Novel ELANE gene mutation in a Korean girl with severe congenital neutropenia

Severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections. Mutation of the ELANE gene encoding human neutrophil elastase is the most common genetic alteration. A Korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation. She had a past history of omphalitis and isolated neutropenia at birth. The peripheral blood showed a markedly decreased absolute neutrophil count, and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage. Her direct DNA sequencing analysis demonstrated an ELANE gene mutation (c.607G > C; p.Gly203Arg), but her parents were negative for it. She showed only transient response after subcutaneous 15 μg/kg/day of granulocyte colony stimulating factor administration for six consecutive days. During the follow-up observation period, she suffered from subsequent seven febrile illnesses including urinary tract infection, septicemia, and cellulitis.     

An unusual association of Felty syndrome and TCR gamma delta lymphocytosis.

Felty syndrome, comprised of neutropenia, rheumatoid arthritis and splenomegaly, occurs in approximately 1% of patients with rheumatoid arthritis. Up to one third of these patients have an increased number of large granular lymphocytes. The usual immunophenotype of these cells is CD3+, CD8+, CD57+, T cell receptor (TCR) alpha beta. A patient with Felty syndrome and large granular lymphocytosis, who had an unusual immunophenotype CD3+, CD4-, CD8-, TCR gamma delta, is described. Her neutropenia responded to treatment with granulocyte colony stimulating factor (G-CSF), which was given in order to raise her neutrophil count prior to bilateral knee replacement surgery. Thus, Felty syndrome with large granular lymphocytosis is a heterogeneous condition, one in which TCR gamma delta large granular lymphocytosis may be found, and also shows a response to treatment with G-CSF.     

Different Clinical Phenotypes in Familial Severe Congenital Neutropenia Cases with Same Mutation of the ELANE Gene

Severe congenital neutropenia (SCN) is a heterogeneous group of disorders with a defect in granulopoiesis causing marked neutropenia and severe bacterial infections. A 17-month-old girl (patient 1) was admitted due to cervical lymphadenitis caused by methicillin-resistant Staphylococcus aureus, with neutropenia. She had Pseudomonas aeruginosa sepsis and peritonitis with perforated appendicitis at 8-month of age. Her sister, a 37-month-old girl (patient 2), had recurrent stomatitis with profound neutropenia, and her mother, a 32-yr-old woman (patient 3), had had recurrent stomatitis until her early 20s with neutropenia. We found an ELANE gene mutation (c.597+1G > A) from them in direct DNA sequencing analysis. Patients 1 and 2 did not respond to granulocyte colony stimulating factor and patient 1 was treated with prolonged antibiotics and excision. We demonstrated inherited SCN cases showing different severity even with the same mutation of the ELANE gene in a family.

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Correction of DiGeorge anomaly with EBV-induced lymphoma by transplantation of organ-cultured thymus and Epstein-Barr-specific cytotoxic T lymphocytes

A young woman with DiGeorge anomaly showed normal immune tests as a child and did not experience the symptoms of profound T cell immunodeficiency. However, she had chronic pulmonary infections which led to bronchiectasis. At age 14, she developed an Epstein-Barr virus-induced lymphoma and her T cell function tests were markedly abnormal. After intensive chemotherapy, she received an organ-cultured thymus transplant but because of an abnormally high EBV DNA titer was also given autologous EBV-specific cytotoxic T cells, prepared prior to transplant. Titers fell from 80,000 genome copies/mg DNA to 2000 within 6 weeks. She was clinically well and her T cell tests improved. Sixteen months after the transplant, however, her tumor returned; EBV DNA levels had risen to 40,000 copies/mg DNA. She again received autologous EBV-specific cytotoxic T lymphocytes and valcyclovir and Cytogam as well. Her tumor resolved on this therapy and she has remained well to this date, 29 months after the recurrence. T cell tests, which had deteriorated with the recurrence of the tumor, now show normal responses. This experience records a number of unique features of thymus transplantation. This is the first recorded successful thymus transplant in a patient with partial T cell immunity and thus expands the potential of this treatment modality to patients other than infants with complete DiGeorge anomaly. The patient demonstrates cytotoxic activity against mouse cells, demonstrating the ability to respond to a new antigen which requires host antigen presenting cells. Measurement of alpha 1 TRECs (T cell receptor excision circles) shows evidence of increasing and sustained thymopoiesis since the transplant at a level consistent with the age of the transplant donor rather than that of the recipient.     

Successful pregnancy by transmyometrial and transtubal embryo transfer after IVF in a patient with congenital cervical atresia who underwent uterovaginal canalization during Caesarean section: case report

Successful pregnancy in a patient with congenital cervical atresia is a great challenge for assisted reproductive techniques and reproductive medicine. We report a case of successful pregnancy by transmyometrial and transtubal embryo transfer simultaneously after in-vitro fertilization (IVF) in a 33 year-old patient with congenital cervical atresia diagnosed at the age of 18 years. The patient had experienced cyclic abdominal pain and amenorrhoea since she was 13 years old. She had had two unsuccessful attempts to create a new uterovaginal canal in another hospital. At the age of 32 years, she was referred to our unit and had a successful pregnancy after transmyometrial and transtubal embryo transfer. Caesarean section was performed at 36 weeks gestation due to progressive pre-eclampsia and gestational diabetes. A healthy male baby weighing 2812 g was safely delivered. Uterovaginal canalization with amniotic membrane for the covering of the neo-endocervical wall was performed during Caesarean section. Normal menstrual outflow and symptomatic relief have continued for 5 months after the operation. To the best of our knowledge, this is the first reported case of successful pregnancy by transmyometrial and transtubal embryo transfer as well as uterovaginal canalization performed during Caesarean section in a patient with congenital cervical atresia.     

Polymyxin B-immobilized fiber hemoperfusion with low priming volume in an elderly septic shock patient with marked endotoxemia

An 84-year-old woman with septic shock caused by pyelonephritis is described herein. She was admitted for severe back pain and high fever. Her white blood cell (WBC) count and C-reactive protein (CRP) and endotoxin levels were elevated at 38,000/microl, 40.0 mg/dl, and 8,400 pg/ml, respectively. Her blood pressure was 80/34 mm Hg. Urinalysis revealed occult blood with innumerable WBCs. Plain abdominal radiography showed calcium stones in both kidneys. Septic shock with endotoxemia was diagnosed, and the patient was treated with antibiotics, gamma-globulin, and dopamine. However, her plasma endotoxin level remained high for 3 days. We performed direct hemoperfusion twice using a polymyxin B-immobilized fiber (PMX-F) column with a low priming volume. After PMX-F treatment, the patient's temperature decreased to 36.8 degrees C; her WBC count and CRP level decreased to 9,200/microl and 3.8 mg/dl, respectively. Her plasma endotoxin level decreased to 840 pg/ml after the first treatment and to 188 pg/ml after the second treatment. The next day, her blood endotoxin level further decreased to 32 pg/ml. Her blood pressure increased to 92/60 mm Hg after the first treatment and to 118/76 mm Hg after the second treatment. The patient was discharged on day 26 after admission. Our experience in this case suggests that PMX-F treatment with a low priming volume may be beneficial in elderly patients with septic shock and marked endotoxemia.     

Polymyxin B-immobilized fiber hemoperfusion in a patient with active ulcerative colitis

A case involving a 31-year-old woman with active ulcerative colitis is described. She suffered symptoms of infraumbilical abdominal pain, severe diarrhea, and low-grade fever that did not improve with conventional treatment, including antidiarrheal drugs and antibiotics. Ulcerative colitis was diagnosed according to endoscopic and histologic findings. She was treated with prednisolone and sulfasalazine, and her symptoms disappeared after 1 month. Sulfasalazine therapy was continued for 3 months, and the patient's condition remained stable for 4 years. Recently, she was admitted with abdominal pain, severe diarrhea, and melena. She was again treated with prednisolone and intravenous hyperalimentation, but her symptoms did not improve. Colonoscopy showed multiple ulcers with bleeding and polyposis and severe edema in the colon. In addition, she had a high blood endotoxin concentration (38.0 pg/ml; normal < 9.8 pg/ml). She underwent polymyxin B-immobilized fiber (PMX-F) hemoperfusion therapy twice. After 2 weeks, her symptoms resolved completely, colonoscopy showed disappearance of the edema, revascularization of the mucosa, and improvement of the ulcers, and blood endotoxin concentration decreased to 5.0 pg/ml. These results suggest that PMX-F treatment may be beneficial for the management of ulcerative colitis with endotoxemia.     

Severe Rejection of an HL-A Identical Sibling Renal Transplant

A twenty-year-old patient with end-stage pyelonephritis received an HL-A identical renal transplant from her brother. She remained well for 28 days and then suffered a severe rejection episode while on decreased immunosuppressive therapy because of low white blood counts, reducing renal function to a creatinine clearance of 32 ml/min. Two weeks later she suffered a second major rejection episode which was arrested at a clearance of 10 ml/min. For the last 10 months renal function has remained stable at this level.     

A case of focal segmental glomerulosclerosis associated with aplastic anemia

The pathogenic mechanism of focal segmental glomerulosclerosis (FSGS) and aplastic anemia are associated with immunologic events which lead to glomerular cell injury or hematopoietic cell destruction. We present an extremely rare case of FSGS with aplastic anemia in a 30-yr-old woman. The laboratory examination showed hemoglobin 7.2 g/dL, white blood count of 4,200/ microL, platelet count 70,900/microL. Proteinuria (2+, 3.6 g/day) and microscopic hematuria were detected in urinalysis. The diagnosis of FSGS and aplastic anemia were confirmed by renal and bone marrow biopsy. She was treated with immunosuppressive therapy of prednisone 60 mg/day orally for 8 weeks and cyclosporine A 15 mg/kg/day orally. She responded with gradually improving her clinical manifestation and increasing peripheral blood cell counts. Prednisone was maintained at the adequate doses with tapering after 8 weeks and cyclosporine was given to achieve trough serum levels of 100-200 ng/mL. At review ten month after diagnosis and initial therapy, the patient was feeling well and her blood cell counts increased to near normal (Hb 9.5 g/dL, Hct 32%, WBC 8,300/microL, platelet 123,000/microL) and renal function maintains stable with normal range proteinuria (0.25 g/day).     

Psoriasiform eruption triggered by recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) and exacerbated by granulocyte colony stimulating factor (rG-CSF) in a patient with breast cancer.

Colony-stimulating factors (CSFs) are commonly used for the treatment of neutropenia following chemotherapy and for the mobilization of peripheral blood stem cells (PBSC). We recently experienced a rare case of a new onset of psoriasiform eruption by GM-CSF (granulocyte-macrophage colony-stimulating factor) which was exacerbated by G-CSF (granulocyte colony-stimulating factor) in a patient with breast cancer. A 36-year-old woman had received neoadjuvant chemotherapy (cyclophosphamide, epirubicin and 5-fluorouracil), modified radical mastectomy and adjuvant chemotherapy with paclitaxel and mitoxantrone followed by GM-CSF administration for the treatment of locally advanced breast cancer. She had developed a psoriatic skin lesion on face and both upper arms during leukocyte recovery in spite of no previous history of psoriasis. Next, the chemotherapy course was complicated by a flare of mild psoriatic skin lesion, although CSF was changed into G-CSF due to GM-CSF-associated psoriasis. Subsequently, she had had high-dose chemotherapy and autologous peripheral blood stem cell transplantation for consolidation therapy. GM-CSF was administered for the mobilization of PBSC and post-transplant period, but psoriatic skin lesion did not appear. During 6 months after PBSCT, psoriasiform eruption did not appear.     

Achondroplasia-hypochondroplasia complex in a newborn infant.

We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia complex. The diagnosis was suggested antenatally when obstetrical ultrasonography at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither had had genetic counseling or molecular testing prior to the pregnancy. Antenatal ultrasound study at 29 weeks of gestation showed a large head, very short limbs, and a small chest; the findings were more severe than in achondroplasia or hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of gestation and had rhizomelic shortness of limbs with excess skin creases, large head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness of the long bones and flaring of the metaphyses. She had mild hypoplasia of lungs. Molecular testing showed both the G1138A and the C1620G mutations in FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8 months, she has disproportionate shortness of the long bones and a large head with frontal bossing and a depressed nasal bridge. Her chest remains small, and she is on home oxygen at times of respiratory stress. She has a large gibbus. She is delayed in her motor development and has significant head lag. To our knowledge, there is only one previously published report of achondroplasia-hypochondroplasia complex.     

Epithelioid trophoblastic tumor after induced abortion with previous broad choriocarcinoma: a case report and review of literature

Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum β-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy.     

Distichiasis-lymphedema syndrome: Tetralogy of Fallot,chylothorax, and neonatal death

We describe a newborn female with a severe presentation of distichiasis-lymphedema syndrome (McKusick 15340). She was initially evaluated because of a phenotype suggestive of Ullrich-Turner or Noonan syndrome (low posterior hairline, cupped ears, severe pterygium colli, heart murmur, and pectus excavatum). Distichiasis was noted at age 6 weeks. Subsequent to surgery for tetralogy of Fallot, patent ductus arteriosus, and branch pulmonic stenosis, she developed persistent chylothorax and sepsis. She died at 3 months. Family history indicated segregation of distichiasis-lymphedema syndrome. She was the sixth member in her family to have this disorder and was the most severely affected. © 1996 Wiley-Liss, Inc.     

Quetiapine use for the treatment of manic episode during pregnancy

Summary The foregoing is a case report about a 30-year-old woman, who was referred to our psychiatry clinic with a clinical picture of manic episode, at the 21st week of her first pregnancy. She had a history of bipolar affective disorder for 12 years, had two previous manic episodes and had stopped taking lithium 6 months ago because of her plans to become pregnant. Quetiapine was begun and the dose was slowly increased to 1200 mg/day after 2 weeks. She continued to receive quetiapine throughout her pregnancy. Her obstetrical and perinatal examinations were done by a consultant obstetrician. At the follow-up, she had given birth to a boy, at 39th week of her pregnancy, with an Apgar score of 10. Follow-up of the infant up to 3 months reveals normal physical and psychomotor development. The pros and cons of quetiapine use during pregnancy are discussed.     

Neutropénies constitutionnelles et acquises

Evaluating a neutropenia induces first documenting its aetiology. Beside the specific aspects of the newborn, neutropenia in a child may be 1) acquired - the most frequent type -, 2) constitutional, part of a complex genetic disease, 3) constitutional, isolated. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children. It is usually well tolerated and has a frequent favourable outcome in 12-36 months. Many complex genetic diseases include a neutropenia, among which several immunologic disorders that must be ruled out before considering the diagnosis of isolated constitutional neutropenia. Severe congenital neutropenia is the main primary constitutional neutropenia. It is profound, usually < 500 polymorphonuclear leukocytes/mm³ and exposes to severe pyogenic and fungal infections. Mutations in the gene encoding neutrophil elastase (ELA2) are the most common genetic abnormalities in this group of patients, as well as for patients with cyclic neutropenia. In the neonatal period, neutropenia must primarily suggest a bacterial infection, although other aetiologies have to be known, particularly neonatal neutropenia caused by passive transfer of maternal antibodies and neutropenia related to gravidic hypertension. In adulthood, most neutropenias are related to an infection, to the side effect of a drug, to a malignant haemopathy or to an autoimmune disease. A clinical entity, the idiopathic neutropenia, is described, however, apparently completely primitive and acquired. The treatment of severe chronic neutropenia is directed towards the prevention of infections. It includes prophylactic antibiotherapy such as the trimetroprim-sulfamethoxazole association, the most commonly used, and granulocyte colony stimulating factor (G-CSF). G-CSF has considerably improved patients' conditions. It is usually well tolerated, but side effects have been reported (bone pain, thrombocytopenia, glomerulonephritis, vasculitis). Long-term treatment by high-dose G-CSF has been shown to increase the spontaneous natural risk of leukaemia in patients with congenital severe neutropenia.     

A case of severe asthma and peach allergy that improved with omalizumab therapy: a case report

A 30-year-old woman had refractory asthma. She had also experienced twice severe anaphylaxis episodes after ingesting peaches. The patient was extremely wary about reoccurrence of anaphylaxis and avoided ingesting any fruits, including peaches. She visited our hospital for testing and treatment for asthma and the peach allergy. Skin and serologic testing showed that she had a severe allergy to house dust, mites, and peaches. The food challenge test results showed that ingesting 6.5 g of the peach fruit induced dyspnea in the patient. Her asthma could not be controlled despite treatment involving a leukotriene receptor antagonist and combination inhalation of high-dose salmeterol xinafoate/fluticasone propionate. We advised the patient to keep strict avoidance ingesting peaches because of her food allergy. However, she hoped to overcome her food restrictions, especially those for fruits. We initiated treatment involving the recombinant humanized monoclonal anti-IgE antibody omalizumab (150 mg, once a month) to ensure that the asthma was controlled well and to improve the patient's diet. The asthmatic symptoms ameliorated, and the peak expiratory flow increased in a short time. We gradually reduced the restriction on peach consumption. This was achieved by rechallenging the patient with increasing doses of 290 mg of the peach fruit and was initiated at 28 weeks after starting omalizumab therapy. The restriction on peach consumption was lifted eventually, and the patient did not experience any allergic symptoms subsequently on ingesting peaches. Thus, for our patient, omalizumab therapy was highly effective in achieving remission from both asthma and peach allergy.     

Successful pregnancy outcome following Tompkins metroplasty done early in pregnancy

A hysterosalpingogram revealed a septate uterus in a 29 year old nulliparous woman with a history of recurrent pregnancy loss. The patient underwent Tompkins metroplasty in the proliferative phase of the menstrual cycle. One month after the operation she presented with a delay in her menses and a positive pregnancy test. Ultrasound revealed a viable fetus commensurate with 10 weeks gestation, making the gestation period 5 weeks at the time of surgery. After reviewing the patient's menstrual history it was found that the period the patient had before surgery was on time but with unusually minimal bleeding. A repeat ultrasound scan for anomaly done 7 weeks later was commensurate with 17 weeks gestation. The patient carried her pregnancy for the first time until approximately 37 weeks when she delivered by Caesarean section a healthy female baby weighing 3700 g.      

Polycythemia Vera treated with 32P and Myleran: Development of chronic granulocytic leukemia with chromosomal abnormalities in one patient

Chronic granulocytic leukemia developed in a 59–year-old woman who had previously received a total of 21 mCi ³²P for polycythemia Vera. She was treated with Myleran (busulphan) for her chronic granulocytic leukemia. Cytogenetic studies revealed deletion of chromosomes No. 8 and 12, and translocation between 1 and 8. The patient also developed a severe autoimmune hemolytic anemia, for which she received prednisone treatment. She died with a perforated stomach ulcer.     

Emergence of chronic myelogenous leukemia in a patient with primary thrombocythemia and absence of BCR/ABL rearrangement

A 65-year-old woman presented with clinical features of primary thrombocythemia (PT), and absence of the BCR/ABL fusion gene. She responded to hydroxyurea treatment, although after 1 year she required progressive increases in the dose. Six years later, she maintained a high platelet count despite hydroxyurea at 2 g/day and treatment was changed to anagrelide. After 3 weeks, both platelet and leukocyte counts increased. A karyotype study detected the Philadelphia chromosome in all of the 24 metaphases studied. Fluorescent in situ hybridization (FISH) analysis revealed the BCR/ABL rearrangement. The patient was treated with imatinib mesylate and achieved a normal platelet and leukocyte count in 3 weeks. Patients presenting clinical features of PT expressing the Ph chromosome or the BCR/ABL fusion gene have been well documented but, to our knowledge, this is the first report of evolution from typical PT to chronic myeloid leukemia.     

Pregnancy outcomes in a patient-heterozygous carrier of R506Q mutation of factor V (Leiden)

The aim was to review currently available evidence on the association between thrombophilia and adverse pregnancy outcomes. Maternal thrombophilia has recently been identified as a major cause of thromboembolism, placental thrombosis and adverse pregnancy outcome including severe preeclampsia, placental abruption, intrauterine growth retardation, recurrent pregnancy loss, and stillbirth. The relatively high prevalence of thrombophilia defects in the general population and the association with adverse maternal and fetal outcomes have prompted obstetricians to focus their interest on this area. We focused on genetic thrombophilias (factor V Leiden mutation) and its possible impact on severe preeclampsia, placental abruption and intrauterine fetal death. A 39-year-old patient was regularly treated at our Department. Her mother had placental abruption and deep venous thrombosis of lower extremities in medical history. Our patient was suffering from multiple sclerosis from 1990. Until this pregnancy she had been pregnant for six times and had delivered one healthy child. She had four cesarean sections, one for preeclampsia (live-born infant died three days after birth), two for placental abruption (both stillbirths), one spontaneous abortion and one artificial abortion. Having in mind her family and medical history, we focused on genetic thrombophilia. Using the PCR-method we identified activated protein C resistance due to factor V Leiden mutation. The patient was treated by low-molecular weight heparin. A healthy infant was born by cesarean section after 37 weeks of gestation. Therapy with low-molecular weight heparin continued for ten days postpartum.