Congenital Metabolic Disorders Research Articles

Postpartumzorg in de eerste lijn: samenvatting van een multidisciplinaire richtlijn (deel 1)

Postpartum care in primary care: summary of a multidisciplinary guideline The lying time at the maternity ward for a healthy woman giving birth to a healthy baby is now on average less than 3 days. Therefore, primary care providers have a greater responsibility in the follow-up of the mother and newborn during the postpartum period. This article is a summary of the first part of the multidisciplinary guideline Postpartum care in primary care developed by the national Working Group Development of Primary Care Guidelines (WOREL) according to the internationally recognised methods of guideline development. The guideline formulates recommendations for quality postpartum care in collaboration with all involved healthcare providers with the aim of recognising and addressing complications in the newborn and mother in a timely manner. It is important that healthcare providers know what is normal, which red flags they should not miss, have basic knowledge about conditions and situations, and timely refer the patient to primary or secondary care. The article describes what attitude to adopt in case of life-threatening and serious complications in the maternity woman (postpartum haemorrhage, pre-eclampsia, venous thromboembolism and endometritis) and the newborn (jaundice, neonatal sepsis, congenital heart defect, dehydration, nutritional difficulties and metabolic disorders), as well as in case of less severe complications or complaints in the maternity woman (perineal pain, headache, constipation, haemorrhoids, urinary incontinence, fatigue and back pain) and the baby (gastro-oesophageal reflux, thrush, nappy dermatitis, intestinal cramps, conjunctivitis, cord infections and fever). Finally, specific situations in both the mother (prevention of antibody formation, rubella vaccination, thyroid disorders and gestational diabetes) and the newborn (cord care, prevention of sudden death, vitamin K and vitamin D substitution, and child abuse) are highlighted.

Multivariate logistic regression analysis of risk factors for birth defects: a study from population-based surveillance data

ObjectiveTo explore risk factors for birth defects (including a broad range of specific defects).MethodsData were derived from the Population-based Birth Defects Surveillance System in Hunan Province, China, 2014–2020. The surveillance population included all live births, stillbirths, infant deaths, and legal termination of pregnancy between 28 weeks gestation and 42 days postpartum. The prevalence of birth defects (number of birth defects per 1000 infants) and its 95% confidence interval (CI) were calculated. Multivariate logistic regression analysis (method: Forward, Wald, α = 0.05) and adjusted odds ratios (ORs) were used to identify risk factors for birth defects. We used the presence or absence of birth defects (or specific defects) as the dependent variable, and eight variables (sex, residence, number of births, paternal age, maternal age, number of pregnancies, parity, and maternal household registration) were entered as independent variables in multivariate logistic regression analysis.ResultsOur study included 143,118 infants, and 2984 birth defects were identified, with a prevalence of 20.85% (95%CI: 20.10–21.60). Multivariate logistic regression analyses showed that seven variables (except for parity) were associated with birth defects (or specific defects). There were five factors associated with the overall birth defects. The risk factors included males (OR = 1.49, 95%CI: 1.39–1.61), multiple births (OR = 1.44, 95%CI: 1.18–1.76), paternal age < 20 (OR = 2.20, 95%CI: 1.19–4.09) or 20–24 (OR = 1.66, 95%CI: 1.42–1.94), maternal age 30–34 (OR = 1.16, 95%CI: 1.04–1.29) or > = 35 (OR = 1.56, 95%CI: 1.33–1.81), and maternal non-local household registration (OR = 2.96, 95%CI: 2.39–3.67). Some factors were associated with the specific defects. Males were risk factors for congenital metabolic disorders (OR = 3.86, 95%CI: 3.15–4.72), congenital limb defects (OR = 1.34, 95%CI: 1.14–1.58), and congenital kidney and urinary defects (OR = 2.35, 95%CI: 1.65–3.34). Rural areas were risk factors for congenital metabolic disorders (OR = 1.21, 95%CI: 1.01–1.44). Multiple births were risk factors for congenital heart defects (OR = 2.09, 95%CI: 1.55–2.82), congenital kidney and urinary defects (OR = 2.14, 95%CI: 1.05–4.37), and cleft lip and/or palate (OR = 2.85, 95%CI: 1.32–6.15). Paternal age < 20 was the risk factor for congenital limb defects (OR = 3.27, 95%CI: 1.10–9.71), 20–24 was the risk factor for congenital heart defects (OR = 1.64, 95%CI: 1.24–2.17), congenital metabolic disorders (OR = 1.56, 95%CI: 1.11–2.21), congenital limb defects (OR = 1.61, 95%CI: 1.14–2.29), and congenital ear defects (OR = 2.13, 95%CI: 1.17–3.89). Maternal age < 20 was the risk factor for cleft lip and/or palate (OR = 3.14, 95%CI: 1.24–7.95), 30–34 was the risk factor for congenital limb defects (OR = 1.37, 95%CI: 1.09–1.73), >=35 was the risk factor for congenital heart defects (OR = 1.51, 95%CI: 1.14–1.99), congenital limb defects (OR = 1.98, 95%CI: 1.41–2.78), and congenital ear defects (OR = 1.82, 95%CI: 1.06–3.10). Number of pregnancies = 2 was the risk factor for congenital nervous system defects (OR = 2.27, 95%CI: 1.19–4.32), >=4 was the risk factor for chromosomal abnormalities (OR = 2.03, 95%CI: 1.06–3.88) and congenital nervous system defects (OR = 3.03, 95%CI: 1.23–7.47). Maternal non-local household registration was the risk factor for congenital heart defects (OR = 3.57, 95%CI: 2.54–5.03), congenital metabolic disorders (OR = 1.89, 95%CI: 1.06–3.37), congenital limb defects (OR = 2.94, 95%CI: 1.86–4.66), and congenital ear defects (OR = 3.26, 95%CI: 1.60–6.65).ConclusionIn summary, several risk factors were associated with birth defects (including a broad range of specific defects). One risk factor may be associated with several defects, and one defect may be associated with several risk factors. Future studies should examine the mechanisms. Our findings have significant public health implications as some factors are modifiable or avoidable, such as promoting childbirths at the appropriate age, improving the medical and socio-economic conditions of non-local household registration residents, and devoting more resources to some specific defects in high-risk groups, which may help reducing birth defects in China.

Congenital Hematological and Metabolic Disorders Causing Intrinsic Discoloration of Pediatric Dentition at Pre-Eruptive Stage

The current review assesses the literature and depicts the hematological and metabolic diseases of newborns resulting in intrinsic stains of primary dentition. The appearance of dentition is an esthetic concern to the child as well as to the caregivers. The correct diagnosis claims prime importance to the dentist as it has profound value in deciding the appropriate treatment protocol and describing it to the patient. The review describes the hematological and metabolic diseases of newborns which can affect the color of normal pediatric dentition. Erythroblastosis fetalis, icterus gravis neonatorum, congenital erythropoietic porphyria, thalassemia, sickle cell anemia, and alkaptonuria are found to have a definite impact on the intrinsic discoloration of deciduous teeth. The article is an overview of those congenital hematological and metabolic disorders and their direct and indirect effects on primary dentition at the pre-eruptive stage resulting in discoloration.

Engineered Probiotics for the Management of Congenital Metabolic Diseases: A Systematic Review.

Engineered probiotics (EPs) can be used to treat/manage chronic and congenital diseases. However, to the best of our knowledge, no systematic review has evaluated the effects of EPs on congenital metabolic disorders in murine models and human subjects. Thus, the present study systematically reviewed interventional studies that assessed the effects of EPs on congenital metabolic disorders. PubMed, Web of Science, and Scopus databases were searched up to February 2023 to retrieve related publications. Seventy-six articles were obtained in the primary step. After screening the titles/abstracts based on the inclusion and exclusion criteria, 11 papers were included. Finally, only seven articles were included after performing full-text evaluation. The included articles evaluated the effects of EPs on managing phenylketonuria (PKU, n=4) and hyperammonemia (n=3). Moreover, these studies examined mice and/or rats (n=6), monkeys (n=1), and humans (n=2). Studies on EPs and hyperammonemia revealed that some wild strains such as Lactobacillus plantarum have an innate ammonia-hyper-consuming potential; thus, there was no need to manipulate them. However, manipulation is needed to obtain a phenylalanine-metabolizing strain. In conclusion, EPs can be used to manage or treat congenital metabolic diseases including PKU.

A phenylalanine-free recombinant nutritional protein for the dietary management of phenylketonuria.

Phenylketonuria (PKU) is a congenital metabolic disorder that causes the systemic elevation of phenylalanine (Phe), which is neurotoxic and teratogenic. PKU is currently incurable, and management involves lifelong adherence to an unpalatable protein-restricted diet based on Phe-free amino acid mixtures. Seeking a palatable dietary alternative, we identified a Bacillus subtilis protein (GSP16O) with a well-balanced but low-Phe amino acid profile. We optimized the sequence and expressed a modified Phe-free version (GSP105) in Pseudomonas fluorescens, achieving yields of 20 g/L. The purified GSP105 protein has a neutral taste and smell, is highly soluble, and remains stable up to 80°C. Homozygous enu2 mice, a model of human PKU, were fed with diets containing either GSP105 or normal protein. The GSP105 diet led to normalization of blood Phe levels and brain monoamine neurotransmitter metabolites, and prevented maternal PKU. The GSP105 diet thus provides an alternative and efficacious dietary management strategy for PKU.

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.

Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls.Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.

Определение диагностической значимости маркеров наследственных болезней обмена с применением метода хромато-масс-спектрометрии

Thorough investigation of metabolome by mass spectrometry is of great importance for personalized and preventive medicine. It is only timely laboratory diagnosis involving the use of high-tech chromatographic analysis methods that can help identify the patients with disorders of amino acid and acylcarnitine metabolism. The study was aimed to determine the efficacy of conventional and additional markers of metabolic disorders of amino acids and acylcarnitines detected by chromatography–mass spectrometry for the diagnosis of congenital metabolic disorders in children, as well as to create specific panels of the most effective indicators and determine the potential diagnostic efficacy of indentification of the relationships between the levels of amino acids and acylcarnitines in pediatric patients with congenital metabolic disorders. We assessed amino acid and acylcarnitine profiles in blood spots by high-performance liquid chromatography–tandem mass spectrometry in patients aged 6 months to 16 years (48 boys and 32 girls) with suspected aminoacidopathy and organic aciduria/acidemia. The comparison group consisted of 35 children with suspected peroxisomal metabolic disorders, the control group included 40 generally healthy children of various age groups. The data obtained were used to conduct the analysis of correlations between the groups of markers. Strong correlation was revealed for the levels of metabolically most closely related compounds (r &lt; 0.8, р &lt; 0.001). However, a similar relationship between metabolically not closely related compounds (correlation coefficient 0.45–0.73 (р &lt; 0.001)) was revealed for some groups of compounds. Thus, the acylcarnitine profile can be proposed as an additional potential marker to be used in cases of borderline phenylalanine levels, and the sum of normalized acylcarnitine levels (С12+С16) can be a potential secondary marker of phenylketonuria.

Assessing the Effectiveness of the Combined Apgar Scoring System in Predicting the Short-Term Outcomes of Newborns

Background: Many clinicians have used the Apgar scoring system to evaluate newborn babies at the first minutes of birth. Expanded and combined Apgar have been introduced due to the interventions done for babies in the first minutes of life. This study evaluates the predicting values of combined Apgar scores in short-term neonatal outcomes. Methods: A diagnostic test was conducted on alive preterm and term babies without major anomalies between October 2021 and August 2022. Infants with congenital heart disease, congenital metabolic disorders, and those transferred to another hospital were excluded. Demographic data, feeding volume, conventional, expanded, and combined Apgar scores were assessed at 5 minutes of birth and recorded. The area under the receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of the combined Apgar score to predict short-term outcomes (need to admission, duration of hospitalization, and oral feeding progression). Results: Of 599 babies (339 boys and 260 girls) with a mean gestational age of 35.3 ± 3.8 weeks (25 - 42 weeks), 280 (46.7%) babies were admitted. As the average Apgar score decreased, progression to full oral feeding was associated with longer delay. The area under the ROC curve for the Combined Apgar score was 80% and 55% in correlation with the need for admission and duration of hospitalization, respectively. Conclusions: This study showed that the 5th-minute combined Apgar score is a good predictor of the need for admission and oral feeding progression but does not seem suitable for predicting the duration of hospitalization.

Adenylosuccinate lyase deficiency affects neurobehavior via perturbations to tyramine signaling in Caenorhabditis elegans.

Adenylosuccinate lyase deficiency is an ultrarare congenital metabolic disorder associated with muscle weakness and neurobehavioral dysfunction. Adenylosuccinate lyase is required for de novo purine biosynthesis, acting twice in the pathway at non-sequential steps. Genetic models can contribute to our understanding of the etiology of disease phenotypes and pave the way for development of therapeutic treatments. Here, we establish the first model to specifically study neurobehavioral aspects of adenylosuccinate lyase deficiency. We show that reduction of adsl-1 function in C. elegans is associated with a novel learning phenotype in a gustatory plasticity assay. The animals maintain capacity for gustatory plasticity, evidenced by a change in their behavior in response to cue pairing. However, their behavioral output is distinct from that of control animals. We link substrate accumulation that occurs upon adsl-1 deficiency to an unexpected perturbation in tyrosine metabolism and show that a lack of tyramine mediates the behavioral changes through action on the metabotropic TYRA-2 tyramine receptor. Our studies reveal a potential for wider metabolic perturbations, beyond biosynthesis of purines, to impact behavior under conditions of adenylosuccinate lyase deficiency.

Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning.

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hypercholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75-85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20-40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype.

A Patient Diagnosed with Li-Campeau Syndrome and Biotinidase Deficiency

Biotinidase (BTD) enzyme deficiency is a congenital metabolic disorder with autosomal recessive inheritance. Main symptoms in its deficiency are nervous system and skin manifestations. A 15-month-old patient who was diagnosed with Li-Campeau syndrome, was also diagnosed with BTD deficiency and his clinic rapidly improved with biotin treatment. With the awareness of different clinical presentations of BTD deficiency, patients presenting with clinical symptoms raising the suspicion of this disorder must be evaluated for enzyme activity and genetic analysis must be planned. It is of great importance to keep in mind the possibility of this rare but treatable neurometabolic disorder, even in countries with neonatal screening programme and include it in differential diagnoses in order to prevent irreversible symptoms.

A Patient Diagnosed with Li-Campeau Syndrome and Biotinidase Deficiency

Biotinidase (BTD) enzyme deficiency is a congenital metabolic disorder with autosomal recessive inheritance. Main symptoms in its deficiency are nervous system and skin manifestations. A 15-month-old patient who was diagnosed with Li-Campeau syndrome, was also diagnosed with BTD deficiency and his clinic rapidly improved with biotin treatment. With the awareness of different clinical presentations of BTD deficiency, patients presenting with clinical symptoms raising the suspicion of this disorder must be evaluated for enzyme activity and genetic analysis must be planned. It is of great importance to keep in mind the possibility of this rare but treatable neurometabolic disorder, even in countries with neonatal screening programme and include it in differential diagnoses in order to prevent irreversible symptoms.

Identification of an α-l-iduronidase (IDUA) M1T mutation in a Chinese family with autosomal recessive mucopolysaccharidosis I.

Mucopolysaccharidoses (MPS) are a group of rare congenital metabolic disorders caused by the deficiency or low activity of enzymes required for glycosaminoglycans degradation. Mutations in the α-l-iduronidase gene (IDUA) are associated with mucopolysaccharidosis type I (MPS I). Our study here aims to identify an MPS-related gene mutation in a typical patient with MPS and to further explore the possible pathogenic mechanism. We identified a homozygous c. 2T>C (p.M1T) change in IDUA as the pathogenic mutation in this individual (both parents were identified as carriers of the mutation), with IDUA enzyme activity significantly decreased. We further established an MPS I-related zebrafish model using IDUA-specific morpholino (MO) to suppress gene expression, and found that IDUA-MO zebrafish exhibited characteristic disease phenotypes with deficiency of IDUA. Transcriptome profiling of zebrafish larvae revealed 487 genes that were significantly altered when IDUA was depleted. TP53 signaling and LC3/GABARAP family protein-mediated autophagy were significantly upregulated in IDUA-MO zebrafish larvae. Moreover, leukotriene A4 hydrolase-mediated arachidonic acid metabolism was also upregulated. Introduction of wild-type human IDUA mRNA rescued developmental defects and aberrant signaling in IDUA-MO zebrafish larvae. In conclusion, our study provides potential therapeutic targets for the treatment of MPS I.

Identification of deep intronic variants of PAH in phenylketonuria using full-length gene sequencing

BackgroundPhenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes.MethodsIn this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis.ResultsWe identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH.ConclusionDeep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments.

The role of the pregnancy heart team in clinical practice.

Significant maternal and fetal morbidity and mortality risk has been shown to be associated with cardiovascular disease in pregnancy. Several determinants, such as the increasing number of females with corrected congenital heart disease in reproductive age, a more advanced maternal age associated with cardiovascular risk factors, and a greater prevalence of preexisting comorbidities related to cardiac disorders such as cancer and COVID-19), lead to a higher incidence of cardiac complications in pregnancy in the last few decades. However, adopting a multidisciplinary strategy may influence maternal and neonatal outcomes. This review aims at assessing the role of the Pregnancy Heart Team, which should ensure careful pre-pregnancy counseling, pregnancy monitoring, and delivery planning for both congenital and other cardiac or metabolic disorders, addressing several emerging aspects in the multidisciplinary team-based approach.

Genetic analysis of a child patient with rare fibrochondrogenesis due to COL11A1 gene variant

To analyze the clinical data and genetic characteristics of a child with fibrocartilage hyperplasia type 1 (FBCG1). A child who was admitted to Gansu Provincial Maternity and Child Health Care Hospital on January 21, 2021 due to severe pneumonia and suspected congenital genetic metabolic disorder was selected as the study subject. Clinical data of the child was collected, and genomic DNA was extracted from peripheral blood samples from the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. The patient, a 1-month-old girl, had presented with facial dysmorphism, abnormal skeletal development, and clubbing of upper and lower limbs. WES revealed that she has harbored compound heterozygous variants c.3358G>A/c.2295+1G>A of the COL11A1 gene, which has been associated with fibrochondrogenesis. Sanger sequencing has verified that the variants have been respectively inherited from her father and mother, both of whom were phenotypically normal. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3358G>A variant was graded as likely pathogenic (PM1+PM2_Supporting+PM3+PP3), and so was the c.2295+1G>A variant (PVS1＋PM2_Supporting). The compound heterozygous variants c.3358G>A/c.2295+1G>A probably underlay the disease in this child. Above finding has facilitated definite diagnosis, genetic counseling for her family.

Peripheral blood parameters for predicting PICU admission and mechanical ventilation in pediatric inpatients with human parainfluenza virus-induced pneumonia.

Human parainfluenza viruses (hPIVs)-induced pneumonia is an important cause of pediatric hospitalization, and some develop severe pneumonias requiring pediatric intensive care unit (PICU) admission and mechanical ventilation (MV). The aim of this study is to investigate the value of peripheral blood (PB) parameters available on admission in predicting the need for PICU admission and MV due to pneumonia caused by hPIVs. A total of 331 cases including 277 (83.69%) on the general ward (GW) and 54 (16.31%) on the PICU were enrolled between January 2016 and June 2021. Of 54 patients admitted to the PICU, 24 patients (7.25%) received MV, whereas 30 (9.06%) did not. For both the PICU and GW groups, infants accounted for the highest proportion while school children had the lowest. Compared with the GW group, the PICU group had significantly higher rates of premature birth, fatigue, sore throat, headache, chest pain, tachypnea, dyspnea, and underlying diseases including congenital tracheal stenosis, congenital heart disease (CHD), metabolic disorder, and neurological disorder (ND), but significant lower proportion of exclusive breastfeeding and Z-scores for weight-for-height, weight-for-age, height-for-age, and body-mass-index (BMI)-for-age (BMIZ). Higher levels of some leukocyte differential counts (LDC)-related parameters including counts of neutrophil (N), ratios of neutrophil-to-lymphocyte ratio (NLR), derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR), and platelet-to-lymphocyte ratio (PLR), lower levels of some other LDC-related parameters including lymphocyte (L) and monocyte (M) counts, ratios of lymphocyte-to-monocyte ratio (LMR), lymphocyte-to-C-reactive protein ratio, and prognostic nutritional index (PNI), and lower levels of PB protein (PBP)-related parameters including red blood cell (RBC), hemoglobin, total protein (TP), and serum albumin were observed in the PB of patients in the PICU compared with those in the GW. Notably, higher PLR level and two comorbidities including CHD and ND were identified as independent risk factors for PICU admission, while lower PNI level as well as smaller numbers of RBC and L as good predictors. Low levels of TP might be a useful predictor of the need for MV. Overall, the relative contributions of LDC- and PBP-related factors for accurate identification of patients required PICU admission accounted for 53.69% and 46.31%, respectively. Thus, determination of whether a patient with hPIVs-induced pneumonia is admitted to PICU involves consideration of both the LDC- and PBP-related parameters.

Photosensitive dermatoses in paediatric practice

Photodermatoses represent a heterogeneous group of disorders characterized by the development of pathological skin reaction to solar radiation. The development or intensification of inflammatory skin reaction after exposure to ultraviolet or electromagnetic spectrum that is visible to the human eye is a distinctive feature of all photosensitive photodermatoses. Although photodermatoses are less common in children than in adults, they are often associated with genetic or congenital metabolic disorders, and may also point to diffuse connective tissue diseases. Paediatric photodermatoses are often the result of genetic or congenital metabolic disorders, and may also indicate diffuse connective tissue diseases. The epidemiological studies have showed that the global prevalence of photodermatoses diagnosed with photopatch tests is above or equal to 5.7%. The authors presented a modern classification of photosensitive dermatoses according to the etiological factor. The article provides up-to-date information about photosensitive dermatoses, including statistical epidemiological data, pathogenesis features, and also emphasis is placed on the issues of the quality of life of children and their parents. The authors described the clinical presentations of the most common paediatric photosensitive dermatoses and the basic principles of their therapy. Among topical glucocorticosteroids, methylprednisolone aceponate has proven itself in the treatment of paediatric photodermatoses as it has not only a pronounced anti-inflammatory effect, but also is easy-to-use. The timely diagnosis of paediatric photosensitivity will help to minimize the development of complications associated with delayed treatment and insufficient prevention (photoprotection).

Застосування кетогенної дієти в педіатрії: спектр можливостей

Purpose - to describe the possibilities of using a ketogenic diet (KD) in the pediatric population for therapeutic purposes in refractory seizure syndrome and congenital metabolic disorders. The historical aspects of the development of special medical nutrition to achieve stable ketosis in children for the treatment of seizures of various genesis are briefly highlighted; the development of the evidence base for the effectiveness of the KD in children is presented. A review of current data on the multifactorial mechanisms of neuroprotective effects of KD is carried out. In particular, individual ways of modulating fundamental biochemical pathways, presynaptic and postsynaptic changes in vesicular transport and release of excitotoxic and inhibitory substrates at synapses are considered. Four types of diets are described according to the distribution of proteins, fats, and carbohydrates: the classic, modified Atkins diet, medium-chain triglyceride diet, and low glycemic index diet. The indications and contraindications for the appointment of medical ketogenic dietary therapy are considered. The most appropriate age periods of childhood for the type of KD are outlined to achieve maximum effectiveness. The authors describe in detail the main objectives of the stages of preparation of the child and family for the start of dietary treatment, the principles of initiation of KD, laboratory and instrumental monitoring and discontinuation of ketogenic dietary therapy. Particular attention is paid to the issue of counseling a child before starting a KD, the main steps in calculating the proportion of macronutrients and the principles of daily nutrition. The possibilities of prescribing medical ketogenic dietary therapy outside of refractory seizures, in particular, in glucose transaminase 1 deficiency syndrome, pyruvate dehydrogenase deficiency, mitochondrial disorders, heart failure, and brain injury, are analyzed. Available special products for medical purposes (clinical nutrition) for the organization of medical ketogenic therapy in pediatric patients, especially in the first years of life, are presented. No conflict of interests was declared by the authors.

High frequency of heterozygous rare variants of the SLC34A1 and SLC9A3R1 genes in patients with atypical femur fracture

Atypical femur fractures (AFFs) are rare fragility fractures originating at the lateral cortex of the femur, affecting the subtrochanteric or diaphyseal area of thebone with a transverse morphology. Occurrence of AFF is specifically associated with a small number of rare monogenic congenital metabolic bone disorders, such as hypophosphatasia, and with long-term treatment with antiresorptiondrugs. The exact pathogenesis of these fractures remains poorly understood and, except for cases of diagnosed HPP or other AFF-causing bone diseases, it is not possible to assess which patients are at higher riskof developing AFFs as a consequence of anti-resorption therapy. We genetically screened 25 unrelated patients who had developed at least one AFF. Genetic screening was performed through a nextgeneration sequencing analysis with a customized panel containing 76 human genes involved in the regulation of the mineralization processWe genetically screened 25 unrelated patients who had developed at least one AFF. We found a relatively high frequency (32.0%) of heterozygous rare variants inthe SLC34A1 and SLC9A3R1 genes, two genes whose heterozygous inactivating mutations have been respectively associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis types 1 and 2 (NPHLOP1and NPHLOP2). Other heterozygous rare variants were found in the BMPR1B, CYP27B1, FBN1, MEPE, PIGO, and PHOSPHO1 genes, each in a single AFF case (4.0%). Our findings suggest that rarevariants of SLC34A1 and SLC9A3R1 could represent a possible genetic risk factor for the occurrence of AFFs. On the other hand, AFFs could represent an unsuspected clinical manifestation and/or an anti-resorption therapycorrelatedadverse event in patients with NPHLOP disorders.