Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder that affects many organs. The diagnosis of this condition is primarily clinical and it can be confirmed by molecular analysis of the genes known to cause this disease, although about 30% of CdLS patients are without a genetic diagnosis. Here we report clinical and genetic findings of a patient with CdLS type 4, a syndrome of which the clinical features of only 30 patients have been previously described in the literature. The index patient presented with clinical characteristics previously associated with CdLS type 4 (short nose, thick eyebrow, global development delay, synophrys, microcephaly, weight < 2DS, small hands, height < 2DS). She also presented cardiac anomalies, cleft palate and laryngomalacia, which was never described before. The index patient was diagnosed with a novel de novo RAD21 variant (c.1722_1723delTG, p.Gly575SerfsTer2): segregation analysis, bioinformatic analysis, population data and in silico structural modelling indicate the pathogenicity of the novel variant. This report summarizes previously reported clinical manifestations of CdLS type 4 but also highlights new clinical symptoms, which will aid correct counselling of future CdLS type 4 cases.
Learning disabilities are relatively common conditions in pediatric population. The incidence of learning disability ranges from 1% to 17%, reflecting that learning disability may be not a single clinical entity but a wide distribution of cognitive traits in the population. As reported by the American Association on Intellectual and Developmental Disabilities (AAIDD), among the prenatal learning disability causes, chromosomal disorders, genetic syndromes, and inborn errors of metabolism must be taken into account. In this chapter, we will focus the attention on RASopathies, genetic disorders characterized by germline mutations in the RAS-MAPK pathway whose role is crucial in the regulation of the cell cycle, differentiation, growth, and cell senescence. This group of disorders includes Noonan syndrome, neurofibromatosis type 1, Costello syndrome (CS), Legius syndrome, Noonan syndrome with multiple lentigines, and cardiofaciocutaneous syndrome. Mutations in RAS-MAPK pathways lead to impairments in synaptic plasticity, necessary for normal brain function, especially for learning and memory. Variation across the RAS/ MAPK pathway syndromes suggests that different gene mutations affecting this pathway can have markedly different developmental effects.
Background The genetic approach to Marfan syndrome (MFS) has evolved over the last few decades, as has our understanding of the variants’ potential structural and functional consequences. It has been proposed that next-generation sequencing be used to improve genetic diagnosis and patient management. To this end, we used a targeted NGS custom panel to perform genetic analysis in a patient with MFS and his or her family members. Case presentation Here, we describe a novel germ-line heterozygous missense variant (transversion c.5371 T > A) found in exon 43 of the FBN1 gene of a patient (proband) with MFS. FBN1 (ENSG0000166147) and TGFB2 (ENSG0000166147) were included in a targeted sequencing panel for MFS (ENSG0000163513). This new variant c.5371 T > A was identified only in the proband, not in unaffected family members or healthy controls. Conclusions Given the massive amount of data generated by gene panel analysis, clinical interpretation of genetic variants may become more difficult. As a result, 3D modeling and multidisciplinary approaches should be used in the analysis and annotation of observed variants. The analysis of the protein’s conformational structure in relation to the identified variant could provide useful information. These data can be used to classify observed variants (pathogenic vs non-pathogenic) linked to the MFS phenotype, as well as to track disease progression and potential target treatments.
Introduction: Skeletal dysplasias, also termed as osteochondrodysplasias, are a large heterogeneous group of disorders characterized by abnormalities of bone or cartilage growth or texture. They occur due to genetic mutations and their phenotype continues to evolve throughout life. Reduced growth is a common feature.Objective: To evaluate and discuss data about growth and growth hormone axis in patients with the main common skeletal dysplasias, such as achondroplasia, hypochondroplasia, 3M syndrome, and Leri-Weill syndrome.Design: Evaluate retrospectively the data on growth, final height (FH), height velocity (HV), growth hormone deficiency, and growth hormone response after growth hormone (GH) treatment in patients with these disorders. However, this chapter provides an updated picture of growth hormone axis and endocrinological features in skeletal dysplasia.
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