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

Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay

Although delayed puberty is relatively common and often familial, its molecular and pathophysiologic basis is poorly understood. In contrast, the molecular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are clearer, following the description of mutations in the genes KAL, GNRHR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia congenita and HH. Affected boys usually present with primary adrenal failure in infancy or childhood and HH at the expected time of puberty.DAX1 mutations have also been reported to occur with a wider spectrum of clinical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete BH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clinical presentation in men and women with DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation in patients with idiopathic sporadic or familial HH or constitutional delay of puberty. Direct sequencing of DAX1 was performed in 106 patients, including 85 (80 men and 5 women) with sporadic HH or constitutional delay of puberty and patients from 21 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified (T114C, G498A). This study suggests that mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency

Exploring C-peptide loss in type 1 diabetes using growth curve analysis

Objectives: C-peptide (CP) loss in type 1 diabetes (T1D) is highly variable, and factors influencing it are poorly understood. We modelled CP values in T1D patients from diagnosis for up to 6 years, treating the serial data as growth curves plotted against time since diagnosis. The aims were to summarise the pattern of CP loss (i.e. growth curve shape) in individual patients in simple terms, and to identify baseline characteristics that predict this pattern in individuals. Materials and methods: Between 1976 and 2011, 442 T1D patients initially aged <18y underwent 120-minute mixed meal tolerance tests (MMTT) to calculate area under the curve (AUC) CP, at 3, 9, 18, 30, 48 and 72 months after diagnosis (n = 1537). The data were analysed using the novel SITAR mixed effects growth curve model (SuperImposition by Translation And Rotation). It fits a mean AUC growth curve, but also allows the curve’s mean level and rate of fall to vary between individuals so as to best fit the individual patient curves. These curve adjustments define individual curve shape. Results: The square root (√) AUC scale provided the best fit. The mean levels and rates of fall for individuals were normally distributed and uncorrelated with each other. Age at diagnosis and √AUC at 3 months strongly predicted the patient-specific mean levels, while younger age at diagnosis (p<0.0001) and the 120-minute CP value of the 3-month MMTT (p = 0.002) predicted the patient-specific rates of fall. Conclusions: SITAR growth curve analysis is a useful tool to assess CP loss in type 1 diabetes, explaining patient differences in terms of their mean level and rate of fall. A definition of rapid CP loss could be based on a quantile of the rate of fall distribution, allowing better understanding of factors determining CP loss and stratification of patients into targeted therapies

The growth hormone receptor gene deleted for exon three (GHRd3) polymorphism is associated with birth and placental weight.

Human growth hormone receptor (GHR) transcripts have two isoforms, full-length (GHRfl) or exon 3 deleted (GHRd3). An association of these isoforms has been found with small for gestational age (SGA) infants but does not influence adult height. The role of this polymorphism in the birth size spectrum in the general population is unclear

Late clinical presentation of congenital adrenal hyperplasia in older children: findings from national paediatric surveillance

To describe the clinical presentation and sequelae, including salt-wasting crises of newly-diagnosed congenital adrenal hyperplasia (CAH) in children aged over 1 year in a contemporary population without screening. To appraise the potential benefit of newborn screening for late-presenting CAH

Enhanced roughness of lipid membranes caused by external electric fields

The behavior of lipid membranes in the presence of an external electric field is studied and used to examine the influence of such fields on membrane parameters such as roughness and show that for a micro sized membrane, roughness grows as the field increases. The dependence of bending rigidity on the electric field is also studied and an estimation of thickness of the accumulated charges around lipid membranes in a free-salt solution is presented.Comment: 9 pages, 6 figures, to appear in Computational Materials Scienc

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

Big bang simulation in superfluid 3He-B -- Vortex nucleation in neutron-irradiated superflow

We report the observation of vortex formation upon the absorption of a thermal neutron in a rotating container of superfluid $^3$He-B. The nuclear reaction n + $^3$He = p + $^3$H + 0.76MeV heats a cigar shaped region of the superfluid into the normal phase. The subsequent cooling of this region back through the superfluid transition results in the nucleation of quantized vortices. Depending on the superflow velocity, sufficiently large vortex rings grow under the influence of the Magnus force and escape into the container volume where they are detected individually with nuclear magnetic resonance. The larger the superflow velocity the smaller the rings which can expand. Thus it is possible to obtain information about the morphology of the initial defect network. We suggest that the nucleation of vortices during the rapid cool-down into the superfluid phase is similar to the formation of defects during cosmological phase transitions in the early universe.Comment: 4 pages, LaTeX file, 4 figures are available at ftp://boojum.hut.fi/pub/publications/lowtemp/LTL-95009.p

Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is an X-linked disorder caused by mutations in a gene referred to as DAX-1. AHC is characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. The DAX-1 protein is structurally related to orphan nuclear receptors, although it lacks the characteristic zinc finger DNA-binding domain that is highly conserved in other members of this family. In this report, we describe the clinical features and genetic alterations in six families with AHC. These patients reveal the variable clinical presentation of adrenal insufficiency in AHC and underscore the importance of considering this diagnosis. Nonsense mutations that introduce a stop codon were found in three cases (W171X, W171X, Y399X). Frameshift mutations (405delT, 501delA, and 702delC), each of which resulted in a premature stop codon at amino acid 263, were found in the other three families. Three of these mutations (Y399X, 405delT, 702delC) are novel. Using transient gene expression assays to assess DAX-1 function, these mutations were shown to eliminate the ability of DAX-1 to repress the transcription of genes that are stimulated by a related nuclear receptor, steroidogenic factor-1. These studies reveal the variable clinical presentation of DAX-1 mutations and emphasize the value genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC

Approaching the diagnosis of growth-restricted neonates: a cohort study

<p>Abstract</p> <p>Background</p> <p>The consequences of <it>in utero </it>growth restriction have been attracting scholarly attention for the past two decades. Nevertheless, the diagnosis of growth-restricted neonates is as yet an unresolved issue. Aim of this study is the evaluation of the performance of simple, common indicators of nutritional status, which are used in the identification of growth-restricted neonates.</p> <p>Methods</p> <p>In a cohort of 418 consecutively born term and near term neonates, four widely used anthropometric indices of body proportionality and subcutaneous fat accretion were applied, singly and in combination, as diagnostic markers for the detection of growth-restricted babies. The concordance of the indices was assessed in terms of positive and negative percent agreement and of Cohen's kappa.</p> <p>Results</p> <p>The agreement between the anthropometric indices was overall poor with a highest positive percent agreement of 62.5% and a lowest of 27.9% and the κ ranging between 0.19 and 0.58. Moreover, 6% to 32% of babies having abnormal values in just one index were apparently well-grown and the median birth weight centile of babies having abnormal values of either of two indices was found to be as high as the 46^thcentile for gestational age (95%CI 35.5 to 60.4 and 29.8 to 63.9, respectively). On the contrary, the combination of anthropometric indices appeared to have better distinguishing properties among apparently and not apparently well-grown babies. The median birth weight centile of babies having abnormal values in two (or more) indices was the 11^thcentile for gestational age (95%CI 6.3 to 16.3).</p> <p>Conclusions</p> <p>Clinical assessment and anthropometric indices in combination can define a reference standard with better performance compared to the same indices used in isolation. This approach offers an easy-to-use tool for bedside diagnosis of <it>in utero </it>growth restriction.</p