In the last decade, the development of high-throughput sequencing methodologies has significantly improved the gathering of genomic information and consequent under-standing of the genetic and ...epigenetic background of complex and monogenetic endocrine disorders ...
Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic agents used in the treatment ...of pediatric osteoporosis, X-linked hypophosphatemic rickets, and achondroplasia (ACH).
Vitamin D3 and Ca supplementation remains the basis of childhood osteoporosis treatment. Bisphosphonate (BP) therapy is the main antiresorptive therapeutic option, while denosumab, a human monoclonal IgG2 antibody with high affinity and specificity for a primary regulator of bone resorption - RANKL, represents a possible alternative. Its potent inhibition of bone resorption and turnover process leads to continuous increase of bone mineral density throughout the treatment also in the pediatric population. With a half-life much shorter than BPs, its effects are rapidly reversible upon discontinuation. Safety and dosing concerns in children remain. Novel treatment options have recently become available in two rare bone diseases. Burosumab, a monoclonal antibody against FGF-23, has been approved for the treatment of children with X-linked hypophosphatemic rickets older than 1 year. It presents an effective, more etiology-based treatment for rickets compared to conventional therapy, without the need for multiple daily oral phosphate supplementation. Its long-term efficacy and safety are currently being investigated. After years of anticipation, a novel treatment option for ACH has become available. C-type natriuretic peptide analog vosoritide effectively increases proportional growth and has a reasonable safety profile in children >2 years. Its effect on other features of the disease and the final height is yet to be determined. Several other treatment options for ACH exploring different therapeutic approaches are currently being investigated.
Denosumab is effective in the treatment of childhood-onset osteoporosis; however, further studies are necessary to determine the optimal treatment protocol. Burosumab is more etiology-based and convenient in comparison to conventional treatment of X-linked hypophospha-- temic rickets in children and adults. Vosoritide importantly changes the natural course of achondroplasia, at least in the short term.
Background
Duodenojejunal bypass liner (DJBL) is an endoscopic, reversible bariatric procedure resulting in weight loss and metabolic co-morbidities improvements in the adults.
Objectives
To ...determine safety and effectiveness of 12-month treatment with DJBL in adolescents with severe obesity (BMI > 35 kg/m
2
) and co-morbidities.
Methods
Post-pubertal subjects were treated with DJBL in an open-label, prospective clinical trial (NTC0218393). They were examined at 3 monthly intervals during the 12 months of DJBL treatment and 12 months of follow-up.
Results
DJBL was successfully placed in 19/22 adolescents (13 females, mean age (95%CI); 17.3 (16.7–17.9) years, BMI-SDS 3.7 (3.6–3.9)). There were no serious device-related adverse effects. Clinically relevant percent total weight loss (%TWL) (mean (95%CI)) 11.4 (7.4–15.3) % and BMI decrease − 4.9 (− 2.4 to − 7.4) kg/m
2
was observed at DJBL removal (
n
= 19). At 12 months after device removal, %TWL was 4.1 (− 2.6–10.8) % and BMI decrease − 2.6 (0.2 to − 5.4) kg/m
2
when compared with values at baseline (
n
= 13). HOMA-IR (− 2.1 (− 3 to − 1.3), WBISI 1.15 (0.23 to 2.07), total cholesterol, LDL-c, and triglycerides levels also improved during DJBL treatment and relapsed similarly to weight at 12-month follow-up. A decrease in iron stores, Zn, and Se levels was determined during DJBL treatment and spontaneously improved at follow-up.
Conclusions
Twelve months of DJBL treatment was safe and effective in adolescents with morbid obesity. Weight regain following device removal and relapse of metabolic complications should be expected.
Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the ...need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the
,
,
,
and
genes could reduce the societal burden and improve the clinical management of early severe childhood obesity and its implementation should be further investigated.
The major part of craniopharyngioma (CP) morbidity is the tumor and/or treatment-related damage, which results in impaired function of the hypothalamic-pituitary axes and metabolic derangements. The ...aim of the study was to analyze the prevalence of long-term endocrine and metabolic comorbidities in a national cohort of CP patients based on the age at diagnosis and histology criteria.
A retrospective-prospective longitudinal cohort analysis.
Forty-six patients with CP treated from 1979 onwards (19 with childhood-onset disease) in a single university institution were included in our study. Median follow-up from presentation was 12.8 years (interquartile range: 8.3-22.2 years) and comparable between age-at-diagnosis and histological subtype groups. Data on tumor histology were extracted from patients' records and re-evaluated if tissue samples were available (n = 32).
Childhood-onset patients presented more frequently with headache, and adult-onset with visual impairment. Prevalence of at least one pituitary axis affected increased from 54% at presentation to 100% at follow-up in childhood-onset and from 41 to 93% in adult-onset CP. Growth hormone deficiency, central diabetes insipidus, and panhypopituitarism were more prevalent in childhood-onset adamantinomatous CP (aCP) and least prevalent in adult-onset papillary CP (pCP). At follow-up, metabolic syndrome (MetS) was diagnosed in 80% of childhood-onset and 68% of adult-onset patients (p = 0.411). In the latter group, it tended to be more frequent in the aCP than pCP subtype (80 vs. 50%, p = 0.110).
Long-term endocrine and metabolic complications are very frequent in childhood- and adult-onset CP patients of both histological subtypes. The prevalence of MetS was higher compared to the largest cohort previously reported.
Short stature is a common growth disorder defined as a body height two standard deviations (SD) or more below the mean for a given age, gender, and population. A large part of the cases remains ...unexplained and is referred to as having idiopathic short stature (ISS). One of the leading genetic causes of short stature is variants of short stature homeobox-containing gene (
) and is considered to be responsible for 2-15% of ISS. We aimed to analyse the regulatory and coding region of
in Slovenian children and young adults with ISS and to investigate the pathogenicity of detected variants. Our cohort included 75 children and young adults with ISS. Multiplex ligation-dependent probe amplification (MLPA) was performed in all participants for the detection of larger copy number variations (CNVs). Sanger sequencing was undertaken for the detection of point variants, small deletions, and insertions. A total of one deletion and two duplications were discovered using the MLPA technique. Only one of these four variants was identified as disease-causing and occurred in one individual, which represents 1.3% of the cohort. With Sanger sequencing, two variants were discovered, but none of them appeared to have a pathogenic effect on height. According to the results, in the Slovenian population of children and young adults with ISS,
deficiency is less frequent than expected considering existing data from other populations.
Slovenian children are facing considerable health challenges from the rapid social changes that influence their opportunity to engage in daily physical activity.
To overlay the social changes to the ...established Report Card model as a means of contextualising the extreme changes in physical activity and fitness observed over several years.
Benchmarks were graded for 10 core indicators, plus two (Sleep, Seasonal Variations). Active Healthy Kids Slovenia members met (predominantly via zoom) liaising with team leader(s) on a flexible, individual basis, based on coronavirus disease 2019 (COVID-19) regulations, over the ∼2-year assessment period of the project. Data were separated to the years prior to, ‘pre’ 2018–2020, and ‘during’ the global pandemic (2020–2021). Where sufficient data existed for both timeframes, grades were averaged to produce an overall grade.
Grade results are expressed as pre/during/final grade, where the final grade (bolded) is a straight average of the two preceding time epochs: Overall Physical Activity (A-/A-/A-), Organized Sport and Physical Activity (C+/C/C), Active Play (D/C+/C), Active Transport (C/INC/C), Sedentary Behaviour (B/C/C+), Physical Fitness (A+/A-/A), Family and Peers (B+/INC/B+), Schools (A/A/A), Community and Environment (A+/A+/A+), Government (A/F/D), Sleep (D-/INC/D-), Seasonal Variations (D/C-/D+).
Although Slovenia has some of the most consistently physically-active children in the world, the effects of the COVID-19 pandemic exerted significant reductions in physical activity opportunities, and especially when coupled with funding re-distributions, resulted in the steepest decline of child physical fitness observed within the >35-year history of Slovenia's well-established national fitness surveillance system.
Heterozygous variants in the NPR2 gene, which encodes the B-type natriuretic peptide receptor (NPR-B), a regulator of skeletal growth, were reported in 2–6% cases of idiopathic short stature (ISS). ...Using next-generation sequencing (NGS), we aimed to assess the frequency of NPR2 variants in our study cohort consisting of 150 children and adolescents with ISS, describe the NPR2 phenotypic spectrum with a growth pattern including birth data, and study the response to growth hormone (GH) treatment. A total of ten heterozygous pathogenic/likely pathogenic NPR2 variants and two heterozygous NPR2 variants of uncertain significance were detected in twelve participants (frequency of causal variants: 10/150, 6.7%). During follow-up, the NPR2 individuals presented with a growth pattern varying from low–normal to significant short stature. A clinically relevant increase in BMI (a mean gain in the BMI SDS of +1.41), a characteristic previously not reported in NPR2 individuals, was observed. In total, 8.8% participants born small for their gestational age (SGA) carried the NPR2 causal variant. The response to GH treatment was variable (SDS height gain ranging from −0.01 to +0.74). According to the results, NPR2 variants present a frequent cause of ISS and familial short stature. Phenotyping variability in growth patterns and variable responses to GH treatment should be considered.
A Caucasian girl with consanguineous parents presented with early severe obesity and retinal dystrophy. A novel, homozygous gene truncating variant (c.1897C>T) in the
gene confirmed the diagnosis of ...MORMS (OMIM #610156). A novel clinical finding in the presented syndrome is progressive cone-rod type retinal dystrophy diagnosed at the age of four months that progressed in the 1
decade of life. Severe obesity, insulin resistance with hyperinsulinism, and impaired glucose tolerance developed alongside other components of the metabolic syndrome - dyslipidemia, arterial hypertension, and obstructive hypopnea in sleep. At the age of 14 years, primary amenorrhea persists. The patient is managed by regular nutritional advice, metformin, antihypertensive medication, and non-invasive respiratory support during sleep. Differential diagnosis of this rare entity is discussed in extend.
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