Trait-like characteristics of the sleep EEG across adolescent development

Waking and sleep data in adults show high heritability and trait-like characteristics in EEG spectra. This phenomenon has not been examined in children and adolescents where brain development influences the EEG. The present study examines whether a trait-like sleep EEG pattern is detectable across adolescent development. Two consecutive nights of standard sleep recordings were performed in 19 9-10-year-old children and 26 15-16-year-old teens, and were repeated 1.5-3 years later. EEG spectra averaged across the night for non-rapid eye movement and rapid eye movement sleep separately were classified using hierarchical cluster analysis, which showed that all 4 nights of a participant clustered together for a majority of participants. Intraclass correlation coefficients were also very high (>0.7) across nights separated by several years, indicating a trait-like feature of the sleep EEG. In summary, our results, using two measures of stability, indicate that a "trait-like" aspect can be detected in the sleep EEG across adolescent development despite considerable neurodevelopmental changes. This finding indicates that the brain oscillators responsible for generating the sleep EEG signal remain relatively stable across adolescent development

Clinical case seminar - Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse

The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

OBJECTIVE. Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias. DESIGN AND METHODS. Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network. RESULTS. Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients. CONCLUSIONS. SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common

Non-rapid eye movement sleep with low muscle tone as a marker of rapid eye movement sleep regulation

BACKGROUND: It was recently reported that epochs of non-REM sleep (NREMS) with low muscle tone represent a partial correlate of REM sleep (REMS). To further investigate this phenomenon, episodes of restricted night-time sleep (23:00 – 03.00h) and subsequent morning sleep (10:00 – 13:00h) were analysed. RESULTS: Epochs of NREMS with low muscle tone (NLMT) were identified. Their frequency was higher in morning sleep than in night sleep. At night, the latency to the first occurrence of NLMT showed a bimodal distribution with modes at sleep onset and close to REMS onset. In morning sleep, the distribution was unimodal with the mode at sleep onset. An episode of NLMT at sleep onset occurred in 35.5% of the night sleep episodes and in 60.9% of the morning sleep episodes without sleep onset REMS (SOREMS). Also SOREMS occurred predominantly in morning sleep. REMS episodes were longer and NREMS episodes shorter in morning sleep than in night sleep, whereas cycle duration did not differ. Simulating the time course of slow-wave activity revealed a close correspondence between empirical and computed values for night sleep, and some discrepancies for morning sleep. CONCLUSION: The results provide further evidence that NREMS with low muscle tone is a marker of REMS regulation. NLMT at sleep onset may represent an early manifestation of REMS

Naps not as effective as a night of sleep at dissipating sleep pressure

The two-process model of sleep posits that two processes interact to regulate sleep and wake: a homeostatic (Process S) and a circadian process (Process C). Process S compensates for sleep loss by increasing sleep duration and intensity. Process C gates the timing of sleep/wake favouring sleep during the circadian night in humans. In this study, we examined whether taking six naps throughout a 24-hr period would result in the same amount of dissipation of homeostatic pressure at the end of the day as a night of sleep, when time in bed is equivalent. Data from 46 participants (10-23 years; mean = 14.5 [± 2.9]; 25 females) were analysed. Slow-wave energy, normalized to account for individual differences in slow-wave activity, was used as a measure of sleep homeostasis. In the nap condition, slow-wave energy of six naps distributed equally during a 24-hr period was calculated. In the baseline condition, slow-wave energy was measured after 9-hr time in bed. A paired t-test was used to compare nap and baseline conditions. A linear regression was used to examine whether slow-wave energy varied as a function of age. Slow-wave energy was greater during baseline than the nap condition (p < .001). No association between age and slow-wave energy was found for baseline or nap conditions. Our findings indicate that multiple naps throughout the day are not as effective at dissipating sleep pressure as a night of sleep. This is likely due to the influence of the circadian system, which staves off sleep during certain times of the day

Asymptomatic Periprosthetic Joint Infection of the Hip with High-Virulence Pathogens: Report of Two Cases

Periprosthetic joint infection (PJI) may be a life-threatening condition, particularly when caused by pathogens with high virulence, capable of developing secondary bloodstream infection. We report two cases of chronic PJI of the hip, one with Staphylococcus aureus in a 27-year-old female with severe anorexia, the other one with Staphylococcus lugdunensis in a 74-year-old female suffering from morbid obesity. Both infections did not cause relevant symptoms over time despite the absence of suppressive antibiotic treatment. To our knowledge, there are no similar cases described in the literature. While it remains difficult to recommend postponing treatment in such cases, this option may be an alternative to suppressive antibiotic therapy

New Technologies for the Identification of Novel Genetic Markers of Disorders of Sex Development (DSD)

Although the genetic basis of human sexual determination and differentiation has advanced considerably in recent years, the fact remains that in most subjects with disorders of sex development (DSD) the underlying genetic cause is unknown. Where pathogenic mutations have been identified, the phenotype can be highly variable, even within families, suggesting that other genetic variants are influencing the expression of the phenotype. This situation is likely to change, as more powerful and affordable tools become widely available for detailed genetic analyses. Here, we describe recent advances in comparative genomic hybridisation, sequencing by hybridisation and next generation sequencing, and we describe how these technologies will have an impact on our understanding of the genetic causes of DSD

Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient

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

Goal-Directed Personalized Upper Limb Intensive Therapy (PULIT) for Children With Hemiparesis: A Retrospective Analysis

Importance: Children with hemiparesis experience limitations in activities of daily living (ADLs) as a result of upper limb impairments. To address these limitations, we developed a group-based Personalized Upper Limb Intensive Therapy (PULIT) program combining modified constraint-induced movement therapy, bimanual intensive therapy, and exergame-based robotics. Objective: To determine the effectiveness of PULIT in helping children with upper limb impairments achieve individually set goals and enable transfer of the attained motor skills into ADLs. Design: Retrospective analysis. Setting: Day camp at a pediatric rehabilitation clinic in Switzerland. Participants: Twenty-three children with upper limb impairment (unilateral cerebral palsy, n = 16; acquired brain injury, n = 7); 13 boys and 10 girls (M age = 7 yr, 8 mo, SD = 2 yr, 1 mo; Manual Ability Classification System Level I-IV). Intervention: Thirty hours of PULIT over the course of 8 days. Outcomes and measures: Goal attainment scaling (GAS) was assessed on the first and last day of intervention. The Canadian Occupational Performance Measure (COPM) and dexterity tests, such as the Box and Block Test (BBT), were administered 3 wk before and 3 wk after the intervention. Results: Total goal achievement was 85.7%. GAS, parent- and child-rated COPM Performance and Satisfaction, and the BBT of the affected and dominant upper limb improved significantly. Conclusions and relevance: PULIT effectively increases children's dexterity of the impaired and dominant upper limb, improves ADL performance, and achieves individual goals. This retrospective analysis could serve as a basis for a future randomized trial. What This Article Adds: This article informs occupational therapy practitioners about a therapy program that includes conventional and rehabilitation technology interventions and enables children with hemiparesis of the upper limb to improve relevant ADL tasks in 8 days' time