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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.

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.

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.

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.

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.