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Flow cytometric analysis of bone marrow aspirate. Flow cytometric analysis of bone marrow aspirate was done to phenotype the abnormally present lymphocytes. These cells were strongly CD3+ (A) and CD5+ (B) but did not express CD20 antigen.
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Seckel syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism, skeletal defects, mental and prenatal growth retardation. About 50 cases have been reported in the literature. Hematologic abnormalities with associated chromosomal fragility have been noted in about 15% of the reported cases. We report a patient wi...
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... small number of normal appearing lympho- cytes were also identified in the bone marrow biopsy. Cell marker analysis by flow cytometry of this bone mar- row aspirate showed these cells to be CD3+, CD5+ and CD45+ suggesting a T-cell origin (Figure 3). Using a semi-quantitative gene rearrangement assay based on our modification of a published procedure (13), these T cells were found to be clonal (Figure 4). ...
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... In addition to delayed bone age, 11 pairs of ribs, strabismus, dysplastic ears, cryptorchidism, clitoromegaly, hirsutism, crowded teeth with malocclusion, agenesis of the corpus callosum, pachygyria, microphthalmia, optic nerve hypoplasia, high-arched palate, enamel hypoplasia, and hypodontia or oligodontia could happen with this disorder [4], [5], [6]. Cardiovascular, hematopoietic, endocrine, and central nervous systems disorders are sometimes found in this syndrome [7], [8], [9]. ...
... In most cases, the working-up diagnosis of Seckel syndrome has been made by the clinical manifestation, even though the definitive diagnosis is made from gene analyses such as SCKL 1,2 or 3. Availability of the tools and cost become the common problem. Additional examinations needed are an X-ray to check the bone age, frequent hip dysplasia, and dislocation of the head of the radius [9], [10]. ...
INTRODUCTION: Seckel syndrome is a rare case. It belongs to an autosomal recessive disorder. It commonly leads to osteodysplastic, microcephaly, and dwarfism, which are proportional to prenatal onset. Microcephaly, bird-headed-like appearance, and mental retardation are common dysmorphic in the future. This case report present a patient with Seckel syndrome and this case will be discussed comprehensively. CASE REPORT: A patient 9-month-old girl came to the hospital with a chief complaint of growth disturbance. Her growth was not the same as her peer. She was stunted and failed to thrive. Microcephaly and a dysmorphic face (bird-headed) appeared with a broad face, prominent forehead, large eyes, prominent curved nose, and micrognathia were found in physical examination. Her organ was in normal condition. According to the radiology examination, the bone age was appropriate for the age of a newborn (<3 months). Patient had global developmental delay. Based on clinical manifestation patient can be witnessed with Seckel syndrome, to confirm the diagnosis chromosomal test is needed. There is no specific treatment. Management for the patient was growth and developmental intervention. CONCLUSION: Seckel syndrome is a rare disease. The diagnosis was challenging and sometimes could miss diagnosed with another syndrome. In this case, the diagnosis was made by clinical presentation and laboratory examination. There was no specific treatment. We assess the patient with Seckel syndrome. A gene or chromosome examination is needed. Meanwhile, the examination was limited and need a high cost. Educating the family about the patient’s condition has been done.
... In adult mice, ATR depletion causes a premature aging-like syndrome that has been attributed to stem cell loss (Ruzankina et al., 2007) and appears akin to Seckel syndrome, a complex form of microcephalic primordial dwarfism that occurs in humans with ATR gene mutations (O'Driscoll et al., 2003). Interestingly, loss of ATR does not predispose such individuals to cancer, like loss of ATM (Chanan-Khan et al., 2003;Qvist et al., 2011). ATR is activated in response to ssDNA accumulation at stalled DNA replication forks, at resected DSBs, or following deoxyribonucleotide triphosphate (dNTP) depletion. ...
To preserve genome integrity when faced with DNA lesions, cells activate and coordinate a multitude of DNA repair pathways to ensure timely error correction or tolerance, collectively called the DNA damage response (DDR). These interconnecting damage response pathways are molecular signal relays, with protein kinases (PKs) at the pinnacle. Focused efforts in model eukaryotes have revealed intricate aspects of DNA repair PK function, including how they direct DDR pathways and how repair reactions connect to wider cellular processes, including DNA replication and transcription. The Kinetoplastidae, including many parasites like Trypanosoma spp. and Leishmania spp. (causative agents of debilitating, neglected tropical infections), exhibit peculiarities in several core biological processes, including the predominance of multigenic transcription and the streamlining or repurposing of DNA repair pathways, such as the loss of non-homologous end joining and novel operation of nucleotide excision repair (NER). Very recent studies have implicated ATR and ATM kinases in the DDR of kinetoplastid parasites, whereas DNA-dependent protein kinase (DNA-PKcs) displays uncertain conservation, questioning what functions it fulfills. The wide range of genetic manipulation approaches in these organisms presents an opportunity to investigate DNA repair kinase roles in kinetoplastids and to ask if further kinases are involved. Furthermore, the availability of kinase inhibitory compounds, targeting numerous eukaryotic PKs, could allow us to test the suitability of DNA repair PKs as novel chemotherapeutic targets. Here, we will review recent advances in the study of trypanosomatid DNA repair kinases.
... ATR-Seckle Syndrome which also presents with microcephaly and "bird-like" facial features occurs due to abnormal function in ATR, a protein that monitors single stranded DNA replication errors at replication forks [43]. However cases reported have a normal immunological profile although some have developed lymphoid malignancies [28,44]. The crucial biochemical difference between ATR-Seckle and LIG4 is that ATR-Seckle cells do not display radiosensitivity to ionising radiation. ...
DNA ligase IV deficiency is a rare primary immunodeficiency, LIG4 syndrome, often associated with other systemic features. DNA ligase IV is part of the non-homologous end joining mechanism, required to repair DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by reactive oxygen species and ionising radiation.
Within developing lymphocytes, DNA ligase IV is required to repair programmed DNA double stranded breaks induced during lymphocyte receptor development.
Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to severe combined immunodeficiency. All, however, manifest sensitivity to ionising radiation. Commonly associated features include primordial growth failure with severe microcephaly and a spectrum of learning difficulties, marrow hypoplasia and a predisposition to lymphoid malignancy. Diagnostic investigations include immunophenotyping, and testing for radiosensitivity. Some patients present with microcephaly as a predominant feature, but seemingly normal immunity. Treatment is mainly supportive, although haematopoietic stem cell transplantation has been used in a few cases.
... The common clinical features of MOPD II include microcephaly and disproportionate, skeletal dysplasia, and certain facial characteristics (Majewski and Goecke 1998), although the patients may not have severe microcephaly at birth and their intellectual development may apparently be normal (Hall et al. 2004;Piane et al. 2009;Rauch 2011). Additional clinical manifestations that some patients may exhibit include anemia, bone marrow failure, T-cell clonality, myelodysplasia, acute myeloid leukemia (Lilleyman 1984;Hayani et al. 1994;Chanan-Khan et al. 2003), thrombocytosis (Moftakhar et al. 2010;Unal et al. 2014), leukocytosis and thrombocytosis (Verloes et al. 1987;Unal et al. 2014), and cerebral aneurysms or moyamoya angiopathy (Hall et al. 2004;Piane et al. 2009). ...
Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a highly detrimental human autosomal inherited recessive disorder. The hallmark characteristics of this disease are intrauterine and postnatal growth restrictions, with some patients also having cerebrovascular problems such as cerebral aneurysms. The genomic basis behind most clinical features of MOPD II remains largely unclear. The aim of this work was to identify the genetic defects in a Chinese family with MOPD II associated with multiple intracranial aneurysms. The patient had typical MOPD II syndrome, with subarachnoid hemorrhage and multiple intracranial aneurysms. We identified three novel mutations in the PCNT gene, including one single base alteration (9842A>C in exon 45) and two deletions (Del-C in exon 30 and Del-16 in exon 41). The deletions were co-segregated with the affected individual in the family and were not present in the control population. Computer modeling demonstrated that the deletions may cause drastic changes on the secondary and tertiary structures, affecting the hydrophilicity and hydrophobicity of the mutant proteins. In conclusion, we identified two novel mutations in the PCNT gene associated with MOPD II and intracranial aneurysms, and the mutations were expected to alter the stability and functioning of the protein by computer modeling.
... Delayed dental age was observed in the present case, as it was also reported in previous literature. [13] Hematopoietic disorders have been reported in approximately 15% of patients with SS. [15] This case also presents with microcytic, hypochromic anemia. ...
Seckel syndrome (SS) is a rare, autosomal recessive syndrome; characterized by severe intrauterine and postnatal growth retardation, microcephaly, mental retardation, and typical facial appearance with beaklike protrusion of the midface (bird headed). In addition to the characteristic craniofacial dysmorphism and skeletal defects, abnormalities have been described in the cardiovascular, hematopoietic, endocrine, gastrointestinal, and central nervous systems. Usually such patients have poor psychomotor development. This case report presents an 8-year-old child with SS born to parents, exposed in Bhopal gas disaster.
... Anemia, bone marrow failure, T-cell clonality, myelodysplasia, and even acute myeloid leukemia (AML) have been reported in patients with Seckel syndrome [8][9][10]. The leukocyte and thrombocyte counts have been provided in only 2 MOPD II patients, previously: one patient had thrombocytosis [11] and the other had leukocytosis and thrombocytosis [12]. ...
... Pancytopenia with hypoplastic marrow, myelodysplasia, or acute myelogenous leukemia has been reported to occur in as many as 15% of patients with Seckel syndrome [8][9][10]. Hematological findings in patients with MOPD II have rarely been reported. ...
Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center.
The study included eight patients with MOPD II that were analyzed via molecular testing, and physical and laboratory examinations.
Molecular testing showed that seven of the eight patients had pericentrin (PCNT) gene mutations. Hematological evaluation showed that 7 (87.5%) patients had thrombocytosis, 6 (75%) had leukocytosis, 5 (62.5%) had both leukocytosis and thrombocytosis, and 2 (25%) had anemia.
We report leukocytosis and thrombocytosis as a common hematologic abnormality in patients with MOPD II. The present findings may improve our understanding of the potential function of the PCNT gene in hematopoietic cell proliferation and differentiation. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
... Hematopoietic disorders have been reported in approximately 15% of patients with SS 6 . Acute myeloid leukaemia 7 and pancytopenia were described 2,8 . ...
Seckel Syndrome (SS) is a rare form of primordial autosomal recessive dwarfism involving multiple malformations. The major characteristic features of SS are intrauterine and postnatal growth deficiency, severe microcephaly, craniofacial dysmorphism which includes characteristic 'Bird-headed' appearance, prominent nose, sloped forehead, receding jaw, low-set ears with hypoplastic lobules and large eyes with down-slanting palpebral fissures. Characteristic skeletal anomalies include premature closure of the cranial sutures and fifth finger clinodactyly. In addition to the characteristic craniofacial dysmorphism and skeletal defects, abnormalities have been described in the cardiovascular, hematopoietic, endocrine and central nervous systems. Dental abnormalities include enamel hypoplasia, hypodontia, microdontia, taurodontic root morphology and a high-arched palate. Retarded bone age and moderate to severe mental retardation (I.Q. < 50 in 50% of cases) are observed in patients with Seckel Syndrome. The purpose of this paper is to describe craniofacial morphology and dentition in two siblings with Seckel Syndrome and to present the dental treatments provided for these patients.
... However, it has been shown very recently that a splicing mutation affecting expression of the ATR protein results in the Seckel syndrome [27] . The Seckel syndrome is characterized by marked microcephaly, and cells derived from such a patient show an impaired DNA damage response [27][28][29][30] . Nevertheless, only a subset of Seckel syndrome patients carries an ATR mutation [31][32][33][34] . ...
Pentoxifylline, a caffeine-related compound, was shown to suppress human immunodeficiency virus type 1 (HIV-1) replication. This effect is thought to be mediated by inhibition of tumor necrosis factor-alpha (TNFalpha)-mediated long-terminal repeat (LTR)-driven expression. We now demonstrate that pentoxifylline efficiently inhibits transduction by HIV-1-based vectors. This latter effect is independent of LTR-driven expression, and correlates with a reduced efficiency of the completion of the integration process in infected cells. Finally, the effect of pentoxifylline is dramatically reduced in cells expressing a dominant negative ATR protein, and in primary human cells that exhibit low level of ATR activity, suggesting that the effect of pentoxifylline on HIV-1 transduction and replication is at least partly mediated by suppression of the ATR kinase.
... Too few patients with ATR-Seckel have been identified to assess whether this syndrome is also associated with cancer predisposition. Nevertheless, there are reports of lymphoid abnormalities in genetically uncharacterized patients with Seckel syndrome [81][82][83] . ...
The efficient repair of DNA double-strand breaks is crucial in safeguarding the genomic integrity of organisms. Responses to double-strand breaks include complex signal-transduction, cell-cycle-checkpoint and repair pathways. Defects in these pathways lead to several human disorders with pleiotropic clinical features. Dissection of the molecular basis that underlies the diverse clinical features is enhancing our understanding of the damage-response mechanisms and their role in development, and might ultimately facilitate treatment.
... Seckel syndrome and FA share several clinical features, including varying degrees of microcephaly, dwarfism, thumb abnormalities, aplastic anemia, and cancer susceptibility (Chanan-Khan et al. 2003), suggesting the possibility of a mechanistic link between these diseases. We examined FANCD2 monoubiquitination in a Seckel syndrome cell line with biallelic mutation in ATR ( Fig. 3A; O'Driscoll et al. 2003). ...
Fanconi anemia (FA) is a multigenic autosomal recessive cancer susceptibility syndrome. The FA pathway regulates the monoubiquitination of FANCD2 and the assembly of damage-associated FANCD2 nuclear foci. How FANCD2 monoubiquitination is coupled to the DNA-damage response has remained undetermined. Here, we demonstrate that the ATR checkpoint kinase and RPA1 are required for efficient FANCD2 monoubiquitination. Deficiency of ATR function, either in Seckel syndrome, which clinically resembles Fanconi anemia, or by siRNA silencing, results in the formation of radial chromosomes in response to the DNA cross-linker, mitomycin C (MMC), thus mimicking the chromosome instability of FA cells.
