Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is a rare skeletal dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a ...short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal dysplasia with autosomal-recessive inheritance and a distinct phenotype.
Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital syndrome in which thrombocytopenia and the absence of radius can be accompanied by various organ anomalies. Bilateral phocomelia is ...the most severe form in this clinic. Thumbs are always present. The deletion of the RNA-binding motif protein 8A (RBM8A) gene on chromosome 1q21.1 in Array Comparative Genomic Hybridization confirms the diagnosis of TAR syndrome. Thrombocytopenia, which can cause complications, tends to resolve in the first year of life. Although there are delays in motor development, mental retardation is not one of the common clinical findings of this syndrome. In the differential diagnosis of severe radial defects, TAR syndrome, Holt-Oram syndrome, Roberts syndrome, Fanconi anemia, and VACTERL association are included. The presence of key findings of each syndrome is important in the differential diagnosis. Here, we aimed to evaluate the approach to the differential diagnosis of severe radial anomalies in a patient with TAR syndrome and neuromotor retardation. Keywords: Phocomelia, TAR syndrome, RBM8A, 1q21.1
Proinflammatory cytokines (such as interleukin-1β, tumor necrosis factor-α) and nitric oxide are known to have both direct and indirect modulating effects on neurons and neurotoxic neurotransmitters ...released during excitation or inflammation. We measured interleukin-1β, tumor necrosis factor-α, and nitrite levels in the peripheral blood and cerebrospinal fluid of children with febrile seizures and compared our results with those of children with febrile illnesses without seizures. Twenty-nine children with febrile seizure and 15 controls were studied. The mean concentrations of interleukin-1β and nitrite were significantly increased in the cerebrospinal fluid (P < .01) of the children with febrile seizure. There were no significant changes in serum interleukin-1β, tumor necrosis factor-α, nitrite, and cerebrospinal fluid tumor necrosis factorα levels. Our data support the hypothesis that increased production of interleukin-1β in the central nervous system or increased diffusion of interleukin-1β through the blood-brain barrier is involved in the pathogenesis of febrile seizures. (J Child Neurol 2002;17:749—751).
Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease characterized by dense and fragile bone, caused by a defect in osteoclasts responsible for the bone destruction. In this study, ...we aimed to investigate the mutations in TCIRG1 and SNX10 that are responsible for 50% and 4% of the cases, respectively. All amplicons were sequenced by Sanger sequencing following PCR amplification. As a result, six different mutations of the TCIRG1 gene were found in five of the twelve unrelated cases. These include two novel mutations, namely c.630 + 1G > T mutation and c.1778_1779delTG mutation of the gene which are identified as homozygous. A compound heterozygosity of known mutations c.649_674del26 and c.1372G > A and homozygous presence of the known c.2235 + 1G > A mutation were also observed in different patients. In addition, as a result of the prenatal testing in a family with osteopetrosis infant, the c.1674-1G > A mutation was detected as homozygous for the fetus. In TCIRG1, c.166C > T change, which is indicated as likely benign according to ClinVar database, was heterozygous. Several known polymorphisms; c.117 + 83 T > C, c.417 + 11A > G and c.714-19C > A in TCIRG1 gene; c.24 + 36 T > A and c.112-84G > A in SNX10 gene were also detected. In conclusion, our study revealed that five of the twelve cases carry at least one mutation of TCIRG1 gene. Further studies with more patients and other genes would help better understanding of genetic etiology of the disease.
•There is a significant genetic heterogeneity among Turkish osteopetrosis patients.•TCIRG1 gene mutations accounted for five among twelve osteopetrosis patients.•We report two novel mutations in TCIRG1 gene, c.630 + 1G > T, c.1778_1779delTG.
Multiple sulfatase deficiency is a rare autosomal recessive disorder in which affected individuals present a complex phenotype due to the impaired activity of all sulfatases. There are different ...types of multiple sulfatase deficiency; among them, the neonatal form is the most severe, with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. The disorder is caused by homozygous or compound heterozygous mutations in the sulfatase-modifying factor-1 (SUMF1) gene. In this article, we describe a non-ichthyotic neonatal multiple sulfatase deficiency patient with a novel mutation in the SUMF1 gene. The missense mutation c.777C>G, for which the patient was homozygous, had been caused by a p.N259K amino acid substitution. We evaluated the patient using clinical findings, neuroimaging studies and molecular analysis via the literature; we also wanted to note the difficulties in the diagnosis of this rare disease.
Recent Advances in Craniosynostosis Yilmaz, Elanur; Mihci, Ercan; Nur, Banu ...
Pediatric neurology,
October 2019, 2019-10-00, Letnik:
99
Journal Article
Recenzirano
Craniosynostosis is a pathologic craniofacial disorder and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of nonossified ...mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, and visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens, and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes have been linked to craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be nonsyndromic, formed without any additional anomalies. More than 50 nuclear genes that relate to craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. As craniosynostosis is a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetic analysis, epigenetic or environmental factors, or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic and environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.
An atypical teratoid/rhabdoid tumor of the central nervous system (CNS) is a rare, aggressive neoplasm found in infants and children that has similar characteristics to CNS primitive neuroectodermal ...tumors/medulloblastomas. The authors present the case of a patient with an atypical teratoid/rhabdoid tumor and discuss the imaging, histopathological, immunohistochemical, and cytogenetic findings. Tumor cells displayed positive reactions for vimentin, epithelial membrane antigen, and cytokeratin, and they displayed no reaction for glial fibrillary acidic protein, desmin, and actin. The karyotype was 46, XY. The phenotype of an atypical teratoid/rhabdoid tumor appears heterogeneous when examined by histological, immunohistochemical, and genetic analysis. The authors describe the case of a 4-year-old boy who harbored an atypical teratoid/rhabdoid tumor in the clivus, which appeared as a chordoma on neuroimages. To their knowledge, this location of an atypical teratoid/rhabdoid tumor has not been described in the literature.
Background/aim: Declined morbidity rates after craniosynostosis surgery indicate bypassing the pediatric intensive care unit (PICU) course to minimize treatment costs and bed usage. The aim of this ...study is to examine the incident rates of PICU admission and assess its necessity. Materials and methods: A retrospective analysis of 41 patients (operated on by open surgical techniques) between July 2011 and December 2015 was carried out. Intraoperative/postoperative vital signs, hemodynamic and metabolic parameters, estimated blood loss (EBVloss), blood transfusions, length of PICU, and hospitalizations were recorded. Results: Major and minor events reached 51.2% and 82.9%, respectively. EBVloss within 24 h was calculated as 39.58 ± 8.19 (median: 38.44, 25.68-66.34) with 75.6% blood transfusion rate. Hypotension and hypothermia were associated with prolonged surgery (P = 0.001 and P = 0.007, respectively), but were not related to age (P = 0.054, P = 0.162) or procedure types (P = 0.558, P = 0.663). Prolonged surgery and younger age had an impact on the complications. One patient died of persistent hemorrhage at 96 h. Conclusion: Monitoring cardiovascular and metabolic dynamics at PICU during the first 24 h after surgery is crucial. Additional studies are needed to define the threshold values of several metabolic and hemodynamic markers in risk assessment after cranial vault surgery.
•The clinical and genetic manifestations of SMA are diverse and heterogeneous.•In this paper, we report on the final mutation profiles of the SMN1 and SMN2 genes in terms of exonic deletions.•This is ...significant because the exact copy number of the SMN2 gene seems to be the determiner in our patients with SMA.•Furthermore, the chaotic manner of the SMN1 and SMN2 gene structures within their respective exonic regions resulted in different inheritance patterns in a family that was segregated in this study.•We also produced an “MLPA-SMA signature” which can be helpful in the initial preparation of patient reports.
SMA is a neuromuscular disease and occurs primarily through autosomal recessive inheritance. Identification of deletions in the SMN1 gene especially in the exon 7 and exon 8 regions (hot spot), are used in carrier testing.
The exact copy numbers of those exons in the SMN1 and SMN2 genes in 113 patients who presented with a pre-diagnosis of SMA were determined using MLPA method. We aimed to reveal both the most common copy number profiles of different SMA types.
It was found that the frequency of homozygous deletions in SMN1 was 15.9%, while heterozygous deletions was 16.9%. The most common SMN-MLPA profile was 0–0-3–3. In the cases with homozygous deletion, SMA type III diagnosis was observed most frequently (44%), and the rate of consanguineous marriage was found 33%. Two cases with the same exonic copy number profile but with different clinical subtypes were identified in a family. We also detected distinct exonic deletion and duplication MLPA profiles for the first time.
We created “the SMA signature” that can be added to patient reports. Furthermore, our data are important for revealing potential local profiles of SMA and describing the disease in genetic reports in a way that is clear and comprehensive.
PDF
