 alanine residues found in normal controls. In one patient with hypoplasia, the polyalanine tract consisted of 12 heterozygous alanine residues. The reduced polyalanine tracts were not detected in 101 normal individuals. However, the expression study showed that the transcriptional activities of TITF2 with reduced polyalanine-tract lengths were equal to that of TITF2 with an unreduced polyalanine tract. Conclusion: These results suggest that the polymorphism of the polyalanine tract of TITF2 is not a frequent cause of developmental defects of the human thyroid gland.

Abstract. Studies on thyrotropin receptor autoantibodies (TRAb) by measurement of both thyroid-stimulating antibodies (TSAb) and thyrotropin-binding inhibitory immunoglobulins (TBII) in serum from children with Graves' disease are limited in number of studies. The aim of this study was to investigate the levels of serum TSAb and TBII in children with Graves' disease, and to evaluate the clinical significance of these antibodies. We measured the serum TSAb and TBII at diagnosis and during management in 65 children with Graves' disease. Patients were divided into four groups according to their metabolic state: those with untreated active Graves' disease, those receiving treatment with antithyroid drugs, those in remission, and those in relapse. At diagnosis, both TSAb and TBII assays had high sensitivities and high specificities. In follow-up, the levels of both TSAb and TBII paralleled the course of the disease. There was a strong positive correlation between TSAb and TBII. TBII levels were significantly higher in the patients with ophthalmopathy than those without ophthalmopathy in untreated Graves' children. It was concluded that TSAb and TBII measurements are valuable in the diagnosis and management of children with Graves' disease.

Key wordssubclinical hypothyroidism, thyrotropin receptor mutation.Subclinical hypothyroidism is defined as an elevated serum TSH concentration, and normal serum free thyroxine (T 4 ) and 3,5,3 ′ -triiodothyronine (T 3 ) concentrations associated with few or no symptoms or signs of hypothyroidism. 1,2 Recently, not only infants with overt hypothyroidism but also those with subclinical or mild hypothyroidism have been found by neonatal screening for congenital hypothyroidism.We identified a missense mutation in the thyrotropin receptor (TSHR) gene in a patient with subclinical hypothyroidism found by neonatal screening. Case reportThe propositus (a girl) was the first child of non-consanguineous Japanese parents. She was born at 39 weeks of gestation following an uncomplicated pregnancy and delivery, with a weight of 2682 g. She was referred because of a TSH level of 15 mU/L on neonatal screening at day 5 of life. The family history revealed no thyroid disease. At recall examination at day 46 of life, a serum TSH concentration of 12.0 mU/L in conjunction with normal serum concentrations of T 4 (10.4 µ g/dL) and T 3 (181 ng/dL) were detected. She did not have a goiter nor abnormal physical findings. Though her serum thyroid hormone levels were within normal limits, she was followed up for hyperthyrotropinemia. At the age of 3 years, an excessive TSH response to intravenous administration of thyrotropin releasing hormone (TRH) was considered diagnostic of congenital primary hypothyroidism, and subsequently, she was treated with levothyroxine (L-T 4 ). Figure 1 shows the clinical course of the propositus until 13 years of age. Before treatment with L-T 4 , the serum TSH level fluctuated between 10 and 30 mU/L. It declined to within normal limits after treatment with L-T 4 . The serum T 3 and T 4 levels were almost within normal limits throughout the course. At the age of 8 years, she underwent 123 I scintigraphy and TRH testing after the discontinuation of L-T 4 treatment. 123 I scintigraphy showed a normal-sized eutopic thyroid gland. Her 24 h 123 I uptake value was 17%. The perchlorate discharge test was negative. After the intravenous administration of 300 µ g/m 2 of TRH, her serum TSH concentration increased from 18.8 mU/L to a peak of 93.7 mU/L, while serum T 3 did not increase from the basal level of 111 ng/dL to 100 ng/dL at 120 min.

The rdw rat (gene symbol: rdw) with hereditary dwarfism has been shown immunohistochemically to have subnormal numbers not only of GH- but also of prolactin- and thyrotrophin-positive cells. To characterize the dwarfism of this strain, the expression of pituitary hormone mRNAs was examined by Northern hybridization. The pituitary gland in the rdw rat expressed 30-100 times less GH and prolactin mRNAs than normal controls, whereas mRNAs for pro-opiomelanocortin and the alpha subunit of rat glycoprotein hormone revealed a significant increase. There was a non-significant difference in rat LH-beta subunit and FSH-beta subunit between normal and rdw rats. The suppressed expression of a pituitary-specific transcription factor, Pit-1, is considered to cause hereditary dwarfism in mouse strains Snell and Jackson, whose phenotypes resemble those of the rdw rat. In this study, however, no difference in mRNA expression for Pit-1 was found between rdw rats and controls. This work indicates that the rdw rat may not have the same genotype as the phenotypically similar dwarf mice, Snell, Jackson and Ames.

The rdw rat was initially reported as having hereditary dwarfism caused by pituitary dysfunction. Subsequent studies on the rdw rat, however, have demonstrated that the primary cause of rdw dwarfism is present in the thyroid gland but not in the pituitary gland. The primary cause of rdw rat disorders is a missense mutation of the thyroglobulin (Tg) gene by a one-point mutation.In the present study, we attempted to rescue the dwarfism of the rdw rats using a diet supplemented with thyroid powder (T-powder) and a thyroid graft (T-graft). The infants of the rdw rat were successfully raised to a mature stage body weight, accompanied by elevation of serum growth hormone (GH) and prolactin (PRL), by the T-powder. Furthermore, the T-graft successfully increased the body weight with fertility. The serum GH and PRL levels in the T-graft rdw rat significantly increased. The serum thyroid-stimulating hormone (TSH) levels in the T-graft rdw rat were significantly decreased but were significantly higher than those in the control rat. The GH and PRL mRNA expression in the rdw rat with the T-graft was virtually the same as that of the control, but the TSH β mRNA differed from that of the control rats. Thus, the dwarfism in the rdw rat is rescued by thyroid function compensation, such as that afforded by T-powder and T-graft. Key words: growth, rdw rat, thyroid therapyThe rdw rat (gene symbol: rdw/rdw) was raised by Koto et al. [13] from a closed colony of the Csk: WistarImamichi strain as a variant with pituitary dysfunction. On the basis of an immunohistochemical analysis, the same researchers suggested that the rdw dwarfism was caused by hypoplasia of the pituitary gland. Subsequently, it was revealed that the expressions of mRNA (Received 28 February 2005 / Accepted 1 September 2005 Address corresponding: S. Furudate, Department of Laboratory Animal Science, Japan of growth hormone (GH) and prolactin (PRL) in the rdw rat are drastically decreased [18,21]. In addition, the GH and PRL proteins in the rdw rat are decreased to a level 1/30 to 1/100 of those of a normal rat [17,18].In the rdw rat, the thyroxine (T 4 ) levels in serum are drastically decreased [19,21,23], but the thyroid-stimu-

Ontogenic expression of somatostatin (SRIF)—messenger RNA (mRNA) in the gastrointestinal tract was examined in neonatal rats aged from 1 day preterm to 60 days postpartum in comparison with that in the hypothalamus. SRIF‐mRNA in the hypothalamus was already expressed in prenatal rats and its developmental change was relatively small. In contrast, a unique pattern of SRIF‐mRNA expression was seen in the different intestinal regions, gastric antrum, duodenum, jejunum and colon. In the duodenum, SRIF‐mRNA level was low at birth, markedly increased during the postnatal 3 days and declined to the previous level by day 21. Jejunal SRIF‐mRNA was found in neonates but progressively decreased in a similar way to duodenum. On the contrary, gastric SRIF‐mRNA level, which was low during early development, rose rapidly to a peak on day 21 and gradually declined to an adult level. In the colon age‐related change was not conspicuous, remaining at a low level. These results indicate that (1) expression of SRIF gene in the intestinal tract is regulated by local factor(s) as well as developmental stage, and (2) shift of SRIF‐mRNA pattern occurs during weaning from the duodenum‐dominant infantile pattern to the gastric‐dominant adult pattern.

Objective: To report on 15 Japanese patients with acrodysostosis and PHP and analyze them using the newly proposed classification of the EuroPHP network to determine whether this classification system is suitable for Japanese patients. Design: We divided them into three groups based on hormone resistance, the number of fingers with short metacarpals, the existence of cone-shaped epiphyses and gene defects. Methods: We carried out clinical, radiological and genetic evaluations of two patients in Group A (iPPSD5), 6 patients in Group B (iPPDS4) and 7 patients in Group C (iPPSD2). Results: Group A consisted of two siblings without hormone resistance who had the most severe bone and physical developmental delays. PDE4D gene defects were detected in both cases. Group B consisted of 6 patients who showed hormone resistance without hypocalcemia. Short metacarpal bones with corn-shaped epiphyses were observed in all patients. In two cases PRKAR1A gene defects were detected; however, their clinical and radiological features were not identical. The facial dysmorphism was less severe and PRKAR1A gene defects were detected in case B-3. Severe facial dysmorphism and deformity of metacarpal bones were observed but no gene defect was detected in case B-1. Group C consisted of 7 patients with PHP1a, 4 of whom had maternally inherited heterozygous inactivating mutations in one of the GNAS genes. The clinical and radiological features of the patients in Group C were not identical either. Conclusions: The newly proposed classification is suitable for Japanese patients, however; heterogeneities still existed within Groups B and C.