Congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is a group of autosomal recessive disorders leading to multiple complex hormonal imbalances caused by various enzyme deficiencies in the adrenal steroidogenic pathway. The most common type of congenital adrenal hyperplasia is due to steroid 21-hydroxylase (21-OHase, henceforth 21OH) deficiency. The rare, classic (severe) form caused by 21OH deficiency is characterised by life-threatening adrenal crises and is the most common cause of atypical genitalia in neonates with 46,XX karyotype. After the introduction of life-saving hormone replacement therapy in the 1950s and neonatal screening programmes in many countries, nowadays neonatal survival rates in patients with congenital adrenal hyperplasia are high. However, disease-related mortality is increased and therapeutic management remains challenging, with multiple long-term complications related to treatment and disease affecting growth and development, metabolic and cardiovascular health, and fertility. Non-classic (mild) forms of congenital adrenal hyperplasia caused by 21OH deficiency are more common than the classic ones; they are detected clinically and primarily identified in female patients with hirsutism or impaired fertility. Novel treatment approaches are emerging with the aim of mimicking physiological circadian cortisol rhythm or to reduce adrenal hyperandrogenism independent of the suppressive effect of glucocorticoids.

Transition Readiness in Adolescents and Young Adults Living With Congenital Adrenal Hyperplasia.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect cortisol biosynthesis and the need for glucocorticoid treatment is lifelong. The complexities of CAH can greatly affect teenage life and the transition from pediatric to adult care. The aim was to assess transition readiness and the impact on quality of life (QoL) as well as medication adherence rates in adolescents and young adults with CAH. METHODS: Prospective assessment of transition readiness was conducted through standardized questionnaires for adolescents and young adults (aged 16-35 years). Four open-ended questions on self-care were summarized in adolescents (aged 18-19 years) and their parents. Transition readiness was assessed using a modified CAH specific questionnaire: "Transition preparation and readiness to transfer from pediatric to adult care" with a cutoff level of >25 defined as good transition readiness. Measurement of QoL was performed using Rand 36. Medication adherence rate was measured using the self-reported questionnaire Adherence Starts with Knowledge. RESULTS: Thirty-eight adolescents and young adults with CAH were included in the study. Transition readiness was classified as good in 26 (68%) of the participants. Good transition readiness was more frequent in participants with good medication adherence rates. A general linear model analysis showed a good transition readiness affected QoL by increasing QoL scores. CONCLUSION: Self-reported transition readiness was found in the majority of adolescents and young adults with CAH. A good medication adherence rate was associated with a better transition readiness and a good transition readiness was associated with increased QoL scores.

The impact of adherence and therapy regimens on quality of life in patients with congenital adrenal hyperplasia.

OBJECTIVE: Varying outcomes regarding the quality of life (QoL) have been reported in patients with congenital adrenal hyperplasia (CAH). To assess the impact of adherence rate to medical therapy regimens on QoL in patients with CAH. PATIENTS: Adolescents and adults aged 15-72 years with CAH due to 21-hydroxylase deficiency at Karolinska University Hospital, Stockholm, Sweden. MEASUREMENTS: QoL was assessed using the Addison QoL (n = 72) and RAND 36 questionnaires (n = 75). Adherence to therapy regimens was measured using the Adherence Starts with Knowledge questionnaire (ASK-12). Associations between QoL, type of glucocorticoid therapy prescribed and ASK-12 results were examined. Results were compared to reference RAND 36 data obtained from a representative sample from the general Swedish population. RESULTS: A good adherence rate to therapy regimens and a younger age were key factors for a better QoL in study participants with CAH. Younger patients on hydrocortisone and with good adherence had higher RAND 36 scores than older patients on prednisolone independently adherence. Participants with classic CAH (both the salt-wasting and simple virilizing form) reported higher QoL than those with nonclassic CAH. Patients with CAH, especially nonclassic, more frequently reported an impaired QoL than the general population, especially regarding limitations related to body pain, vitality and mental health. CONCLUSION: A poor adherence rate to therapy regimens, rather than type of glucocorticoid was associated with impaired QoL in adolescents and adults with CAH.

Growth, puberty and testicular function in boys born small for gestational age with a nonspecific disorder of sex development.

OBJECTIVE: Being born small for gestational age (SGA) is frequently associated with unexplained disorders of sex development (nonspecific DSD) in boys. Little is known about their future growth, puberty and testicular function. Our objective is to determine the long-term endocrine outcome of boys born SGA who have a nonspecific DSD. DESIGN: Boys with a nonspecific DSD born SGA and appropriate for GA (AGA) were retrieved through the International Disorders of Sex Development registry and retrospective data collected, based on a spreadsheet containing 102 items. PATIENTS AND MEASUREMENTS: In total, 179 boys were included, of which 115 were born SGA and 64 were born AGA. Their growth and pubertal development were compared. Serum LH, FSH, testosterone, AMH and inhibin B levels in infancy and puberty were analysed to assess testicular function. RESULTS: At 2 years of age, 30% of SGA boys had incomplete or absent catch-up growth. Boys born SGA also had higher LH during minipuberty and lower testosterone in stimulation tests (p = 0.037 and 0.040, respectively), as compared to boys born AGA. No differences were observed in timing or course of puberty or end-pubertal hormone levels. CONCLUSIONS: Almost one out of three SGA boys with a nonspecific DSD experiences insufficient catch-up growth. In addition, our data suggest dysfunction of infantile Leydig cells or altered regulation of the hypothalamic-pituitary-gonadal axis in SGA boys during childhood. Sex steroid production during puberty seems unaffected.

Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function.

BACKGROUND: Previous studies have suggested that sexual function may be compromised in women born with differences of sex development (DSD) or early loss of gonadal function. AIM: To describe sexual function and sexual wellbeing in women with complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (GD) and premature ovarian insufficiency (POI) in relation to gynecological measures and in comparison with unaffected women. METHODS: A cross sectional study including 20 women with CAIS, 8 women with 46,XY GD, 8 women with 46,XX GD, 21 women with POI, and 62 population-derived controls. Study participants underwent gynecological examination for anatomical measurements and evaluation of tactile sensitivity. They responded to the validated Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and the Personal Distress Scale (PDS). RESULTS: The women with CAIS, XY GD, XX GD and POI showed overall satisfying sexual function in comparison to unaffected age-matched population female controls with a median of 1 to 2 satisfying sexual episodes per week among both the patients and the controls depending on available partner. Women with CAIS had shorter vagina and smaller clitoris and women with XY GD had a significantly shallower vagina in comparison to controls. Clitoral width was also significantly smaller among women with XX GD compared to controls. However, results showed overall good genital touch sensitivity with no significant differences between groups. CLINICAL IMPLICATIONS: Women with DSD or POI can be informed on overall satisfactory sexual function and normal genital touch sensitivity. STRENGTHS & LIMITATIONS: The strength is the use of age-matched population-based controls to these rare conditions of DSD and POI. Limitations are the nonresponder rate of recruited controls, as well as the small groups of women with DSD. CONCLUSION: Women with differences of sex development or early loss of gonadal function show overall good sexual well-being, however clinicians have to make efforts to optimize caretaking and treatment to ensure good sexual quality of life for all patients. Engberg H, Strandqvist A, Berg E, et al., Sexual Function in Women With Differences of Sex Development or Premature Loss of Gonadal Function. J Sex Med 2022;19:249-256.

Assessment of medication adherence in children and adults with congenital adrenal hyperplasia and the impact of knowledge and self-management.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is caused by a deficiency of one of the enzymes required for cortisol biosynthesis. The disease is classified as either classic (severe phenotype), subdivided into simple virilizing (SV) and salt-wasting (SW), or non-classic (NC) CAH. The treatment regime involves life-long glucocorticoid replacement, especially in classic phenotype. OBJECTIVES: We aimed to assess medication adherence, endocrine knowledge and self-management in patients with CAH and to compare patients' and physicians' assessments of medication adherence. METHODS: A prospective cross-sectional study of 108 patients with CAH (52 children and 56 adults) and 45 parents/caregivers. Two adherence measures were used, a self-reported questionnaire named Adherence Starts with Knowledge (ASK-12) with a cut-off level > 22 defined as poor adherence rate, and an assessment by a physician based on growth rate, 17-hydroxyprogesterone profile, and medical history, ranked using a five-point Likert scale. Measurements of the patients'/parents' knowledge and self-management were performed using Endocrine Society Clinical Practice Guidelines. RESULTS: Self-reported medication adherence was good with 74% of the participants reported good adherence with higher adherence in patients with the SW form. The highest endocrine knowledge and self-management were found in parents compared with children and adults with classic CAH. There was 30% discordance between the assessments by a physician and the self-reported ASK-12 scores independent of the severity of CAH. CONCLUSION: Patients and endocrinologists reported high medication adherence, however, discordance was found in 30% of the studied patients. Patients with the more severe form of CAH had higher adherence rates and demonstrated good endocrine knowledge/self-management.

Altered Gray Matter Structure and White Matter Microstructure in Patients with Congenital Adrenal Hyperplasia: Relevance for Working Memory Performance.

Congenital adrenal hyperplasia (CAH) has been associated with brain structure alterations, but systematic studies are lacking. We explore brain morphology in 37 (21 female) CAH patients and 43 (26 female) healthy controls, aged 16-33 years, using structural magnetic resonance imaging to estimate cortical thickness, surface area, volume, subcortical volumes, and white matter (WM) microstructure. We also report data on a small cohort of patients (n = 8) with CAH, who received prenatal dexamethasone (DEX). Patients with CAH had reduced whole brain volume (4.23%) and altered structure of the prefrontal, parietal, and superior occipital cortex. Patients had reduced mean FA, and reduced RD and MD, but not after correcting for brain volume. The observed regions are hubs of the visuospatial working memory and default mode (DMN) networks. Thickness of the left superior parietal and middle frontal gyri was associated with visuospatial working memory performance, and patients with CAH performed worse on this task. Prenatal treatment with DEX affected brain structures in the parietal and occipital cortex, but studies in larger cohorts are needed. In conclusion, our study suggests that CAH is associated with brain structure alterations, especially in the working memory network, which might underlie the cognitive outcome observed in patients.

Mental Health of a Large Group of Adults With Disorders of Sex Development in Six European Countries.

OBJECTIVE: The aim of the study was to evaluate psychiatric symptoms among 1022 persons with various disorders of sex development (DSDs). METHODS: The study was a European multicenter cross-sectional clinical evaluation in six countries. The mean (SD) age of participants was 32.1 (13.4) years. The cohort consisted of 325 individuals with Turner syndrome, 219 individuals with Klinefelter syndrome (KS), female individuals with various XY-DSD conditions (107 with and 67 without androgenization), 87 male individuals with XY-DSD conditions, and 221 female individuals with congenital adrenal hyperplasia. The Hospital Anxiety and Depression Scale, the Short Autism Spectrum Quotient, the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale, and self-reported mental health history were used to assess psychiatric symptoms. RESULTS: Across the six DSD diagnostic groups, clinical cutoff symptom scores were reached in 19.5% of participants for anxiety, in 7.1% for depression, in 4.1% for attention-deficit/hyperactivity disorder, and in 9.1% for autism. The mean depression and anxiety scores were higher compared with population norms in men with KS and men with XY-DSD. Compared with participants with other DSD conditions, men with KS reported significantly more mental health symptoms. Self-esteem, satisfaction with care, body dissatisfaction, and experiences of shame were associated with psychiatric symptoms in many DSD conditions. CONCLUSIONS: A substantial minority of adults with DSD, with KS in particular, experience psychiatric morbidity. Across DSD conditions, adults may share feelings of shame. Developing a positive self-esteem and body image may be challenging. Multidisciplinary DSD care that involves specialized mental health support can be of important value. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072.

No difference in cognitive performance or gender role behavior between men with and without hypospadias.

BACKGROUND: Hypospadias is a common malformation of the male external genitalia that results in urethral displacement with different levels of severity. Male genital development during the fetal period is dependent on androgen function, while the etiology of hypospadias differs and can be multifactorial. The psychosocial outcome is sometimes affected, but according to several studies acceptable. The question of whether hypospadias is associated with differences in psychosexual development has been investigated previously, with mixed results. There are no previous investigations of cognitive abilities in men with hypospadias. OBJECTIVE: The aim of this study was to investigate whether hypospadias is associated with differences in performance on cognitive tests and/or gender role behavior. PARTICIPANTS: Eighty-six men with hypospadias were compared to male and female controls from the general population. PROCEDURE: Cognitive tasks, previously shown to yield group level sex differences and questions regarding self-reported childhood gender role behavior, were administered either at an outpatient clinic visit or via online participation. RESULTS: The cognitive performance of men and women in the control groups differed significantly in the expected directions. Men and women also differed on self-reported childhood gender role behavior questions. There were no significant differences between men with and without hypospadias on any of the measures. Men with proximal hypospadias performed slightly lower on many of the cognitive tasks in comparison to men with distal hypospadias and controls. CONCLUSION: In general, hypospadias is not associated with differences in performance on cognitive tests that typically yield sex differences or with altered gender role behavior in childhood. Further studies on cognitive abilities in boys and men with proximal hypospadias are warranted.

Sexuality in Adults with Differences/Disorders of Sex Development (DSD): Findings from the dsd-LIFE Study.

For various reasons, sexuality of individuals with differences/disorders of sex development (DSD) may be affected. The aim of the study was to describe sexual activity, satisfaction with sex life, satisfaction with genital function, and sexual problems in people with different DSD conditions. Data were collected from 1,040 participants in Europe. Many people with a variety of DSD conditions do not appear to be satisfied with their sex life, experience a variety of sexual problems, and are less sexually active than the general population; therefore sexuality should be explicitly addressed in the care of people with DSD.

Psychiatric symptoms in men with hypospadias - preliminary results of a cross-sectional cohort study.

AIM: Population studies have shown an increased risk of neurodevelopmental disorders in males born with the congenital condition hypospadias, where the opening of the urethra is on the underside of the penis. We investigated overall psychiatric morbidity in cases and matched controls. METHODS: This study compared 167 men born with hypospadias from 1959 to 1994 in Stockholm or Gothenburg in Sweden using hospital registers. They were compared with controls from the Swedish population registry, who were contacted by regular mail and students who were recruited by local advertisements. The total sample had a mean age of 33.5 years (range: 19-54). They completed self-rating scales for depressive, anxiety and obsessive-compulsive symptoms and symptoms of attention deficit hyperactivity disorder. In addition, 33 cases and 47 controls underwent psychiatric morbidity interviews that covered the 17 most common psychiatric diagnoses. RESULTS: A fifth (21%) of both the cases and controls reported current or previous psychiatric symptoms. There were no significant differences in self-rated depression, anxiety or obsessive-compulsive disorder symptoms between the patients and controls or between the different phenotype groups. The distribution was not significantly affected by the severity of hypospadias. CONCLUSION: Psychiatric morbidity was no higher in men with hypospadias than population-based controls.

Karyotype - Phenotype Associations in Patients with Turner Syndrome.

Variation in karyotype may be associated with the phenotype of patients with Turner syndrome (TS). Our objective was to identify these associations between karyotype and phenotype in TS patients. This study was part of the European multicentre dsd-LIFE study. We evaluated the associations between different karyotypes of TS patients and age at diagnosis, Turner stigmata, cardiac/renal involvement and gonadal function. Information was available for 328 TS patients. Participants had a monosomy 45,X (46%), mosaicism 45,X/46,XX (10%), karyotype with isochromosome (18%), or other karyotype (26%). The clinical signs of TS were the most severe in patients with monosomy 45,X and the least severe in patients with mosaicism 45,X/46,XX. Patients with isochromosome and y-material showed an intermediate phenotype. Despite the more severe features in patients with monosomy 45,X, the median age at diagnosis was only slightly lower compared to patients with other karyotypes, which suggests opportunities for improvement of knowledge and diagnostics.

Hormone therapy and patient satisfaction with treatment, in a large cohort of diverse disorders of sex development.

OBJECTIVES: To describe and investigate the hormone treatments in individuals with different forms of disorders of sex development (DSD) and the patients' own views on their treatment. DESIGN: Multicentre cross-sectional clinical evaluation, dsd-LIFE in 6 European countries from February 2014 to September 2015. PARTICIPANTS: A total of 1040 adolescents and adults (≥16 years) with different DSD conditions. MAIN OUTCOMES MEASURES: Hormone replacement, information received and patient satisfaction. RESULTS: Included were women with Turner syndrome (301), 46,XX GD (n = 20), and women with 45,X/46XY (n = 24). Individuals with Klinefelter syndrome (n = 218), 46,XX males (n = 6), individuals with different forms of 46,XY DSD (n = 243): 46,XY DSD conditions (n = 222), men with 45,X/46XY (n = 21) 46,XX CAH, (n = 226). Oestrogen ± progestin was used by 306 (81%) individuals, 72 (19%) received ethinylestradiol and 198 had testosterone treatment. The overall adherence was good, with 10% of women with oestrogen and 5% of those on testosterone had stopped the medication despite 20% reporting dissatisfaction with the treatment, mostly because of psychological side effects. Glucocorticoid replacement in patients with CAH was very seldom stopped. More than 75% were satisfied with the information about the treatment, but the satisfaction with information about treatment options and side effects was lower. CONCLUSIONS: More than 50% in the total cohort had hormone replacement. Although adherence was generally good, this study shows that hormone replacement therapy may be improved. This may be achieved by better individualization of the treatment and by providing specific information to patients regarding both long-term and short-term hormonal effects and side effects.

Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish children and adolescents at risk of congenital adrenal hyperplasia.

Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but potential long-term adverse effects are largely unknown. In this report we intended to explore potential side effects of DEX therapy to enhance the adequacy of future risk benefit analyses of DEX treatment. We investigated the long-term effects of first trimester prenatal DEX treatment on behavioral problems and temperament in children and adolescents aged 7-17 years. The study included 34 children and adolescents, without CAH, who had been exposed to DEX during the first trimester and 67 untreated controls. Standardized parent-completed questionnaires were used to evaluate adaptive functioning and behavioral/emotional problems (CBCL), social anxiety (SPAI-C-P), and temperament (EAS) in the child. Self-reports were used to assess the children's perception of social anxiety (SASC-R). No statistically significant differences were found between DEX-treated and control children and adolescents, suggesting that, in general, healthy children treated with DEX during early fetal life are well adjusted.

Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study.

BACKGROUND: Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD. AIM: To assess gender change and gender dysphoria in a large sample of individuals with different DSDs. METHODS: A cross-sectional study was conducted in 14 European centers with 1,040 participants (717 female-identifying and 311 male-identifying persons and 12 persons identifying with another gender) with different forms of DSD. The cohort (mean age = 32.36 years, SD = 13.57) was divided into 6 major subgroups: women with 45,X DSD and variants (Turner syndrome; n = 325), men with 47,XXY DSD and variants (Klinefelter syndrome; n = 219), women with XY DSD without androgen effects (n = 107) and with androgen effects (n = 63), men with XY DSD (n = 87), and women with 46,XX congenital adrenal hyperplasia (n = 221). Data on psychosexual outcome were gathered by medical interviews and questionnaires. OUTCOMES: Gender change and gender dysphoria. RESULTS: Although gender changes were reported by 5% of participants, only in 1% (3% if those with Klinefelter and Turner syndromes-conditions in which gender issues are not prominent-are excluded) did the gender change take place after puberty and was likely initiated by the patient. 39 participants (4%) reported gender variance: between male and female, a gender other than male or female, or gender queer, alternating gender roles, or a gender expression that differed from the reported gender. This group had lower self-esteem and more anxiety and depression than the other participants. CLINICAL IMPLICATIONS: Clinicians should be aware of and sensitive to the possibility that their patients with DSD not only might have transgender feelings and a desire to change gender, but also identify as different from male or female. The complexity of their feelings might require counseling for some patients. STRENGTHS AND LIMITATIONS: The study is unique in the large number of participants from many different clinics, with sizable numbers in most subgroups, and in the large number of aspects that were measured. However, the very broadness of the study made it impossible to focus in detail on gender issues. Also, there is a need for instruments specifically measuring gender dysphoria in individuals with DSD that take non-binary genders into account. CONCLUSION: To make appropriate gender care possible for people with DSD, the gender-normative and gender-variant development of children with DSD should be studied in longitudinal studies. Kreukels BPC, Köhler B, Nordenström A, et al. Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. J Sex Med 2018;15:777-785.

Multicentre cross-sectional clinical evaluation study about quality of life in adults with disorders/differences of sex development (DSD) compared to country specific reference populations (dsd-LIFE).

BACKGROUND: Previous studies in quality of life (QOL) in individuals with disorders/differences of sex development (DSD) have been restricted to subpopulations of the condition. We describe QOL in adult persons with DSD compared to country specific references and assess the impact of diagnosis. METHODS: The multicentre cross-sectional clinical evaluation (dsd-LIFE) took place in 14 specialized clinics in six European countries. Adolescents (≥16 years) and adults having a DSD condition were included from 02/2014 to 09/2015. The main outcome QOL was measured by the WHOQOL-BREF (domains of physical health, psychological, social relationships, and environment). QOL was compared to country specific reference populations by using unpaired t-tests. Linear regression models explained the additional variance of the diagnosis on QOL. RESULTS: Three hundred one individuals with Turner Syndrome, 219 with Klinefelter Syndrome (including XYY), 226 with 46,XX CAH and 294 with rare DSD conditions (gonadal dysgenesis, androgen insensitivity syndrome, severe hypospadias, and androgen synthesis errors or other diagnosis) took part. Compared to healthy European populations, QOL was similar in psychological, slightly worse in physical health, and slightly better in environment. In social relationships, QOL was significantly poorer compared to healthy and non-healthy reference populations. In linear regression models health status was the most important predictor of QOL; additional variance was explained by feelings about household's income in all domains, and the relationship status in social relationships. Diagnosis explained nearly no additional variance. CONCLUSIONS: Except for social relationships, most people with DSD adapt well to their life circumstances and report a good QOL. Not diagnosis, but the individual's health status is much more important than previously thought. Therefore care for people with DSD should focus more on chronic physical or mental health problems both related and unrelated to the diagnosis itself. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072 .

Role of testosterone and Y chromosome genes for the masculinization of the human brain.

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. METHODS: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. RESULTS: Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern. CONCLUSION: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. © 2017 Wiley Periodicals, Inc.

Cognitive impairment in adolescents and adults with congenital adrenal hyperplasia.

OBJECTIVE: Impaired cognition has been reported in patients with congenital adrenal hyperplasia (CAH), although the findings have been conflicting. It has been hypothesized that the major causes of the deficits are prenatal hormonal imbalances and/or excessive glucocorticoid treatment. DESIGN: An observational study investigating cognition in patients with CAH. PATIENTS: A total of 55 patients with CAH and 58 control subjects from the general population, aged 16-33 years. Nine CAH subjects had been treated prenatally with dexamethasone. SETTING: Singel research institute. MEASUREMENTS: Standardized neuropsychological tests (Wechsler Scales and Stroop Interference Test) and questionnaires (Barkley Deficit in Executive Functioning Scale) were used. RESULTS: Compared to controls, patients with CAH had impaired performance in tests measuring verbal working memory (P = .024), visual-spatial working memory (P = .005 and P = .003) and inhibition (P = .002). In measures of fluid intelligence/nonverbal logical reasoning, males with CAH performed poorer than control males (P = .033). Patients with salt-wasting CAH performed equally compared to patients with simple virilizing CAH. However, patients with a null genotype performed poorer than patients with a non-null genotype and significantly worse on fluid intelligence/nonverbal logical reasoning (P = .042). Prenatally-treated women performed worse on most cognitive measures than women with CAH not treated prenatally. CONCLUSIONS: Patients with CAH had normal psychometric intelligence but impaired executive functions compared with population controls. A null CAH genotype was associated with poorer general cognitive capacity.

Are carriers of CYP21A2 mutations less vulnerable to psychological stress? A population-based national cohort study.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of one in 15 000. About one in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic-pituitary-adrenal axis. We investigated vulnerability to psychological stress in obligate carriers. METHOD: The Swedish CAH Registry encompasses more than 600 patients. Parents, that is obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias and (iii) parents of children with diabetes mellitus type 1 (T1DM). RESULTS: Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0·6), an affective disorder (OR, 0·5) or substance misuse (OR, 0·5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0·6, 0·4 and 0·2, respectively) and parents of a child with T1DM (OR 0·7, 0·6 and 0·2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child. CONCLUSION: Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage.

Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population.

BACKGROUND: dsd-LIFE is a comprehensive cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). This study focuses on various rare genetic conditions characterized by impaired gonadal or adrenal functionality. METHODS/DESIGN: The study aims to assess quality of life (QoL) as a measure of psychosocial adaptation, psychosexual and mental health aspects as major outcomes. Health status and functioning, medical and surgical therapies, participants' views on health care, psychological and social support, sociodemographic factors and their interrelations will be investigated as factors associated with the outcomes. In addition, ethical considerations in the field of DSD are addressed and previous experiences with health care were gathered. One thousand and forty participants with different DSD conditions were recruited by 14 study centres in 6 European countries (France, Germany, the Netherlands, Poland, Sweden and the United Kingdom) from February 2014 until September 2015. The conditions included were: Turner syndrome (n = 301); 45,X0/46,XY conditions (n = 45); Klinefelter syndrome (n = 218); 47,XYY (n = 1); 46,XY gonadal dysgenesis/ovotestes (n = 63); complete androgen insensitivity (CAIS) (n = 71); partial androgen insensitivity (PAIS) (n = 35) and androgen synthesis disorders (n = 20); severe hypospadias (n = 25); other or non-classified 46,XY DSD (n = 8); 46,XX congenital adrenal hyperplasia (CAH) (n = 226); 46,XX gonadal dysgenesis/ovotestis (n = 21); and 46,XX in males (n = 6). For an add-on study, 121 46,XY male-assigned individuals with CAH due to 21-hydroxylase deficiency were recruited. Mean age of participants' was 32.4 (+/- 13.6 years). DISCUSSION: Participation was high in conditions not commonly described as DSD, such as Turner and Klinefelter syndromes or CAH. Recruitment of individuals with XY DSD conditions proved to be more difficult. The data collection of PROs resulted in high data quality. Within medical and physical examination data, more missings and/or inaccurate data were found than expected. The European dsd-LIFE study recruited and evaluated the largest cross-sectional sample of individuals with different conditions classified under the term DSD. The data from this large sample will provide a sufficient basis for evidence-based recommendations for improvement of clinical care of individuals affected by a DSD condition. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072 .