Dyskeratosis congenita and a rare brain abscess / Disqueratosis congénita y absceso del sistema nervioso central

Abstract Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

Resumen La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmuno deficiencia heredable.

Dyskeratosis congenita

Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.

Recurrent pulmonary infection and oral mucosal ulcer / 中国当代儿科杂志

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.

Disceratose congênita - relato de caso e revisão de literatura / Dyskeratosis congenita - case report and literature review

A Disceratose Congênita (DC) é uma síndrome hereditária rara que exibe marcada heterogeneidade clínica e genética, constituindo-se em anormalidades cutaneomucosas, falência medular e predisposição ao câncer. Esta é caracterizada pela tríade de pigmentação reticulada da pele, distrofia ungueal e leucoplasia em mucosas. Alterações dentárias, gastrintestinais, geniturinárias, neurológicas, oftalmológicas, pulmonares e esqueléticas associadas têm sido relatadas. A falência medular é a principal causa de morte precoce e também é descrita predisposição para doenças malignas. Afeta principalmente homens e, reconhecem-se formas recessivas ligadas ao X, autossômicas dominantes e recessivas. Relata-se o caso de um paciente de 40 anos, sexo masculino, que há 7 evolui com quadro de anemia e necessidades transfusionais (sanguíneas). Investigadas causas hemofílica e carencial sem êxito. Mielograma com normocelularidade das linhagens; solicitada biópsia de medula óssea por suspeita de Disceratose Congênita, tendo em vista sintomatologia com presença da tríade da Disceratose Congênita: leucoplasia mucosa, distrofia ungueal, e áreas de hiperpigmentação reticular. Paciente progride sob acompanhamento no serviço hematológico do Hemocentro do Pará. Em função da raridade da doença, pouco mais de 500 casos relatados no mundo, da dificuldade de se chegar ao seu diagnóstico, e de sua gravidade, é de fundamental importância a difusão do conhecimento e ratifica-se a necessidade do acompanhamento médico multidisciplinar, de modo a permitir diagnóstico e tratamento precoce das possíveis complicações.

Dyskeratosis Congenita (DC) is a rare hereditary syndrome that shows marked clinical and genetic heterogeneity, like mucocutaneous abnormalities, bone marrow failure and predisposition to cancer. Dyskeratosis congenita triad is: abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal disorders have been reported. The leading cause of early death and an additional predisposition to malignancy is bone marrow failure. Dyskeratosis congenita mainly affects men and recessive X-linked, autosomal dominant and recessive forms are recognized. We report the case of a 40-year-old male, 7 years evolving symptoms of anemia and transfusion requirements. Unsuccessfully research by deficiency causes and hemophilia were done. Normal cellular lineages myelogram. Patient progresses under supervision of Hemocenter of Pará (HEMOPA). Depending on the rarity of the disease, little more than 500 cases reported worldwide, the difficulty of arriving at a diagnosis, and its severity, is crucial to spreading knowledge and it confirms the need for a multidisciplinary approach, the to enable early diagnosis and treatment of possible complications.

Revesz syndrome

Revesz syndrome is a rare variant of dyskeratosis congenita and is characterized by bilateral exudative retinopathy, alterations in the anterior ocular segment, intrauterine growth retardation, fine sparse hair, reticulate skin pigmentation, bone marrow failure, cerebral calcification, cerebellar hypoplasia and psychomotor retardation. Few patients with this syndrome have been reported, and significant clinical variations exist among patients. This report describes the first Brazilian case of Revesz syndrome and its ocular and clinical features.

A síndrome de Revesz é uma rara variante de disceratose congênita caracterizada por retinopatia exsudativa bilateral, alterações no segmento anterior ocular, retardo do crescimento intrauterino, pilificação fina e escassa, pigmentação cutânea reticular, falência da medula óssea, calcificações cerebrais, hipoplasia cerebelar e retardo neuropsicomotor. Há variações clínicas significativas entre os poucos relatos desta patologia existentes na literatura. Descrevemos o primeiro caso brasileiro de síndrome Revesz e suas características clínicas e oculares.

Genotype analysis and telomere length measure in patients with dyskeratosis congenita / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analysze genotype and measure telomere length in two Chinese patients with dyskeratosis congenita(DC).</p><p><b>METHODS</b>The 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).</p><p><b>RESULTS</b>Abnormal 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.</p><p><b>CONCLUSIONS</b>Physician 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.</p>

The study of genetic instability in patients with Dyskeratosis congenital / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the genetic instability in patients with Dyskeration congenita.</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>①PNH 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).</p><p><b>CONCLUSION</b>DC 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.</p>

Molecular diagnosis and hematopoietic stem cell transplantation in 17 children with inherited bone marrow failure syndrome / 中华儿科杂志

<p><b>OBJECTIVE</b>To 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).</p><p><b>METHOD</b>Next-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).</p><p><b>RESULT</b>Three 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%.</p><p><b>CONCLUSION</b>NGS-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.</p>

Clinical features and genotype analysis in a case of dyskeratosis congenita / 南方医科大学学报

<p><b>OBJECTIVE</b>To analyze the clinical features and genotype in a 8-year-old boy with dyskeratosis congenita (DC).</p><p><b>METHODS</b>We 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.</p><p><b>RESULTS</b>DNA 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.</p><p><b>CONCLUSION</b>The 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.</p>

Current insights into inherited bone marrow failure syndromes / 소아과

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.

Dyskeratosis congenita- management and review of complications: a case report

Among the inherited bone marrow failure disorders, dyskeratosis congenita is an X-linked inherited disorder arising as a consequence of short telomere and mutations in telomere biology. Production of the altered protein dyskerin, leads to vulnerable skin, nails, and teeth which lead to higher permeability for noxious agents which can induce carcinogenesis accounting for the classical triad of skin pigmentation, nail dystrophy and oral leukoplakia. This condition is fatal and patients succumb to aplastic anemia, malignancy or immunocompromised state. We present a young male with the classic clinical triad and avascular necrosis of both femoral heads, with no evidence of hematologic anomaly or any malignancy. He was managed for osteonecrosis with uncemented total hip arthroplasty for the symptomatic left hip. Our case represents a benign form of such a fatal and rare condition, which if detected and managed early can result in improved quality of life for the patient suffering from this disorder. This patient is under our meticulous follow-up for the last 2 years in order to determine any late development of complications before being labelled as a variant of this syndrome

Interstitial Lung Disease in a Patient with Dyskeratosis Congenita / 결핵및호흡기질환

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.

Keratinization and its disorders

Keratins are a diverse group of structural proteins that form the intermediate filament network responsible for maintaining the structural integrity of keratinocytes. In humans, there are around 30 keratin families divided into two groups, namely, acidic and basic keratins, which are arranged in pairs. They are expressed in a highly specific pattern related to the epithelial type and stage of cellular differentiation. A total of 54 functional genes exist which codes for these keratin families. The expression of specific keratin genes is regulated by the differentiation of epithelial cells within the stratifying squamous epithelium. Mutations in most of these genes are now associated with specific tissue fragility disorders which may manifest both in skin and mucosa depending on the expression pattern. The keratins and keratin-associated proteins are useful as differentiation markers because their expression is both region specific and differentiation specific. Antibodies to keratin are considered as important tissue differentiation markers and therefore are an integral aid in diagnostic pathology. The present review discusses the structure of keratin, the various types of keratin and their distribution and the disorders associated with keratinization with special emphasis on the disorders of the oral cavity. A brief note on the clinical significance of keratin is also mentioned

Dyskeratosis congenital: clinical features and genotype analysis in two Chinese patients / 中华血液学杂志

<p><b>OBJECTIVE</b>To analysis the clinic and genotype in two Chinese patients with Dyskeratosis congenita (DC).</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>An 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.</p><p><b>CONCLUSION</b>We 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.</p>

Clinical and genetic characteristics of a patient with dyskeratosis congenita / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical features and gene mutation of a patient with dyskeratosis congenita, who was admitted in our hospital for thrombocytopenia.</p><p><b>METHOD</b>The clinical and laboratory data of a 4 years and 10 months old boy were summarized. DKC1 gene was analyzed using PCR amplification and DNA sequencing.</p><p><b>RESULT</b>The age of onset of the boy was 1 year. He presented with abnormal cutaneous pigmentation, nail dystrophy and mucosal leukoplakia accompanied by multi-system abnormalities. DKC1 (1058C-T, A353V) was detected in the patient.</p><p><b>CONCLUSION</b>The patient presented with classical features of dyskeratosis congenita and DKC1 (1058C-T, A353V) did exist in this patient. X-linked recessive dyskeratosis congenita was confirmed.</p>