Kazuhiko Shimozawa

Sleep Disturbance in Children with Growth Hormone Deficiency

We examined the effects of growth hormone (GH) deficiency on sleep development by performing all-night polysomnography in three female children with GH deficiency (GHD). The percentage of REM sleep seemed to be reduced before the treatment in 2 cases, and human GH (hGH) compensation slightly increased it. Submental twitch movements (mTMs), i.e., body movements during sleep localized in the submental muscle and lasting less than 0.5 seconds, were commonly disturbed in the three patients. Rapid eye movements in REM sleep (REMs) were reduced before the therapy in one case, this decrease being reversed on hGH compensation. REMs also seemed to increase after hGH treatment in the other two cases. Dopamines and cholinergic muscarinic agonists can cause GH release, while mTMs and REMs might be related to dopaminergic and cholinergic systems in the human brain. It is intriguing that GHD, and the disturbance of mTMs and REMs coexisted in children with GHD. Since a relatively poor social outcome in patients with GHD has been reported, even after hGH compensation, it is important to monitor their neurological development by means of evaluation of their sleep disturbance.

Repetitive Monomorphic Ventricular Tachycardia in a 4‐Year‐Old Boy with Toxic Multinodular Goiter

ABSTRACT. A case of toxic multinodular goiter associated with repetitive monomorphic ventricular tachycardia (VT) is reported. A 4‐year‐old boy was found to have asymptomatic VT. When treatment with antiarrhythmic agents turned out to be ineffective, thyrotoxicosis was suspected due to the rapid enlargement of the left thyroid gland and associated thyroid function studies. A diagnosis of toxic multinodular goiter was made on the basis of subsequent scintigraphy and ultrasonography. Treatment with antithyroid drugs and inorganic iodine restored the thyroid function to normal, and was accompanied by the disappearance of VT. A left thyroid lobectomy was performed, and the pathological findings were compatible with toxic multinodular goiter. After the operation, the patient was transiently hypothyroid and had no VT without medication. A review of the literature revealed no previously documented cases of VT with toxic multinodular goiter.

Changes of Several Adrenal Δ4-Steroids Measured by HPLC-UV Spectrometry in Neonatal Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

We have developed an easy and rapid method of reverse-phase high-performance liquid chromatography (HPLC)-UV spectrometry for measuring adrenal delta 4-steroids. Three female neonates with adrenal 21-hydroxylase deficiency (2 salt-losers and 1 simple virilizer), two of whom were recalled by neonatal mass-screening for congenital adrenal hyperplasia (CAH), were diagnosed using this method. Changes of several adrenal steroids were examined in these patients before and after treatment with hydrocortisone. Before treatment, the cortisone and cortisol peaks were very low and those of 17 alpha-hydroxyprogesterone (17-OHP) and 21-deoxycortisol (21-DOF) were high in all 3 patients (17-OHP: 79.9-997 nmol/l, 21-DOF: 83.7-324 nmol/l). The androstenedione peak was also high in 2 of them. A peak produced by 21-deoxycortisone, which is a product of oxidation of 21-DOF at the C-11 position, was also detected in all cases (14.5-297 nmol/l). After treatment, all of these abnormally elevated delta 4-steroids decreased or disappeared. This new method is thought to be valuable for the rapid diagnosis of CAH, and especially for use in neonatal mass-screening for CAH.

Analysis of Blood Spot 17α-Hydroxyprogesterone Concentration in Neonates

Blood spot 17α-hydroxyprogesterone (17-OHP) concentrations were measured in 515 infants aged from the 4th to the 81 st day of life, using a fluorescence enzyme immunoassay method, and the values obtained were analyzed with respect to birth weight, gestational age at birth and sampling age, to obtain accurate reference ranges and to decide appropriate cut-off limits in a neonatal mass screening for steroid 21 -hydroxylase deficiency. The results obtained indicate that the blood spot 17-OHP values in neonates should be interpreted using several different reference ranges obtained on the basis of the equivalent age of gestation at blood sampling. In the mass screening, therefore, the cut-off limits for recall are decided by these reference ranges as follows: (1) for blood resampling, 120, 30 and 25 nmol/l for the equivalent sampling ages of 31 weeks or less, 32–41 weeks and 42 weeks or more, respectively, and (2) for rapid confirmation of the disease by means of physical and laboratory examinations, 210, 60 and 60 nmol/l, respectively.

Adrenocorticotropic Hormone Unresponsiveness Associated with Hypertrophic Cardiomyopathy

ABSTRACT. The clinical and autopsy findings in a case of adrenocorticotropic hormone unresponsiveness associated with hypertrophic cardiomyopathy are reported. A four‐month‐old female with feeding difficulties and skin hyperpigmentation from two months of age was admitted with convulsions. She was hypoglycemic with normal serum electrolytes and the presence of hypertrophic cardiomyopathy was indicated by electrocardiogram and echocardiogram. Cardiac arrest occurred on the second hospital day. Low serum Cortisol, high plasma adrenocorticotropic hormone, low urinary 17‐ketosteroids, and normal urinary aldosterone excretion were documented after her death. Hypoplasia of the adrenal cortex with a persistent fetal zone and concentric hypertrophy of the heart were found at autopsy. We propose that the pathogenesis of this disease lies in impaired remodelling of the fetal adrenal cortex into the permanent cortex, and postulate an effect of adrenocorticotropic hormone on the myocardium as the cause of hypertrophic cardiomyopathy.

Sleep development in children with congenital and acquired hypothyroidism

To determine how thyroid hormone deficiency before birth influences early development of the human central nervous system, we examined sleep development in children with congenital hypothyroidism using all-night polysomnography. Although the sleep-wakefulness circadian rhythm was not disturbed, two patients under 1 year of age showed mild decreases of REM sleep. Rapid eye movements during REM sleep were significantly decreased in one patient in whom thyroxine replacement was delayed. Regarding phasic body movements during sleep, generalized gross movements were more frequently disturbed than localized muscle twitches, and even after L-thyroxine replacement, they were significantly reduced when compared with those in controls. Children with acquired hypothyroidism and neonatal transient hyperthyrotropinemia showed no severe abnormalities of the sleep parameters examined here. Sleep development in patients with congenital hypothyroidism is believed to be useful for regional evaluation of the brain impairment in congenital hypothyroidism.

Neonatal mass screening for congenital adrenal hyperplasia in Tokyo

Abstract Nation-wide neonatal mass screening for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) has been performed in neonates in Japan since January 1989. In Tokyo, between April 1989 and March 1991, 190,094 newborns were screened, and 12 cases of CAH were detected. There were 2 cases with the simple virilizing (SV) type, and 10 of the salt-losing (SL) type. The incidence of CAH was I in 15,841 live births, which is two- to threefold higher than previously found in case-assessment studies in this country. The ratio of the SL to the SV type was also higher than previously reported, and the patients clinical symptoms were less marked than previously reported. The usefulness of mass screening for CAH is strongly recommended, especially for salvaging those with the severe type of 21-OHD, and detecting symptomatic patients with the SV type.

血中17α-hydroxypregnenolone, 17α-hydroxypregnenolone sulfateおよび17α-hydroxyprogesteroneの同時測定法

It is well recognized that in the fetal adrenal cortex, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity is lower and in fetal tissues, steroid sulfokinase (SK) is higher than in the adult. In order to clarify a part of the development processes of the adrenal cortex or steroidgenesis in humans, a combined radioimmunoassay (RIA) method to estimate serum 17 alpha-hydroxypregnenolone (17-OH-delta 5 P), 17 alpha-hydroxypregnenolone sulfate (17-OH-delta 5 P-S) and 17 alpha-hydroxyprogesterone (17-OH-delta 4P) was devised. The method consisted of the following procedures: 1) diethyl ether extraction and chromatographic separation of unconjugated steroids (17-OH-delta 5P and 17-OH-delta 4P), 2) enzymatic hydrolysis of 17-OH-delta 5P-S using the residue of diethyl ether extraction for a material, 3) diethyl ether extraction and chromatographic purification of hydrolyzed 17-OH-delta 5P-S, and 4) RIAs for 17-OH-delta 5-P to estimate 17-OH-delta 5P and 17-OH-delta 5P-S concentration, and for 17-OH-delta 4P. Extracted 17-OH-delta 5P was well separated from 17-OH-delta 4P by Sephadex LH-20 microcolumn chromatography, using a benzene/methanol = 95/5 (v/v) solvent as a mobile phase. Several procedures for hydrolysis or solvolysis of 17-OH-delta 5P-S were compared using available tritiated delta 5-3 beta-hydroxysteroids including dehydroepiandrosterone (DHA), DHA sulfate (DHA-S) and 17-OH-delta 5P, and it was found that the most suitable method was an enzymatic hydrolysis by arylsulfatase from Helix Pomatia in an appropriate condition in which the percent hydrolysis was 92.9 +/- 1.2 (mean +/- SEM)%. The final percent recoveries were 88.7 +/- 1.2% in 17-OH-delta 4P, 90.7 +/- 1.4% in 17-OH-delta 5P and 78.1 +/- 2.1% in 17-OH-delta 5P-S, respectively. A suitable antiserum and its final dilution titer for RIA of 17-OH-delta 5P (hydrolyzed 17-OH-delta 5P-S also) was 1:12,000 dilution of anti-17-OH-delta 5P-3-succinate-BSA serum. An anti-7-oxo-17-OH-delta 5P-7-carboxymethyloxime-BSA serum was considered to be unsuitable for the measurement of hydrolyzed 17-OH-delta 5-P-S, presumably because of a significant cross-reactivity with a large amount of unknown steroid sulfates simultaneously hydrolyzed.(ABSTRACT TRUNCATED AT 400 WORDS)

Urinary pregnanetriol-3-glucuronide excretion in neonates and the use of urinary pregnanetriol-3-glucuronide/creatinine ratio in differentiating 21-hydroxylase deficiency

Introduction: A number of neonatal patients with 21-hydroxylase deficiency (21-OHD) have been discovered since the initiation of a nationwide mass screening program for congenital adrenal hyperplasia (CAH) in Japan. At the same time more than 80% of the referred neonates were found to be free from 21-OHD after detailed examination. Therefore, a simple method for identifying 21-OHD among referred neonates from mass screening or a second screening method for referred neonates is required. Methods: In order to examine whether measurements of pregnanetriol-3-glucuronide (PT-3-G) in a single spot urine enable us to diagnose neonatal patients with 21-OHD. urinary PT-3-G concentrations were measured with our newly developed enzyme-linked immunosorbent assay method in 163 urine specimens from 107 infants and those from 21 referred neonates from a mass-screening program for CAH. Results: Median PT-3-G concentrations in 5-, 6-and 14-day-old infants were 11.5 nmol/l (range: 2.9–85.6, n = 35), 20.1 nmol/l (range: 5.4–89.1, n = 43) and 38.8 nmol 1 (range: 8.9–143.5, n = 34), respectively. Median values of the molar ratio of PT-3-G to excreted creatinine (PT-3-G, creatinine; × 105) were 0.82 (range: 0.23–2.95), 1.2 (range: 0.40–6.5) and 3.7 (range: 0.92–8.2). respectively. Both concentrations and ratios increased significantly with age (5 days vs. 6 days: P < 0.001 for the concentrations, P < 0.01 for the ratios; 6 days vs. 14 days: P < 0.01 for the concentrations, P < 0.001 for the ratios). Seven of the 21 neonates were diagnosed with 21-OHD, while the remaining 14 neonates did not have this disease. PT-3-G concentrations and the ratios in the 14 false-positive cases ranged from 21.2 to 909 nmol/l and 1.7 to 28.0. Those in the 7 diagnosed patients ranged from 1161 to 2814 nmol/l and 81.4 to 365, respectively. Discussion: Neither value overlapped between the patients and the false-positive cases. Therefore, measurement of urinary PT-3-G was a useful method of detecting neonates with 21-OHD among referred neonates. However, the ratios appeared to be more useful than concrete concentrations in distinguishing the neonates with 21-OHD.

Age-related Changes of Serum 17^|^alpha;-Hydroxypregnenolone and 17^|^alpha;-Hydroxypregnenolone Sulfate Concentrations in Infancy and Childhood

In order to clarify a part of the developmental processes of the human adrenal cortex or steroidgenesis in infancy and childhood, serum concentrations of 17 alpha-hydroxypregnenolone (17-OH-delta 5 P), 17 alpha-hydroxypregnenolone-3-sulfate (17-OH-delta 5 P-S) and 17 alpha-hydroxyprogesterone (17-OH-delta 4 P) were measured using a combined radioimmunoassay method previously reported, and age-related changes of these steroids were evaluated. In addition to the serum concentrations, a ratio of 17-OH-delta 5 P-S to 17-OH-delta 5 P (S/delta 5 P ratio) and that of 17-OH-delta 4 P to 17-OH-delta 5 P (delta 4 P/delta 5 P ratio) were also estimated as the indices of the activities of steroid sulfokinase (SK) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), respectively. Serum 17-OH-delta 5 P, 17-OH-delta 5 P-S and 17-OH-delta 4 P concentrations in umbilical cord blood were 13.5 +/- 6.02 (Mean +/- SD) ng/ml, 965 +/- 363 ng/ml and 46.3 +/- 21.1 ng/ml, respectively. These values decreased consecutively to the nadirs which were 0.47 +/- 0.16 ng/ml in subjects 1 to 2 years old, 1.26 +/- 0.82 ng/ml in subjects 3 to 6 years old and 0.17 +/- 0.007 ng/ml in subjects 3 to 4 months old, respectively, and they were followed by gradual increases up to the adult levels. S/delta 5 P ratio also showed the same profile.(ABSTRACT TRUNCATED AT 250 WORDS)