Dyskeratosis Congenita/genetics* ; Enterocolitis/genetics* ; Fetal Growth Retardation ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics*

Dyskeratosis Congenita/therapy* ; Humans

An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Routine blood tests and immune function tests performed in other hospitals had shown normal results. Multiple lung CT scans showed pulmonary infection. The patient had recurrent fever and cough and persistent presence of some lesions after anti-infective therapy. The antitubercular therapy was ineffective. Routine blood tests after admission showed agranulocytosis. Gene detection was performed and she was diagnosed with dyskeratosis congenita caused by homozygous mutation in RTEL1. Patients with dyskeratosis congenita with RTEL1 gene mutation tend to develop pulmonary complications. Since RTEL1 gene sequence is highly variable with many mutation sites and patterns and can be inherited via autosomal dominant or recessive inheritance, this disease often has various clinical manifestations, which may lead to missed diagnosis or misdiagnosis. For children with unexplained recurrent pulmonary infection, examinations of the oral cavity, skin, and nails and toes should be taken and routine blood tests should be performed to exclude dyskeratosis congenita. There are no specific therapies for dyskeratosis congenita at present, and when bone marrow failure and pulmonary failure occur, hematopoietic stem cell transplantation and lung transplantation are the only therapies. Androgen and its derivatives are effective in some patients. Drugs targeting the telomere may be promising for patients with dyskeratosis congenita.
Child ; Dyskeratosis Congenita ; complications ; therapy ; Female ; Humans ; Mouth Diseases ; etiology ; Mouth Mucosa ; pathology ; Recurrence ; Respiratory Tract Infections ; etiology ; Telomere ; drug effects ; Ulcer ; etiology

OBJECTIVETo analyze the clinical features and genotype in a 8-year-old boy with dyskeratosis congenita (DC).

METHODSWe reviewed the clinical data of the case and amplified 7 DC-related genes (including DKC1,TERT,TERC,TINF2,NOP10, NHP2 and WRAP53) using polymerase chain reaction for DNA sequence analysis to identify the abnormal exons.

RESULTSDNA sequence analysis showed a c.85-15T>C mutation in DKC1 gene of the patient. His mother was a carrier of the mutated gene and presented with partial clinical features such as abnormal nails.

CONCLUSIONThe mutation of c.85-15T>C in DKC1 gene was reported for the first time in China. The diagnosis of DC should be considered if a young patient presents with mucocutaneous abnormalities, bone marrow failure, cancer susceptibility and a family history of cancer. Early genetic tests can improve the diagnosis rates and reduce misdiagnosis and missed diagnosis.

Cell Cycle Proteins ; genetics ; Child ; China ; Dyskeratosis Congenita ; genetics ; pathology ; Exons ; Genotype ; Humans ; Male ; Mutation ; Nuclear Proteins ; genetics ; Polymerase Chain Reaction ; Sequence Analysis, DNA

OBJECTIVETo enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS).

METHODNext-generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS. Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November. 2005-June 2015).

RESULTThree patients were diagnosed only by clinical manifestation before 2012. After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients). Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype-analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses. Seventeen IBMFS patients (10 FA,5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n=2), matched unrelated donors (n=8) or mismatched unrelated donors (n=7). The source of stem cells for transplantation included peripheral blood (n=12) and cord blood (n=5). With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning. Median age at the time of HSCT was 36 months (7-156 months). The number of infused mononuclear cells and CD34⁺ cells was (10.6 ± 6.7) × 10⁸ and (5.9 ± 7.0) × 10⁶ per kilogram of recipient body weight, respectively. The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days). Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3 ± 6.0) days vs. (30.0 ± 17.1) days,t=-2.487,P=0.026). During a median follow-up of 17 months (range: 2-114 months), except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT. The failure-free survival rate of the patients three years after HSCT was 94%.

CONCLUSIONNGS-based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited.

Anemia, Aplastic ; Anemia, Diamond-Blackfan ; therapy ; Bone Marrow Diseases ; Child ; Dyskeratosis Congenita ; therapy ; Fanconi Anemia ; therapy ; Fetal Blood ; Hematopoietic Stem Cell Transplantation ; Hemoglobinuria, Paroxysmal ; diagnosis ; genetics ; therapy ; Humans ; Retrospective Studies ; Siblings ; Survival Rate ; Transplantation Conditioning ; Unrelated Donors ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVETo analysze genotype and measure telomere length in two Chinese patients with dyskeratosis congenita(DC).

METHODSThe peripleral blood DNA was extracted in two patients characterized by mucocutaneous abnormalities (abnormal nails, lacy reticulated skin pigmentation, and oral leukoplakia), bone marrow failure, DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons. Lymphocyte telomere length was measured by flow cytometry-fluorescence in situ hybridization(Flow-FISH).

RESULTSAbnormal peaks were found in exon 6 of TINF2 gene of the two patients and a 811C→T transition in TINF2 gene in one patient. DNA sequencing showed a 848C→A transition in TINF2 gene in another patient. Relative telomere length was remarkable less than that of normal children with same age.

CONCLUSIONSPhysician should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. Early detection of related genes and measurernant of tolomere length may contribute to avoid misdiagnosis. TINF2 c.811C→T (Q271X) and TINF2 c.848C→A (P283H) exist in the two patients, it is reported in China for the first time.

Base Sequence ; Bone Marrow ; China ; Dyskeratosis Congenita ; Exons ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Telomere ; Telomere-Binding Proteins

OBJECTIVETo investigate the genetic instability in patients with Dyskeration congenita.

METHODSThe spontaneous chromosome instability of lymphocytes from 4 DC patients, 29 FA patients and 24 healthy volunteers was assessed with comet assay. The percent of DNA in comet head (HeadDNA%）, the percent of DNA in comet tail (TailDNA%）, tail moment (TM), olive tail moment (OTM), the comet cell percentage (CCP) were compared between groups. And the results of MMC test, PNH clones and karotype were analysed additionally. The correlation between TM, OTM, CCP and the severity degree of bone marrow failure in DC group were evaluated.

RESULTS①PNH clones and karotype abnormalities were not found in 4 DC patients. ②TM (6.77 ± 0.90), OTM（6.19 ± 0.80) and CCP [(46.00 ± 5.03) %] in DC were significantly higher than those in normal control group [0.61 ± 0.49, 0.66 ± 0.42, (5.91 ± 3.19)%, P<0.05], however, not distinguished from FA patients [7.81 ± 3.58, 6.65 ± 2.21, (56.03 ± 13.47) %, P ≥ 0.05]. The aberrant cell percent at the MMC concentration of 80 μg/L in DC group was significantly lower than that in FA group [(21.00 ± 3.16) % vs (31.97 ± 6.33)%, P=0.003]. ③The correlation between TM, OTM, CCP and the severity of bone marrow failure in DC group were not found (P>0.05).

CONCLUSIONDC patients were of significantly increased genetic instability and normal DNA repair, which was different from that in FA patients. And there was no correlation between the degree of genetic instability and the severity of bone marrow failure in DC patients presenting as aplastic anemia.

Case-Control Studies ; Chromosomal Instability ; Comet Assay ; Dyskeratosis Congenita ; genetics ; Fanconi Anemia ; genetics ; Humans ; Lymphocytes ; Pancytopenia

Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.
Anemia, Diamond-Blackfan ; Organelle Biogenesis ; Blood Cells ; Bone Marrow* ; Diagnosis ; DNA ; Dyskeratosis Congenita ; Fanconi Anemia ; Follow-Up Studies ; Humans ; Leukocyte Elastase ; Neutropenia ; Neutrophils ; Phenotype ; Recombinational DNA Repair ; Ribosomes ; Telomere

Dyskeratosis congenita is a rare congenital disorder characterized by a triad of reticular pigmentation of the skin, dystrophic nails, and leukoplakia of the mucous membrane. Sometimes it is associated with bone marrow failure, secondary malignancy and interstitial lung disease. Though it is rare, Dyskeratosis congenita is diagnosed relatively easily when clinicians suspect it. It can be diagnosed just by gross inspection with care. Dyskeratosis congenita should be considered as one cause associated with interstitial lung disease. In Korea, interstitial lung disease with dyskeratosis congenita has not been reported. We report a case and review the literature.
Anemia, Aplastic ; Bone Marrow ; Congenital, Hereditary, and Neonatal Diseases and Abnormalities ; Dyskeratosis Congenita ; Humans ; Korea ; Leukoplakia ; Lung Diseases, Interstitial ; Mucous Membrane ; Nails ; Pigmentation ; Skin

OBJECTIVETo analysis the clinic and genotype in two Chinese patients with Dyskeratosis congenita (DC).

METHODSThe two patients were characterized by mucocutaneous abnormalities (abnormal nails, lacey reticular pigmentation, and oral leukoplakia), bone marrow failure. They were diagnosed with DC. DC genes were amplified by polymerase chain reaction (PCR), including DKC1, TERT, TERC, TINF2, NOP10, NHP2, then DNA sequencing was performed for abnormal exons.

RESULTSAn abnormal peak was found in exon 6 of TINF2 gene of the two patients. DNA sequencing showed a 845G→A transition in TINF2 gene in the two patients.

CONCLUSIONWe should think about DC if the young patients with mucocutaneous abnormalities and marrow failure. TINF2 c.845G→A(R282H) does exist in the two patients. It is reported in China for the first time.

Base Sequence ; Child, Preschool ; DNA Mutational Analysis ; Dyskeratosis Congenita ; diagnosis ; genetics ; Exons ; Female ; Humans ; Infant ; Male ; Telomere-Binding Proteins ; genetics