We have analyzed the androgen receptor (AR) of a young Japanese man with sporadic Reifenstein syndrome. Androgen binding assays in cultured genital skin fibroblasts showed a normal maximum binding capacity and a normal apparent dissociation constant. However, androgen binding in fibroblasts decreased to 37% when the assay temperature was raised from 30°C to 41°C, indicating thermolability of the AR. Sequence analysis of the AR gene revealed a single nucleotide substitution (G→A) at nucleotide position 2, 598 in exon E (or 5), resulting in conversion of valine (GTG) to methionine (ATG) at amino acid position 746 within the hormone-binding domain of the AR. This missense mutation may explain thermolability of the AR, which is thought to be the pathogenesis of Reifenstein syndrome in this patient. Sequence analysis also revealed that his mother was not a heterozygous carrier of this AR mutation. Moreover, sequence analysis of the D loop in the mitochondrial deoxyribonuleic acid (DNA) confirmed the familial relationship between this patient and his mother. These findings strongly suggest that this AR mutation is a de novo mutation newly occurring in this patient's generation.

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This is a 12 year and 5 month old prepubertal boy, who was followed from the neonatal period because of tertiary hypothyroidism. Endocrinological examinations were performed on three occasions. All the data revealed growth hormone (GH) deficiency and hypothyroidism. GH responses to insulin, arginine and GH-releasing factor (GRF), and the nocturnal GH secretion test, were low and sometimes undetectable. In addition, the serum insulin-like growth factor I (IGF-I) values were always low. Thyroid-stimulating hormone (TSH) responses to the TSH-releasing hormone (TRH) provocation test showed a tertiary hypothyroidism pattern. The values of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were in the pre-pubertal stage and prolactin was in the normal range. Magnetic resonance (MR) imaging showed a small pituitary with stalk interruption, in spite of normal delivery.
With the use of levothyroxine, growth has been maintained in the range between -1 standard deviation (SD) and -2 SD. In this case GH and IGF-I are not indispensable for maintaining physical growth, and the abnormal pituitary imaging is not caused by perinatal insult. Further detailed investigations, including a search for some growth-promoting bioactivity other than GH, are needed to elucidate the mechanism of this patient's growth.

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A 16-month-old male patient with severe growth and mental retardation is reported. Although his thyroid function tests showed high circulating levels of free 3, 5, 3′-triiodothyronine (T₃), free thyroxin (T₄) and thyrotropin (TSH), he had no clinical manifestations suggesting hyperthyroidism. Physical responses to exogenous T₃ were normal. T₄ supplement (7-10μg/kg/day) dramatically improved his growth and mental development, suggesting that his clinical symptoms were due to a relative shortage of thyroid hormone. Direct sequencing confirmed that he carried a normal thyroid hormone receptor β (TRβ) gene. The mechanism causing hypo-responsiveness to thyroid hormone in this patient is unclear.

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A 10-year-old boy with growth hormone (GH) deficiency began to receive subcutaneous injections of recombinant human GH (rhGH) five times a week. Serum creatine kinase (CK) was determined monthly during therapy. Serum CK became abruptly elevated 11 months after the start of GH therapy. Neither myalgia nor proximal muscle weakness developed. The CK rapidly returned to a near-normal level within 14 days after the cessation of rhGH injections. The precise etiology of this serum CK elevation is unknown.

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A 13-year-old girl presented with isosexual precocious puberty and later developed polycystic ovary syndrome (PCO). Laboratory examination revealed high levels of plasma luteinizing hormone (LH), estrone and androgens. Because of significantly high levels of plasma dehydroepiandrosterone sulfate (DHEAS) and hyperresponsiveness to adrenocorticotropin (ACTH) of DHEAS, it appeared that the PCO was caused by not only hypothalamic-pituitary dysregulation of gonadotropin secretion but also by hypersecretion of adrenal androgens.

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Thyroid hormone greatly influences postnatal growth in children and secretion of growth hormone (GH). To study the relation between serum GH-binding protein (GHBP), which is expressed as tissue GH-receptor concentrations and influenced by the nutritional state, thyroid hormone and growth development, we measured serum GHBP in six children with hyperthyoidism and six children with hypothyroidism using samples taken before and during treatment. Mean treatment periods of these diseases are 13 and 10 months, respectively. Mean height velocity standard deviation (SD) score decreased from 2.51 to -0.62, but was not significantly related to the treatment, in hyperthyroidism, and significantly increased from -3.02 to 5.27 due to the treatment in hypothyroidism. There was no significant difference of GHBP levels before the treatment between hyper- and hypothyroidism (mean 9.59 vs. 8.53ng/mL). In hyperthyroidism, GHBP levels decreased significantly during the treatment. In hypothyroidism, insulin-like growth factor I (IGF-I) and IGF binding protein-3 (IGFBP-3) increased, but percent overweight decreased significantly, and GHBP levels did not significantly change during the treatment.
ΔGHBP was defined as the change in GHBP during treatment to examine whether or not the change in GHBP was parallel to the change in thyroid hormone. ΔGHBP showed no correlation with Δ height velocity SD score. ΔGHBP showed a significant positive correlation with ΔT₄ level and negative correlation with Δpercent overweight. However, only ΔT₄ was identified as an influencing factor on ΔGHBP by stepwise multiple regression analysis.
The data demonstrate that the changes in serum GHBP level were influenced by the changes in T₄ levels during the treatment of abnormal thyroid function. The data also show that GHBP was unrelated to height gain associated with treatment in hyperthyroidism and hypothroidism.

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Cerebrospinal fluid (CSF) was collected from two patients with periodic ACTH and antidiuretic hormone (ADH) discharge syndrome, both during attacks and during attack-free periods. The concentration of neurotransmitter metabolites was measured by the high performance liquid chromatographic (HPLC) method with electrochemical detection, and compared with metabolite concentrations in CSF from normal controls. The levels of CSF 5-hydroxyidoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were found to be increased during attacks in both patients, compared to control levels. In contrast, the levels of CSF homovanillic acid (HVA) decreased during attacks in both patients. During attack-free periods, the levels of CSF 5-HIAA, MHPG, and HVA did not differ from control level. These results suggest that there is increased activity of the serotonergic system in this syndrome. A relation between the attacks and the activity of the serotonergic system is further suggested by the observation that attacks were reduced or eliminated in these patients by the administration of granisetron hydrochloride. The possibility that the elimination of attacks by this drug is related to decreased serotonergic activity is discussed.

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Nonclassical 3β-hydroxysteroid dehydrogenase deficiency (N3βHSDD) or nonclassica 121-hydroxylase deficiency (N21OHD) are considered to be one of the causes of premature pubarche (PP) and hirsutism, but the diagnostic criteria for N3βHSDD are not well established. Among 44 Japanese children with PP, hirsutism, acne and/or accelerate growth, 13 and elevated 60min ACTH-stimulated 17-hydroxypregnenolone (Δ⁵-17P)/17-hydroxyprogesterone (17-OHP), more than 2 SD above the mean of 31 other patients. Four had evevated 60 min Δ⁵-17P/17-OHP, more than 5 SD above the mean of 31 other patients. According to the stringent criteria, none had N3βHSDD. None had N21OHD. Less well defined criteria for diagnosing N3βHSDD may lead to overdiagnosis of this disease. It is not known whether this elevated ratio is a physiological or a pathological response.

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