An assessment of what Hans Asperger knew about child euthanasia in Vienna during the Nazi occupation.

AIM: Hans Asperger is probably best known for Asperger syndrome. However, he has been accused of knowingly and willingly participating in the National Socialist Child Euthanasia programme by referring patients to the Am Spiegelgrund children's home in Vienna. This later became notorious for euthanising disabled children. We investigated those allegations. METHODS: Clinicians and historians examined original documents and transcripts related to Asperger's referrals from the Viennese Therapeutic Pedagogy Unit, and corresponding Am Spiegelgrund admissions, up to 25 March 1943, when he was drafted. RESULTS: Asperger referred 13 children to Am Spiegelgrund. Eleven survived and apparently received adequate care that allowed them to achieve positive developments, but two girls died. Asperger referred these two girls during June and October 1941, before most of the deaths at Am Spiegelgrund occurred and before its euthanasia programme became public knowledge. Our detailed investigation of the medical records, Unit referral practices and Am Spiegelgrund provided no evidence that Asperger knew about the euthanasia programme at the time of the referrals. One death was probably due to euthanasia, but the other was less clear. CONCLUSION: There was no evidence that Asperger knew about the euthanasia programme when he referred two patients who died at Am Spiegelgrund.

Child Health Care Services in Austria.

We describe child health care in Austria, a small country in Central Europe with a population of about 9 million inhabitants of whom approximately 1.7 million are children and adolescents under the age of 20 years. For children and adolescents, few health care indicators are available. Pediatric and adolescent health provision, such as overall health provision, follows a complex system with responsibilities shared by the Ministry of Health, 19 social insurance funds, provinces, and other key players. Several institutions are affiliated with or cooperate with the Ministry of Health to assure quality control. The Austrian public health care system is financed through a combination of income-based social insurance payments and taxes. Pediatric primary health care in Austria involves the services of general pediatricians and general practitioners. Secondary care is mostly provided by the 43 children's hospitals; tertiary care is (particularly) provided in 4 state university hospitals and 1 private university hospital. The training program of residents takes 6 years and is completed by a final examination. Every year, this training program is completed by about 60 residents.

The history of circadian rhythm research in Austria.

In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by a new generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings.

A homozygous L299P mutation in the CYP11B1 gene leads to complete virilization in 46,XX individuals with 11-beta-hydroxylase deficiency.

BACKGROUND/AIM: 11-beta-hydroxylase deficiency (11betaOHD) is caused by CYP11B1 gene defects and leads to congenital adrenal hyperplasia associated with hypertension. Recently, a novel L299P mutation has been described in a compound heterozygous male individual. We observed two 46,XX siblings with a homozygous L299P mutation and investigated the functional properties of this CYP11B1 variant. PATIENTS: The index patient from a consanguineous Turkish family showed complete external virilization and was diagnosed incidentally at the age of 19 months during hospital admission for severe combined bacterial (urosepsis) and viral (CMV and EBV) infection. The younger sibling was diagnosed at the age of 5 months. Their genital phenotype was identical and both demonstrated borderline elevated blood pressure. RESULTS: Biochemical findings revealed 11betaOHD. A homozygous L299P mutation of the CYP11B1 gene was detected. In vitro expression studies performed in HCT116 cells showed a markedly decreased CYP11B1 activity in the L299P mutant (1.6 +/- 0.8%) for the conversion of 11-deoxycortisol to cortisol. CONCLUSIONS: Our study provides clear data on the functional properties and clinical phenotype in 46,XX individuals homozygous for this point mutation. Adrenal insufficiency might have contributed to the severe infectious disease that was present in the index patient at diagnosis.

Correlation between AVPR2 mutations and urinary AQP2 excretion in patients with nephrogenic diabetes insipidus.

Activation of the V2 receptor by arginine vasopressin (AVP) results in trafficking of the water channel AQP2 to the luminal plasma membrane and a small amount into the urine. Mutations in the A VPR2 gene, encoding the AVP V2 receptor, result in congenital nephrogenic diabetes insipidus (CNDI). To determine a correlation between A VPR2 mutations and urinary AQP2 excretion, immunobloting was used to detect AQP2 in the urine of patients with CNDI before and after a dehydration test. The patients' genotype was determined using PCR amplification and direct sequencing of the complete A VPR2 gene. Urinary AQP2 excretion was absent in patients with severely debilitating mutations, a novel total deletion of the A VPR2 gene, and a novel nonsense mutation W296X. However, it was detected in siblings with a V88M missense mutation. Urinary AQP2 excretion correlated well with other tested phenotype markers. Urinary AQP2 excretion could be used to evaluate the remaining in vivo integrity of the AVP-V2 receptor-AQP2 cascade in patients with CNDI.

Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function.

Depot gonadotropin releasing hormone (GnRH) agonist (GnRHa) therapy is the treatment of choice for patients with central precocious puberty (CPP). It is still unclear whether long-term exposure to GnRHa is associated with impaired reproductive function in adulthood. The present study was performed on 46 women, former CPP patients, 12.5+/-3.7 years after the discontinuation of treatment with depot GnRHa. In a structured interview, we assessed general health status, clinical signs possibly associated with hyperandrogenism, menstrual cycle, gynaecological diseases and reproductive function. It appears that long-term treatment with depot GnRHa is safe and does not impair reproductive function. The risk of former CPP patients to develop hirsutism and/or polycystic ovary syndrome does not seem to be increased compared to the normal population but this issue needs to be addressed in further long-term follow-up studies.

Estimation of the false-negative rate in newborn screening for congenital adrenal hyperplasia.

OBJECTIVE: Newborn screening based on measurement of 17alpha-hydroxyprogesterone (17-OHP) in a dried blood spot on filter paper is an effective tool for early diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Its most important rationale is prevention of a life-threatening salt-wasting (SW) crisis; in moderate forms of CAH, early diagnosis and treatment may prevent permanent negative effects of androgen overproduction. Our target was to analyse if all CAH patients who had been identified clinically before puberty would have been detected by the newborn screening. METHODS: Newborn screening cards of 110 CAH patients born between 1988 and 2000 in five Middle-European countries and diagnosed prior to puberty (77 SW and 33 moderate) and cards from 920 random, healthy newborn controls were analysed. CAH screening had not yet been introduced during this time. The diagnosis was based on clinical and laboratory signs and, in most cases, on CYP21 gene mutation analysis. All 17-OHP measurements in dried blood spots were carried out using a time-resolved fluoroimmunoassay kit. RESULTS: In the newborn screening blood spots, the median of 17-OHP levels was 561 nmol/l (range 91-1404 nmol/l) in subjects with the SW form and 40 nmol/l (4-247 nmol/l) in the moderate form. All 77 SW patients would have been detected by newborn screening using the recommended cut-off limits (30 nmol/l). However, 10 of 33 patients with moderate CAH would have been missed. 17-OHP levels of all controls were below the cut-off. CONCLUSION: Newborn screening is efficient for diagnosing the SW form of CAH, but is inappropriate for identifying all patients with a moderate form of CAH. It appears that the false-negative rate is at least one-third in children with the moderate form of CAH.

Increase in 6-hydroxymelatonin excretion in humans during ascent to high altitudes.

Melatonin (MLT), the pineal gland hormone involved in the regulation of circadian rhythms, shows characteristic diurnal variation. Its physiological role in humans is not clear. Exposure to high altitudes may disrupt the circadian rhythm and lead to various endocrine changes. MLT in humans has not been studied under these conditions. Urinary 6-hydroxy-MLT sulfate (aMT6s) excretion was analyzed during the day (0700-2200 h) and night (2200-0700 h) phases. A cohort of 33 healthy volunteers, aged 19-65 yr, was studied during an ascent to a high altitude in the Himalayas on three occasions (at a lower altitude, at 3400 m, and after reaching maximal altitudes of 5600-6100 m). aMT6s excretion during the daytime remained unchanged during exposure to high altitudes. As expected, nocturnal values were higher than diurnal values at each point in time. However, there was a significant increase in nocturnal MLT excretion after the ascent to high altitudes. Ascent to high altitudes is associated with increased nocturnal excretion of aMT6s. The mechanism and physiological significance of this MLT increase are unclear.

Prevalence of congenital adrenal hyperplasia among sudden infant death in the Czech Republic and Austria.

This study aimed to estimate the number of infants who died of unrecognized congenital adrenal hyperplasia (CAH) in Austria and the Czech Republic within the past 13 years, before the introduction of adequate neonatal screening. The study was based on retrospective analysis of neonatal screening cards of 242 infants who died suddenly between 7 days and 12 months of age and whose cause of death could not be identified. 17-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay and positive samples were subsequently genotyped. Three infants out of 242 may have had unrecognized CAH due to CYP21 (steroid 21-hydroxylase) gene defect. Their newborn 17-OHP levels and CYP21 genotypes were 706 nmol/l and del/conv//del/conv, 53 nmol/l and I2//I2, and 811 nmol/l and I2//Gln318stop, respectively. CAH due to CYP21 defect can lead to sudden unexpected death without prior symptoms typical for the condition. Hence, newborn screening would have prevented these deaths had it been available. In addition, we have shown that the I2 point mutation that is expected to lead to simple virilizing form may lead to a fatal outcome.

Long-term stability of amino acids and acylcarnitines in dried blood spots.

BACKGROUND: Dried blood filter cards, collected for newborn screening, are often stored for long periods of time. They may be suitable for the retrospective diagnosis of inborn errors of metabolism, but no data are currently available on the long-term stability of amino acids and acylcarnitine species. METHODS: We analyzed amino acids and acylcarnitines by tandem mass spectrometry in 660 anonymous, randomly selected filter cards from 1989 through 2004. We assessed long-term stability of metabolites by linear regression and estimated annual decrease of concentration for each metabolite. RESULTS: Concentrations of free carnitine increased by 7.6% per year during the first 5 years of storage and decreased by 1.4% per year thereafter. Alanine, arginine, leucine, methionine, and phenylalanine decreased by 6.5%, 3.3%, 3.1%, 7.3%, and 5.7% per year, respectively. Acetylcarnitine, propionylcarnitine, citrulline, glycine, and ornithine decreased by 18.5%, 27.4%, 8.1%, 14.7%, and 16.3% per year during the first 5 years, respectively; thereafter the decline was more gradual. Tyrosine decreased by 1.7% per year during the first 5 years and 7.9% per year thereafter. We could not analyze medium- and long-chain acylcarnitine species because of low physiological concentrations. CONCLUSIONS: Estimation of the annual decrease of metabolites may allow for the retrospective diagnosis of inborn errors of metabolism in filter cards that have been stored for long periods of time.

Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis.

BACKGROUND AND OBJECTIVES: Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk. STUDY DESIGN: In this retrospective study we included 54 patients registered at the LCH study reference center in whom the onset of CDI preceded the diagnosis of LCH, and we investigated their presentation and course to define a clinical pattern characteristic for LCH. RESULTS: In 49/54 patients (91%) the detection and biopsy of extracranial lesions led to the diagnosis of LCH. The most frequently involved organs were bones, skin, and lungs; 86% of the patients with bone lesions had skull lesions. In 18% of the patients extracranial lesions were already found at presentation of CDI, in another 51% of the patients extracranial lesions were found within 1 year from onset of CDI. CONCLUSIONS: These observations underline that a comprehensive search for extracranial lesions at presentation and during the first year thereafter may help to achieve a specific diagnosis without a pituitary stalk biopsy.

Urinary 6-hydroxy-melatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome.

The precise etiology of the restless legs syndrome (RLS) is unknown. Sensory and motor symptoms of RLS worsen during evening/night, coincident with the physiological peak of pineal melatonin excretion. Decreased melatonin levels have been reported in insomnia, which is an associated feature of RLS. Melatonin substitution improved insomnia. A potential association between the idiopathic RLS (iRLS) and alterations in melatonin excretion was therefore explored. Daytime (7:00-22:00 hr) and night-time (22:00-7:00 hr) urinary excretion of 6-OH-melatonin-sulfate (aMLTs) was measured in 15 patients with iRLS and 11 controls by a radioimmunoassay. There was no significant difference between daytime and night-time urinary aMLTs excretion in iRLS as compared with controls (daytime: 6.14 +/- 5.20 ng versus 5.02 +/- 5.11 ng, NS; night-time: 21.07 +/- 17.05 ng versus 22.92 +/- 16.52 ng, NS). Our data do not provide evidence for a decrease of cumulative melatonin production in iRLS. Insomnia in RLS does not seem to be correlated with a deficit of melatonin.