We report a rare case of growth hormone and gonadotropin deficiency associated with dysmorphic features. A 16-year-old boy had left anophthalmia, microphallus, bilateral cryptorchidism, and mental retardation. His chromosomal karyotype was normal, 46, XY. Endocrinological studies revealed growth hormone and gonadotropin deficiency, attributed to hypothalamic dysfunction. Magnetic resonance imaging scan of the head showed a hypoplastic pituitary gland, decreased high intensity signals in the pituitary posterior lobe, absence of the left eye, and a hypoplastic left optic nerve with no abnormality of the pituitary stalk, corpus callosum, or septum pellucidum. Although not completely consistent with the features of septo-optic dysplasia (SOD), his condition was considered within the spectrum of SOD. Despite similarities to the Hesx1 knockout mouse, a model of human SOD, mutation analyses revealed no mutations or polymorphisms in coding regions of any exons or intron-exon boundaries of the HESX1 gene. Further genetic studies of this patient may improve understanding of molecular mechanisms involved in pituitary development.

View full abstract

The aim of this study was to investigate the occurrence of polymorphisms of the β-adrenergic receptor gene in short children and to evaluate the possible influence of the polymorphisms on changes in height and obesity index in response to GH treatment. Of the 75 children enrolled in the study, 40 completed at least 5 years of GH treatment. The genotype distribution of the β2 and 3-adrenergic receptor polymorphisms in the study population did not differ significantly from those reported in non-obese subjects. There were no significant differences in the SD score for height at any given time-point between the group with and without the Trp64Arg mutation of the β3-adrenergic receptor gene. In relation to the Gly16Arg polymorphism of the β2-adrenergic receptor gene, the mean SD score for height increased significantly during GH treatment in children with Arg16Arg and Gly16Arg. In those with Gly16Gly, the score did not show any significant increase during all 5 years of GH treatment. In both the groups with and without the Trp64Arg mutation, the changes in obesity index did not reach statistical significance at any time-point. Only children with Gly16Gly had a significantly higher baseline mean obesity index than those with Gly16Arg. The index also decreased markedly from 21.9% to 5.8% in these children during the first 4 years of GH treatment. Thus, when the impact of the polymorphisms of these two receptor genes was studied simultaneously, it appeared that only the β2-adrenergic receptor polymorphism had an important role to play in modulating the regulation of growth rate and energy expenditure in short children.

View full abstract

In this study, we retrospectively analyzed 18 patients in whom antithyroid drug (ATD)-induced agranulocytosis developed during treatment of Graves' disease. All patients were more than 20 years of age, and we saw no correlation between age and the development of agranulocytosis. In 17 of 18 patients, ATD-induced agranulocytosis developed within 2 to 12 weeks of starting ATD treatment. Development of agranulocytosis was related to the dose of ATD. In some patients, agranulocytosis developed abruptly, and even weekly routine WBC and granulocyte counts failed to predict all case occurrences. Fever and sore throat were the earliest symptoms of agranulocytosis; patients who developed either of these symptoms were closely monitored immediately with WBC and granulocyte count examinations. In this series of patients, treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) increased the granulocyte counts, whereas the effectiveness of glucocorticoid treatment was not confirmed.

View full abstract

The current study aimed to investigate the midterm (24 hour) response of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulphate (DHEA-S) to synthetic high-dose adrenocorticotropin (ACTH) in adrenal incidentalomas (AI). Seventeen patients with AI and 40 age- and sex-matched controls received synthetic ACTH (tetracosactide, 1000 μg, IM). Plasma, 17-OHP and DHEA-S were collected in basal conditions and after 1, 4, 6, 8 and 24 hours. (HPA) axis was also evaluated using circadian serum cortisol, urinary free cortisol and over-night 2 mg dexamethasone suppression. Basal plasma 17-OHP levels did not differ among the groups. However, the increment in plasma 17-OHP in patients both in terms of peak [13.76±2.52, 4.77±0.30 ng/ml, mean±S.E.M, p<0.001] and area under the curve [190±46, 96.75±32 ng/ml/h, p<0.001] were significantly higher than that of the controls. Stimulated 17OH-P levels never reached 9.1 ng/ml in controls. Sixty-five (11/17) % of the patients were found to have exaggerated response. Three of the patients were found to have subclinical Cushing's syndrome and interestingly, two augmented their 17-OHP response to ACTH after unilateral adrenalectomy and normalisation of their HPA axis. Basal DHEA-S levels of the patients were significantly lower [99.21±45, 230.18±34 μg/dl, p<0.01] and stayed persistently lower than that of the controls. Evidence of a heterozygous 21 hydroxylase deficiency, as indicated by the exaggerated 17-OHP response to ACTH, has been widely reported in AI patients. However, to our knowledge to date there is no report on augmented 17-OHP response to ACTH after adrenalectomy. Possible reasons for the augmentation were discussed.

View full abstract

We describe a rare case of macroprolactinoma with subclinically synchronous growth hormone (GH) production. A 59-year-old man with a giant adenoma in his pituitary had elevated serum prolactin (PRL) and insulin-like growth factor (IGF)-I levels, despite normal levels of basal GH. Serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). Prolonged exposure to glucose as a result of oral glucose tolerance testing (oGTT) failed to decrease GH levels. Two-week treatment with cabergoline, a dopamine D2 receptor agonist, decreased serum PRL and GH levels, and size of the tumor. Immunohistochemistry and in situ hybridization revealed PRL-producing cells capable of synchronous GH production. Acidophilic stem cell adenoma may be responsible for these phenomena. The nature of high proliferation and invasive tumor growth should be kept in mind when managing patients with this cell type of adenoma. IGF-I levels should be followed in PRLoma, even when basal GH levels are within the normal range, because mixed PRL- and GH-producing tumors would lie underneath. Further endocrinological examinations such as TRH test and oGTT are recommended when elevated IGF-I levels are detected.

View full abstract

Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. It has recently been reported that this syndrome is caused by mutations in the AAAS gene. In the present study, we analyzed the AAAS gene in a Japanese patient with triple A syndrome. The patient was a Japanese girl previously reported by Hirose et al. (J Jpn Pediatr Soc 102: 912-915, 1998). The parents of the patient were first cousins. The patient was confirmed to have alacrima and isolated glucocorticoid deficiency at the age of 2 years. She later developed achalasia of the cardia, and was diagnosed as having triple A syndrome. The AAAS gene was amplified by the PCR method, and the PCR products were directly sequenced. The patient was homozygous for a novel nonsense mutation Q237X, changing codon 237 encoding Gln (CAA) to a stop codon (TAA). The parents were heterozygous for the Q237X mutation. The AAAS gene encodes a protein of 546 amino acids, ALADIN. The Q237X mutation is predicted to result in a truncated and presumably non-functioning ALADIN protein, thus causing the clinically manifest syndrome in the patient. To our knowledge, this is the first report on AAAS gene mutations in Japan.

View full abstract

Purpose: Uptake and washout ratios of thallium-201 chloride (²⁰¹TlCl) were studied to confirm their clinical applicability in the differential diagnosis of benign and malignant follicular lesions of the thyroid. Patients and Methods: Sixty-six patients with follicular tumor of the thyroid underwent preoperative thallium scintigram after an intravenous injection of 2 mCi (74 MBq) of ²⁰¹TlCl. The early accumulation and washout ratios of ²⁰¹TlCl were obtained by an online data-processing system. All tumors were surgically resected and histopathologically diagnosed as either follicular adenoma (49 patients) or follicular carcinoma (17 patients). Scintigraphic values in terms of the early accumulation and washout ratios were compared between follicular adenoma and follicular carcinoma. Results and Conclusion: Both the early accumulation and washout ratios were significantly higher in follicular carcinoma than in follicular adenoma. It was concluded that dynamic studies on accumulation and washout rates of ²⁰¹TlCl might be clinically reliable to differentiate between follicular adenoma and follicular carcinoma.

View full abstract

The expression of protein gene product 9.5 (PGP9.5), a known neuron marker, was immunohistochemically investigated in rat pancreas. In fetal pancreas, a cluster of cells expressed PGP9.5 among the initial epithelial buds at embryonic day 11.5 (E 11.5). At E 13.5, PGP9.5 appeared among elongated and branching epithelial cells as well as along nerve fibers in the mesenchyme. On E 17.5, tubular cells became ductal cells with lumen, which strongly expressed PGP9.5. In newborn rats, ductal cells of the common bile duct (CBD) to the centroacinar cells and islet cells expressed PGP9.5. Ten days after birth, the number of the ductal cells expressing PGP9.5 was reduced, and PGP9.5-negative cells appeared in half of the duct cells. On day 21, all centroacinar cells and intercalated ductal cells became PGP9.5-negative, but some CBD and interlobular ductal cells remained positive for PGP9.5. On day 28 and thereafter, PGP9.5 was no longer detected. In a pancreatic duct ligation model, acinar cells changed to cells with duct-like structure after duct ligation. These cells strongly expressed PGP9.5 on the fifth day after duct ligation. Three to four weeks after ligation, the cells with duct-like structure changed to acinar cells, islets of Langerhans and ductal cells, but the ductal cells were PGP9.5-negative at this point. These results suggested that PGP9.5 is expressed in ductal cells that possess a potential for differentiation to pancreatic endocrine cells, and therefore can serve as a marker for the progenitor of pancreatic endocrine cells.

View full abstract

The effect of castration on apoptosis in the mouse epididymis during postnatal development was examined. The weight of the epididymis slowly increased from day 0 (day of birth) to day 20 after birth, followed by a rapid increase thereafter. Castration on days 0, 5, 10, 20, 30, 40 and 60 increased apoptotic indices (percentages of apoptotic cells) of epithelia of the caput (head), corpus (body), and cauda (tail) epididymis, their apoptotic indices reaching maximal levels on day 2 after castration with the exception of a maximal apoptotic index on day 4 in the tail after castration on day 60. The maximal levels of apoptotic indices of the head, body and tail after castration on days 0, 5, 10 and 20 were significantly lower than those after castration on days 40 and 60. DNAs extracted from the epididymides 2 days after castration on days 0, 5, 10 and 60 showed a ladder pattern on agarose gel electrophoresis, which is a characteristic of apoptosis. When testosterone propionate (10 μg/g body weight) was injected twice a day into mice which had been castrated on day 10, 30 or 60, the increases in apoptotic indices of the head, body and tail of the epididymis were completely inhibited. The weights of the paired epididymides 6 days after castration on days 0, 5, 10, 20, 30, 40 and 60 were significantly lower than those of sham-operated mice, indicating the secretion of androgen by the testes from birth to adulthood. The present results indicated that androgen deprivation caused by castration induces apoptosis in the epithelium of the epididymis of mice from birth to adulthood, and suggested that a proportion of epithelial cells, the survival of which is dependent on the testes, is smaller in the epididymides during a slow growth stage than in the epididymides after this stage.

View full abstract

Patients with prostate cancer generally respond to androgen withdrawal therapy, but progression to androgen-independence is frequently observed later. To examine whether pretreatment serum androgen status could predict disease progression in metastatic prostate cancer, pretreatment serum testosterone, histological grade, extent of bony metastasis, serum prostate-specific antigen (PSA) response to hormone therapy, and prognosis of the 40 patients with untreated metastatic prostate cancer who received endocrine therapy were evaluated. Although there were no differences in age, pretreatment PSA level, extent of bony disease and histological grade between patients with normal testosterone and those with low testosterone, PSA response after endocrine therapy was better in normal testosterone group. There was a significantly longer interval to disease progression in patients with normal testosterone than in those with low testosterone. The patients with metastatic prostate cancer with low serum testosterone were in the high risk group of worse response to endocrine therapy. Additional therapy might be considered in those patients.

View full abstract

Gitelman syndrome is a renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria due to the defective tubular reabsorption of magnesium and potassium. This disease is caused by mutations of thiazide-sensitive Na-Cl cotransporter (TSC) gene. Gitelman syndrome is usually distinguished from Bartter syndrome by the presence of both hypomagnesemia and hypocalciuria. However, a phenotypic overlap is sometimes observed. We encountered two sporadic Japanese patients with Gitelman syndrome and analyzed their TSC gene. These patients were diagnosed as Gitelman syndrome by the typical clinical findings and biochemical abnormalities, such as mild muscular weakness, periodic paralysis, tetany, metabolic alkalosis, hypomagnesemia and hypocalciuria. In patient 1, a novel two base deletion (del TG at nucleotide 731 and 732) in exon 5 and a two base deletion (del TT at nucleotide 2543 and 2544) in exon 21 previously reported in a Japanese patient were identified. The patient 2 had a missense mutation (L623P), that was also identified in Japanese patients, and a novel in-frame 18 base insertion in exon 6 as a heterozygous state. Family analysis of two patients confirmed an autosomal recessive inheritance. In conclusion, we add two new mutations of the TSC gene in Japanese patients with Gitelman syndrome. Because the differential diagnosis between Bartter syndrome and Gitelman syndrome is sometimes difficult, molecular analysis would be a useful diagnostic tool, particularly in unusual cases with phenotypic overlapping.

View full abstract