Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

Objective: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Design: Mutational analysis of MC2R by direct sequencing. Patients: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Results: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. Conclusions: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosi

Holistic management of DSD

Disorder of sex development (DSD) presents a unique challenge, both diagnostically and in terms of acute and longer-term management. These are relatively rare conditions usually requiring a multidisciplinary approach from the outset and the involvement of a tertiary centre for assessment and management recommendations. This article describes the structure of the multidisciplinary team (MDT) at our centre, with contributions from key members of the team regarding their individual roles. The focus is on the newborn referred for assessment of ambiguous genitalia, rather than on individuals who present in the adolescent period or at other times, although the same MDT involvement is likely to be required. The approach to the initial assessment and management is discussed and the subsequent diagnosis and follow-up presented, with emphasis on the importance of careful transition and long-term support

Management of Cushing syndrome in children and adolescents: experience of a single tertiary centre

The diagnosis and management of paediatric Cushing syndrome (CS) is highly challenging. This study aims to characterise its presentation, diagnosis, management and outcome by a retrospective case review of 30 patients (14 females) followed at a single tertiary paediatric endocrinology centre over a 30-year period. At presentation, median age was 8.9 years (0.2-15.5) and the commonest manifestations were weight gain (23/30), hirsutism (17/30), acne (15/30) and hypertension (15/30). Growth retardation was present in 11/30. Median body mass index (BMI) was +2.1 standard deviation score (SDS) (-6.5 to +4.6). Urinary free cortisol (UFC) was abnormal in 17/18 (94 %), midnight cortisol in 27/27 (100 %) and low-dose dexamethasone suppression (LDDS) test in 20/20 (100 %). High-dose dexamethasone suppression (HDDS) test was abnormal in 6/6 (100 %) of adrenal tumours, 1/10 (10 %) of Cushing disease (CD) and 1/2 (50 %) of ectopic tumours. Bilateral inferior petrosal sinus sampling (IPSS) identified five CD cases and one ectopic tumour. All patients underwent surgery and subsequently required cortisol replacement. Final diagnoses were 16 CD, 11 adrenal disease, 2 ectopic ACTH-secreting lesions and 1 case of unidentified aetiology. One year post-diagnosis, median BMI was 0.5 SDS (-2.5 to +3.7), hypertension was present in 4/14 (28 %), and 43 % (12/30) of individuals were off hydrocortisone. CONCLUSION: The prevalence of the clinical manifestations differs from that reported in other series. Screening tests were highly sensitive, with UFC, midnight cortisol and LDDS performing well. One year post-treatment, BMI and BP normalised in the majority of patients and almost half of them were able to discontinue replacement hydrocortisone. WHAT IS KNOWN: •Cushing syndrome is an extremely rare entity in the paediatric and adolescent age groups, so not many cohort studies have been published in this population. •Several tests can be employed to firstly diagnose hypercortisolaemia and secondly identify the source of origin of it. The efficacy and safety of these tests in children is still uncertain. What is New: •This study includes cases due to the different aetiologies of endogenous hypercortisolaemia (pituitary, adrenal and ectopic hypercortisolaemia) allowing us to compare the differences in presentation, diagnosis, management and long-term outcome between the groups. •There is a difference in the prevalence of Cushing syndrome symptoms and in the performance of the tests in our cohort compared to previously published studies in the literature

Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment

There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status

Modeling community integration in workers with delayed recovery from mild traumatic brain injury

Background: Delayed recovery in persons after mild traumatic brain injury (mTBI) is poorly understood. Community integration (CI) is endorsed by persons with neurological disorders as an important outcome. We aimed to describe CI and its associated factors in insured Ontario workers with delayed recovery following mTBI. Methods: A cross-sectional study of insured workers in the chronic phase following mTBI was performed at a rehabilitation hospital in Ontario, Canada. Sociodemographic, occupational, injury-related, clinical, and claim-related data were collected from self-reports, medical assessments, and insurers’ referral files. Community Integration Questionnaire (CIQ) scores were compared using analysis of variance or Spearman’s correlation tests. Stepwise multivariable linear regression models were used to evaluate the associations with CI. Results: Ninety-four workers with mTBI (45.2 ± 9.9 years old, 61.2 % male) at 197 days post-injury (interquartile range, 139–416 days) were included. The CIQ total and subscale scores were similar to those reported in more severe TBI samples. The CIQ scores were moderately to strongly correlated with various sociodemographic, claim-related, and clinical variables. In the multivariable regression analysis, several covariates accounted for 36.4 % of the CIQ variance in the final fully adjusted model. Discussion: This study evaluated CI in workers with mTBI, and analyzed its associated variables. Analysis revealed insomnia, head or neck pain, being married or in a relationship, time since injury, and a diagnosis of possible/probable malingering were independently associated with limited CI. Conclusions: Workers with delayed recovery from mTBI experience difficulty with CI. Insomnia is a particularly relevant covariate, explaining the greater part of its variance. To enhance participation, care should focus on clinical and non-clinical covariates

Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies