Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement.

A randomized controlled pilot study was performed with a sample of extremely preterm infants to evaluate the impact of postnatal estradiol and progesterone replacement on postnatal bone mineral accretion. Twenty-five of 30 infants in the pilot study survived, and of these, 24 infants were available for the follow-up examination at a median chronological age of 18.1 months (minimum-maximum, 17.0--20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9--17.4). Somatic growth data and bone mineralization showed no differences between the hormone-treated and control group infants. The deviation of the skeletal age from the corrected age was 0.0 months (minimum-maximum, -7.7 to 7.4) for hormone-treated infants compared with -1.7 months (minimum-maximum, -7.5 to 5.9) for the control group. The Bayley scales mental and psychomotor developmental indexes were 89 (minimum-maximum, 71--107) and 101 (minimum-maximum, 49--121) for the hormone-treated infants and 93 (minimum-maximum, 49--111) and 71 (minimum-maximum, 49--121) for the control group infants, respectively (mental developmental index, P = 1.0; psychomotor developmental index, P = 0.14). The normal psychomotor development in the hormone-treated infants compared with the below average development in the control group infants is encouraging and indicates the potentially important integrative role of sex steroids for the developing brain. Larger studies on the effects of the postnatal replacement of estradiol and progesterone in extremely preterm infants are warranted.

Familial occurrence of agonadism and multiple internal malformations in phenotypically normal girls with 46,XY and 46,XX karyotypes, respectively: a new autosomal recessive syndrome.

We report on 2 phenotypic sisters, one with 46,XY; the other with 46,XX. The 2 girls had similar related internal malformations, including agonadism, hypoplasia of the right pulmonary artery, hypoplasia of the right lung, isolated dextrocardia with complex vitium cordis, and diaphragmatic hernia (only sib 1) or omphalocele (only sib 2). This combination of malformations did not fit into any of the previously described syndromes. For this syndrome we suggest the acronym PAGOD ([hypoplasia of the] pulmo, and pulmonary artery, agonadism, omphalocele/diaphragmatic defect, dextrocardia). The occurrence of a basically similar set of malformations in 2 unlike sex is interpreted as evidence for autosomal recessive inheritance. The different gonosomal status excludes the Y chromosome as a responsible factor. The peculiar finding of a 46,XX sex chromosome constitution combined with agonadism and an intact urogenitral tract emphasizes the concept of secondary regression of Wolffian and Müllerian structures. The associated malformations of mesodermal structures can be interpreted as midline defects. We suggest that, from the developmental field perspective, secondary regression of midline structures including the gonadal anlage explains the pathogenesis reasonably well.

Agonadism in two sisters with XY gonosomal constitution, mental retardation, short stature, severely retarded bone age, and multiple extragenital malformations: a new autosomal recessive syndrome.

We report on 12- and 14-year old sisters with a 46, XY chromosome constitution, normal female external genitalia, and absence of gonadal tissue. Except for omphalocele, right renal agenesis and malrotation of the colon in the elder sister, the internal organs were normal. Both were mentally retarded, of short stature, and had extremely retarded bone age. In addition, they had an almost identical pattern of minor anomalies: peculiar face, hypodontia, short neck, inverted nipples, thoracolumbar scoliosis, "dysplastic" hips, partial clino-/syndactyly of toes. The occurrence of a basically similar set of malformations in two sisters and the first cousin consanguinity of the parents suggests autosomal recessive inheritance. The conserved region of the SRY gene ([high mobility group] HMG box) was sequenced in the elder sib and was normal. No consistent malformations are observed at present in agonadal patients. This supports the idea that several autosomal genes have the potential of influencing the sequence of events of sex determination.

Asymmetry of the lipid-bilayer of Sindbis virus.

The organization of the lipid bilayer of the enveloped Sindbis virus has been studied. In the model membrane which consists only of two virus specific glycoproteins and host derived lipids the latter were radioactively labelled with 14C-palmitic acid by prelabelling their BHK 21 host cell lipids. The purified virus particles were submitted to neuramidase, bromelain and combromelain-neuraminidase treatment. It could be demonstrated that N-acetyl neuraminic acid residue of the total hematoside present in the virion is hydrolyzed by neuraminidase leaving the particles fully intact. Proteolysis of the spikes leads to particle aggregation yet an unchanged hematoside content. This was fully transformed into ceramidelactoside by subsequent neuraminidase treatment. The analyses of the ceramide species present in hematoside of the control particles and ceramidelactoside derived thereof by neuraminidase hydrolysis are in very close agreement. From these experiments it is concluded that all hematoside molecules are organized in the outer half of the bilayer of the envelope.

Hemoglobin A1c and body mass index in children and adolescents with IDDM. An observational study from 1976-1995.

In adult patients with type 1 diabetes good metabolic control was associated with an undesired weight gain. In the present report the possible association of HbA1c and body mass index (BMI) in children and adolescents with type 1 diabetes (IDDM) was investigated in a long-term retrospective study from 1976 to 1995. Further, the relationship between BMI on one hand and age, gender, duration of IDDM, the number of units of insulin used and the number of injections per day on the other hand were considered. Statistical analysis was performed using repeated measurements analyses of variance. The 208 girls and 201 boys were 5-17 years old and had diabetes for beyond one year. For analysis 2512 data sets, in part measurements on the same patient in the course of the disease, were available. In various statistical models, the results show that age, gender, the daily amount of insulin, and the HbA1c level (p<0.001-0.005) were associated with the BMI. Extremely high HbA1c levels coincided with a remarkably low BMI. Hence, in children and adolescents with IDDM it may be difficult to achieve a constantly good metabolic control accompanied by a normal body weight.

Assessment of hypothalamic-pituitary-adrenocortical axis function in dexamethasone treated very low birth weight infants by a single dose metyrapone test and gas chromatographic mass spectrometric determination of urinary steroids.

In order to assess hypothalamic-pituitary-adrenocortical axis function, we conducted low and single oral dose metyrapone tests (35 mg/kg) in dexamethasone treated very low birth weight infants with bronchopulmonary dysplasia (n = 12). The responses to metyrapone of tetrahydro-11-deoxycortisol (THS) and cortisol metabolites were analyzed by gas chromatography and mass spectrometry in 24-h urinary specimens. For comparative reasons, morning plasma 11-deoxy-cortisol and cortisol were measured by radioimmunoassay before and after metyrapone. No side effects of metyrapone were observed in our patients. In 5 of 12 patients, no urinary THS could be stimulated after metyrapone and most of the other patients had small increases in urinary THS. These findings suggest suppressed or strongly impaired hypothalamic-pituitary-adrenocortical axis function in most patients. While the concentrations of plasma 11-deoxycortisol showed little variation, those of plasma cortisol were grossly different from the respective urinary values. We recommend steroid analysis in 24-h urinary specimens by gas chromatography and mass spectrometry, because urinary steroids provide more information and the highly specific analytical technique is independent of phenomena such as cross reactivity or matrix effects. The low and single oral dose metyrapone test in combination with urinary steroid analysis by gas chromatography and mass spectrometry therefore provides a noninvasive, convenient and safe means of evaluating the integrity of the hypothalamic-pituitary-adrenocortical axis in very low birth weight infants.

Pubertal development in obese children and adolescents.

OBJECTIVE: To investigate clinical and laboratory markers of pubertal development in a large sample of obese children and adolescents. METHODS: Analysis of parameters of sexual maturation in 1232 obese individuals (582 boys) aged 6-18 years (mean 13.0+/-2.42 years). Clinical evaluation of pubertal stage and determination of bone age in a subset (227 patients). RESULTS: Mean Height--standard deviation scores (height-SDS) was positive during childhood and reached zero approximately at age 14 years followed by a turn to negative mean height-SDS in both genders. Accordingly, bone age was accelerated until age 14. No significant differences in average time points of occurrence of pubic hair stages PH 2 to PH 4 in boys and PH 2 to PH 5 in girls were observed as compared to references of the First Zurich Longitudinal Study. In girls, breast stage B 3 was reached earlier (11.6 vs 12.2 years, P=0.03). In boys, mean volume of testis revealed no significant deviation from reference. Mean dehydroepiandrosterone sulfate (DHEAS) levels were elevated in boys (within age ranges 8-10 years and 12-16 years, P<0.02) and in girls (within age ranges 6-8 years and 12-18 years, P<0.005) and mean testosterone levels in boys >12 years were lower as compared to reference ranges (all P-values <0.0001). CONCLUSION: The study data suggest normal development of pubarche and gonadarche in obese German boys and normal timing of pubarche in girls. Breast development in obese girls seems to be slightly advanced. In obese boys, an obvious dissociation of clinical and laboratory parameters of pubertal development was observed. Despite significantly increased height-SDS and increased DHEAS levels, gonadal development was normal and testosterone levels were decreased. Elevated DHEAS levels in both genders may contribute to the acceleration of bone maturation, a lower final body height and could increase cardiovascular risk.

[Virilization caused by methandrostenolone-containing cream in 2 prepubertal girls]. / Virilisierung durch methandrostenolonhaltige Crème bei zwei präpuberalen Mädchen.

Two prepubertal girls were treated with Dianabol cream by their family physicians during 6 and 8 months because of an anal exzema. In both of them, growth velocity and bone maturation were accelerated, and there was hypertrophy of the clitoris and deepening of the voice. In one girl, all symptoms with the exception of the deep voice had disappeared six years after the discontinuation of treatment. In the other girl, final evaluation is not yet possible. The two observations show that androgens and anabolic steroids may have a marked systemic action if applied percutaneously. Treatment with these compounds is indicated very rarely in children and should be restricted to pediatric endocrinologists.

[Diagnosis and therapy of gigantism]. / Diagnostik und Therapie des Grosswuchses.

Some of the most important types of nonfamilial tall stature are discussed by stressing the clinical features, diagnostic aspects and therapeutic possibilities. The indications of treatment, the diagnostic procedures and steroid therapy of the familial type of tall stature, the predominant variant of tall stature, are presented in detail. The effects, side effects and contraindications of high dose steroid treatment are described. The important prerequisite for the evaluation of psychosomatic problems of tall stature is the understanding of the dynamics and variations of normal growth. This and the knowledge of methods concerning growth analyses continue to be the basis of an accurate diagnosis.

Radioimmunoassay of progesterone in saliva.

A rapid specific radioimmunoassay for progesterone in mixed, unstimulated saliva is described. Column chromatography is not necessary. One single extraction with petroleum ether provides a fractional recovery of 75-95%. The assay sensitivity is 9 pg progesterone/tube. The intra- and interassay variation for low, medium, and highly concentrated progesterone pools is 13.1-9.5 and 17.4-13.9%, respectively. Analytical recovery documents excellent correlation between expected and detected progesterone concentrations (r = 0.994). Data from salivary progesterone of a regularly menstruating girl and of a patient with XO Turner's syndrome are provided.

[Minor diphtheria epidemic in a Cologne children's home (author's transl)]. / Klein-Epidemie von Diphtherie in einem Kölner Kinderheim

Between May and July 1972, 12 children aged from 7 to 14 were admitted to the Cologne University Children's Hospital suspected of having diphtheria. In 10 cases the tonsils or pharyngeal cavity were affected. One case of wound diphtheria and one of nasal diphtheria were observed. The clinical suspicion was confirmed in 8 of 12 cases by detection of the pathogen Coryne-bacterium diphtheroides mitis. 11 patients were discharged from the hospital after being treated for between 2 to 6 weeks, but 5 of them needed ambulant cardiac observation. One patient died of malignant diphtheria with symptoms of cardiovascular failure. He had not been treated specifically for 1 week at first. Not one of the 12 patients had been satisfactorily immunized by active inoculation with diphtheria toxoid.

[T3-thyrotoxicosis in a 12 year old girl (author's transl)]. / T3-Hyperthyreose im Kindesalter. Beobachtung eines 12 2/12 Jahre alten Mädchens.

Isolated Triiodothyronine (T3) hyperthyroidism in childhood is rate. The incidence among hyperthyroid children is about 10%. The authors present a case history of a 12 2/12 year old girl with T3-thyrotoxicosis. Cause, diagnosis and therapy are thoroughly discussed. The importance to estimating serum T3 concentration for establishing the diagnosis of T3 hyperthyroidism is emphasized.

Testosterone-secreting adrenocortical tumor in a pubertal girl. Case report and review of the literature.

A girl aged 12 years and 10 months presented with deepening of the voice first noted 7 months earlier. Pubertal development was almost completed. The girl had regular monthly menses and no signs of hirsutism, clitoris enlargement or Cushing's disease. Serum testosterone was about threefold above normal, whereas dehydroepiandrosterone was in the upper normal range. The 17-ketosteroids as well as the gas-chromatographically analyzed 5 alpha and 5 beta derivatives of testosterone from urine were slightly increased. Other serum and urinary steroids were normal. Dynamic tests of the endocrine function exhibited inconclusive results. Ultrasonography revealed no ovarian cysts. A small, left-sided adrenal mass was identified by computed axial tomographic scan and removed by surgery. There were no signs of local metastasis nor of vascular extension. The histopathological diagnosis was adrenocortical carcinoma. 5 months after surgery, the preoperatively elevated steroid levels had returned to normal.

Critical analysis of height reduction in oestrogen-treated tall girls.

Twenty-one girls with familial tall stature were reevaluated at 18 years of age. Fourteen of them had been treated with high-dose oestrogens (I), while seven girls had not been treated (II). The untreated group is comparable but not a strict control group. Recordings on initiation of the study were: Chronologic age: 12.0 +/- 1.4 (I) versus 13.5 +/- 1.5 years (II; means +/- SD), Bone age: (1) Greulich-Pyle: 11.8 +/- 1.4 (I) versus 13.1 +/- 1.1 years (II), (2) Tanner-Whitehouse II: 12.7 +/- 1.0 (I) versus 13.6 +/- 1.1 years (II). Mean height predictions according to (1) Bayley-Pinneau, (2) Roche-Wainer-Thissen and Tanner (3) with, and (4) without allowance for mid-parent height ranged from 179.4-184 (I) to 175.7-179.5 cm (II). In the treated group there was an average reduction of predicted height of between 2.3 and 6.5 cm, depending on which of the four methods was used. In the untreated group the average differences between calculated and observed mature height varied from 0.2-3.4 cm. The difference in the reduction of predicted height between the treated and untreated groups was significant (P less than 0.05) only with the Bayley-Pinneau method and not with the others. In the treated group highly significant correlations were found between height reduction and the initial chronologic age, bone age and duration of therapy.

Longitudinal anthropometric measurements in patients with growth hormone deficiency. Effect of human growth hormone treatment.

The effect of human growth hormone (6IU/m2 twice weekly i.m.) on standing, sitting, and subischial leg height, on arm length, head circumference, fronto-occipital and biparietal head diameter, bi-iliac (pelvis) and bihumeral (shoulder) width, body weight, triceps and subscapular skinfold thickness, and upper arm and calf circumferences was studied longitudinally over a period of 2 years in 37 prepubertal growth hormone deficient patients (29 boys, 8 girls). Thirteen of them had isolated growth hormone deficiency, 18 combined defects with other anterior pituitary hormone deficiencies, and 6 had been operated for a craniopharyngioma. The most retarded height and length measurements were influenced most markedly by treatment in the fashion of a characteristic catch-up growth, while head circumference, which was less retarded initially, increased more slowly. With exception of craniopharyngioma patients, who became slightly eunuchoid, both proportions (sitting height versus subischial leg height) were not changed by treatment. The disproportions of shoulder and hip width (relatively wide pelvis, narrow shoulders before treatment) tended to be normalized. The results in patients with operated craniopharyngioma were not as good as in those with idiopathic growth hormone deficiency.

Combined pituitary deficiencies of growth hormone, thyroid stimulating hormone and prolactin due to Pit-1 gene mutation: a case report.

UNLABELLED: A child exhibited postnatal obstipation and icterus together with severe growth failure during the 1st year of life, a small facial skull and a prominent forehead. Endocrine work-up established the diagnosis of combined pituitary deficiencies of growth hormone, TSH and prolactin. Subsequently, the Pit-1 gene was analysed in the patient and both parents. A single point mutation was detected in exon 6 of the child: a C to G transversion on one allele, causing arginine in position 271 to be substituted by tryptophan (R271 W). This position is known as a "hot spot" for mutations. The inheritance is autosomal-dominant, as the mutated gene product interferes with DNA-binding of the wild-type protein. In contrast, other mutations in the PIT-1 gene are inherited in an autosomal-recessive mode. CONCLUSION: Diagnosing Pit-1 gene mutations as a rare cause of combined pituitary deficiency is important both for genetic counselling as well as for predicting the future course in the patient (spontaneous puberty, no glucocorticoid substitution necessary during stress periods).

Age at onset and long-term metabolic control affect height in type-1 diabetes mellitus.

UNLABELLED: Reduced height as a consequence of type-I-diabetes mellitus in childhood has been reported in many studies. However, it is still debated whether good metabolic control can normalize the growth rate. A total of 436 children (204 boys, 232 girls, mean age at diagnosis of diabetes 8.2+/-0.2 years) were followed at our outpatient diabetes centre. Z-scores for height were evaluated in relation to duration of diabetes, age at onset and long-term metabolic control. At diagnosis, height in children with diabetes was significantly above the reference population (+0.43+/-0.09). Standardized height decreased during the subsequent course of diabetes. This likely represents a delay of growth, as the final height (chronological age > 18 years, n = 144) was +0.27+/-0.09. Growth reduction was more pronounced in patients diagnosed before the onset of puberty and final height in patients with a prepubertal onset of diabetes was significantly lower (+0.10+/-0.13) compared to patients with a pubertal/postpubertal onset (+0.52+/-0.14). Among patients with a prepubertal onset, the subgroup with "poor" metabolic control (long-term median HbA(Ic) >7%) lost significantly more height compared to patients with "good" metabolic control. CONCLUSION: Despite modern treatment regimens, reduced longitudinal growth can still be demonstrated in type-I diabetes. This parameter therefore provides a valuable endpoint for quality control in paediatric diabetology.

Transient impairment or delay of urinary trihydroxypregnanone (THS) response to metyrapone in boys with delayed adolescence and in patients with isolated growth hormone deficiency.

Twenty three boys with delayed adolescence (age 15.7 +/- 2.0, bone age 12.4 +/- 2.1 years) were studied. Their cortisol response to insulin was normal. After oral metyrapone (500 mg/m2 by mouth) one to three consecutive 12 h urine samples were collected for analysis of THS. Thirty seven tests with 37 first, 21 second, and 11 third samples were carried out. The results could be divided into two main groups: 25 tests (group A) were subnormal in the first sample, 12 of them with a very weak (40 +/- 8 micrograms/m2/12 h) and 13 with an insufficient (191 +/- 16 micrograms/m2/12 h) THS response. Values in the second and third sample were higher, indicating a delayed response. In 12 tests (group B), the results were normal (1016 +/- 143 micrograms/M2/12 h) in the first and lower in the second and third samples. In three patients with repeated tests, there was improvement with increasing bone age. The THS-responses to metyrapone did not correlate with those of growth hormone, gonadotrophins, and TSH to stimuli. It is concluded that the THS-response to a single dose of metyrapone may be temporarily insufficient or delayed in delayed adolescence. We interpret this finding as showing transiently reduced or slow hypothalamic responsiveness.

Suppression of growth hormone by oral glucose in the evaluation of tall stature.

Excess secretion of growth hormone is a rare diagnosis in children or adolescents with tall stature. An oral glucose tolerance test (OGT) with determination of growth hormone is generally recommended to exclude this disorder. In order to test the validity of this approach in pediatric subjects, OGT tests were performed in 126 tall subjects (age: 12.4 +/- 1.8 years; height: 3.1 +/- 0.8 SDS). Nonsuppression was present in 39 subjects, however, anthropometric analysis and follow-up excluded the diagnosis of eosinophilic pituitary adenoma in all patients. The lowest GH concentration was reached 90 min after ingestion of oral glucose, GH rose above baseline at 180 min. Plasma concentrations of glucose and insulin did not differ between suppressors and nonsuppressors. In conclusion, absent suppression of growth hormone by oral glucose is common in tall children and adolescents. The test is therefore not recommended as a general screening for excess growth hormone. Prolonging the test beyond 120 min does not increase the diagnostic value.

Contributions of age, gender and insulin administration to weight gain in subjects with IDDM.

Overweight in insulin-dependent diabetes mellitus (IDDM) has been repeatedly reported, especially in girls during adolescence. Potential pathophysiologic factors include tight metabolic control, insulin dose, treatment regimen, puberty and genetics. A standardized data-base from all IDDM patients treated at our institution was evaluated. IDDM patients with hypothyroidism or celiac's disease as well as all records from the first year of diabetes were excluded, resulting in a total of 427 patients (2454 patient-years) available for analysis. BMI and SD-score for BMI based on the Zurich longitudinal growth study were evaluated. Standardized BMI was higher in pubertal children ( + 1.07+/-0.06) compared to prepubertal children (+ 0.68+/-0.07; p < 0.002). This increase was present both for boys and girls. Increasing overweight during puberty was found irrespective of the age at diagnosis of diabetes (prepubertal or pubertal). The daily dose of insulin and the long-term metabolic control had only a minor impact on the development of overweight. In contrast, in pubertal children, SDS-BMI was significantly higher in patients on intensified insulin regimens (3 or 4 daily injections) compared to patients with 2 injections (p < 0.05). These data demonstrate that both boys as well as girls with IDDM develop overweight during puberty. Multiple injection therapy, not daily dose of insulin or the level of metabolic control achieved, was the main predictor of weight gain. This finding may be explained by increased caloric intake due to the flexibility allowed by intensified treatment.