Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia : epidemiological studies in a nonbiased national cohort in Sweden

Context: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. Objective: To study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. Design: An epidemiological study with a matched cohort control design. Setting: All known CAH patients in Sweden. Participants: 588 patients, >95% with known severity of CAH; 100 controls per patient matched for sex, year and place of birth. Main outcome and measures: Proxies for quality of life were selected: level of education, employment, income, sick-leave, disability pension, marriage and children. Results: Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) SW women were more likely to have an income in the top 20 percentile (OR 2.0 ). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Conclusions: This study shows important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.The Swedish Research CouncilAccepte

Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency : a Swedish population-based national cohort study

CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.Magn. Bergvalls FoundationKarolinska InstitutetStockholm County CouncilSwedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences, SIMSAM 340-2013-5867Manuscrip

Hypospadias and increased risk for neurodevelopmental disorders

BACKGROUND: Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients. METHODS: Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood. RESULTS: Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found. CONCLUSIONS: This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.The Swedish Research CouncilThe Polish Ministry of Science and Higher EducationAccepte

Patient journey experiences may contribute to improve healthcare for patients with rare endocrine diseases

Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients' experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison's disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients' everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system

Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol

The External Genitalia Score (EGS): A European Multicenter Validation Study

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research

Reggio Emilia – En filosofisk pedagogik

Reggio Emilia-filosofin har varit ett intresse hos oss genom hela lärarutbildningen. I samband med examensarbetet fick vi möjlighet att göra ett studiebesök på en förskola i Reggio Emilia i Italien, där vi även valde att genomföra delar av denna studie. Syfte och val av metod: Syftet med studien är att undersöka hur Reggio Emilia-filosofin kan vara tillämpbar på en svensk förskola i enlighet med Lpfö98. Fokus har vi valt att lägga på miljön, dokumentationen och förhållningssättet som är tre av de grundläggande aspekterna inom Reggio Emilia-filosofin. Undersökningen baseras främst på direktobservationer men även en samtalsintervju med tre pedagoger, som en uppföljning av observationerna. Resultat: Resultatet i vår studie har vi främst kommit fram till genom direktobservationerna vi genomförde på förskolan, varav vi valt ut tre situationer att skriva om. Något vi kommit fram till genom denna studie är att Reggio Emilia- filosofin är ett förhållningssätt till barn där strävan efter att låta barnen utveckla sina hundra språk är en av grundvärderingarna. Reggio Emilia-filosofin är ingen metodik utan en ständig process som utgår från barnet här och nu

Congenital adrenal hyperplasia, CYP21 deficiency, screening and clinical aspects

Congenital adrenal hyperplasia (CAH) is a group of recessively inherited disorders. More than 90% of all cases of CAB are caused by 21-hydroxylase deficiency. This enzyme deficiency results in reduced ability to synthesize cortisol and aldosterone and at the same time increased secretion of androgens. There is a wide spectrum of severity of the disease. The most severe forms of CAH are life-threatening, with the risk of a salt crisis in the neonatal period. CAH has special implications for girls since it causes virilization of the external genitalia, sometimes to the extent that they are assigned the wrong gender. Patients with milder forms of the disease do not show signs of prenatal virilization at birth but develop symptoms of excess androgen production later in life. A limited number of mutations in the 21-hydroxylase gene (CYP21) are responsible for around 95% of all affected Scandinavian CYP21 alleles. There is a clear genotype-phenotype correlation. Neonatal screening for CAH started in Sweden in 1986. Elevated blood levels of 17-hydroxy progesterone (17OHP) are used as an indicator of CAR The outcome for patients diagnosed with CAH before and after the screening program was initiated was studied. Screening resulted in earlier diagnoses and thereby prevented salt crises and led to earlier correct gender assignment in affected girls. We concluded that there are clear benefits of neonatal screening for CAR Neonatal screening is complicated by the fact that there is a spectrum of the severity of the disease. Screening 17-OHP levels were correlated with the CYP21 genotypes. We were able to show that the screening 17-OBP level provides some information on disease severity on a group level, but it cannot be used to predict disease severity in an individual case. Genotyping can be used to predict disease severity in children who are diagnosed through screening before any signs of salt loss have developed. In addition, genotyping can be used to distinguish between false and true positive cases with slightly elevated 17OHP. In order to investigate whether the screening can be optimized for preterm infants, we correlated screening 17OHP levels with gestational age in pretem infants. We compared direct measurements of 17-OHP and values after ether extraction, and the number of recalls that would result from different putative cut-off levels were calculated. The possible effects of influencing factors, such as prenatal glucocorticoid treatment, mode of delivery, and neonatal asphyxia, on the screening results were studied. We concluded that with direct measurements of 17-OHP, we can detect patients with salt-wasting CAH born Preterm and obtain the results faster (which is essential to prevent salt crises) without increasing the number of recalls. New recall procedures for the screening of preterm infants were implemented in Sweden based on these findings. 11beta-hydroxysteroid dehydrogenase type I (11 beta-HSD1) activates cortisone to cortisol. A patient with insufficient response to treatment with cortisone-acetate was found to have an apparent 11 beta-HSD 1 deficiency with a greatly increased ratio of cortisone to cortisol metabolites. Treatment with hydrocortisone resulted in normalization of 17-OHP, reduced pregnanetriole excretion as well as the ratio of cortisone to cortisol metabolites. We could not detect any mutations in the 1 1 beta-HSD I gene. Some patients with CAH seem to be unable to activate cortisone to cortisol due to deficient 1 1beta-HSD I; hence, hydrocortisone should be the drug of choice in these patients. Further studies are needed to investigate the prevalence as well as the mechanisms behind the inter-individual differences in the activity of this enzyme. Girls with CAH were studied in a structured play situation, using masculine, feminine, and neutral toys. They were videotaped when playing alone and when playing with a parent. CAH girls played more with masculine toys than the controls did. The degree of masculinization in toy play correlated with disease severity, i.e. the level of prenatal exposure to androgen, as assessed by CYP21 genotyping. The CAH girls played somewhat less with the masculine toys when a parent was present, indicating that the presence of the parent influenced them to behave in a less masculine fashion. Our results point to a direct, causative effect of prenatal androgens as an explanation for the differences in sex-typed behavior that can be seen between girls affected with CAH and controls. An increased knowledge of the specific situation for girls with CAH is important for improving the care of the patients. An increased understanding of the girl's preferences is also valuable to the families

Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours

Background: Overall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET. Methods: Patients operated for a siNET between 1998 and 2016 at Skåne University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ-GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11®. Results: One hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035). Conclusions: Male gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life

The Success of a Screening Program Is Largely Dependent on Close Collaboration between the Laboratory and the Clinical Follow-Up of the Patients

Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and death. The screening laboratory can also play an important role in increasing the general awareness of the disease and act as the source of information and education for clinicians to facilitate improved initial care, ensure prompt and correct glucocorticoid dosing to optimize the long-term outcome for the patients. A National CAH Registry and CYP21A2 genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described