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The phenotypes of chromosomal 22q11.2 microdeletion are quite variable among individuals and hypoparathyroidism (HP) constitutes a definite portion of the clinical spectrum. For the correct diagnosis and pertinent follow up of the HP children due to del22q11.2, we tried to delineate the clinical characteristics of such patients. By employing fluorescence in situ hybridization (FISH) to all the patients diagnosed as HP in our clinic, ten possessed the 22q11.2 microdeletion. Among them, the incidence of cardiac defect (5/10), recurrent infection (1/10) and cleft palate (1/10) was modest. Additionally, seven of them had been diagnosed as HP during the infantile period, when their facial abnormality and intellectual problem had not become evident. Notably, two patients were complicated by Graves disease, while the association of idiopathic thrombocytopenic purpura was also observed in two girls.HP due to del22q11.2 may be misdiagnosed as idiopathic, especially in an infant who lacks apparent complications like cardiac anomaly. They should be closely followed up for auto-immune complications.

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.

To identify the developmental changes in monthly urinary gonadotropin and ovarian hormone excretion, consecutive 30-d first morning void urinary specimens were collected from 36 normal girls, one normal woman, and 15 female patients with idiopathic precocious puberty. Of these children, three normal girls and three patients with precocious puberty volunteered to collect these specimens on 2-3 occasions over a time interval of 0.5-3.2 y. When sampled, six were early prepubertal, nine late prepubertal, eight early pubertal, eight mid-pubertal, and eight late pubertal normal girls, and six were early pubertal and 14 mid-pubertal patients with precocious puberty. The mean level of monthly urinary LH, FSH, and total estrogen excretions increased with pubertal maturation. In prepuberty, the mean LH level was lower than the mean FSH level, and neither showed significant episodic fluctuations. In early puberty, mean FSH levels increased with remarkable fluctuations, and mean LH levels were low with few variations in the course of a month. At the onset of puberty, gonadotropin excretory patterns underwent specific changes, showing at the same time periodically and every other day fluctuating patterns. Urinary total estrogen and pregnanediol excretion fluctuated independently from these periodic variations in urinary gonadotropins. These patterns were observed in six out of 16 patterns in normal pubertal girls and 10 out of 20 patterns in precocious puberty. Once the urine LH level exceeded the urine FSH level, however, these periodic variations disappeared. The cycle of a normal postmenarcheal girl aged 14 y showed a pattern similar to that of a normal adult. In patients with precocious puberty, the hormonal patterns were similar to those of sexual stage-matched normal girls.

There are few reports about reactivation of gonadal function and progress through puberty after withdrawal of therapy with LHRH-A in patients with central precocious puberty (CPP). Eight patients (5 females and 3 males) with CPP were treated with LHRH-A (D-Ser6-LHRH) with a dose of 10μg/kg by single or twice daily subcutaneous injections for periods ranging from 3 to 5.3 years. We have studied 30-day consecutive patterns of first morning voided urinary gonadotropin and ovarian hormone excretion in these patients during and after withdrawal of therapy with LHRH-A. During the treatment, the mean and maximum concentrations of urinary LH and FSH in 7 patients studied were low. After withdrawal of therapy, a rapid resumption of puberty was observed in 3 patients, who also had a hypothalamic hamartoma. In the remaining 5 patients with idiopathic CPP, the testes increased rapidly in size in one boy; but among 4 girls, only 1 had regular menstruation and the other 3 had irregular or no menstruation. The urinary patterns of these hormones did not return quickly to a pubertal pattern after withdrawal of treatment in these girls. This may be partly related to the long-term use of LHRH-A, but seems to be partly caused by psychological factors. These patients treated with long-term LHRH-A will head follow-up and evaluation of the reproductive function.

We present two Japanese siblings with a new congenital malformation syndrome. The patients, who are an older sister and a younger brother, were born to healthy and unrelated parents. The clinical features are characterized by proportional short stature (-5.1SD, -3.6SD), craniofacial dysmorphism related to craniosynostosis, and generalized osseous dysplasia.The skeletal changes consist of brachymesophalangy and metaphyseal dysplasia with spontaneous regression. The metaphyseal changes, which are localized in the wrists and knees, were initially cup-like radiolucencies mimicking those of rickets. The metaphyseal bony defects have been spontaneously remodeled, turning into ovoid radiolucencies and finally leaving only subtle radiolucencies at 3 or 4 years of age.GH provocation tests showed stunted response with peak serum GH of 6.7, 12.1, 1.9 ng/mL in the older sister and 7.7, 7.7, 7.9 ng/mL in the younger brother after insulin, clonidine, and I-dopa loading. The endocrinological abnormality, however, was not thought to be the cause of severe short stature in our patients.

A newly developed enzyme-linked immunosorbent assay (ELISA) for dehydroepiandros terone sulfate (DHEAS) and the chronological alterations of serum DHEAS levels in normal children are reported. The ELISA for DHEAS was developed by means of dehydroepiandrosterone (DHEA) -3-succinate conjugated to horseradish peroxidase and anti-DHEA-succinate-bovine serum albumin (BSA) serum. DHEAS was used as a standard. The sensitivity of the assay was 12.5 pg/well and the IC50 was about 400 pg/well. The intra- and inter- assay coefficients of variation were

We report the case of a short girl with incomplete GH secretion, who was born by breech delivery with severe asphyxia. GH responses to provocation tests, including insulin and clonidine, and during sleep were partially preserved. Her IGF- I level was very low. MRI showed transection of the pituitary stalk with an ectopic posterior lobe, and syringomyelia involving the whole spinal cord without a Chiari I malformation.

The retrospective longitudinal data of height measured annually from 6 to 17 years old were studied in 439 boys and 483 girls aged between 18 and 22 years old (group I). Retrospective longitudinal growth data from 300 boys and 270 girls under the age of 6 years were also investigated (group II). Plotting these data on a graph, an individual growth curve was drawn by eye fitting technique, height at every three months of age was graphically obtained and height velocity over a whole year was calculated in each case. The average age at peak height velocity (PHV) during adolescence was 13.05±0.94 years in boys and 11.05±1.05 years in girls. The mean PHV of 135 boys ans 148 girls who had PHV at the average age of PHV (subjects with average growth tempo) was 9.9±1.5 and 8.3±1.0 cm/yr. respectively.The mean height curves of children in group II and children with average growth tempo in group I were drawn and both curves were connected smoothly at the age of 6 years in each sex. The mean height velocity curves of both groups were also smoothly connected at the age of 6 3/12 in each sex as well. Finally the smoothed standard curves for height and height velocity for clinical use were produced for each sex.

Urinary gonadotropin concentrations were determined by polyclonal double antibody RIA after ammonium sulfate extraction. Good correlation was observed between urinary gonadotropin/creatinine ratios in first morning voided and full 24-h urine collections. Using consecutive 30-d first morning voided urine specimens from normal children and from patients with sexual disorders, we have studied the monthly patterns of nighttime gonadotropin secretion. In normal prepubertal girls, the levels of urinary LH were low with few variations and those of urinary FSH were higher with episodic fluctuations. In early pubertal girls, the levels of urinary LH increased with striking, rhythmic fluctuations. The same changes were seen in urinary FSH. A single big surge of urinary gonadotropins was observed in postmenarcheal girls. In normal boys, the secretory patterns of urinary gonadotropins were similar to those of normal girls, but varied less. In patients with idiopathic precocious puberty, the patterns of urinary gonadotropins were similar to those of normal subjects matched for sexual stage. The measurement of 30-d first morning voided urinary gonadotropins can provide a simple and physiologic test of gonadotropin function in children.

Autonomous ovarian activity persists throughout adolescence in some patients with McCune-Albright syndrome (MAS). There have been few studies of longitudinal assessment of ovarian function in these patients. We investigated the first morning voided urinary gonadotropin and ovarian steroid levels consecutively in three patients aged 3 to 7 years after withdrawal of therapy for precocious puberty. They had the triad of MAS with onset of menses within the first 3 years of life. Excessively elevated urinary estrogen levels with one or two peaks per cycle were found in all patients. In two patients, café-au-lait spots and dysplastic bones were located unilaterally. These two patients showed significantly increased urinary pregnanediol levels, suggesting ovulation, with low levels of gonadotropins in one patient and moderately low levels with an LH surge in the other. Thus, only a unilateral ovary was anticipated to be mutated with persistent autonomous ovarian activity. In the remaining patient with bilateral involvement of tissues, relatively high LH and low FSH levels throughout a cycle were found with no rise in urinary pregnanediol.

A simple and improved method for the quantification of urinary LH and FSH was developed. Urinary gonadotropin concentrations were determined by polyclonal double antibody RIA after ammonium sulfate extraction. Urinary LH and FSH concentrated by ammonium sulfate were coeluted with an iodinated LH and FSH tracer. Gel chromatography of the urine revealed that the majority of immunoreactive LH and FSH were eluted coincident with 125I-LH and 125I-FSH. Good correlation was observed between urinary gonadotropin/creatinine ratios in first morning voided and full 24-h urine collections. Age-de-pendent changes in urinary LH excretion were significant in normal boys and girls 6–17 y of age. Urinary FSH excretion in these children did not change in an age-dependent fashion.

Electron microscopic cytochemistry was used to evaluate the behavior of cytochrome c oxidase (COX) in cultured skin fibroblasts from 4 patients with decreased COX activity (Leigh encephalopathy, fatal infantile COX deficiency). In patients with Leigh encephalopathy, all mitochondria reacted to COX staining either equivocally or negatively, indicating that all mitochondria were abnormal in these patients. In 1 patient with fatal infantile COX deficiency, intercellular heterogeneity of mitochondria was observed by COX staining. In another patient with fatal infantile COX deficiency, intracellular heterogeneity of mitochondria was observed. Patients with Leigh encephalopathy appeared to have a different type of mitochondrial COX deficiency than those with fatal infantile COX deficiency. Our result suggest that these 2 diseases may result from different genetic mechanisms.

LATE ADRENARCHE IN A PATIENT WITH PSEUDORYPOPARATHYROIDISM (PHP): APPLICATION OF OF A NEWLY DEVELOPED ELISA FOR DUEAS

We have already reported a simple and improved method for the quantification of urinary gonadotropins needed in amounts of urine smaller than those previously reported. Good correlation was observed between urinary gon-adotropin and ovarian steroid/creatinine ratios in first morning voided(FMV) urine and 24-h urine collections in children. Using consecutive 30-d FMV urine specimens from 29 normal children and from 9 patients with idiopathic precocious puberty, we have studied the monthly patterns of nighttime gonadotropin and ovarian steroid excretions. Urinary LH levels in normal prepubertal girls were low with few fluctuations. FSH levels were higher and showed remarkable, episodic fluctuations. In early pubertal girls, urinary LH and FSH excreted with alternate every other day variations at the same time. Their urinary total estrogen excretions remained low levels. In mid-pubertal girls, urinary LH excretion increased to near the levels of urinary FSH and they fluctuated with alternate every other day variations. Urinary total estrogen also increased and fluctuated with an opposite way to these variations in urine LH and FSH. With progressive sexual maturation, urine LH excretion increased. The cycle of a normal postmenarcheal girl aged 14 years showed a pattern similar to those of normal adults. In patients with idiopathic precocious puberty, those hormonal patterns showed similar to those of normal subjects matched for sexual stage. Measuring monthly urinary gonadotropins and ovarian steroids seems to be useful to investigate the process of sexual maturation and the endocrine requirements for ovulation.

Serum levels of IGF-I were radioimmunoassayed after acid ethanol extraction in 1075 normal subjects from infants through young adults, and the normal range for each age was established. The mean value for infants which was relatively low increased gradually with age, and rose sharply after that reaching the peak levels at mid adolescence, then it decreased slowly to the young adult levels. Significantly higher mean values were observed in females at the age of 9, 10, 11 and 12 years. Each of 23 cases with pituitary dwarfism exhibited a lower concentration than the lower limit of the bone age matched normal range. All of the 59 normal variant short children except three showed normal values, but the values were distributed over the lower side of the range.

Basal and LH-RH induced plasma FSH and LH levels were determined longitudinally in 41 patients aged 4 to 22 years with Turner's syndrome and in 4 male patients with prepubertal castration. In 12 patients with Turner's syndrome over 18 yrs of age without pubertal change, basal and LH-RH induced FSH levels studied at age 11--22 yrs were all significantly increased over normal levels. However, some of these patients had normal basal and LH-RH induced LH levels. In 5 patients with mosaic Turner's syndrome with spontaneous puberty, basal and LH-RH induced FSH and LH levels studied at age 6--12 yrs were always within the normal range for age-matched controls. In 10 patients studied at age 11--18 yrs, basal and LH-RH induced FSH levels were also strikingly increased over normal levels except for one patient. This patient had normal basal FSH and LH levels and serum estradiol level was increased from 49 to 199 pg/ml after HMG test. In 14 patients aged 4--10 years, nine patients had elevated basal FSH levels and abnormally high responses to LH-RH. The remaining 5 patients had normal basal FSH levels, and 3 of them also had normal FSH responses to LH-RH. The data on the 5 patients studied again at the age of greater than 13 yrs rose to high levels in adult castrated ranges. In 24 patients aged 4 to 17 years, 23 patients were thought to have no ovarian function, and one was thought to have spontaneous puberty. In 4 male patients with prepubertal castration, basal and LH-RH induced FSH levels were increased over normal levels after 11 yrs of age. However, basal LH levels in some patients were within the normal range for age-matched controls after 12 yrs of age. From these results, we conclude that basal and LH-RH induced FSH levels may provide definitive evidence of absent ovaries or testes in patients over 11 yrs of age with primary hypogonadism.

In order to clarify the disturbance of plasma lipoprotein metabolism and the effect of supplement therapy, changes occurring in plasma lipoprotein composition and apoprotein levels after plasma infusion were studied in two sibling patients with classical abetalipoproteinemia. The patients' plasma completely lacked both apoproteins B100 and B48. After infusion of 10 ml per kilogram of body weight of normal plasma, the plasma apoprotein B level increased to 11 and 13 mg/dl and the half-life of apoprotein B to 10h and 6h respectively in the two brothers. In contrast, the plasma apoprotein E level decreased slightly or remained unchanged. On sodium dodecylsulfate polyacrylamide gel electrophoresis, apoprotein B appeared in the low-density lipoprotein fraction and the content of apoprotein E in the high-density lipoprotein fraction decreased. The mean particle size of high-density lipoprotein decreased on analysis by high-performance liquid chromatography. These results indicate that the catabolic rate of apoprotein B at low plasma levels (

We observed prolonged genital bleeding during the first 2-3 months after treatment in five of 13 female patients with salt-losing 21-hydroxylase deficiency. Their relatively low concentrations of serum follicle-stimulating hormone and luteinizing hormone before therapy increased rapidly to high levels which were maintained for 1-3 wk and then decreased. The duration of these relatively high levels after therapy was longer in the patients with genital bleeding than those without. Before therapy, there was no release of serum follicle-stimulating hormone and luteinizing hormone following the administration of synthetic luteinizing hormone-releasing hormone in two patients; 1 month after therapy, the response to luteinizing hormone-releasing hormone increased significantly. Serum estradiol increased above 300 pg/ml in four patients with genital bleeding but was less than 175 pg/ml in three patients without bleeding. The etiology of genital bleeding in these female patients may be more prolonged activation of the hypothalamo-pituitary-ovarian axis and a greater increase in the responsiveness of internal genitalia to gonadotropins and sex hormones, perhaps induced by prolonged exposure to excessive adrenal steroids starting before birth.

Effects of LH-RH on LH and FSH release were studied in 26 normal children and six patients with Turner's syndrome (two of them showed 45 x karyotype and the others were mosaics). Synthetic LH-RH (2µg/kg of body weight) was given intramuscularly after an overnight fast. The increase of serum FSH level was significantly greater in normal female infants than male infants. A similar tendency was observed in normal female children aged 2 to 9 years. No sex difference was observed in the LH response to LH-RH in all the normal subjects Studied. The response of FSH release to LH-RH was significantly greater than that of LH in female infants and young female children. The responsiveness of LH to LH-RH gradually increased with advancing age. Basal serum levels of FSH rather than LH were high in the patients with Turner's syndrome. Again a much greater increase of serum FSH than of LH was noted after the administration of LH-RH to patients with Turner's syndrome.

It was possible to obtain a sufficient amount of homogeneous chondrocytes from 13-day old chick embryo-sterna in an 8-day suspension culture. Serum somatomedin (SM) activity was measured on the basis of the ability of serum to stimulate labelled sulphate uptake in these chondrocytes. Somatomedin A and multiplication stimulating activity (MSA) stimulated the sulphation in this assay. Serum SM activity in term cord sera and newborn sera was lower than that in normal adults. Serum SM activity in early infants increased rapidly and attained the levels of that in normal adults within 1 month following birth. Serum SM activity in infants (1 month—2 years) and pubertal children (10–16 years), when the annual height increment is greatest, was higher than that in normal adults. Serum SM activity in children with constitutinal dwarfism aged 6–10 years and over 10 years was normal and lower, respectively, compared to that in age-matched controls. Pituitary dwarfs had markedly low SM activity compared to age-matched controls. Diagnostic evaluation of serum SM activity in children requires comparison with age-matched controls. Assay for serum SM activity may provide a useful and simple procedure for differentiating the cause of growth disorders from growth hormone deficiency.

The urocanic acid content of the skin was measured photometrically in a large number of normal and histidinemic infants. A very high content was demonstrated in the normal newborn infants, followed by a rapid decrease throughout early infancy. In contrast, 36 measurements in 17 infants with histidinemia revealed a much lower content even in their newborn periods. Thus, the quantification of skin urocanic acid was considered to be simple and useful for confirming the diagnosis of histidinemia, especially in a neonatal mass-screening program.

Two cases of neonatal hypophosphatasia are described. In case 1, hypercalcemia developed at 2 1/2 months of age and continued until death at 10 1/2 months of age. Serum calcium levels decreased transiently in response to phosphate supplementation, prednisolone, and calcitonin. Significantly elevated levels of PTH were detected at 2 1/2 months of age. At autopsy, no parathyroid glands were found. In case 2, hypercalcemia was not detected in his course. Elevated level of serum PTH was recorded on the 17th day of life. A post-mortem examination revealed the presence of one normal parathyroid gland.

An autopsy case of a 10-year, 8-month-old boy with Hunter's syndrome is reported with emphasis on the ultrastructural findings of almost all the organs, except the brain. Intracytoplasmic inclusion bodies were observed in various organs as follows: nerve cells and glia in the spinal cord, hepatocytes and Kupffer cells in the liver, sinusoidal endothelium of the spleen, proximal tubules, podocytes and epithelium of Bowman's capsule of the kidney, interstitial fibroblast-like cells among cardiac muscle bundles, cardiac valves and aorta, exocrine and endocrine cells of the pancreas, adrenocortical cells, follicular epithelial cells of the thyroid. Leydig cells of the testis, chondrocytes, fibroblasts and endothelium of capillaries throughout the body. Three types of inclusion bodies were morphologically distinguishable. Type 1: clear vacuole, Type 2: zebra body, Type 3: clear vacuole with a lipid-like lamellar structure. The clear vacuole (Type 1) was thought to represent an accumulation of glycosaminoglycans, and the zebra body (Type 2), probably ganglioside. The type 3 inclusion body might be an intermediate and mixed form of the type 1 and type 2 inclusions. Histochemical study also suggested that the type 3 inclusion body contained glycosaminoglycan and a type of lipid.

A 16-month-old female infant with severe mental and motor retardation, clinically diagnosed as Leigh's encephalomyelopathy, forms the basis of this study. This infant was found to have lactic acidosis, low cerebrospinal fluid glucose, hyperalaninemia, and increased levels of urine lactate, pyruvate and alanine. These laboratory studies suggested an inborn error in gluconeogenesis. Further investigation revealed a low level of hepatic pyruvate carboxylase activity. The patient's elder sister who also had mental and motor deterioration was then also found to have an elevated blood lactate. These two siblings clinically and biochemically showed improvement with treatment consisting of thiamine and lipoic acid.

Using antibodies to somatomedin C/insulin-like growth factor I (SmC) produced in rabbits using the recombinant hormone, we have developed a radioimmuno-assay for SmC. Gel-chromatography of urine revealed that the vast majority of immunoreactive SmC was eluted coincident with 125I-SmC and a small portion eluted with fractions having a mol. wt. range of 30,000–40,000. The SmC concentration in urine was determined by radioimmuno-assay after ammonium sulfate extraction. Values did not ordinarily exceed 1 ng/ml. When the values from normal subjects were expressed as ng/mg creatinine, high levels were observed in the neonatal period. These values fell rapidly in infancy, declined more gradually in childhood, were slightly elevated at early puberty, and were lowest in adulthood. Urine SmC concentrations in 15 pituitary dwarfs were lower than the averages obtained from age-matched control subjects, and six of them showed abnormally low values. Three patients with active acromegaly had high SmC values in urine. In conclusion, 1) SmC, mainly of monomeric form, was immunologically detected in urine. 2) Radioimmunoassay for urine SmC revealed that values varied considerably with age in normal subjects and were partially dependent on the human growth hormone status. However, the full meaning of the findings remains to be elucidated.

Congenital primary hypothyroidism due to thyrotropin (TSH) unresponsiveness is a very rare disorder and only a few cases have been documented previously. To elucidate whether structural abnormalities in the TSH receptor (TSHR) could be a primary underlying mechanism of this disorder, we analyzed nucleotide sequence of the entire coding region of the TSHR gene in three patients diagnosed with congenital primary hypothyroidism associated with TSH unresponsiveness. Diagnosis of TSH unresponsiveness was largely made based on the following criteria: (a) congenital primary hypothyroidism with autosomal recessive inheritance, (b) a nongoitrous thyroid gland in a normal position with low thyroidal radioactive iodine uptake, (c) normal in vitro TSH bioactivity or absent in vivo response to exogenous TSH, and (d) absence of thyroid autoantibodies. The TSHR cDNA was successfully obtained from RNA of peripheral mononuclear leukocytes with reverse transcription and polymerase chain reaction, and was sequenced directly. Comparison of these nucleotide sequences with the normal TSHR sequence revealed no difference in the predicted amino acid sequence with a heterozygous polymorphism in codon 601 in one patient, indicating absence of TSHR structural abnormalities in these patients. Our results indicate that congenital primary hypothyroidism associated with TSH unresponsiveness is unlikely to be due to mutations in the TSHR-structure gene.

Defects in water excretion and urinary dilution have been well known in patients with hypopituitarism and adrenal insufficiency, but there are few reports of nocternal polyuria in these patients. Serial studies were done in 8 children (aged 5-13) with pituitary dwarfism and ACTH deficiency (A), 4 of them had enuresis, 5 with pituitary dwarfism and no ACTHdeficiency (aged 2-10) and 14 constitutional dwarfs (aged 3-15) as controls. Daily urine volumes of these patients with A were 0.8-1.81/day with highly concentrated urine (>500mOsm/1) at day-time(D) and diluted urine ( 80% of the water. After an over-night fast, they could not concentrate their urine maximally, but it was also corrected by steroid administration. Their 6-hourly urine samples showed low 17 KGS without circadian rhythm. Our results suggest that they may not able to excrete ingested water in the morning in the absence of appropriately elevated levels of glucocorticoids and excrete water lately at night. We are now investigating serym levels of ADH and our results seem to support that the elevated levels of circulating ADH are involved in the impaired water diuresis in the patients.