ABSTRACT
OBJECTIVE@#To explore the clinical feature, diagnosis and phenotype of Majeed syndrome.@*METHODS@#Clinical manifestation, diagnostic process, imaging feature and genetic testing of an ethnic Han Chinese patient with Majeed syndrome were reviewed.@*RESULTS@#The patient, a 3-year-9-month-old boy, had featured psychomotor retardation and developed bone pain from 8 month on. The child had tenderness of the lower limbs and presented with repeatedly joint swelling and pain accompanied by fever. Physical signs included limb muscle weakening, slightly decreased muscle tone, reduced muscle volume and positive Gower sign. High-throughput sequencing revealed that the child has carried compound heterozygous variants of the LPIN2 gene, including c.1966A>G and c.2534delG. MRI showed multiple lesions in bilateral knee joints and distal middle tibia presenting as patchy SPAIR high signals with unclear edge, in addition with edema of soft tissue surrounding the right distal femur.@*CONCLUSION@#Majeed syndrome is characterized by chronic and recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and growth retardation. Surrounding muscle tissue of osteomyelitis may also be involved. The syndrome may also affect the central nervous system, resulting in delayed language and motor development. Discovery of multiple pathological variants of the LPIN2 gene suggested that the clinical phenotype of this syndrome may vary between patients to some extent.
Subject(s)
Child , Humans , Infant , Male , Anemia, Dyserythropoietic, Congenital/genetics , Genetic Testing , Immunologic Deficiency Syndromes/genetics , Osteomyelitis/geneticsABSTRACT
OBJECTIVE@#To identify the pathogenic variants of 4 patients with hemolytic anemia of unknown cause.@*METHODS@#Peripheral blood samples of the patients and their family members were collected to extract DNA. The coding region and splice region in all exons of gene of erythrocyte related diseases were analyzed by using target sequence capture and high-throughput sequencing technology. Suspected pathogenic variants were verified by PCR combined Sanger sequencing technology.@*RESULTS@#Each of the probands was detected two compound heterozygous variants, and CDA II was diagnosed. Six variants were detected in the 4 probands, four variants were reported and the other two were first reported.@*CONCLUSION@#By high-throughput sequencing, gene variant of CDA II be analyzed fast and accurately. It is an effective supplement to convenional diagnostic methods. Furthermore, the novel variant sites have enriched the variant database of the SEC23B gene.
Subject(s)
Humans , Anemia, Dyserythropoietic, Congenital/genetics , Exons/genetics , High-Throughput Nucleotide Sequencing , Mutation , Vesicular Transport Proteins/geneticsABSTRACT
Introducción: Las anemias diseritropoyéticas congénitas constituyen un grupo de trastornos hereditarios caracterizados por anemia refractaria, eritropoyesis ineficaz y alteraciones morfológicas de los eritroblastos. La anemia diseritropoyética congénita tipo I es la más frecuente, no obstante, constituye una rara enfermedad con particularidades morfológicas y moleculares. Objetivo: Analizar los aspectos más novedosos en cuanto a la patogenia molecular, el diagnóstico genético y el tratamiento de la anemia diseritropoyética congénita tipo I. Métodos: Se realizó una revisión de la literatura, en inglés y español. Se utilizaron motores de búsqueda como Google académico y Pubmed que permitió el acceso a artículos actualizados del tema. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: La anemia diseritropoyética congénita tipo I es una enfermedad hereditaria autosómica recesiva. Se caracteriza por anemia de grado variable, reticulocitopenia, alteraciones morfológicas de la serie roja en la lámina periférica y un número elevado de eritroblastos binucleados conectados por puentes internucleares en el aspirado de médula ósea. Se han identificado múltiples alteraciones moleculares que involucran fundamentalmente a los genes CDAN1 y C15orf41. Las proteínas codificadas por estos genes participan en proceso vitales como el ciclo celular, la reparación del ADN y la transcripción de ARN. Conclusiones: El estudio de las bases moleculares de la anemia diseritropoyética congénita tipo I ha cambiado la perspectiva en el diagnóstico de esta enfermedad. Los protocolos de tratamiento son similares a otras anemias hemolíticas hereditarias aunque se destaca el uso del Interferón-α(AU)
Introduction: Congenital dyserythropoietic anemias belong to a group of hereditary disorders characterized by refractory anemia, ineffective erythropoiesis and morphological alterations of erythroblasts. Congenital dyserythropoietic anemia type I is the most frequent; however, it is a rare disease with morphological and molecular characteristics. Objective: To analyze the most updated aspects regarding molecular pathogenesis, genetic diagnosis and treatment of congenital dyserythropoietic anemia type I. Methods: A review of the literature in English and Spanish was carried out. Search engines such as Google Scholar and Pubmed were used, which allowed access to updated articles on the subject. An analysis and summary of the revised bibliography was carried out. Information analysis and synthesis: Congenital dyserythropoietic anemia type I is an autosomal recessive hereditary disease. It is characterized by anemia of variable degree, reticulocytopenia, morphological alterations of the red series in the peripheral lamina, and high number of binucleated erythroblasts connected by internuclear bridges in the bone marrow aspirate. Multiple molecular alterations have been identified, mainly involving the CDAN1 and C15orf41 genes. The proteins encoded by these genes participate in vital processes, such as the cell cycle, DNA repair, and RNA transcription. Conclusions: The study of the molecular bases of congenital dyserythropoietic anemia type I has changed the perspective concerning the diagnosis of this disease. Treatment protocols are similar to other hereditary hemolytic anemias, although the use of Interferon-α stands out(AU)
Subject(s)
Humans , Pathogenesis, Homeopathic/methods , Interferons/therapeutic use , Genetic Diseases, Inborn/epidemiology , Anemia, Dyserythropoietic, Congenital/diagnosis , Anemia, Dyserythropoietic, Congenital/therapyABSTRACT
It has been known that extramedullary hematopoiesis occurring after birth can be developed in various diseases, and it is often found in hematologic diseases. Among these, congenital dyserythropoietic anemia is a rare disease characterized with increase of ineffective hematopoiesis and morphological abnormalities of erythroblasts. In congenital dyserythropoietic anemia, extramedullary hematopoiesis is very rare and only a few cases have been reported. Although treatment is not required if there is no symptom in extramedullary hematopoiesis, surgery or radiation therapy is effective in case that there is symptom or unresponsive anemia despite blood transfusion. This case report is about surgical treatment for extramedullary hematopoiesis in 23-year-old patients diagnosed of congenital dyserythropoietic anemia.
Subject(s)
Humans , Young Adult , Anemia , Anemia, Dyserythropoietic, Congenital , Blood Transfusion , Erythroblasts , Hematologic Diseases , Hematopoiesis , Hematopoiesis, Extramedullary , Parturition , Rare DiseasesABSTRACT
<p><b>OBJECTIVE</b>To detect potential mutation in a family affected with congenital dyserythropoietic anemia type II (CDA II).</p><p><b>METHODS</b>Targeted sequence capture and next-generation sequencing (NGS) were used to analyze the exons and exon-intron boundaries of the SEC23B gene in a clinically suspected CDA II patient. Genotypes of the relatives were validated by Sanger sequencing. Potential impact of amino acid substitution on the structure and function of SEC23B protein was predicted with MutationTaster and PolyPhen-2. The protein structure was predicted with SWISS-MODEL software.</p><p><b>RESULTS</b>The proband was found to harbor double heterozygous mutations of the SEC23B gene, c.1727T>C (p.F576S) and c.1831C>T (p.R611W), which resulted in amino acid substitutions p.F576S and p.R611W. Both mutations were confirmed by Sanger sequencing. The sister of the proband was found to have carried c.1727T>C (p.F576S), while her father and son have carried c.1831C>T (p.R611W) mutation. In addition, the proband was detected to have carried c.211C>T (p.R71X) of the HFE gene, which resulted in substitution of arginine by a stop codon. The impact of above mutations on the structure or function of protein was predicted to be harmful. Splenectomy and iron chelation therapy have achieved effective improvement of anemia and iron overload. Computer simulation suggested that the mutations have altered the 3D structure of the SEC23B protein.</p><p><b>CONCLUSION</b>The novel compound mutations of c.1727T>C and c.1831C>T of the SEC23B gene probably underlie the CDA II in the family, and there is a strong correlation between the genotype and phenotype.</p>
Subject(s)
Adult , Female , Humans , Anemia, Dyserythropoietic, Congenital , Genetics , Computer Simulation , Family , Genotype , High-Throughput Nucleotide Sequencing , Mutation , Phenotype , Vesicular Transport Proteins , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To report novel mutations SEC23B gene in congenital dyserythropoietic anemia (CDA).</p><p><b>METHODS</b>By direct sequencing method, we sequenced CDAN1 and SEC23B genes in a Chinese CDA II patient, presented with chronic fatigue and dark urine, as well as his family members. Serum hepcidin was assayed by mass spectrometry.</p><p><b>RESULTS</b>We found a c.71G>A mutation and a c.74C> A mutation in the patient. In addition, a heterozygous c.55A>G mutation of HFE2 gene was found in some family members. The level of serum hepcidin of the patient was below the detection limit (<1 nmol/L).</p><p><b>CONCLUSION</b>Contrary with what have been reported previously in the Europe, especially in the Italy, the gene mutations identified in this case was different and novel. The two novel mutations contribute to the diagnosis of CDAII and are the first report in East Asian CDAII patients.</p>
Subject(s)
Adolescent , Adult , Humans , Male , Middle Aged , Anemia, Dyserythropoietic, Congenital , Genetics , Asian People , Genetics , GPI-Linked Proteins , Genetics , Glycoproteins , Genetics , Hepcidins , Blood , Mutation , Pedigree , Vesicular Transport Proteins , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To investigate the clinical and laboratory features of congenital dyserythropoietic anemia type II (CDA-II) in order to improve the recognition of the disease.</p><p><b>METHODS</b>A case of CDA-II was reported and the related literatures were reviewed.</p><p><b>RESULTS</b>The 32-years old female presented with moderate anemia, jaundice and hepatosplenomegaly from her childhood and was misdiagnosed as hereditary spherocytosis for a long time. There were no increased reticulocytes in the peripheral blood and her bone marrow showed erythroid hyperplasia with 43% of binucleated erythroblasts. Electron microscopy examination revealed stretches of double membrane lining the inner surface of the erythroblast cell membrane.</p><p><b>CONCLUSIONS</b>CDA-II is a rare congenital anemia characterized by ineffective erythropoiesis with unique laboratory features, and is relatively easy to be misdiagnosed. It is necessary to improve the awareness of CDA-II, and to set-up its responsible gene analysis, i.e., CDAN2 gene and SEC23B gene detection.</p>
Subject(s)
Adult , Female , Humans , Anemia, Dyserythropoietic, Congenital , Diagnosis , Genetics , Vesicular Transport Proteins , GeneticsABSTRACT
La anemia diseritropoyética congénita se engloba dentro de un grupo raro y heterogéneo de trastornos eritrocitarios caracterizados por eritropoyesis ineficaz, anemia megaloblástica, hemosiderosis secundaria e hidrops fetal. Presentamos el caso de un feto de 20 semanas con hidrops como consecuencia de una anemia fetal intensa por eritropoyesis ineficaz. Ante el hallazgo de hidrops fetal no inmune es fundamental un diagnóstico etiológico precoz para ofrecer a la pareja las alternativas terapéuticas más adecuadas.
Congenital dyserythropoietic anemia is a rare group of heterogeneous disorders characterized by ineffective erythropoiesis, megaloblastic anemia, secondary hemosiderosis and fetal hydrops. We report a case of a 20 week old fetus with hydrops as a consequence of a severe fetal anemia resulting from ineffective erythropoiesis. When non-immune fetal hydrops is found, it is essential an early etiological diagnosis to give the parents the most appropriate therapeutic options.
Subject(s)
Humans , Female , Pregnancy , Adult , Anemia, Dyserythropoietic, Congenital/complications , Anemia, Dyserythropoietic, Congenital/diagnosis , Hydrops Fetalis/etiology , Abortion, Eugenic , ErythropoiesisABSTRACT
Las anemias diseritropoyéticas congénitas (ADC) son un grupo de trastornos heridatarios de la hematopoyesis caracterizados por anemia refractaria de severidad variable. Se distinguen 3 tipos fundamentales: 1, 2 y 3. El gen responsable de la ADC-1 (CDAN1) se localiza en el cromosoma 15q15, aunque estudios moleculares recientes evidencian la heterogeneidad de esta enfermedad. Se presenta una paciente de 3 años con diagnóstico de ADC-1 que a los 3 meses de edad comenzó con anemia severa, hiperbilirrubinemia indirecta, reticulocitosis ligera, altos requerimientos transfusionales y alteraciones del desarrollo pondoestatural dado por baja talla. La prueba de Ham fue negativa y en sangre periférica predominó la macrocitosis. En el examen de la médula ósea se observó diseritropoyesis con hiperplasia eritroide, hematopoyesis megaloblástica, precipitados intracitoplasmáticos, núcleos irregulares, cariorrexis, binuclearidad y puentes internucleares. No hubo respuesta al tratamiento con interferón alfa recombinante. La paciente se encuentra con tratamiento quelante con deferroxamina y se ha planteado la posibilidad de un trasplante de células progenitoras hematopoyéticas alogénico no relacionado
The congenital dyserytropoietic anemias (CDT) include a series of hematopoiesis hereditary disorders characterized by a refractory anemia of variable severity. There are three fundamental types: 1, 2 and 3. The gen accounted for CDT-1(CDAN1) is located in 15q15 chromosome, although recent studies demonstrate the heterogeneity of this disease. This is the case of a female patient aged 3 diagnosed with CDT-1who at three months old had a severe anemia, indirect hyperbilirubinemia, slight reticulocytosis, high transfusion requirements and stature disorders due to its low height. Hams was negative and in peripheral blood there was macrocytosis predominance. Bin bone marrow examination it was possible to observe dyserytropoiesis with erythroid hyperplasia, megaloblast hematopoiesis, intracytoplasm precipitates, irregular nuclei, karyorresis, binuclearization and internuclear bridges. There wasnt response to treatment with the recombinant type α interferon. Patient is under chelation treatment with deferoxamine and it was proposed the possibility of no-related allogenic of hematopoietic parent cell
Subject(s)
Humans , Female , Child, Preschool , Anemia, Dyserythropoietic, Congenital/complications , Anemia, Dyserythropoietic, Congenital/epidemiology , Case ReportsABSTRACT
<p><b>OBJECTIVE</b>To analyze the clinical and laboratory features of patients with congenital dyserythropoietic anemia type I (CDA-I), and improve the clinical diagnostic accuracy.</p><p><b>METHODS</b>The clinical and hematological features of 5 patients diagnosed as CDA-I in our hospital between July 2002 and July 2007 were analyzed retrospectively, and the related literatures was reviewed.</p><p><b>RESULTS</b>Five CDA-I patients, 1 male and 4 females, all had a long history of varied degree of chronic anemia. One patient had congenital malformations, 3 jaundice and 4 hepatosplenomegaly. Bone marrow specimens invariably showed hypercellularity due to erythroid hyperplasia with megaloblastic changes, irregularly shaped nuclear, and chromatin bridges in 0.2% to 0.6% of all erythroblasts. All the 5 patients' bone marrow erythroblasts showed spongy heterochromatin appearances (swiss-cheese) with electron microscopy examination. There was no morphologic abnormality in the granulocytes and megakaryocytes. Serum ferritin levels were increased in 3/4 patients. One patient had been misdiagnosed as hereditary spherocytosis and performed splenectomy in the local hospital with no improvement in Hb level.</p><p><b>CONCLUSIONS</b>CDA-I is a rare congenital anemia characterized by ineffective erythropoiesis, jaundice, hepatosplenomegaly and iron overload, and may be misdiagnosed. Keeping these manifestations in mind should avoid misdiagnosis.</p>
Subject(s)
Adolescent , Adult , Female , Humans , Male , Young Adult , Anemia, Dyserythropoietic, Congenital , Blood , Diagnosis , Retrospective StudiesABSTRACT
The study was aimed to investigate the ultranstructural feature and diagnostic criteria of congenital dyserythropoietic anemia-type I (CDA-type I). Nucleated red cells in bone marrow from two patients with CDA-type I were analyzed by transmission electron microscopy (TEM). The results indicated that the erythropoietic/granulopoietic ratio was markedly increased with megaloblastic morphology in all stage of erythrocyte. Most proerythroblast showed of irregular nuclei, while the Swiss-cheese-appearance of the heterochromatin was usually found in basophilic and polychromatic erythroblast. About half of orthochromatic erythroblast illustrated karyolysis and karyorrhexis. Some orthochromatic erythroblast exhibited karyolysis and plasmolysis simultaneously. The inter-nuclear chromatin bridge between separated erythroblasts was seldom found by TEM. The nuclear membrane and rough endoplasmic reticulum were destructed at all stage of erythrocytes in different degree. In conclusion, the megaloblastic erythrosis was the main characteristic of CDA-type I, and then nuclear membrane disruption in polychromatic erythroblast and karyolysis or karyorrhexis in orthochromatic erythroblast. The universal breakdown of cytoplasm membranous system was fundamental pathogenesis of CDA-type I.
Subject(s)
Female , Humans , Infant , Male , Anemia, Dyserythropoietic, Congenital , Blood , Pathology , Bone Marrow Examination , Erythroblasts , Erythrocytes , Iron , Blood , Microscopy, Electron, TransmissionABSTRACT
Congenital dyserythropoietic anemia (CDA) is a rare disorder, which manifests clinically with varying degrees of anemia and hepatosplenomegaly. These features are not pathognomic and a diagnosis of CDA is generally considered after other causes of chronic hemolytic anemia have been ruled out. The clinico-hematological profile of 10 patients with CDA is presented in this communication. Six patients had CDA type II and four had CDA type I. Age at onset of pallor ranged from birth to 9 years. Blood transfusion requirements varied from nil to monthly. This is the first report of CDA type I from India.
Subject(s)
Anemia, Dyserythropoietic, Congenital/blood , Child , Child, Preschool , Female , Ferritins/blood , Humans , Infant , Infant, Newborn , Male , Reticulocyte CountABSTRACT
Congenital dyserythropoietic anemia Type II (herditary erythroblatic multinuclearity with positive acidified serum test; HEMPAS) is characterized by binuclearity, multinuclearity, pluripolar mitoses, karyorrhexis of normoblasts, and the presence of abnormal antigens on the red cells. We experienced a case of HEMPAS in a 2 month old girl patient who had an intermittent fever, abdominal distention with palpable liver & spleen, and generalized jaundice. The blood analysis revealed anemia, and thrombocytopenia. Peripheral blood smear showed an averge of 6 mature normoblast per 100 leukocyte count. The red cells showed moderate anisocytosis, poikilocytosis, irregularly crenated, contracted cells and occasional spherocytes. The leukocytes showed relative lymphocytosis, and there were occasional villous lymphocytes. The marrow smear showed abnormality in erythroid series. About ten percent of the erythroblasts showed 2~7 nuclei or lobulated nuclei. The mitotic forms of the erythroid precursors were also increased in frequency. The M:E ratio was 1:3.2. Blood culture on this patient showed a pure growth of Coxiella burnetti. Medical treatment with Doxycycline and Rifampin was performed. After treatment, she became afebrile showing improved general condition with decreased size of liver & spleen. In spite of clinical improvement, she died suddenly 3 weeks after initial treatment.
Subject(s)
Female , Humans , Infant , Anemia , Anemia, Dyserythropoietic, Congenital , Bone Marrow , Coxiella , Doxycycline , Erythroblasts , Fever , Hempa , Jaundice , Leukocyte Count , Leukocytes , Liver , Lymphocytes , Lymphocytosis , Mitosis , Rifampin , Spherocytes , Spleen , ThrombocytopeniaABSTRACT
Coxiella burnetii(C. burneii)was first recognized as the agent of Q fever in 1937. Q fever is an acute self-limited febrile illness. However, it manifests with several clinical symptoms depending upon the organs that are involved. The association of C. burnetii with human neoplasia has been rarely reported. We prospectively studied the 55 patients with fever of unknown origin, pneumonia, hepatosplenomegaly, lymphadenopathy, leukemia, lymphoma, and immunodeficiency and 14 persons who contacted the Q fever patients. The patient's sera were tested for antibodies specific for C. burnetii, using indirct fluorescent antibody techniques (IFA). 1) We serologically confirmed 23 C. burnetii infection. The 23 children with Q fever ranged in age from 0 to 15 years, with mean age of 4 years 11 months. Seventeen were boys and 6 were girls. 2) Characteristic symptoms and signs were fever (9/12 cases), rash (8/14 cases), hepatosplenomegaly (8/8 cases)and lymphadenopathy (14/27 cases). Five cases among 14 asymptomatic cases who contacted Q fever patients showed positive IFA test. One suffered from irregular uterine contraction, 4 weeks after contact with a Q fever patient. 3) There were no history of exposure to domestic animal carriers or contaminated dust, or drinking raw milk except one family. Three attending doctors and her father infected by a patient with Q fever. These suggested the person to person transmission of Q fever in a family and house staffs infected by a patient of Q fever. 4) Q fever (9 cases), acute lymphoblastic leukemia (2 cases), acute myelomonocytic leukemia (1 case), hairy cell leukemia (1case), Kawasaki disease (4 cases) and congenital dyserythropoietic anemia (1 case) showed positive IFA test. 5) Of 9 cases who suffered from lnly Q fever, 7 cases were confirmed hairy cell formation in their peripheral blood. One case was diagnosed as hairy cell leukemia after bone marrow study. Of 7 cases who showed hairy cells, all had hepatomegaly, 6 cases had lymphedenopathy and 5 cases showed splenomegaly. All except 1 case who was not followed cured after treatment. 6) We treated Q fever patients with rifampin and/or ciprofloxacin, and/or tetracyclin (over 8 year-old of age)for 2-4 weeks. One 25 month-old patient with hairy cell leukemia was treated with rifampin, ciprofloxacin and tetracyclin for 4 weeks, and rifampin for 8 months. A pregnant patient was administered with rifampin, and treated with rifampin and ciprofloxacin after delivery. We gave rifampin in one nweborn baby. In conclusion, we suggest that Q fever should be considered in the differential diagnosis of patients with FUO, hepatosplenomegaly and/or immunodeficiency.