Osteogenesis imperfecta and rheumatoid arthritis: connective issues.

The coexistence of osteogenesis imperfecta and inflammatory arthritis has been very rarely described. Nevertheless, systemic inflammation has been found in osteogenesis imperfecta. The COL1A1 mutations may affect collagen synthesis as well as post-translational modifications, extracellular matrix interactions, and receptor-mediated signaling. Major collagen binding ligands forming the interactome, such as cytokines, cell adhesion molecules, matrix metalloproteinases, proteoglycans, and other molecules, are autoimmunity targets involved in rheumatoid arthritis pathogenesis. Cross-talk between bone remodeling and inflammatory pathways involving osteoclasts is important in osteogenesis imperfecta and rheumatoid arthritis. In osteogenesis imperfecta, the structural abnormalities and repeated traumatism, including fractures, could activate locally the innate immunity and trigger arthritis, similar to post-traumatic arthritis. Currently, the therapy of osteogenesis imperfecta is a suboptimally met need. Understanding the complex putative pathogenic links between osteogenesis imperfecta and inflammatory arthritis could hopefully lead to new therapeutic targets. Raising awareness regarding a possible association between osteogenesis imperfecta and arthritis could help improve the quality of life in these patients.

A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects.

Congenital heart defects (CHDs) have had an increasing prevalence over the last decades, being one of the most common congenital defects. Their etiopathogenesis is multifactorial in origin. About 10-15% of all CHD can be attributed to copy number variations (CNVs), a type of submicroscopic structural genetic alterations. The aim of this study was to evaluate the involvement of CNVs in the development of congenital heart defects. We performed a cohort study investigating the presence of CNVs in the 22q11.2 region and GATA4, TBX5, NKX2-5, BMP4, and CRELD1 genes in patients with syndromic and isolated CHDs. A total of 56 patients were included in the study, half of them (28 subjects) being classified as syndromic. The most common heart defect in our study population was ventricular septal defect (VSD) at 39.28%. There were no statistically significant differences between the two groups in terms of CHD-type distribution, demographical, and clinical features, with the exceptions of birth length, weight, and length at the time of blood sampling, that were significantly lower in the syndromic group. Through multiplex ligation-dependent probe amplification (MLPA) analysis, we found two heterozygous deletions in the 22q11.2 region, both in patients from the syndromic group. No CNVs involving GATA4, NKX2-5, TBX5, BMP4, and CRELD1 genes were identified in our study. We conclude that the MLPA assay may be used as a first genetic test in patients with syndromic CHD and that the 22q11.2 region may be included in the panels used for screening these patients.

Reply to Kawasaki et al. Comment on "Manole et al. Primary Pericardial Synovial Sarcoma: A Case Report and Literature Review. Diagnostics 2022, 12, 158".

Thank you for your comment; it adds value to the article and highlights the importance of molecular testing [...].

Exploratory Longitudinal Analysis of the Circulating CHIT1 Activity in Pediatric Patients with Obesity.

Macrophage activation and cytokine release play a pivotal role in inflammation-mediated metabolic disturbances in obesity. The proinflammatory macrophage secretes human chitotriosidase (CHIT1). The expression of the CHIT1 in visceral adipose tissue is associated with cytokine production. Our study aimed to assess whether the CHIT1 circulating activity, as a macrophage activation indicator, reflects the change of the adiposity level and the insulin resistance (IR) in children with obesity. We longitudinally (median follow-up period of 7 months; IQR [5 to 8.5] and {2 to 13} months) evaluated the CHIT1 circulating activity, the adiposity level (waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), and body mass index (BMI)-for-age z score), and two surrogate markers of IR (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR and the triglycerides-to-high density lipoprotein cholesterol ratio, TG/HDLc) in 29 pediatric patients (16 girls and 13 boys) with obesity. We found a significant reduction in CHIT1 circulating activity (Wilcoxon test, p = 0.015) and a decrease in TG/HDLc at the follow-up evaluation (Wilcoxon test, p < 0.001). Indicators of adiposity were positively correlated with HOMA-IR at baseline, among which WC was the sole indicator associated with HOMA-IR (Spearman's rank correlation coefficients, p < 0.05) at follow-up. Human chitotriosidase has the potential to be a valuable measure of the progression of subclinical inflammation in children with obesity. Subclinical inflammation, as expressed by the circulating CHIT1 activity, progresses independently of the abdominal adiposity, as measured by the clinical indicators, and is associated with a change in insulin resistance.

Diagnosis and Management of Genetic Causes of Middle Aortic Syndrome in Children: A Comprehensive Literature Review.

Middle aortic syndrome (MAS) is a rare vascular disease representing an important cause of severe hypertension in children. MAS is characterized by segmental or diffuse narrowing of the abdominal and/or distal descending aorta with involvement of the renal and visceral branches. Most cases of MAS are idiopathic, but MAS may occur in genetic and acquired disorders. The most common genetic causes of MAS are neurofibromatosis type I, Williams syndrome, Alagille syndrome, tuberous sclerosis and mucopolysaccharidosis. This review article discusses the pathophysiological aspects, distinctive associated features, and management of genetic forms of MAS in children.

Severe early-onset manifestations of generalized arterial calcification of infancy (mimicking severe coarctation of the aorta) with ABCC6 gene variant - Case report and literature review.

Introduction: Generalized arterial calcification of infancy (GACI) is a rare cause of infantile heart failure and systemic hypertension with a poor prognosis, characterized by extensive calcification and proliferation of the intimal layer of large and medium sized arteries. Case report: We present the first case report of successful surgical treatment of severe aortic arch obstruction by calcified plaques mimicking severe coarctation of the aorta and the outcome (of bisphosphonate therapy) in a newborn with GACI. Furthermore, we report the identification of a variant in ATP Binding Cassette Subfamily C, Member 6 (ABCC6) gene, possibly associated with severe early-onset manifestations of GACI. Conclusion: This case report highlights the importance of considering GACI in an infant with heart failure, systemic hypertension, and evidence of increased echogenicity of the arterial vessels. We noted the favorable outcome in improving the aortic calcification in our patient after surgical treatment and bisphosphonates therapy. Early diagnosis and treatment improve the long-term prognosis. A better understanding of this rare genetic disease could lead to new therapeutic strategies.

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability.

BACKGROUND: Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population, the genetic etiology being often involved. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the chromosomal microarray analysis. METHODS: We analyzed 189 patients diagnosed with global developmental delay/intellectual disability, presented in Clinical Emergency Hospital for Children, Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic and internal malformations evaluation, psychiatric, neuropsychological and metabolic evaluation, standard karyotyping. Genomic analysis was done using chromosomal microarray analysis. RESULTS: Pathogenic findings (including uniparental disomy) and variants of unknown significance were detected in 53 of 189 patients (28.04%). Pathogenic copy number variants and uniparental disomy were observed in 35 of 189 patients (18.51%). Two patients presented uniparental disomy for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. Within the category of pathogenic findings, the recurrent copy number variants were seen in 21 of 35 patients (60%). CONCLUSIONS: The increased percentage of pathogenic structural variants observed in patients with global developmental delay/intellectual disability analyzed by chromosomal microarray technique supports its use in patients with a non-specific phenotype such as these neurodevelopmental disorders. The high percentage of recurrent pathogenic variants between these findings is a finding that support their initial evaluation when a genetic testing algorithm could be a useful option.

Evaluation of Circulating Chitotriosidase Activity in Children with Obesity.

Childhood obesity progresses to metabolic disturbances via low-grade inflammation. Identifying novel molecules that reflect the activity of the immune responses is critical in understanding its underlying pathogenesis. Our exploratory study aimed to evaluate the change of chitotriosidase (CHIT1) plasma activity according to Body Mass Index (BMI)-for-age z score in pediatric patients. The study evaluated 68 children consisting of 47.1% girls with a mean age of 12.47 ± 3.71 years and 52.9% boys with a mean age of 11.93 ± 3.18 years. The effect of the most frequent CHIT1 gene variants, the 24 base pair duplication (dup24) and G102S polymorphism, upon the association between circulating CHIT1 activity and the obesity level, was also investigated. A significantly higher logCHIT1 plasma activity was found in children with extreme obesity than in children with overweight (p = 0.048 for the uncorrected CHIT1 and 0.026 for the corrected CHIT1). The BMI-for-age z score significantly (p = 0.031) predicts increased CHIT1 activity in children with overweight, obesity, and extreme obesity after controlling for the two gene variants, age, gender, and time since weight gain. Dup24 and G102S polymorphism were significant independent predictors (p-values < 0.002) for the change of CHIT1 plasma activity. Circulating CHIT1 might be an accurate indicator of inflammation in children with obesity. Its role and the effect of the dup24 and G102S variants on the CHIT1 activity should be validated in a larger cohort.

Primary Pericardial Synovial Sarcoma: A Case Report and Literature Review.

We report a case of a 52-year-old woman who was referred to our institution with a superior vena cava syndrome and was investigated through echocardiography, CT and MRI revealing a well-defined, encapsulated pericardial mass. The pathology, correlated with the immunohistochemical analysis, concluded it was an extremely rare primary pericardial synovial sarcoma. The patient underwent surgery and chemotherapy with a 16-month disease-free survival and passed away after a contralateral aggressive relapse. Moreover, we discuss the role of each imaging modality together with their pericardial synovial sarcoma reported features.

Non-Syndromic Hearing Loss in a Romanian Population: Carrier Status and Frequent Variants in the GJB2 Gene.

The genetic causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) are heterogeneous and highly ethnic-specific. We describe GJB2 (connexin 26) variants and carrier frequencies as part of our study and summarize previously reported ones for the Romanian population. In total, 284 unrelated children with bilateral congenital NSHL were enrolled between 2009 and 2018 in northwestern Romania. A tiered diagnostic approach was used: all subjects were tested for c.35delG, c.71G>A and deletions in GJB6 (connexin 30) using PCR-based methods. Furthermore, 124 cases undiagnosed at this stage were analyzed by multiplex-ligation-dependent probe amplifications (MLPA), probe mix P163, and sequencing of GJB2 exon 2. Targeted allele-specific PCR/restriction fragment length polymorphism (RFLP) established definite ethio-pathogenical diagnosis for 72/284 (25.35%) of the cohort. Out of the 124 further analyzed, in 12 cases (9.67%), we found compound heterozygous point mutations in GJB2. We identified one case of deletion of exon 1 of the WFS1 (wolframin) gene. Carrier status evaluation used Illumina Infinium Global Screening Array (GSA) genotyping: the HINT cohort-416 individuals in northwest Romania, and the FUSE cohort-472 individuals in southwest Romania. GSA variants yielded a cumulated risk allele presence of 0.0284. A tiered diagnostic approach may be efficient in diagnosing ARNSHL. The summarized contributions to Romanian descriptive epidemiology of ARNSHL shows that pathogenic variants in the GJB2 gene are frequent among NSHL cases and have high carrier rates, especially for c.35delG and c.71G>A. These findings may serve in health strategy development.

Case Report: Uncommon Association of ITGB4 and KRT10 Gene Mutation in a Case of Epidermolysis Bullosa With Pyloric Atresia and Aplasia Cutis Congenita.

Background: Epidermolysis bullosa is a rare form of genodermatosis produced by different gene mutations. The junctional form of the disease (JEB-PA) can associate pyloric atresia, renal abnormalities, and aplasia cutis congenita. Case Description: A case of a male preterm newborn with suspicion of digestive tube malformation at fetal ultrasound and who was born by cesarian section. At birth, he presented extensive cutaneous aplasia on the lower limbs and bilaterally under ears; outer ear agenesis; nasal septum hypoplasia; micrognathia; multiple blisters on the face, trunk, and limbs; lower limb deformities and absence of toe nails. Pathological examination following a surgical procedure with unfavorable outcome showed pyloric atresia, junctional form of epidermolysis bullosa and aplasia cutis congenita. Homozygous variants in two genes were identified: c.3111+1G>A in ITGB4 (class 5) and c.1498G>T in KRT10 (class 3). Conclusion: The particularity of our case is the novel finding of a coincidental occurrence in the context of consaguinity of two mutations in the ITGB4 and KRT10 genes, and clinical characteristics of epidermolysis bullosa.

46,XX DSD: Developmental, Clinical and Genetic Aspects.

Differences in sex development (DSD) in patients with 46,XX karyotype occur by foetal or postnatal exposure to an increased amount of androgens. These disorders are usually diagnosed at birth, in newborns with abnormal genitalia, or later, due to postnatal virilization, usually at puberty. Proper diagnosis and therapy are mostly based on the knowledge of normal development and molecular etiopathogenesis of the gonadal and adrenal structures. This review aims to describe the most relevant data that are correlated with the normal and abnormal development of adrenal and gonadal structures in direct correlation with their utility in clinical practice, mainly in patients with 46,XX karyotype. We described the prenatal development of structures together with the main molecules and pathways that are involved in sex development. The second part of the review described the physical, imaging, hormonal and genetic evaluation in a patient with a disorder of sex development, insisting more on patients with 46,XX karyotype. Further, 95% of the etiology in 46,XX patients with disorders of sex development is due to congenital adrenal hyperplasia, by enzyme deficiencies that are involved in the hormonal synthesis pathway. The other cases are explained by genetic abnormalities that are involved in the development of the genital system. The phenotypic variability is very important in 46,XX disorders of sex development and the knowledge of each sign, even the most discreet, which could reveal such disorders, mainly in the neonatal period, could influence the evolution, prognosis and life quality long term.

Genetic testing in pediatric endocrine pathology.

In genetic endocrine diseases, genetic testing is necessary for a precise diagnosis, which will provide a better knowledge of the evolution and prognosis and also indicate the adequate therapy, targeting the precise etiopathogenesis of the disease. Genetic testing in endocrinology is often based on classical cytogenetic techniques, molecular cytogenetic analysis or molecular biology techniques. Genetic testing in disorders of sex development includes the karyotype and SRY gene analysis and depending on the presence of associated clinical signs and on the observations at paraclinical examination, these tests will be followed by chromosomal array techniques and NGS sequencing. In short stature, the decision to perform a genetic test is taken depending on clinical, paraclinical and imaging signs. In case of a short stature associated with a low weight/length for gestational age, genetic testing is proposed to evaluate a Russell-Silver syndrome or if the short stature is associated with other clinical signs (e.g. intellectual disability), chromosomal analysis by microarray is proposed. If the short stature is disproportionate, it is indicated to perform a next generation sequencing (NGS) of a panel of genes involved in skeletal dysplasia. If an endocrine cause for short stature is observed at the hormonal evaluation, it is indicated to test a panel of genes involved in these pathways. In genetic obesity, depending on clinical signs associated to obesity, it will be a more targeted genetic testing. If obesity is associated with intellectual disability or other nonspecific neurological changes, a chromosomal analysis by microarray will be indicated. If monogenic obesity is suspected, NGS testing will be indicated (as genes panel or whole exome or genome analysis). Genetic testing in endocrine diseases brings an etiological diagnosis, but a favorable cost-benefit ratio derives from an adequate indication of these tests, generally proposed in expert centers for rare endocrine diseases.

Diagnostic, treatment and outcome possibilities in achondroplasia.

INTRODUCTION: Achondroplasia is a common form of chondrodysplasia. It is transmitted by autosomal dominant trait. The disease is determined by mutations in receptor-3 gene of the fibroblast growth factor. The most frequent mutations are c.1138G>A and c.1183G>C; c.1138A. The diagnosis can usually be made on the basis of clinical characteristics and specific features on radiographs. It is not necessary to perform molecular testing in every child with a clinical diagnosis of achondroplasia.The aim of this study is to establish the diagnostic, treatment and outcome possibilities in patients with achondroplasia in our care. METHOD: The study group consisted of 27 patients with achondroplasia. The method consisted of: clinical and radiological examinations. The DNA analasys was performed by PCR-RFLP technique. RESULTS: 80 patients were diagnosed with bone dysplasia; 24 of them were diagnosed (on clinical and radiological basis) with achondroplasia. Out of this group, 16 patients were identified as heterozygotes for G1138A mutation in FGFR3 gene; 3 patients undergoing treatment with somatotropic hormone; the growth rate is improving from 0.1 cm/month to 0.5 cm/month. CONCLUSIONS: In achondroplasia diagnosis is based on clinical and radiological criteria. It is the first study that reports the prevelance of this mutation in Romania.

Challenges in the diagnosis and management of urea cycle disorders in Romanian children.

Pediatricians should be aware of the clinical presentation, emergency intervention, and long-term management of hyperammonemia. In Romania, there are many challenges regarding hyperammonemia: low awareness of the need for prompt diagnosis and adequate management, communication problems between different physicians, lack of knowledge and availability of diagnostic tools and medications, lack of dietitians trained in metabolic diseases. Urea cycle disorders (UCD) are severe diseases, with high mortality in neonates and possible neurologic complications in the survivors. Clinical presentation is variable, with the onset at any age. It is crucial for a correct and early diagnosis that the first physician sees a patient with symptoms of hyperammonemia to think of it. Pediatricians should suspect UCD in neonates or children with hyperammonemia without metabolic acidosis and hypoglycemia. Neonatal sepsis is the most frequent misdiagnosis. Pediatricians and parents of a child with UCD should be aware of the potential triggers of hyperammonemia. Emergency treatment to reduce the ammonia level should be initiated as quickly as possible. Long-term treatment aims to obtain metabolic control and achieve normal development and growth. A multidisciplinary approach in managing these children improves survival chances and the long-term quality of life.

Early clinical signs in lysosomal diseases.

BACKGROUND AND AIM: The lysosomal storage diseases are a group of monogenic diseases with multisystemic impairment and chronic progression induced by the deficiency of lysosomal acid hydrolases involved in the breakdown of various macromolecules. The accumulation occurs in the macrophages of the reticule-endothelial system and causes enlargement and functional impairment. The mainly involved organs are the brain, liver, spleen, bones, joints, airways, lungs, and heart. The aim of this study was to evaluate early symptoms, signs and the delay in the diagnosis of different lysosomal diseases. METHODS: The medical documentation of 188 patients with lysosomal storage disorders, aged 1-70 years, were analyzed. All these patients were specifically diagnosed, by enzyme and molecular assay. RESULTS: The age of clinical signs onset varies in different type of lysosomal diseases, from the first months of life or early childhood in severe form, to adulthood in attenuated forms. The delay between the clinical signs onset and specific diagnosis ranged from 0.5 months to 57.91 years. CONCLUSIONS: The lysosomal storage diseases are rare diseases with childhood onset, but these early signs and symptoms are not recognized and are often taken into account when the vital organs damage becomes manifest.

Case Report: Potocki-Lupski Syndrome in Five Siblings.

Potocki-Lupski syndrome (PTLS) is a rare developmental disorder resulting from the partial duplication of the short arm of chromosome 17. Affected children may have hypotonia, facial dysmorphism, or neurological abnormalities. PTLS is also frequently associated with failure to thrive due to swallowing difficulties or growth hormone deficiency. We report the first Romanian family (a mother and her five children) diagnosed with PTLS (17p11.2 microduplication). Fortunately, they present a less severe form of the disease. The neurological manifestations (speech delay, mild intellectual disability) are associated with craniofacial dysmorphism (microcephaly, micrognathia, triangular face, broad forehead, long chin, prominent ears, dolichocephaly, down slanting palpebral fissures). The diagnostic was established using a multiplex ligation-dependent probe amplification technique (MLPA) test, which detected the duplication of three regions of the 17p11.2 chromosome (RAI1, DRC3-6, LLGL1-4RA). Children with PTLS have specific phenotypes (craniofacial dysmorphism or neurological manifestations), which must draw the pediatrician's attention to a possible genetic condition. However, every child with this disease is unique and may have a different clinical presentation. A multi-disciplinary team is needed for the management of these patients. The parent's counseling and genetic advice are essential for a family with children with PTLS.

Cardiovascular manifestations in Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant inherited disease of the connective tissue with multiorgan involvement (skeleton, cardiovascular, eyes, skin, lungs). Cardiovascular involvement is variable and represents the major cause of morbidity and mortality in Marfan syndrome. We provide a comprehensive description of cardiovascular manifestations in Marfan syndrome, genotype-phenotype correlations and assessment of cardiovascular abnormalities and complications.

Skeletal Abnormalities and VDR1 Gene Polymorphisms in Mucopolysaccharidosis Patients.

INTRODUCTION: Articular and bone damage, which is so disabling in Mucopolysaccharidosis (MPS), requires attention as to the explanatory bias of the pathogenetic mechanisms identified to date. The vitamin D receptor (VDR) has been investigated in many studies in correlation with bone metabolism, osteoporosis, and the impaired bone mineral density associated with certain polymorphisms of the VDR gene. AIM: This study aims to observe whether there is an association between clinical features, phospho-calcium metabolism parameters and the VDR gene polymorphisms in patients with MPS. PATIENTS AND METHOD: We evaluated six patients with MPS type I, 20 patients with MPS type II, two patients with MPS types IIIA and IIIB and three patients with MPS type IVB. In these patients, phospho-calcium metabolism, markers of bone formation, bone radiographs and bone densitometry were evaluated, as were four polymorphisms of the VDR gene (ApaI, BsmI, FokI and TaqI). RESULTS: There was a deficiency in 25 hydroxy vitamin D in MPS type I patients at the final evaluation and in MPS type II patients, both at ERT initiation and at the last evaluation. The analysed polymorphisms were not associated with modified calcium-phosphor levels, but some differences were observed regarding the level of 25 OH vitamin D. Thus, in the case of AA polymorphism, all patients have a 25 OH vitamin D deficiency, and one patient with the AA genotype and three with Aa have a 25 OH vitamin D deficiency and secondary hyperparathyroidism due to this deficiency (four patients), all of them having the Bb phenotype. CONCLUSION: In MPS patients, vitamin D deficiency is observed, as it is in some patients with secondary hyperparathyroidism, which indicates vitamin D supplementation to protect bone metabolism. There are no obvious correlations between VDR polymorphism and bone metabolism in MPS patients.

Cardiac Manifestations in a Group of Romanian Patients with Gaucher Disease Type 1 (a Monocentric Study).

Gaucher disease (GD), one of the most common lysosomal disorders, is characterised by clinical heterogeneity. Cardiac involvement is rare and refers to pulmonary hypertension (PH), valvular abnormalities and myocardial infiltrative damage. The aim of this study was to evaluate cardiac involvement in a group of Romanian GD patients. Phenotypic and genotypic characterisation was carried out in 69 patients with GD type 1. Annual echocardiography and electrocardiography were performed to assess pulmonary pressure, morphology and function of the valves and electrocardiographic changes. Nine patients (13%) exhibited baseline echocardiographic signs suggesting PH. Mitral regurgitation was present in 33 patients (48%) and aortic regurgitation in 11 patients (16%). One patient presented aortic stenosis. Significant valvular dysfunction was diagnosed in 10% of patients. PH was associated with greater age (p < 0.001), longer time since splenectomy (p = 0.045) and longer time between clinical onset and the start of enzyme replacing therapy (p < 0.001). Electrocardiographic changes were present in five patients (7%).