Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia-UK Nationwide Multicenter Assessment.

CONTEXT: Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). OBJECTIVE: Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. DESIGN: To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. SETTING: Tertiary care in 14 UK centers. PATIENTS: Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. INTERVENTIONS: Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. MAIN OUTCOME MEASURE: Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. RESULTS: Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. CONCLUSIONS: In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management.Clinical Trials Registration Number: SCH/15/088.

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.

Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia.

Context: Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises. Objective: We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education. Methods: Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations. Results: A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P ≤ 0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03). Conclusions: Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children.

Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo Assessment of the Cognitive and Structural Impact of Steroid Hormones.

Context: Brain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis. Objective: To examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure. Design, Setting, and Participants: A cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women. Main Outcome Measure: Recruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes. Results: Patients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance. Conclusion: We demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.

Assessment of early atherosclerosis and left ventricular dysfunction in children with 21-hydroxylase deficiency.

AIM: We analysed 25 children with 21-hydroxylase deficiency who received glucocorticoid and/or mineralocorticoid treatment for at least 12 months to determine the effects of the disease and its treatment on vascular structures and ventricular function. METHODS: Twenty-five patients with 21-hydroxylase-deficient congenital adrenal hyperplasia (CAH) and 25 control subjects were enrolled into this observational, cross-sectional study. The patients were investigated in terms of fasting blood glucose and insulin; fasting serum lipid profile; serum 17-hydroxyprogesterone; dehydroepiandrosterone sulphate; androstenedione; and adrenocorticotropic hormone. M-mode tracings of the wall motion of major arteries were obtained to measure carotid intima-media thickness (cIMT), as well as elasticity and distensibility of the aorta and carotid artery. Conventional and relatively new tissue Doppler imaging techniques were employed to assess ventricular systolic and diastolic functions. RESULTS: The median age and weight of patients were 9·4 years (1·5-16·75) and 35·5 kg (7·5-76·3), respectively. The median duration of treatment was 52·2 months. Tissue Doppler imaging measurements revealed left ventricular diastolic impairment in the patient group compared to the controls. Carotid intima-media thickness, stiffness index, elastic modulus of the aorta and carotid artery were significantly higher; meanwhile, aortic distensibility and carotid distensibility were lower in the patient group, all of which indicates the presence of subclinical atherosclerosis. BMI was found to be an independent variable for cIMT (ß: 0·5, P = 0·01) and aortic stiffness index (ß: 0·52, P < 0·001). CONCLUSION: Cardiovascular function and the elastic properties of major arteries are disturbed in children and adolescents with 21-hydroxylase-deficient CAH.

Cipionato de hidrocortisona, comprimidos de 10 mg e 20 mg, para tratamento de hiperplasia adrenal congênita de recém-nascidos diagnosticados no programa nacional de triagem neonatal-PNTN / Hydrocortisone cypionate, 10 mg and 20 mg tablets for treatment of congenital adrenal hyperplasia of newborns diagnosed in the national neonatal screening program - PNTN

INTRODUÇÃO: O Programa Nacional de Triagem Neonatal - PNTN se baseia, para sua atuação, na necessidade de prosseguir e incrementar as políticas de estímulo e aprimoramento da triagem neonatal no Brasil, adotando medidas que possibilitem o avanço de sua organização e regulação. A Portaria GM/MS Nº 2.829, de 14 de dezembro de 2012, e SAS/MS Nº 1.434, de 19 de dezembro de 2012 instituíram a Fase IV do PNTN ou seja, a triagem neonatal para Hiperplasia Adrenal Congênita ­ HAC e Deficiência de Biotinidase para todos os recém-nascidos brasileiros. Um Grupo de Assessoramento Técnico para HAC foi constituído. Este grupo contou com a colaboração de especialistas renomados e experientes que propuseram a atualização do Protocolo Clínico e Diretrizes Terapêuticas para o tratamento da HAC em recém-nascidos. A Hiperplasia Adrenal Congênita engloba um conjunto de síndromes transmitidas geneticamente por padrão autossômico recessivo, caracterizadas por diferentes deficiências enzimáticas na síntese dos esteroides adrenais. O tratamento medicamentoso tem como objetivo tanto evitar o hipercortisolismo quanto o hiperandrogenismo, ou seja, baixas doses causam hiperandrogenismo que resultará em pseudopuberdade precoce e baixa estatura. Doses elevadas causam hipercortisolismo, os quais predispõem à obesidade, hipertensão e resistência à insulina. Logo um fino ajuste da dose é necessário durante todo o seguimento da criança, até que seu desenvolvimento tenha se estabelecido. IMPACTO ORÇAMENTÁRIO: Para fins de cálculo de impacto financeiro da aquisição do medicamento, deduzimos pelo cálculo de incidência (1:7500) descrito no produto do GAT HAC e no PCDT HAC do MS, de que poderemos apresentar cerca de 387 casos novos de HAC em recém-nascidos por ano no Brasil. CONCLUSÃO: Assim, diante dos fatos apresentados e dada a interferência dos demais medicamentos citados no PCDT da HAC que causam supressão no crescimento das crianças, recomenda: -A revisão do PCDT HAC considerando a necessidade de inclusão do tratamento em recém-nascidos; -A incorporação de tecnologia Hidrocortisona (cipionato ou acetato de hidrocortisona) comprimidos de 10 e de 20 mg pela CONITEC e na Relação Nacional de Medicamentos Essenciais ­ RENAME. DECISÃO: PORTARIA Nº 11, de 16 de março de 2015 - Torna pública a decisão de incorporar o cipionato de hidrocortisona em comprimidos de 10mg e 20mg para o tratamento da hiperplasia adrenal congênita no âmbito do Sistema Único de Saúde - SUS.

Neuropsychological assessment in prepubertal patients with congenital adrenal hyperplasia: preliminary study.

AIM: Individuals with congenital adrenal hyperplasia (CAH) provide a test population for the theory that elevated testosterone levels alter pre-/perinatal brain development. METHODS: Seven prepuberal girls with CAH and seven matched controls has been submitted to a neuropsychological evaluation. We measured abilities where gender differences repeatedly has been observed or that had earlier shown differences between CAH subjects and controls. The following cognitive functions were tested: general intelligence, attention, verbal and non-verbal abilities, cerebral dominance for verbal and non-verbal material, frontal functions, peripheral dominance and motor fluency. Since several animal studies shown hippocampal morphological changes induced by prolonged hydrocortisone exposure, we also investigated memory functions. RESULTS: No differences were recorded between two groups on those abilities that are not sexually dimorphic. The mean general intelligence level of the patients was significantly lower than the controls', in agreement with previous studies. The verbal and non-verbal tasks revealed an age-related male-like pattern (i.e., verbal disadvantage) and an inversion of the hemispheric dominances. The latter observation was supported by a right-to-left shift of the peripheral dominances. The patients memory performances were all inferior to the controls'. The results are discussed in the light of possible hormonal influences. CONCLUSION: Our main findings support the hypothesis that elevated pre-/perinatal androgen exposure can influence some cognitive pattern of specific sexual dimorphic abilities in prepubertal subjects.

Congenital adrenal hyperplasia: epidemiology, management and practical drug treatment.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a common disorder, and is characterised by a defect in cortisol biosynthesis with or without a defect in aldosterone synthesis and androgen excess. The classic form, also known as the severe form, occurs in 1:15,000 births worldwide, while the nonclassic or mild form occurs in approximately 1:1,000 births worldwide and is much more common (up to 1:20) in certain ethnic groups. In classic 21-hydroxylase deficiency, glucocorticoids are given in doses sufficient to suppress adrenal androgen secretion, and mineralocorticoids are given to normalise electrolytes and plasma renin activity. The management of CAH may be complicated by iatrogenic Cushing's syndrome, inadequately treated hyperandrogenism, or both. Prenatal treatment may decrease virilisation of the affected female foetus, but the efficacy and safety of treating CAH prenatally remains to be fully defined. Close clinical monitoring of growth and development is essential to optimise treatment outcome. New treatment approaches are currently under investigation in the most severely affected patients, while nonclassic CAH does not always require treatment.

Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency.

Recent work has taught us that our conventional approach to corticosteroid replacement therapy requires review. Specifically, the doses of hydrocortisone we have used are probably too high for the majority, and should ideally be administered in three or more doses through the day. Nevertheless, there is not much hard evidence that excessive glucocorticoid replacement per se will lead to adverse effects such as osteoporosis, even though it may exacerbate any tendency in those who are predisposed to it for other reasons. As such, there is no compelling need for using determinations of either UFC excretion or of the serum cortisol profile in the routine management of patients on replacement therapy. Nevertheless, such measures may be considered in those thought to be at particular risk of osteoporosis, and in whom it is felt that special effort should be made to ensure that they are receiving the minimum dose possible. In such circumstances, a cortisol day curve is likely to be of more value than measurement of UFC.

[Clinical assessment of the role of circadian rhythm of hormone contents in the blood and saliva of children with congenital dysfunction of the adrenal cortex]. / Klinicheskaia otsenka roli sutochnykh ritmov soderzhaniia gormonov v krovi i sliune u detei s vrozhdennoi disfunktsiei kory nadpochechnikov.

It has been shown that data on circadian rhythms of 17-hydroxyprogesterone and testosterone content in children with congenital dysfunction of the adrenal cortex before and during treatment can be used in the control of treatment adequacy. Regular adequate intake of prednisolone brings about a decrease in hormonal content both in the blood and the saliva. Serial collection of salivary samples from children over 3 years of age is feasible and painless as compared to venous puncture, causing no adverse response on the child's part.

Ethical and social aspects of risk predictions.

This paper reviews past, present and future social and ethical considerations of screening carriers of autosomal disorders and other heterozygotes. A body of ethical and social guidance has evolved in the 1970's and 1980's for screening. The values of voluntaristic participation and informed consent are high. The goal of programs should be to provide couples, families, and individuals with knowledge respecting their reproductive choices. The dangers are coercive strategies, stigmatization, and careless communication of risk information. It is assumed that the number of autosomal carrier states that are screenable will undoubtedly increase as will states of heterozygosity that cause susceptibility to common diseases. Before the end of the century, something approaching a "biopsy of the human genome" will be a practical reality. To balance the potential for harmful psychological and social effects of so much new genetic knowledge, new efforts must be made to find treatments for progeny affected by recessive disorders. Maternal and paternal screening, prenatal diagnosis and treatment will be increasingly linked in the future. This paper will report on a case of fetal therapy for congenital adrenal hyperplasia as a paradigm for the future. The argument will be made that society ought to put a higher priority on prenatal care and prevention of disorders of prematurity than genetic disorders with a low frequency, lest genetic screening be distorted by unfounded concern about eugenics.