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Aim Type 1 diabetes is the most common chronic metabolic disease in childhood. Often diagnosis comes with acutely life-threatening ketoacidosis and requires hospitalization. To avoid this, early detection of children at a pre-symptomatic stage is worthwhile. This task is met by a population-based screening in Bavaria, Germany – the Fr1da study. Here, we aim to evaluate the study concept, feasibility and medical evidence of the Fr1da study. Methods 308 pediatricians, 16 diabetes care centers and participating families were asked to evaluate the Fr1da study by completing questionnaires assessing study concept and feasibility, educational program and study organization. The assessment was done anonymously. In order to evaluate the effectiveness of the training the parents had to answer questionnaires to assess their knowledge about diabetes. Results 48% of pediatricians and 56% of pediatric diabetes care centers filled out the questionnaire. The majority positively judged the collaboration with the Fr1da coordinating center and the feasibility to integrate the project into daily routine. Medical evidence of the screening was recognized and most of the respondents endorsed the screening to be permanently integrated into standard care-program. The majority of parents would recommend the study to other parents with young children since they were satisfied with the collaboration with pediatricians, diabetes care centers and the coordinating center. Quality control of the educational program revealed good understanding of the teaching content. Conclusion The Fr1da study received high acceptance and recognition by both, health care providers and participating families, and demonstrated sustainable success with the developed educational program. &nbsp

Background: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. Aim: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. Methods: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. Results: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. Conclusion: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed. Keywords: Type 1 diabetes, Trial recruitment, Trial enrollment, Infants, Children, Asymptomatic

ZusammenfassungDie Ätiologie der unterschiedlichen Wachstumsstörungen wurde während der letzen 20 Jahre in vielen Fällen geklärt, wobei gezeigt werden konnte, dass ganz unterschiedliche genetische Defekte, meist Einzelgendefekte, für den Kleinwuchs verantwortlich sind. In dieser Übersichtsarbeit haben wir uns auf zwei Gruppen von Wachstumsstörungen, die allerdings sehr komplex sind, beschränkt und zwar auf den Kleinwuchs nach intrauteriner Mangelgeburt bzw. den idiopathischen Kleinwuchs. Beide Phänotypen werden häufig in der kinderendokrinologischen Sprechstunde vorgestellt. Erst kürzlich konnte gezeigt werden, dass bei einem kleinen Prozentsatz von Patienten mit einem idiopathischen Kleinwuchs eine SHOX-Mutation ursächlich ist. Anhand eines Fallbeispiels aus unserer endokrinologischen Sprechstunde möchten wir diesen Zusammenhang erläutern.

Introduction Even within high-income countries, treatment and outcome quality of type 1 diabetes (T1D) differ between regions. For example, significant disparities in pediatric diabetes care were observed between the 16 federal states of Germany. Area deprivation might be one of the contributing factors explaining these regional variations. However, the influence of area deprivation on T1D outcomes has been investigated in a few countries only. So far in Germany, merely the influence of individual socioeconomic status (SES) on outcomes of patients with T1D has been investigated. Our objective was to analyze if area deprivation contributes to regional disparities in treatment and outcome quality of children and adolescents with T1D. Methods Pediatric patients ( Results HbA1c worsened with increasing area deprivation from 7.78% in Q1 to 8.02% in Q5. BMI SDS increased steadily with deprivation from 0.28 in Q1 to 0.36 in Q5. By contrast, the rate of severe hypoglycemia decreased from 12.2 events/100 PY in Q1 to 6.9 events/100 PY in Q5. Rapid-acting insulin analogues were more frequently used with increasing deprivation from 66.8% in Q1 to 87.8% in Q5. All results were significant (P After controlling for federal states, associations between area deprivation and outcome quality (HbA1c, rate of severe hypoglycemia, and BMI SDS) remained similar, whereas associations with treatment (use of rapid-acting insulin analogues) were attenuated. Conclusion Area deprivation is associated with medical care of pediatric patients with T1D in Germany. Associations with outcome quality but not with treatment are independent of the federal states. Investigations of potential mediating variables might allow for a better understanding of underlying mechanisms. Further research is necessary to initiate targeted interventions and to reduce regional disparities in pediatric diabetes care, even in high-income countries.

Die Beurteilung des Wachstums sollte jeder Arzt, der Kinder betreut, beherrschen. Ein gesundes Kind wachst gut, ein krankes schlecht. Viele, insbesondere chronische Erkrankungen gehen langfristig mit einer Wachstumsstorung einher. Lesen Sie, wie Sie genetische von ernahrungsbedingten oder hormonellen Ursachen abgrenzen, in welchen Fallen eine weitere Abklarung angezeigt ist und wann Sie zum Abwarten raten konnen.

Background : Over the years, poor medical documentation is a well known phenomenon in medical practice but the magnitude of the problem in our setting has not been defined. Objective : To assess the overall frequency of missed detection of anomalies of external genitalia following the routine newborn physical examination and to describe the general pattern of its documentation. Methods : In this hospital-based descriptive cross-sectional study, 915 full-term newborn infants in an open population survey were systematically screened for anomalies of the external genitalia, using a checklist derived by modifying parameters in the Prader scoring system and the External masculinization score charts. The pattern of documentation was assessed in 915 case files. The findings of the researchers were then compared to those previously documented by the attending physician/midwife. The study was conducted in two Nigerian hospitals (University of Benin Teaching Hospital and St Philomena Catholic Hospital) in Benin City. All members of staff of the two hospitals were blinded to the fact that the previous examination findings documented in the case files were being assessed during this study. Results : Of the 915 infants, 19 (2.1%; 95% CI= 1.2-3.0) had anomaly of the external genitalia at birth. The overall frequency of missed diagnosis of external genital anomalies was 68.4% with undescended testes (UDT) being the most frequently missed. The level of documentation of the findings of the external genital examination was poor in both hospitals. Combining the two hospitals, the external genital examination findings were not documented in 76.1% of case files. Conclusions : The routine newborn examination as currently practiced in the two hospitals was weak in detecting external genital anomalies. Poor documentation of the external genital findings is a common occurrence in the setting where we practice, irrespective of whether the health institution is tertiary or secondary. Key words : Audit, clinical documentation, external genitalia anomalies, missed diagnosis, routine newborn examination.

Die Unterschiede zwischen mannlichen und weiblichen Individuen entstehen durch die Wirkung geschlechtsspezifischer Gene und Hormone. Durch die Wirkung spezifischer Gene entwickelt sich aus einer undifferenzierten Gonadenanlage ein Testes oder Ovar, in dem Geschlechtshormone gebildet werden. Diese sind fur die Differenzierung des inneren und auseren Genitale, fur die Pubertatsentwicklung und Fertilitat notig. Geschlechtstypische Unterschiede werden aber auch im Gehirn gefunden, besonders deutlich im Bereich von Hypothalamus und praoptischer Region. Diese morphologischen Unterschiede bestimmen anscheinend geschlechtstypische Verhaltensweisen im Rahmen der Fortpflanzung und Brutpflege sowie die Entwicklung einer Geschlechtsidentitat und sexuellen Orientierung. Noch sind bei Weitem nicht alle morphologischen und biochemischen Unterschiede zwischen den Geschlechtern bekannt. Allerdings scheint ein groserer Teil geschlechtstypischer Verhaltensweisen genetisch determiniert zu sein. Diese herauszufinden und von den sozial-determinierten Verhaltensweisen zu unterscheiden ist die Herausforderung zukunftiger Untersuchungen.

Der Beginn der Pubertatsentwicklung bei Jungen wie bei Madchen hat sich in den letzten 100 Jahren zunehmend nach vorne verschoben.

Hintergrund:Uber die Plasmaspiegel des Lipoprotein (a), einem bedeutenden kodominant vererbten Risikofaktor fur koronare- und zerebrovaskulare Erkrankungen, ist bei Kindern wenig bekannt. Methode: Wir untersuchten die Lipoprotein-(a)-Werte bei 111 gesunden Kindern (Altersverlaufstudie), davon in 37 Fallen auch die der jeweiligen Eltern (Familienstudie) und dokumentierten mit Hilfe eines Fragebogens anamnestisch erfasbare koronare Risikofaktoren. Ergebnisse: Der Mittelwert der Lipoprotein-(a)-Serumkonzentration in der Altersverlaufstudie betrug 16±20 mg/dl (Medianwert 9 mg/dl). Von den untersuchten Kinder hatten 23 (20%) erhohte Werte (≥30 mg/dl). Dies ging einher mit signifikant erhohten Mittelwerten fur Gesamt- und Low-Density-Lipoprotein-Cholesterin (LDL-Cholesterin) gegenuber der ubrigen Population. Es fand sich eine deutlich positive Korrelation zwischen den Lipoprotein-(a)-Werten und den Serumkonzentrationen von Gesamt- bzw. LDL-Cholesterin (p

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, affected girls are born with ambiguous genitalia due to increased secretion of androgens in utero by the defective adrenal gland. Even though it is generally accepted that there are differences between male and female brain development, determining factors have been difficult to identify. Girls with CAH have frequently been studied to evaluate the impact of prenatal androgen exposure on psychological, psychosocial, and psychosexual development, and impairments in various areas have been identified. However, there is no comprehensive study available regarding the outcome of this chronic disorder in adult life. We studied the quality of life in women with CAH, with particular emphasis on how they cope with genital malformations, genital operations, and chronic disease as well as lifelong medication. The patients filled out questionnaires covering their physical state, psychological well-being, social relationships, and functional capacity, as well as questionnaires on psychosexual identification and psychosocial integration. The results were evaluated using a computerized statistical program for social studies. Out of a total of 94 patients above 18 years of age, 45 agreed to participate and were compared to 46 healthy, age-matched controls. Age at diagnosis was 2. 31 +/- 1.55 years and 38% suffered from the simple-virilizing, 45% from the salt-wasting, and 17.0% from the late-onset form of CAH. About one-third of patients had Prader stage 3 or 4 genital virilization. While the overall quality of life did not differ significantly, CAH patients were more often single (47.8% vs. 66.7%) and fewer of them had children (22.2% vs. 38.6%) compared to controls. Significant impairments were found in regard to body image and attitudes toward sexuality, but there was no increased homosexual preference. The women were successful in adjusting to illness and receiving social support. It is speculated that improved psychosocial adaptation is part of a coping mechanism that helps to maintain a high level of well-being despite impairment. Coping mechanisms should be identified and strengthened in order to help patients cope with their chronic illness.

This paper describes the time course of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in two patients with the complete androgen insensitivity syndrome (AIS) during puberty and adolescence prior to gonadectomy. In early puberty, LH values were comparable to normal male as well as female standards. At the age of 17 and 18.7 years, respectively, a sudden rise in LH occurred just after the start of estradiol supplementation. These high LH concentrations in the late puberty of our patients are comparable to the values found during early puberty in castrated individuals and children with gonadal dysgenesis. In contrast, FSH concentrations continuously showed levels in the normal male or female range with no rise during adolescence. The sudden increase of LH in late puberty is most probably due to defective testosterone receptors in the pituitary/hypothalamus which apparently can no longer be suppressed by rising testosterone levels and an escape from the negative estradiol feedback. The role of estradiol supplementation might be incidental and further investigation into its role is needed. In contrast to the elevated levels of FSH in patients with defective spermatogenesis, FSH is normal in our patients with AIS and testes in situ. This indicates that FSH secretion is regulated by a combined action of estradiol and gonadal hormones like inhibin.

We report on 46,XX true hermaphroditism and 46,XX maleness coexisting in the same pedigree, with maternal as well as paternal transmission of the disorder. Molecular genetic analysis showed that both hermaphrodites as well as the 46,XX male were negative for Y-chromosomal sequences. Thus, this pedigree is highly informative and allows the following conclusions: first, the maternal as well as paternal transmission of the disorder allows the possibility of an autosomal dominant as well as an X-chromosomal dominant mode of inheritance; second, testicular determination in the absence of Y-specific sequences in familial 46,XX true hermaphrodites as well as in 46,XX males seems to be due to the varying expression of the same genetic defect; and third, there is incomplete penetrance of the defect.

Growth is affected by a great number of different genes, hormones and environmental factors that can influence the development of an individual at a variety of stages. This explains the vast number of disorders and the complexity of the symptoms. Every doctor who takes care of children should be able to recognize growth disorders; however, the further diagnosis and treatment belongs in the hands of experienced and specialized paediatric endocrinologists.

Beckwith-Wiedemann syndrome is a common overgrowth syndrome associated with an increased risk of neoplasias which might be explained by the nature and localization of the genetic defect. While malignant tumors are often associated with hemihypertrophy, benign tumors are also found. We report a patient with the typical features of Beckwith-Wiedemann syndrome with two histologically different abdominal tumors, bilateral cystic adrenals and ectopic pancreatic tissue present at birth. In both tumors no malignancy could be detected. Ectopic pancreatic tissue is rarely seen and has been described in Beckwith-Wiedemann syndrome only once. After extirpation of the ectopic pancreatic tissue the cystic adrenals were left in situ since macroscopically no normal adrenal tissue could be identified and separated. Regular ultrasound examinations revealed complete resolution of the cystic adrenals within 24 months. Thus it seems that a conservative approach in selected tumors associated with the Beckwith-Wiedemann syndrome might be acceptable.

A number of genes are known to control the development of the testis but the transcription factor SRY encoded on the Y-chromosome is considered to play the major role in initiating the first step in determining testicular differentiation. Mutations in this gene usually result in gonadal dysgenesis, but it is interesting to note that at least three of these mutations have been found to be familial. Furthermore, fewer than 10% of true hermaphrodites carry an XY karyotype, and so far only two patients have been documented to carry a mutation in the SRY gene. We have identified a familial mutation in the SRY gene involving a previously described locus. The index patient was born with severely ambiguous genitalia and on histological examination the gonads revealed true hermaphroditism, containing ovarian as well as testicular tissue. The father, his three brothers, and his first-born son carry the identical mutation. The severely feminized XY individual was diagnosed shortly after birth, gonadectomized and raised as female. SRY was determined by PCR and subsequently sequenced using cycle sequencing. A previously published point mutation was identified at nucleotide position 680 resulting in a non-conservative exchange of the amino acid iso-leucine at position 90 into methionine. This position represents a mutational 'hot spot', which seems to retain a certain amount of protein activity, enabling normal male development in some individuals. The patient is the third one reported in whom a mutation in the SRY gene results in ovarian-like development. Since ovarian development in XY individuals is extremely rare, its mechanism is of great interest. Further studies in this family might allow the identification of factors initiating and stimulating ovarian development. How far these infantile ovaries would have developed normally, however, is merely speculative.

A 20-year old woman, who underwent an intersex operation during infancy, was presented for evaluation of the gonads because of suspected true hermaphroditism. The phenotype was female with regular menstruations. Examination revealed an ovarian tumour of 8 cm on the left side and a normal right ovary. During the operation, the tumour was revealed as an endometriosis cyst, which could be excised whilst preserving the ovarian tissue. The right gonad was an ovotestis. The testicular part was removed because of a 4% risk of malignancy. The different combinations of ovary/testis and ovotestis are described. Diagnosis and therapy of true hermaphroditism should be performed as early as possible to obtain an adequate gonadal function and an undisturbed psychosexual development.

Persistent hyperinsulinaemic hypoglycaemia is a rare metabolic disorder of glucose regulation. It is however the most common cause of persistent hypoglycaemia in the neonatal period. Various drugs have been used with generally poor results, but diazoxide and a long-acting somatostatin analogue, octreotide, have been found to be rather successful. When medical therapy fails, early pancreatectomy is recommended to maintain euglycaemia. Since pancreatectomy seems to carry the long-term risk of diabetes mellitus, some authors recommend long-term medical therapy as an alternative to surgery. The outcome of treatment seems to correlate with neurological status prior to surgery. Even in early recognised and treated patients, publications suggest that a subtle neurological deficit may be present despite apparently normal intelligence. In view of the varying recommendations on treatment and the variations in outcome, we reviewed our experience over a period of three years (1992-1995) to determine whether we could formulate a rational approach to the management.From our records, we identified 8 children who fullfilled the criteria for the diagnosis of persistent hyperinsulinaemic hypoglycaemia of infancy and retrospectively reviewed their documents. We also included 2 more who presented to us during the study period.Two out of the 10 were born premature and four were considered large for gestational age, mean birth weight was 3679 gms (range 2580-4400 gms). All except three were symptomatic by day two of life. All except one were given hydrocortisone prior to transfer to our care at a mean age of 22 days (range 8-52 days). Our regime included a trial of diazoxide and octreotide. Near total pancreatectomy was performed in nine patients, seven following a short trial of octreotide. Our two most recent cases were given a longer trial of medical therapy of 9 and 6 months respectively prior to pancreatectomy. Our two early cases in the series had recurrence of hypoglycaemia within a week post-pancreatectomy. One still needed insulin therapy 5 months post-surgery. Seven were available for outcome assessment; while longitudinal growth is normal in all, three were developmentally delayed.Based on our experience with short and prolonged course of somatostation analogue, we conclude that early pancreatectomy should be performed on those with inadequate maintenance of euglycaemia while prolonged course of medical therapy is feasible only in selected cases.

Cholelithiasis is being documented with increasing frequency in the paediatric age group. Causes of gallstone formation in infants and neonates seem to differ from those in older children and adolescents. Two infants with pseudohypo-aldosteronism and cholelithiasis are reported. Salt-wasting and dehydration in pseudohypo-aldosteronism are suggested to be the pathogenetic mechanisms leading to gallstone formation possibly beginning in fetal life. The diagnosis of pseudohypo-aldosteronism may be missed, when salt-wasting is transitional. Cholelithiasis may go undetected when asymptomatic. ConclusionPseudohypo-aldosteronism should be con sidered in infants with cholelithiasis even without ob vious salt-wasting signs. Routine ultrasonographic screening for gallstones should be performed in pa tients with pseudohypo-aldosteronism.

Earlier observations on impaired in vitro effects of aldosterone on lymphocytic sodium and potassium pointed to the involvement of a defective nongenomic rather than genomic effector in pseudohypoaldosteronism. In this study, we investigated nongenomic aldosterone action in five patients with pseudohypoaldosteronism with regard to a rapid increase of free intracellular calcium [Ca2+]i in cultured nasal epithelial cells, assumably reflecting calcium influx through calcium channels. Patients were defined by episodes of salt loss despite high plasma aldosterone and renin levels. Four unaffected members of the families and four independent subjects served as controls. Considering an aldosterone-induced increase of [Ca2+]i by at least 10 nm as positive response, only 12% of cells from patients were responsive compared with 25% in normal subjects (P0.05). In terms of absolute changes, mean increase of [Ca2+]i was 1.6 +/- 1.1 nm in the patients (range-1-4) and 9.5 +/- 2.7 nm (P0.025) in the controls (range 1-25). Basal [Ca2+]i was not different between both groups (167 +/- 5 vs. 169 +/- 8 nm, mean +/- SE). These findings show an impaired nongenomic mineralocorticoid effector in patients with pseudohypoaldosteronism, which is in line with a defective sodium channel as shown recently by molecular cloning, and also with the fact that the classical, genomic intracellular receptor is structurally normal in these patients.

Two unrelated patients with small distal deletions of the long arm of chromosome 13 are described, with shawl scrotum and penoscrotal transposition, penoscrotal hypospadias, a reduced perineum, and anal atresia. The patients have small deletions of 13(q32.2qter) and 13(q32q34), respectively. This report and the literature present evidence for one or possibly more gene(s) within region 13q32.2q34 which regulate the development of the ano-genital structures. The clinical spectrum includes bifid or shawl scrotum, hypospadias, biseptate uterus, malplaced and imperforate anus, and common cloaca.

Familial persistent hyperinsulinemic hypoglycemia of infancy is a disorder of glucose homeostasis and is characterized by unregulated insulin secretion and profound hypoglycemia. Loss-of-function mutations in the second nucleotide-binding fold of the sulfonylurea receptor, a subunit of the pancreatic-islet beta-cell ATP-dependent potassium channel, has been demonstrated to be causative for persistent hyperinsulinemic hypoglycemia of infancy. We now describe three additional mutations in the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of the first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted to disrupt the normal splicing pathway of the sulfonylurea-receptor mRNA precursor. These data suggest that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.

Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocorticoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provdes evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families.

Pseudohypoaldosteronism is thought to be a rare salt-losing disorder, caused by resistance to the action of aldosterone. Defective aldosterone receptor binding is present in familial as well as sporadic cases and it has been suggested that the pathogenesis is due to a defect in the aldosterone receptor system. To date, however, molecular genetic analysis has been unable to identify a mutation in the aldosterone receptor gene itself. We have reviewed the findings in patients with pseudohypoaldosteronism, for clues which might enable us to identify the underlying pathogenesis. Although aldosterone receptor binding is regularly decreased or absent in monocytes of patients with pseudohypoaldosteronism, in some patients receptor protein can be detected with a fluorescencelabeled antibody. Receptor protein was detected in patients from familial autosomal dominant families and in sporadic cases, but was undetectable in two patients with the familial recessive form. To further elucidate the pattern of inheritance we studied the response of the renin-angiotensin-aldosterone system to the stimulation by sodium depletion in the familial autosomal dominant form and in two families with sporadic cases. In both “sporadic” families investigated, one parent and one sibling had an exaggerated response of renin and aldosterone to sodium depletion indicating a defect of sodium conservation apparent only during stress, leading to reclassification as familial cases. No additional family member in the “classical” autosomal dominant families responded abnormally to sodium depletion. These findings indicate that pseudohypoaldosteronism is unusually heterogeneous in its clinical, biochemical, and genetic presentations and findings and suggest that its pathogenesis is heterogeneous as well.

The genetics of human sex determination is considered in view of the various disorders of gonad development. The Y chromosome plays an important role in the induction of sex determination by encoding the testis-determining factor (TDF). However, not all deviations in regular development can be explained by mutations of the TDF as unique factor. Therefore, it is necessary to postulate other mutations in still unknown genes of the cascade for male-specific determination as well as the requirement of an ovary-determining factor for regular female development.

Androgen binding sites have been identified in circulating human mononuclear leukocytes of healthy donors of both sexes. Cells were separated from blood samples on a Ficoll gradient and incubated with different concentrations of [ 3 H]testosterone in the presence or absence of a 400-fold excess of unlabelled testosterone. Binding data were derived from Scatchard analysis. The binding sites fulfil the required criteria for specific steroid binding sites however differ somewhat from the classic androgen receptors from genital skin fibroblast: in fertile adult males ( n = 20) the binding sites showed (1) a high affinity for testosterone (1.32 ± 0.49 nM; mean ± SD), (2) a saturable capacity (184 ± 52 binding sites per cell; mean ± SD), and (3) a characteristic competitive binding profile for other steroid hormones (relative binding affinities: testosterone = dihydrotestosterone > 17β-estradiol > progesterone, whereas aldosterone, 17-hydroxy-progesterone and cortisol did not compete appreciably). Furthermore the number of binding sites determined using [ 3 H]dihydrotestosterone, [ 3 H]RU-1881, or [ 3 H]testosterone were comparable. This raises the possibility that androgen receptors in peripheral mononuclear leukocytes differ from those in genital skin fibroblasts. There was no apparent correlation between serum testosterone concentrations and androgen binding sites. In fertile women remarkable changes in androgen binding sites were seen in the course of the menstrual cycle, with a significant increase in the immediate preovulatory period. The presence of androgen receptors in peripheral mononuclear leukocytes provides for the first time the experimental basis for an hypothesis of direct, receptor-mediated effects of androgens on mature immunocompetent cells. The immunological implications of these results are discussed.

Multiple target organ involvement in pseudohypoaldosteronism is known but partial defects involving only a single organ system have also been described. In this report we present a girl with early symptoms and a very mild course of the disease without renal salt wasting and with normal sweat osmolality. Sodium content and the sodium/potassium ratio of stool was highly elevated. Increased plasma renin activity and aldosterone concentration as well as a reduced number of aldosterone receptors in mononuclear leucocytes confirmed the diagnosis of pseudohypoaldosteronism. Partial pseudohypoaldosteronism maybe more frequent than currently diagnosed since salt loss can be compensated by intact organ systems, but nevertheless threatens the young patient during illness. Since various degrees of clinical severity of pseudohypoaldosteronism even in the same family have been described, it seems important to identify mild cases in order to monitor younger siblings.

A 20-year old woman, who underwent an intersex operation during infancy, was presented for evaluation of the gonads because of suspected true hermaphroditism. The phenotype was female with regular menstruations. Examination revealed an ovarian tumour of 8 cm on the left side and a normal right ovary. During the operation, the tumour was revealed as an endometriosis cyst, which could be excised whilst preserving the ovarian tissue. The right gonad was an ovotestis. The testicular part was removed because of a 4% risk of malignancy. The different combinations of ovary/testis and ovotestis are described. Diagnosis and therapy of true hermaphroditism should be performed as early as possible to obtain an adequate gonadal function and an undisturbed psychosexual development.

We report on a 2-year old boy with the characteristic features of Di George syndrome. The diagnosis was confirmed by history, biochemical, immunologic and radiologic findings. After physical exercise he developed an unilateral epiphysiolysis capitis femoris, rarely seen in this age and not known to be a complication of hypoparathyroidism.

Recently, the gene for the determination of maleness has been identified in the sex-determining region on the short arm of the Y chromosome (SRY) between the Y-chromosomal pseudoautosomal boundary (PABY) and the ZFY gene locus. Experiments with transgenic mice confirmed that SRY is a part of the testis-determining factor (TDF). We describe a sporadic case of a patient with intersexual genitalia and the histological finding of ovotestes in the gonad, which resembles the mixed type of gonadal tissue without primordial follicle structures. The karyotype of the patient was 46,XY. By PCR amplification, we tested for the presence of PABY, SRY, and ZFY by using DNA isolated from peripheral blood leukocytes and for the presence of SRY by using DNA obtained from histological gonadal slices. The SRY products of both DNA preparations were further analyzed by direct sequencing. All three parts of the sex-determining region of the Y chromosome could be amplified from leukocytic DNA. The patient's and the father's SRY sequences were identical with the published sequence. In the SRY PCR product of gonadal DNA, the wild-type and two point mutations were present in the patient's sequence, simulating a heterozygous state of a Y-chromosomal gene: one of the mutations was silent, while the other encoded for a nonconservative amino acid substitution from leucine to histidine. Subcloning procedures showed that the two point mutations always occurred together. The origin of the patient's intersexuality is a postzygotic mutation of the SRY occurring in part of the gonadal tissue. This event caused the loss of the testis-determining function in affected cells.

We report two patients with transient pseudohypoaldosteronism due to obstructive renal disease. Both patients presented with a salt-losing episode simulating adrenal insufficiency. In one patient, transient reduction of aldosterone receptors could be documented, while in the second patient the clinical and biochemical parameters were consistent with transient pseudohypoaldosteronism. Aldosterone receptors were normal in both patients when studied after the surgical correction of the obstruction.

Worldwide, many patients with congenital adrenal hyperplasia (CAH) have already reached adulthood, but reports on the long-term outcome are still sparse. In our clinic population of grown-up CAH patients over 16 years of age, 108 subjects could be evaluated (68 females, 40 males). Simple virilizing CAH (SV-CAH) due to 21-hydroxylase deficiency (21-OHD) was present in 56 patients (38 females, 18 males), due to 11-hydroxylase deficiency in 3 patients (1 female, 2 males). Salt-losing 21-OHD (SL-CAH) occurred in 44 patients (24 females, 20 males), late-onset 21-OHD in 5 females. Final height in females was 156.6±5.9 (SD) cm (range:143.0-169.0 cm; n=68). in males 166.9±7.0 cm (range:150.9-181.1 cm; n=40). There was no significant difference between females and males in final height, expressed as standard deviation score (SDS). However, final height in both, females and males, was markedly lower than target height (p

A semiautomatic capillary gas-liquid chromatographic method for the determination of urinary steroids has been developed. Trimethylsilylenol ethers were used as steroid derivatives instead of the more common methoxime trimethylsilyl ethers. The diagnosis of the various enzymatic defects causing congenital adrenal hyperplasia can be made using the characteristic pattern of urinary steroid chromatograms. Furthermore, the method presented can be used routinely to monitor therapeutic control in congenital adrenal hyperplasia. Reference data for patients of different age groups under good therapeutic control are presented.

An age-related dependence of plasma ANP levels was studied in 163 healthy children (94 boys, 69 girls) between the ages of day 1 and 16 yr. In neonates during the first 2–4 days of life, significantly higher plasma ANP plasma levels (range 129–356 pg/ml, mean 227) were found compared with older infants and children (p

In 2 sibs pseudohypoaldosteronism was diagnosed by measurements of high serum aldosterone and elevated plasma renin activity. During their first week of life the first born girl, phenotypically normal, went through a severe salt-losing crisis with hyponatremia and hyperkalemia. Steroids given because of suspected congenital adrenal hyperplasia had no effect. High parenteral and later oral substitution of sodium normalized the serum electrolytes. The younger brother had milder symptoms. His salt-losing crisis developing during the first week of life was treated immediately with salt substitution. Both children developed normally with high oral sodium chloride supplementation, as regulated by the parents, using daily body weight measurements. Both children frequently suffer salt-losing crises, generally preceded by simple upper respiratory tract infections, which have to be treated in the hospital by infusion with a hyperosmolar sodium chloride solution.

In congenital adrenal hyperplasia the incidence of 21-hydroxylase deficiency is very high (approximately 1 :7,000), whereas other enzyme defects such as 11-hydroxylase deficiency, 17-hydroxylase deficiency and 3β-hydroxysteroid dehydrogenase deficiency are much less frequent. The various forms of enzyme defects can be diagnosed by determining specific plasma steroids or specific urinary steroid metabolites. A new semi-automatic capillary gas liquid chromatography method has been introduced for the diagnosis of CAH and assessment of therapy. Heterozygous carriers of 21-hydroxylase deficiency can be detected in the general population by measuring 17-hydroxyprogesterone plasma levels after ACTH stimulation; however, results overlap with the general population. In families with a CAH index case, heterozygosity and homozygosity for the 21-hydroxylase deficiency gene can be detected by HLA-typing. 21-hydroxylase deficiency can be diagnosed prenatally by HLA-typing or by determining 17 OH-progesterone levels in the amniotic fluid.

Pregnant rats were passively immunized against testosterone by injections of rabbit antibodies against testosterone. Fetuses were studied daily starting at day 18 of gestation. Testosterone antibodies were detected in all fetal plasma samples. At day 18 of gestation testicular testosterone content - as an index of gonadotropin stimulation - was unchanged even though circulating free testosterone was reduced by antibody binding. However, at day 19 and all subsequent days of gestation testicular testosterone content was significantly higher in immunized fetuses compared to the controls. These results indicate that in the male rat the negative feedback between testes and the hypothalamopituitary system develops between days 18 and 19 of gestation.

An age-related dependence of plasma ANP levels was studied in 163 healthy children (94 boys, 69 girls) between the ages of day 1 and 16 yr. In neonates during the first 2-4 days of life, significantly higher plasma ANP plasma levels (range 129-356 pg/ml, mean 227) were found compared with older infants and children (p less than 0.001). Beyond the neonatal period through adolescence no significant difference in ANP concentrations could be found between the various age groups. Plasma ANP levels ranged between 2 and 109 pg/ml (mean 47) for all age groups after the newborn period. ANP levels were also determined in 15 adult volunteers and in arterial and venous cord blood of 16 healthy newborns, and concentrations were similar to those found in children. In addition, plasma ANP levels were measured in 40 children with various cardiac diseases; 22 of 40 patients exhibited ANP levels above the upper normal range seen in control children. Of these 22 patients all except two children revealed clinical signs of heart failure. In contrast 15 of 17 children without heart failure showed plasma ANP levels within the range of control children. ANP plasma levels ranged between 93 and 967 pg/ml (mean 284) in patients with heart failure and between 15 and 118 pg/ml (mean 57) in patients without heart failure, respectively. Increased ANP levels in neonates and cardiac patients may result from increased atrial distention and reflect a compensatory mechanism to improve cardiac function by reducing pre- and afterload.