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Abstract Background The Mendelian Disorders of Cornification (MeDOC) comprise a large number of disorders that present with either localised (palmoplantar keratoderma, PPK) or generalised (ichthyoses) signs. The MeDOC are highly heterogenic in terms of genetics and phenotype. Consequently, diagnostic process is challenging and before implementation of the next generation sequencing, was mostly symptomatic, not causal, which limited research on those diseases. The aim of the study was to genetically characterise a cohort of 265 Polish patients with MeDOC and to get insight into the skin lesions using transcriptome and lipid profile analyses. Results We detected causal variants in 85% (226/265) patients. In addition to the primary gene defect, a pathogenic variant in another gene involved in MeDOC pathology was identified in 23 cases. We found 150 distinct variants in 33 genes, including 32 novel and 16 recurrent (present in > 5 alleles). In 43 alleles large rearrangements were detected, including deletions in the STS, SPINK5, CERS3 and recurrent duplication of exons 10–14 in TGM1. The RNA analysis using samples collected from 18 MeDOC patients and 22 controls identified 1377 differentially expressed genes - DEG. The gene ontology analysis revealed that 114 biological processes were upregulated in the MeDOC group, including i.e. epithelial cell differentiation, lipid metabolic process; homeostasis; regulation of water loss via skin; peptide cross-linking. The DEG between TGM1 and ALOX12B patients, showed that RNA profile is highly similar, though fatty acid profile in epidermal scrapings of those patients showed differences e.g. for the very long chain fatty acids (VLCFAs; FAs ≥ C20), the very long-chain monounsaturated fatty acids (VLC-MUFAs, FAs ≥ C20:1) and the n6 polyunsaturated fatty acids (n6 PUFAs). Conclusion Our results show that NGS-based analysis is an effective MeDOC diagnostic tool. The Polish MeDOC patients are heterogenic, however recurrent variants are present. The novel variants and high number of TGM1 and SPINK5 copy number variations give further insight into molecular pathology of MeDOC. We show that secondary variants in MeDOC-related genes are present in a significant group of patients, which should be further investigated in the context of phenotype modifiers. Finally, we provide novel RNA and lipid data that characterise molecularly MeDOC epidermis.

Abstract WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

Becker muscular dystrophy (BMD) is an X-linked recessive disorder caused by in-frame deletions in the dystrophin gene (DMD), leading to progressive muscle degeneration and weakness. We generated a human induced pluripotent stem cell (hiPSC) line from a BMD patient. BMD hiPSCs were then engineered by CRISPR/Cas9-mediated knock-in of missing exons 3–9 of DMD gene. Obtained hiPSC line may be a valuable tool for investigating the mechanisms underlying BMD pathogenesis.

The progression of Duchenne muscular dystrophy (DMD)requires the assessment of nutritional disturbances at each stage of the disease. The purpose of this study was to assess the nutritional status in various ages of boys with DMD using screening and in-depth evaluation methods. Body composition by Dual X-ray Absorptiometry (DXA), basal metabolic rate (BMR) by indirect calorimetry, a questionnaire of nutritional status—Pediatric Nutrition Screening Tool (PNST)—and laboratory parameters were performed. In the cohort of 93 boys aged 8.54 (5.9–12.6 years), inappropriate nutritional status occurred in 41.8% of boys (underweight 11.8%, overweight 16.0%, and obesity 14.0%). In the 10–13 age group, the occurrence of overweight and underweight was the highest. Based on PNST, 15.1% of patients were at nutritional risk (≥2 points)—the most in the 14–17 age group (29%). A negative correlation was identified between PNST and z-scores of body weight, BMI, and FFMI (r Spearman = −0.49, −0.46, and −0.48, respectively; p < 0.05). There were no differences between BMR results from indirect calorimetry and calculations from the Schofield formula for any age group. In obese boys, the caloric requirement in indirect calorimetry was significantly lower than that indicated by the calculations according to the Schofield formula (p < 0.028). Inappropriate nutritional status occurred in almost half of the children with DMD. The age group in which nutritional disorders were most frequently identified was 10–13 years old. PNST could be considered a tool for screening malnutrition after testing a larger group of DMD patients.

Abstract Background Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%. Results We have detected 17p13.3 locus one-allele triplication in a male proband from family 1 (F1.1), and duplication in a male proband from family 2 (F2.1) applying array comparative genomic hybridization (array CGH). The rearrangements mapped to the following chromosomal regions–arr[GRCh38] 17p13.3(960254–1291856)×4 in F1.1 and arr[GRCh38] 17p13.3(1227482–1302716)×3 in F2.1. The targeted quantitative PCR revealed that the 17p13.3 locus was also duplicated in the second affected member from family 2 (F2.2; brother of F2.1). In the next step, we performed segregation studies using quantitative PCR and revealed that F1.1 inherited the triplication from his healthy father—F1.2, whereas the locus was unremarkable in the mother of F2.1 & F2.2 and the healthy son of F2.1. However, the duplication was present in a healthy daughter of F2.2, an asymptomatic carrier. The breakpoint analysis allowed to define the exact size and span of the duplicated region in Family 2, i.e., 78,948 bp chr17:1225063–1304010 (HG38). Interestingly, all symptomatic carriers from both families presented with variable SHFLD3 phenotype. The involvement of secondary modifying locus could not be excluded, however, the Sanger sequencing screening of BHLHA9 entire coding sequence was unremarkable for both families. Conclusions We have shed light on the one-allele CNV triplication occurrence that should be considered when a higher probe (over duplication range) signal is noted. Second, all SHFLD3 patients were accurately described regarding infrequent limb phenotypes, which were highly variable even when familial. Of note, all symptomatic individuals were males. SHFLD3 still remains a mysterious ultra-rare disease and our findings do not answer crucial questions regarding the disease low penetrance, variable expression and heterogeneity. However, we have presented some clinical and molecular aspects that may be helpful in daily diagnostic routine, both dysmorphological and molecular assessment, of patients affected with SHFLD3.

There has been a dramatic worldwide increase in the prevalence of obesity or overweight and physical inactivity in women of reproductive age. Growing evidence suggests that pre-pregnancy maternal abnormal body mass index (BMI) and lower physical activity level are associated with poor maternal health and perinatal outcomes. The aim of this study was to assess how self-perceived exercise and pre-pregnancy BMI are associated with preterm birth, low birth weight, and type of birth. We conducted a retrospective cross-sectional study of 394 Polish women in the postpartum period. We used a questionnaire with the structure of the medical interview. To analyze factors related to birth outcomes, we used the Pearson’s Chi-squared test of independence and odds ratio (OR), with a corresponding 95% confidence interval (CI), followed by a multiple logistic regression. Women who reported being physically active before pregnancy (p = 0.00) and during pregnancy (p = 0.03) were more likely to give birth on time and had a lower incidence of very-premature and extremely premature births compared to inactive women. Importantly, they were more likely to have vaginal birth (p = 0.03). Pre-pregnancy BMI influenced the week of delivery, i.e., inadequate, too-high BMI contributed to an increase in the percentage of premature births [OR (95% CI) = 1.19 (1.06; 1.34)]. The findings indicate that promoting physical activity and weight management remains a priority in public health policy, and women of childbearing age should be encouraged to adopt or maintain an active and healthy lifestyle during pregnancy in order to avoid sedentary- and obesity-associated risks affecting birth and newborns’ health.

Preterm birth (before 37 completed weeks of gestation) is a global health problem, remaining the main reason for neonatal mortality and morbidity. Improvements in perinatal and neonatal care in recent decades have been associated with a higher survival rate of extremely preterm infants, leading to a higher risk of long-term sequelae in this population throughout life. Numerous surveillance programs for formerly premature infants continue to focus on neurodevelopmental disorders, while long-term assessment of the impact of preterm birth and low birth weight on child growth and the associated risk of cardiovascular disease in young adults is equally necessary. This review will discuss the influence of prematurity and low birth weight on childhood growth and cardiovascular risk in children, adolescents and young adults. The risk of cardiovascular and metabolic disorders is increased in adult preterm survivors. In early childhood, preterm infants may show elevated blood pressure, weakened vascular growth, augmented peripheral vascular resistance and cardiomyocyte remodeling. Increased weight gain during the early postnatal period may influence later body composition, promote obesity and impair cardiovascular results. These adverse metabolic alterations contribute to an increased risk of cardiovascular incidents, adult hypertension and diabetes. Preterm-born children and those with fetal growth restriction (FGR) who demonstrate rapid changes in their weight percentile should remain under surveillance with blood pressure monitoring. A better understanding of lifelong health outcomes of preterm-born individuals is crucial for developing strategies to prevent cardiovascular sequelae and may be the basis for future research to provide effective interventions.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is a rare, inherited lysosomal storage disease. The disease is caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S) due to mutations in the IDS gene, which leads to accumulation of glycosaminoglycans (GAGs). Deficiency of I2S enzyme activity in patients with MPS II leads to progressive lysosomal storage of GAGs in the liver, spleen, heart, bones, joints, and respiratory tract. This process disturbs cellular functioning and leads to multisystemic disease manifestations. Symptoms and their time of onset differ among patients. Diagnosis of MPS II involves assessment of clinical features, biochemical parameters, and molecular characteristics. Life-long enzyme replacement therapy with idursulfase (recombinant human I2S) is the current standard of care. However, an interdisciplinary team of specialists is required to monitor and assess the patient’s condition to ensure optimal care. An increasing number of patients with this rare disease reach adulthood and old age. The transition from pediatric care to the adult healthcare system should be planned and carried out according to guidelines to ensure maximum benefit for the patient.

Loricrin keratoderma (LK) is a rare autosomal dominant genodermatosis caused by LORICRIN gene mutations. The pathogenesis of the disease is not yet fully understood. So far, only 10 pathogenic variants in LORICRIN have been described, with all of them but one being deletions or insertions. The significance of rare nonsense variants remains unclear. Furthermore, no data regarding the RNA expression in affected patients are available. The aim of this study is to describe the two variants in the LORICRIN gene found in two distinct families: the novel pathogenic variant c.639_642dup and a rare c.10C > T (p.Gln4Ter) of unknown significance. We also present the results of the transcriptome analysis of the lesional loricrin keratoderma epidermis of a patient with c.639_642dup. We show that in the LK lesion, the genes associated with epidermis development and keratocyte differentiation are upregulated, while genes engaged in cell adhesion, differentiation developmental processes, ion homeostasis and transport, signaling and cell communication are downregulated. In the context of the p.Gln4Ter clinical significance evaluation, we provide data indicating that LORICRIN haploinsufficiency has no skin consequences. Our results give further insight into the pathogenesis of LK, which may have therapeutic implications in the future and important significance in the context of genetic counseling.

Abstract Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

Preterm birth may result from overlapping causes including maternal age, health, previous obstetric history and a variety of social factors. We aimed to identify factors contributing to preterm birth in respect to new social and environmental changes in the reproductive patterns. Our cross-sectional study included 495 mother–infant pairs and was based on maternal self-reporting in an originally developed questionnaire. Neonates were divided into two groups: 72 premature babies (study group) and 423 full-term babies (control group). We analyzed maternal, sociodemographic and economic characteristics, habits, chronic diseases, previous obstetric history and pregnancy complications. For statistical analysis, Pearson’s Chi-squared independence test was used with a statistical significance level of 0.05. Preterm births were more common among mothers living in villages (p < 0.001) and with lower education level (p = 0.01). Premature births were also positively associated with mothers who were running their own businesses (p = 0.031). Mothers with a history of previous miscarriages gave birth at a significantly older age (p < 0.001). The most frequent pregnancy complications were hypothyroidism (41.4%), pregestational and gestational diabetes mellitus (DM; 17.8%) and hypertension (8.1%). Pregestational DM significantly influenced the occurrence of prematurity (p < 0.05). Pregestational DM, being professionally active, a lower education level and living outside cities are important risk factors of prematurity.

IntroductionAutoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.Material and MethodsMedical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization.Results18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.ConclusionsPatients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

Abstract Background Cornelia de Lange syndrome (CdLS), a rare, multisystemic disorder, has been linked to genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 genes. Approximately 60% of CdLS patients harbor various NIPBL variants. Genetic changes predicted to affect NIPBL gene splicing represent 15% of all NIPBL genetic abnormalities. Yet, only a few studies have investigated the molecular consequences of such variants. Case presentation This study reports two novel, intronic NIPBL genetic variants in unrelated CdLS patients with the characteristic phenotype. A c.6954 + 3A > C substitution and a c.5862 + 1delG deletion were identified, one of each, in a 6 year-old boy and 39 month-old girl. Further studies confirmed that both variants introduce premature termination codons, resulting in the formation of truncated proteins p.(Ser2255LeufsTer20) and p.(Leu1955Ter), respectively. Conclusion Single nucleotide alterations located within the conserved splice-donor site of intronic regions of the NIPBL gene can give rise to a premature termination of the translation and cause significant changes in the sequence of mRNA transcripts and NIPBL protein structure and function. The latter underline development of Cornelia de Lange syndrome phenotype.

Introduction: The risk of obesity in children with Down syndrome is high. Undoubtedly, proper nutrition plays an important role in the prevention of excess body weight and is associated with a reduction of metabolic complications. The aim of the study was to assess the problem of disturbances in the nutritional status and eating habits of children with DS. Methods: A total of 39 patients were included in the study. The nutritional status was assessed by anthropometric tests and Dual X-ray Absorptiometry. Eating habits were assessed using the Child Eating Behavior Questionnaire and the Food Frequency Questionnaire. Blood samples were taken to determine the oxidative stress and lipid parameters. Results: Obesity was recognized in 15% of subjects and 23% were overweight. Children that were overweight were characterized by higher levels of triglycerides, atherogenic index of plasma, and apoA2 and apoE levels. Fat mass, fat mass/height2 index, and visceral fat mass correlated with thiobarbituric acid reactive substances and advanced oxidative protein product level. The analysis of the Child Eating Behavior Questionnaire showed that children struggling with being overweight were more interested in food compared to those with normal body weight. A positive correlation was identified between waist circumference and food interest categories. Insufficient consumption of dairy products, vegetables, whole grain products, as well as fruits, seeds, nuts, and fatty fish was noted. Patients were less likely to consume products that are a good source of mono- and polyunsaturated fatty acids. Conclusions: In children with Down syndrome and obesity, disturbances in lipid and oxidative stress parameters are observed. Abnormal eating habits in all children with Down syndrome regardless of their nutritional status were noted. Proper nutritional education, nutritional control, and management of metabolic problems are essential in this group of patients.

Abstract Background Sanfilippo syndrome B (or mucopolysaccharidosis type IIIB [MPS IIIB]) is a severe inherited metabolic disorder caused by mutations in the NAGLU gene, encoding α‐N‐acetylglucosaminidase. Dysfunction of this enzyme results in impaired degradation of heparan sulfate, one of glycosaminoglycans, and accumulation of this complex carbohydrate in lysosomes. Severe symptoms occurring in this disease are related to progressive neurodegeneration and include extreme hyperactivity, sleeping problems, aggressive‐like behavior, reduced fear, and progressive mental and cognitive deterioration. No cure is currently available for Sanfilippo disease. Methods Clinical characterization of the patient's symptoms has been performed. Biochemical analyses included glycosaminoglycan level determination and measurement of α‐N‐acetylglucosaminidase activity. Molecular analyses included exome sequencing and detailed analysis of the NAGLU gene. Psychological tests included assessment of attention, communication and behavior. Results We describe a patient with an untypically mild phenotype, who was diagnosed at the age of 13 years. Many cognitive, communication, and motoric functions were preserved in this patient, contrary to vast majority of those suffering from MPS IIIB. The patient is a compound heterozygote (c.638C>T/c.889C>T) in the NAGLU gene, and relatively high residual activity (about 25%) of α‐N‐acetylglucosaminidase was measured in serum (while no activity of this enzyme could be detected in dry blood spot). Conclusions We suggest that the mild phenotype might arise from the partially preserved function of the mutant enzyme (p.Pro213Leu), suggesting the genotype‐phenotype correlation in this case.

Abstract Background The aim of the study was to assess both patients’ and their parents’ knowledge of phenylketonuria (PKU) treatment and compliance with PKU diet. Methods The study included 173 PKU patients aged 10–19 and 110 parents of PKU children who were enrolled in the study on the basis of questionnaire data. The study also included 45 patients aged ≥20. Results Our study demonstrated that only 45% (n = 74) of PKU patients knew daily Phe intake recommendations, 27% of patients (n = 41) knew the Phe content in a minimum of three out of four researched food products. Patients’ knowledge concerning Phe intake (p = 0.0181) and the knowledge of selected food products (p = 0.041819) improved with age. We did not establish such a correlation in the group of PKU children’s parents. Approximately 31% of patients and 22% of parents reported helplessness, which increased with the child’s age, associated with the necessity to adhere to the diet; 30% of patients reported feeling ashamed of the fact that they could not eat all food products. Regardless of age, children were more likely than parents to report helplessness (p = 0.032005). Among patients, 41.40% declared that they would wish to select products unassisted but their parents did not permit them to do so. The question of whether parents teach children self-reliance in meal preparation was answered affirmatively by 98% of parents and only 81% of children (p = 0.0001). Conclusion Our data demonstrated that parents’ and children’s knowledge concerning treatment recommendations and food products does not have a direct impact on attitude to the PKU diet. Limiting children’s independence in meal selection, growing helplessness in the face of dietary adherence and shame resulting from the necessity to follow a different diet observed in PKU families are responsible for shaping and perpetuating a consistently negative attitude to the diet. The care of PKU paediatric patients requires consistent, long-term family and individual therapy which may counteract the effects of learned helplessness. In regard to the educational effort, a good parent-child relationship as well as the teaching of behaviours motivating patients to comply with the diet are of great importance.

Background: Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex.Methods: Sixty-nine patients with confirmed clinical diagnosis of CdLS were enrolled in the study. Blood and buccal swab samples were collected for molecular studies. Mutational analysis was performed using the Next Generation (deep) Sequencing (NGS) covering 24 genes. In addition, the MLPA technique was applied to detect large rearrangements of NIPBL.Results: MLPA and NGS analysis were performed in 66 (95,7%) and 67 (97,1%) patients, respectively. Large rearrangements of NIPBL were not identified in the studied group. Germline pathogenic variants were detected in 18 (26,1%) patients. Fourteen variants (20,3%) were identified in NIPBL, two (2,9%) in SMC1A, and two (2,9%) in HDAC8. In total, 13 (18,8%) buccal swabs were suitable for deep sequencing. Mosaic variants were found in four (30,8%; 4/13) patients negative for germline alterations. Three mosaic substitutions were detected in NIPBL while one in KMT2A gene.Conclusions: Comprehensive and sensitive molecular techniques allow detecting novel pathogenic variants responsible for the molecular basis of CdLS. In addition, molecular testing of different tissues should be applied since such an approach allows detect mosaic variants specific for a subgroup of CdLS patients. Finally, to test possible pathogenicity of intronic variants, RNA analysis should be conducted.

Data from the Polish Registry of Congenital Malformations (PRCM) suggest that the prevalence of limb reduction defects (LRDs) in some Polish regions is significantly higher in comparison to that reported in the European Surveillance of Congenital Anomalies (EUROCAT) registry, but specific risk factors are still unknown. The objectives of this study were two-fold: to detect risk factors linked to isolated LRDs among Polish natives and to search for geospatial clusters of isolated LRDs to identify high-risk areas across the country. Among the 2,939,001 births accounted for in the PRCM, we determined that there were 852 children with distinct LRDs. Our data demonstrate that lower birth weight, prematurity, and maternal smoking history are strongly associated with isolated LRDs. Furthermore, our investigation pointed to various additional risk factors for isolated LRDs, including paternal education, gestational hypertension, upper respiratory tract infections, and exposure to anti-inflammatory drugs in the first trimester of pregnancy. We did not recognize statistically significant spatial or spatiotemporal clusters over the area of Poland using Kulldorff’s scan. Our study strengthens the hypothesis that maternal factors have an integral role in the etiology of isolated LRDs.

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I (p < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann–Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.

Recently, progress has been observed in the knowledge about Duchenne Muscular Dystrophy (DMD), which is a severe and commonly diagnosed genetic myopathy in childhood, historically resulting in early death. Currently, there are a lot of methods available to improve the clinical course of DMD and extend patients’ life expectancy to more than 30 years of age. The key issue for DMD patients is the period between 16–18 years of age, which is described as a transition from pediatric- to adult-oriented healthcare. Adolescents and adults with DMD have highly complex healthcare needs associated with long-term steroid usage, orthopedic, ventilation, cardiac, and gastrointestinal problems. The current paper provides a comprehensive overview of special healthcare needs related to the transfer of a patient with DMD from child-oriented to adult-oriented care. Additionally, the need to organize effective care for adults with DMD is presented.

Cornelia de Lange Syndrome (CdLS) is a well described multiple malformation syndrome caused by alterations in genes encoding subunits or regulators of the cohesin complex. In approximately 70% of CdLS patients, pathogenic NIPBL variants are detected and 15% of them are predicted to affect splicing. Moreover, a large portion of genetic variants in NIPBL was shown to be somatic mosaicism. Here we report two family members with different expression of the CdLS phenotype. In both individuals, a c.869-2A>G (r.869_1495del) substitution was detected, affecting a conserved splice-acceptor site. Deep sequencing revealed the presence of somatic mosaicism in the mother. The substitution was detected in 23% of the sequencing reads using DNA derived from blood samples and 51% in DNA from buccal swabs. The analysis of blood DNA of the son excluded the presence of somatic mosaicism. Correlation of molecular and clinical data revealed that various distribution of genetic alteration in different cell types had an impact on the expression of observed clinical features in both individuals.

The mitochondrial β-oxidation of fatty acids is a complex catabolic pathway. One of the enzymes of this pathway is the heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and β-subunits. Mutations in MTP genes (HADHA and HADHB), both located on chromosome 2p23, cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by decreased activity of MTP. The most common MTP mutation is long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency caused by the c.1528G>C (rs137852769, p.Glu510Gln) substitution in exon 15 of the HADHA gene.We analyzed the frequency of genetic variants in the HADHA gene in the adults of Kashubian origin from North Poland and compared this data in other Polish provinces.We found a significantly higher frequency of HDHA c.1528G>C (rs137852769, p.Glu510Gln) carriers among Kashubians (1/57) compared to subjects from other regions of Poland (1/187). We found higher frequency of c.652G>C (rs71441018, pVal218Leu) polymorphism in the HADHA gene within population of Silesia, southern Poland (1/107) compared to other regions.Our study indicate described high frequency of c.1528G>C variant of HADHA gene in Kashubian population, suggesting the founder effect. For the first time we have found high frequency of rs71441018 in the South Poland Silesian population.

Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B’. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.

Introduction. Subcutaneous fat necrosis of the newborn (SCFN) isa rare disorder of the subcutaneous adipose tissue. Subcutaneous fat necrosis of the newborn usually appears days to weeks after a complicatedperinatal period and the most frequent risk factors are birthasphyxia, birth trauma and meconium aspiration. Clinically, the diseaseis characterized by oedematous lesions evolving into indurated,erythematous plaques and nodules. Skin lesions dissolve spontaneouslyin weeks/months.Objective. To present a rare case of subcutaneous fat necrosis of thenewborn.Case report. Monthly infant, born at time of caesarean due to fluctuationsin heart rate in a state of severe asphyxia. As a cause of respiratorydistress, meconium aspiration syndrome was confirmed. In the firstdays of life transient thrombocytopenia and elevated markers ofinflammation in the laboratory tests were observed. In addition, oedematouslesions evolving into indurated plaques and nodules on theback and upper limbs appeared. Based on a typical clinical picturediagnosis of subcutaneous fat necrosis of newborn was diagnosed.During the 3-month follow-up a spontaneous regression of the skinlesions without scarring was observed.Conclusions. Subcutaneous fat necrosis of the newborn is a rare diseaseusually with mild course. However, in some cases skin may bea visual marker of life-threatening metabolic disturbances such ashypercalcaemia.