Pediatric Age Range Research Articles

Peculiar lifespan changes of periodic leg movements during sleep in restless legs syndrome.

The objective of this observational cohort study was to analyse the age-related changes of periodic leg movements during sleep using the newest international scoring rules, to expand past analyses, including patients in the paediatric age range, and also to analyse the changes of short-interval and isolated leg movements during sleep throughout the lifespan. Onehundred and sixty-five patients (84 women) with restless legs syndrome were recruited in the following age groups: 16 preschoolers (≤5years of age), 29 school-age children (6-12years), 19 adolescents (13-17years), 17 young adults (19-40years), 47 adults (41-60years) and 37 seniors (>60years). Total, periodic, short-interval and isolated leg movements during sleep and periodicity indexes were obtained by polysomnography. The total index showed (quartic polynomial interpolation) a decrease before 10years, followed by a steady increase up to 30years, a relatively stable period until 60years, and a final increase up to 80years. This course was almost entirely due to changes in periodic movements. Isolated movements did not change significantly and short-interval movements showed only an increase in seniors. Our study indicates that, in restless legs syndrome, the total index shows a peculiar and unique course throughout the lifespan, mainly due to periodic movements. These age-related changes may mirror developmental changes in network complexity known to occur in dopaminergic circuits. These data further confirm the need to better assess the periodicity of leg movements in sleep during the human development period, in order to obtain clinically useful information.

Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1

Purpose of reviewMyotonic dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital myotonic dystrophy) or in the pediatric age range (childhood-onset myotonic dystrophy). These children have a range of disabilities that reduce the lifespan and cause significant morbidity. Currently, there are no agreed upon recommendations for caring for these children.Recent findingsThe Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset myotonic dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the development of clinical care recommendations for this population.SummaryChildren with myotonic dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with myotonic dystrophy.

Applications of lung clearance index in monitoring children with cystic fibrosis.

A sensitive, reproducible and feasible measure of lung function for monitoring the respiratory health is a prerequisite for the optimization of management of the patients with cystic fibrosis (CF). Spirometry has been considered the method of choice, although it is applicable only in children older than 6 years of age, as good cooperation is necessary for its proper performance. However, over the last 15 years, scientific interest in gas dilution techniques and particularly in multiple breath wash out (MBW) method has been revived. The most commonly reported index of MBW is lung clearance index (LCI). The aim of this review is to present the most recent developments in the application of LCI as a monitoring index of respiratory status of CF patients. LCI is a sensitive and reproducible marker of ventilation inhomogeneity. It is more sensitive than spirometry and, unlike spirometry; it can be performed across the whole pediatric age range. Since it is dependent on body size, until at least the age of 6 years, the relative and not the absolute changes are more appropriate for providing clinically meaningful conclusion on ventilation inhomogeneity. Until now, MBW has been mainly used as a research tool. Based on the currently available data LCI cannot safely predict high-resolution computed tomography findings in children with CF, especially in infants. It can be used as an end-point measure for the assessment of beneficial effect of interventions. However, its utility as an outcome measure for the efficacy of therapeutic interventions seems to be dependent on the pathophysiologic mechanisms that underlie each intervention. It seems that more studies, especially longitudinal ones, are required in order to fully clarify the clinical usefulness of LCI, not only in the research setting, but also in every day practice of CF clinic.

Frequency of Obesity and Thinness among first grade Students of Imam Hossein Shahed Elementary School in Tehran, Iran

Background: The obesity epidemic, at one time confined to adults, has now penetrated the pediatric age range and shows every sign of a rapid escalation. Obese children may be at increased risk of becoming obese adults. The aim of this study was to determine the height and weight and body mass index of first grade students at Imam Hossein Shahed elementry School in Tehran, Iran.Materials and Methods: Body weight was measured by digital Microlife scale and height was measured to the nearest 0.1 cm with portable stadiometer in 51 first grade children aged 7-8 years.Results: A total of 51 first grade students were evaluated, 33 (64.17%) had normal body mass index, 4 (7.84%) were underweight, 11 (21.57%) were overweight and 3 (5.88%) were thin.Conclusion: Based on our findings, the prevalence of obesity was more pronounced than that of thinness in schoolchildren. Therefore, preventive measures for controlling obesity are necessary for public health promotion among schoolchildren.

26 THE INTESTINAL MICROBIOME IN INFLAMMATORY BOWEL DISEASE ACROSS THE PEDIATRIC AGE RANGE

The influence of genomics, immune response, and environment on inflammatory bowel disease (IBD) varies among patients. We aimed to characterize the differences and determine age and disease effects on the gut microbiome across the pediatric age range, measured by the maturity of the microbiota. Eight week observational study of patients with very early onset IBD (VEO-IBD), diagnosed ≤6yo, pediatric IBD (>8yo) and healthy pediatric controls (HC) was performed at the Children’s Hospital of Philadelphia, including IBD patients on maintenance therapy. Antibiotic use was not an exclusion criteria. Subjects on/or recent antibiotic use were analyzed separately. Metadata including disease activity, therapies, and diet was collected. Total DNA from stool was sequenced using the Illumina HiSeq paired-end method. MetaPhlAn2 assessed taxonomic composition, identifying clade-specific marker genes from bacterial, fungal, archaeal and viral sources. A Microbiota Maturity Index (MMI) was generated from HC (Subramanian et al, Nature2014). We trained a random forest model to predict age based on 13 bacterial taxa that changed in abundance with age. Subsequently, we built a random forest model to apply to the IBD cohorts, determining age predicted by the taxa abundance. The predicted age is the MMI, which is plotted against the chronological age. 170 subjects were enrolled, 73 HC (4mo-17yo), 10 HC on antibiotics (16mo-6yo), 21 pediatric IBD, and 66 VEO-IBD. CD was diagnosed in 75% of all IBD subjects. Disease activity measured by fecal calprotectin was significantly higher in VEO-IBD than pediatric IBD. Current therapies included anti-TNF and vedolizumab in 28% of the VEO subjects and 90% of pediatric IBD subjects, and 23 VEO-IBD subjects were on antibiotics at baseline. The relative abundance of 6 species were significantly different between VEO-IBD and pediatric IBD, including increasedVeillonella dispar, Haemophilus parainfluenzae, Coprobacillus sp in VEO-IBD. The generated MMI was most influenced by the abundance of Firmicutes and Bacteroidetes. Several of the 13 taxa in the MMI significantly differed between younger and older HC, yet no difference was seen in the IBD cohorts. IBD cohorts were predicted to have a less mature microbiome than expected for their chronological age, however, the relative MMI index was significantly lower in pediatric IBD than VEO-IBD with/without antibiotic use. Both IBD cohorts demonstrated a lower microbiota maturity as compared to HC, indicative of disease effect on the microbial community. The MMI was lowest in pediatric IBD, suggesting that duration of disease may play a role in the maturity of the intestinal microbiome. Interestingly, there were several differences in the microbial community within IBD, suggesting an age effect and different environmental drivers in VEO-IBD and pediatric IBD.

Acute gastric volvulus in children

This study aimed to review pediatric cases of acute gastric volvulus, explore the distinguishing features, and outline the diagnosis and management of this life-threatening condition. We searched PubMed, ScienceDirect, and Ovid Medline in March 2018 for cases of gastric volvulus in the pediatric age range (

Diabetes pharmacotherapy and effects on the musculoskeletal system.

Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo-anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

Pediatric Dosing of Ganciclovir and Valganciclovir: How Model-Based Simulations Can Prevent Underexposure and Potential Treatment Failure.

Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic (PopPK) model‐based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg = 7 × body surface area (BSA) × creatinine clearance according to the Schwarz formula (CrCLS) daily) and i.v. ganciclovir (mg = 3 × BSA × CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (area under the concentration‐time curve (AUC)0–24 40–60 μg ∙ hour/mL) in most pediatric patients across the full pediatric age range. In contrast, ganciclovir and valganciclovir dosing based on body weight, as commonly used in medical practice, leads to underexposure, particularly in younger pediatric patients. This example shows that model‐based dosing algorithms built on clinical pharmacology and implemented using good modeling practice can prevent underexposure and reduce the risk of treatment failure in pediatric patients.

Pediatric reference intervals for clinical chemistry assays on Siemens ADVIA XPT/1800 and Dimension EXL in the CALIPER cohort of healthy children and adolescents

IntroductionAccurate reference intervals (RIs) are essential for clinical interpretation of laboratory test results; however, major gaps exist in pediatric RIs. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has established age- and sex-specific pediatric RIs on various analytical platforms. The current study expands the CALIPER database by establishing age- and sex-specific RIs for biochemical assays on Siemens ADVIA XPT/1800 and Dimension EXL Systems. MethodsSerum samples from a total of 909 and 867 healthy children and adolescents (ages 0–<19 y) were tested on ADVIA XPT/1800 and Dimension EXL systems, respectively. Age- and/or sex-specific RIs were calculated for a total of 54 biochemical assays. ResultsSerum concentrations of several biomarkers remained relatively constant across the pediatric age range and similar between sexes, including sodium and triglycerides. Other biomarkers, such as alkaline phosphatase and creatinine showed both age and sex differences. Furthermore, immunoglobulin A and iron showed only age differences. DiscussionWe established RIs for creatine kinase, random glucose, total iron binding capacity, and several electrolytes for the first time using the CALIPER cohort. Overall, pediatric RIs established in the current study will allow for more accurate laboratory test interpretation worldwide using Siemens chemistry assays.

Informed Consent in Pediatric Anesthesia: A Narrative Review.

Informed consent for pediatric anesthesia challenges practitioners to navigate complex ethical, medical, and legal ambiguities. A patient's status as a minor does not negate the importance of his or her participation in the decision-making process but, rather, necessitates a nuanced evaluation of age and development to involve the patient to an appropriate extent. Given the complexities involved with pediatric informed consent in anesthesia practice and research, it is important to understand the experience of key stakeholders involved. For this review, we searched Medline, the Cochrane database, PROSPERO, and Clinicaltrials.gov for studies involving pediatric anesthesia informed consent. Inclusion and exclusion criteria were designed to select for studies that included issues related to informed consent as primary outcomes. The following data were extracted from included studies: title, authors, date of publication, study type, intervention, data collection method, participant type (ie, parent, pediatric patient, anesthesia provider), number of participants, pediatric patient age range, and primary outcome measures. Twenty-two articles were included for final review: studies of informed consent in pediatric anesthesia span many aspects of informed consent. Parental understanding has been studied most often (7/22 studies), followed by parental preferences (5/22 studies) and provider-related outcomes (5/22 studies) such as time spent interacting with patients, subjective reporting on amount of training related to informed consent, and provider satisfaction with the informed consent process. Outcomes pertaining to pediatric patients themselves constitute the smallest number of studies, including child anxiety (1/22), child understanding (1/22), and child refusal (1/22). Among the parties involved, parents have been most frequently identified as the subjects of these studies (2719/3805 subjects across all included studies, or 71% of all subjects). Pediatric patients are the least frequently involved subjects of studies that investigate informed consent in pediatric anesthesia (493/3805, or 13% of all subjects). Anesthesia providers and investigators have been study subjects (593/3805, or 16% of all subjects) for a range of topics including time spent interacting with patient, nature of informed consent conversation in relation to trainee status, satisfaction with informed consent process, and priorities for informed consent content. The aim of the present narrative review is to summarize the work that has been done on informed consent for pediatric anesthesia.

WHO-2016 Classification in ALL By Cytogenetics, FISH and Molecular Biology - Experience of Two Reference Centers in Brazil

IntroductionAlmost all neoplasms have their prognosis determined by cytogenetic and molecular factors, which determines a tailored approach for each case. According to the World Health Organization, every case of Acute Lymphoblastic Leukemia (ALL) must be classified not only immunophenotypically but also from a genetic point of view. Over the last few years, it has been recognized the differences in incidence and genetic profile of ALL from Latin America (LA). In Brazil, a large country with a distinctive ethnical background when compared to the rest of LA, few reports on ALL have been published and there is a limited availability of genetic tests for classification, especially in public health service.ObjectiveTo describe cytogenetic (karyotype and fluorescence in situ hybridization, FISH), molecular markers and World Health Organization (WHO) -2016 classification of diagnostic samples sent to two reference centers in Brazil.Material and MethodsThis is a cross-sectional study involving patients diagnosed with ALL from January 2014 to May 2018. Diagnostic bone marrow specimens were analyzed by G band conventional karyotyping (Nomenclature according International System for Human Cytogenomic 2016) (n: 157), molecular markers [(genic fusions by RT-PCR - BCR-ABL1 (n: 96), TCF3-PBX1 (n: 77), ETV6-RUNX1 (n: 83), KMT2A-AFF (n:74)] and B-ALL multi-probe FISH (n:54) were employed according to manufacturer's recommendations and following international guidelines. It was attempted to classify all cases by WHO-2016, as well as by age. Samples with no metaphases, non-conclusive or without molecular tests were considered non-classifiableResultsSamples from 157 ALL patients at diagnosis were analyzed. Median age was 8 years old (1 month - 88 years) [6 (3.8%) cases had less than 12 months; 99 (63%) between 1 to 15 years; 22 (14%) between 16 and 39 years and 30 (19.1%) older than 40 years]. The majority were B cell lineage ALL (93%). Thirty cases were excluded due to missing immunophenotyping, karyotype and/or molecular studies. Alterations were detected in 94 (74%) of 127 cases [88 (76%)/116 in B-ALL and 6 (54%)/11 in T-ALL. It was possible to classify by WHO 2016 B-ALL subtypes 116 cases, all of them stratified by age groups (Graphic 1).ConclusionOur results are consistent with the literature, showing that KMT2A rearrangement predominates in infant ALL, while a pediatric age range from 1 to 15 years old, with a predominance of good prognostic subtypes: hyperdiploidy and ETV6-RUNX1. In adults, there is predominance of the BCR-ABL1 subtype, which seems to be more frequent than non-Latin cohorts. B-ALL NOS was detected in 27.8% of the cases, predominating in the age group of 16 to 39 years, which may correspond to Ph-like ALL, a recently described subtype linked to a worse prognosis and seemingly more common in latinos. DisclosuresNo relevant conflicts of interest to declare.

One-day oral polyethylene glycol based cleanout is effective for pre-colonoscopy preparation in children

BackgroundThe adequacy of pre-procedure preparation is the principal determinant of the quality of colonoscopy in pediatric as in adult patients. There is a lack of consensus, among providers on a standard pre-procedure regimen. Professional society guidelines include the use of Polyethylene glycol (PEG). Herein we report on the provider-assessed adequacy of a one day, age-categorized dosing, PEG based cleanout regimen in children undergoing colonoscopy in a tertiary institution.MethodsThe standard bowel preparation regime at our institution includes an age dependent minimum PEG dosing regimen in addition to clear liquids the day prior to the procedure. We retrospectively abstracted relevant indices including patient demographics, prep quality, procedure impairment, duration and completion from an institutional quality monitoring survey tool between 2015 and 2016 and similarly abstracted prospectively recorded indices that included the dataset above as well as additional fields for procedure deviations and additional laxative use.ResultsA total of 642 procedures (mean age 12.2 years; F: 380) were accrued, nonadherence to the cleanout regimen (7.3%) and additional laxative use (3.1%) were observed in a small proportion of the prospective dataset subjects, adequate cleanout defined as thin or thick liquid but no solids present was reported in 79.5% and 15.8% of cases and impaired study from inadequate cleanout was reported in 11.8% of studies albeit the cecum was reached and the terminal ileum was intubated in 97.8 and 93.6% of studies. The duration of the study was significantly longer with the presence of a fellow trainee assisting in the procedure. Patient age and gender did not correlate with prep adequacy or cecal and ileal intubation rates, inadequate cleanout was significantly associated with impairment and incomplete studies.ConclusionA one day, single agent, osmotic laxative (Polyethylene glycol) based cleanout regimen is effective in routine pre-procedure cleanout for standard colonoscopy in pediatric age range patients.

The use of PBPK modeling across the pediatric age range using propofol as a case.

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp®. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration-time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration-time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect.

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect.

Pediatric Insulin Injection Technique: A Multi-Country Survey and Clinical Practice Implications.

IntroductionThe 2015 Insulin Injection Technique Questionnaire survey involving 13,289 patients included 898 (6.8%) patients in the pediatric age range (≤ 18 years).MethodsThe younger patients included in the questionnaire survey were grouped according to age: Group 1 (G1), 0–6 years, n = 85; Group 2(G2), 7–13, n = 423; Group 3 (G3), 14–18, n = 390. The injection technique was evaluated by means of a questionnaire and nurse assessment.ResultsNurses found lipohypertrophy at injection sites in 41.3, 45.2, and 47.3% of patients in G1, G2, and G3, respectively. Unexpected hypoglycemia was common, ranging from 23.8 to 48.1% of patients, and glucose variability was even more common (61.0% in G1, 45.9% in G2, and 52.5% in G3); both conditions were associated with lipohypertrophy. While increasing numbers of patients were using the recommended 4-mm needles, large percentages still used longer ones (33.3% in G1, 45.9% in G2, and 61.5% in G3). The reuse of needles was also common, ranging from 21.1 to 32.5% in the three age groups. Excessive reuse, defined as using a single needle more than five times, was reported by 9.4–21.8% of patients in the three age group. The percentages of patients who had not received any injection training in the last 12 months ranged from 21.2 to 26.8% in the three groups.ConclusionImplications of our study are as follows: (1) pediatric patients should use 4-mm pen needles or 6-mm syringes (inserted at a 45° angle); (2) patients aged ≤ 6 years should always inject into a raised skin fold regardless of which device is used; (3) all patients should rotate sites and use needles only once to avoid lipohypertrophy.FundingBecton–Dickinson (BD) diabetes care.

Impact of severe obesity on cardiovascular risk factors in youth

Rising degree of obesity has been shown to predict increased metabolic risk in obese children and adolescents (1). Nonetheless, it is unclear if BMI categories can be successfully applied to populations of obese children and adolescents for a risk-adapted stratification of therapeutic approaches, and here especially for the indication of pharmacologic and bariatric interventions. Here, Zabarsky et al. demonstrate the limitations of a simple, BMI-based categorization of the degree of obesity in the pediatric age range. As has been shown before, clustering of cardiovascular risk factors rises significantly with increasing degree of obesity and also with increasing weight gain during follow-up. But importantly, the “dose-response” relationship between obesity and metabolic risk seems to plateau above the threshold for class III obesity (BMI 140-160% of the 95th percentile), which – according to the authors – roughly corresponds to an adult BMI >40 kg/m2 in their population. Therefore, the challenge of developing an accurate and easy-to-use clinical classification system for metabolic risk specifically in severely obese children and adolescents remains unsolved for now.

Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach

PurposeChanges in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates.MethodsPharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1–18 years of age after oral administration were analyzed using a physiological population PK modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance.ResultsThe whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5–405) times lower intrinsic gut wall clearance than the intrinsic hepatic clearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8–50.0%).ConclusionIn conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

Paediatric Anti-Müllerian Hormone measurement: Male and female reference intervals established using the automated Beckman Coulter Access AMH assay.

SummaryObjectiveAnti‐Müllerian Hormone (AMH) concentration is high at birth in males, demonstrating the presence of functional testicular tissue in the prepubertal period, and acting as a useful marker in the investigation of paediatric reproductive disorders. AMH also provides a tool in the investigation of female virilization, premature ovarian failure and polycystic ovarian syndrome in childhood. Robust, assay‐specific paediatric AMH reference intervals are therefore required for clinical interpretation of results. The aim of this study was to derive age‐specific AMH reference intervals for males and females aged 0‐18 years.Design and PatientsPlasma samples were obtained from patients at Royal Manchester Children's Hospital and analysed for AMH using the automated Beckman Coulter Access AMH Assay. Patients under investigation for paediatric reproductive or endocrine disorders were excluded from the study.MeasurementsSeven hundred and 2 patient plasma samples (465 male, 237 female) were subject to AMH measurement, and results were analysed in order to derive continuous and discrete reference intervals for the paediatric age range.ResultsClear discrimination between male and female AMH results was evident in the prepubertal age range, with some overlap between the genders following pubertal onset.ConclusionsWe have derived age‐related reference intervals for plasma AMH in the paediatric age range (0‐18 years) using the automated Beckman Coulter Access AMH assay which will aid in the investigation of paediatric endocrine disorders such as disorders of sexual development.

Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.

Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.