Familial panmyelophthisis; Fanconi syndrome in adults

An account is given of a similar and hitherto unknown clinical-hematologicsyndrome in two adult brothers with marked hemorrhagic diathesis, diffuse pigmentation of the skin, violent pain in the bones and panhemocytopenia. In theyounger brother, there is also a certain degree of infantilism. The elder brotherdied with all the symptoms of an intensive aplastic anemia; in the younger brother,the condition was stabilized after splenectomy. The blood picture in both patientswas characterized by a hyperchromic anemia with remarkable micro- and macrocytosis, and an increased number of reticulocytes. In the younger brother, increasedfragility of the red blood cells and an elevated serum iron content were observed.In both cases, an unusual increase of the plasmocytic and reticular cells and of thetissue mast cells was noticed in the bone marrow and, in the final stages of thedisease, the marrow showed marked fibrosis.

The disease is believed to be a variety, in adults, of the syndrome first describedby Fanconi as a constitutional panmyelopathy occurring in children. The illnessis the result of a hereditary pathologic reaction of the reticulo-histiocytic systemand seems to have been caused by an anaphylactic-allergic phenomenon. The possibility is discussed that genetic connections may exist between this conditionand other diseases, such as certain osteoscleroses and Cooley’s anemia, which arecharacterized by simultaneous disturbances of the bone and bone marrow and bya similar blood morphology.

     

Myelodysplastic syndrome with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment for chronic myeloid leukemia

We describe a 60-year-old Japanese patient with chronic myeloid leukemia (CML) who developed myelodysplastic syndrome (MDS) with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment. Most cases that developed chromosomal abnormality in Ph negative cells during imatinib therapy were reported to have less clinical implications, while rare cases developed MDS/AML. The present case suggested that metaphase karyotype analysis and bone marrow examination should be performed for the long term follow-up under imatinib treatment in cases showing cytopenia. The results also suggested that monosomy 7 in Ph negative cells may be an indicator of a poor prognosis.     

Myelodysplastic syndrome with chromosomal abnormality of t(11;21) (q23;q22)

A 33-year-old woman was hospitalized because of bleeding tendency. Hemoglobin was 10.7 g/dl, white blood cell 2,100/microliters and platelet 2.1 X 10(4)/microliters. Bone marrow showed marked dysplasia of trilineage blood cells. Atypical blasts and monocytoid cells accounted for 14.5% in the myelogram. Cytogenetic study of bone marrow cells revealed translocation with t(11;21) in all of 20 metaphasic cells analyzed by G-banding method. A diagnosis of RAEB was made. Familial survey revealed that her elder brother died of acute monocytic leukemia (AMoL). The patient received small dose therapy of Ara-C and BHAC-DMP therapy, but a remission was not obtained. The patient's general condition deteriorated with infection, bleeding tendency and chronic hepatitis due to transfusions, therefore we have followed up the patient with prednisolone and red blood cell transfusion. It has become evident that some types of acute leukemia with monocytic features have a cytogenetic change at 11 q 23. But it is rare that RAEB with increased monocytoid cells has a cytogenetic change at 11q23. In addition, the patient's elder brother died of AMoL. This case is important in relation to cytogenetic change at 11q23 and hematopoietic abnormalities.     

Pseudo-Gaucher Cell Proliferation Associated with Myelodysplastic Syndrome

We report an extremely rare case of pseudo-Gaucher cell proliferation with myelodysplastic syndrome (MDS). A 77-year old Japanese man was referred to our hospital with splenomegaly and thrombocytopenia, and subsequent bone marrow aspiration revealed infiltrates of foamy vacuolated macrophages without any evidence of other morphologic abnormalities. A karyotype analysis showed the presence of 46,XY,del(20)(q11) in 20 of 20 examined bone marrow cells. We performed a splenectomy, and the resulting pathologic findings revealed massive infiltration of foamy vacuolated macrophages, which were morphologically compatible with Gaucher cells. The activities of beta-glucosidase and acid sphingomyelinase were within normal ranges; therefore, the foamy vacuolated macrophages were considered pseudo-Gaucher cells. A diagnosis of MDS, subclassified as refractory anemia, was then made according to World Health Organization classification guidelines. Pseudo-Gaucher cell proliferation and infiltration might therefore be observed in other patients presenting with MDS.     

骨髓增生异常综合征伴难治性中性粒细胞减少1例报告

目的:探讨骨髓增生异常综合征(MDS)伴难治性中性粒细胞减少(RN)患者的临床特点,总结1例MDSRN患者的诊疗体会。方法:回顾性分析1例MDS-RN患者的临床特点、诊治经过、骨髓细胞形态学及遗传学的结果。结果:患者58岁,因乏力就诊,WBC 2.9×109/L,分类N 35%、L 56%、M 9%,Hb 136 g/L,PLT 182×109/L,骨髓象:增生活跃,粒系占57.5%;其中见假P-H畸形、胞浆颗粒减少、分叶障碍等发育异常粒细胞占24%。红系形态未见明显改变。巨核细胞增生,可见胞体小、单圆核巨核细胞。染色体核型检查发现46,xy,add(16)q24[20]。结论:对MDS难治性血细胞减少伴单系发育异常患者,除常规骨髓象、骨髓活检观察细胞形态学外,应做染色体核型分析,2代测序技术检测基因突变,以作出MDS的精准诊断和治疗。     

Successful immunosuppressive therapy for a patient with hypoplastic myelodysplastic syndrome

We encountered a patient with hypoplastic myelodysplastic syndrome (MDS) who responded to immunosuppressive therapy including antithymocyte globulin and cyclosporin A (CsA). A 13-year-old girl was referred to our hospital because of pancytopenia. Bone marrow smears disclosed extreme hypocellularity without cellular atypism. A diagnosis of aplastic anemia was made, and immunosuppressive therapy consisting of ATG, CsA, granulocytecolony-stimulating factor (G-CSF), methylprednisolone, and danazol was started. A month later dysplastic cells appeared in the bone marrow. The karyotype of pretreatment bone marrow cells was 46, XX, del (13) (q12; q14). Therefore, the final diagnosis was hypoplastic MDS. CsA and danazol were continued. The patient became transfusion-independent 1 month later and dysplastic cells disappeared from bone marrow 3 months later. The chromosomal abnormality also became undetectable 6 months after the initiation of treatment. These findings indicated that immunosuppressive therapy is beneficial for patients with hypoplastic MDS.     

老年黄斑变性与遗传因素

目的探讨老年黄斑变性（ＡＲＭＤ）是否存在遗传因素。方法分析一个７姊妹兄弟的家族中，４位成员的老年黄斑变性患病情况。结果在被检查的６位６０岁以上的姊弟中，３位男性均患ＡＲＭＤ，且其中２姊弟为湿性型，其线粒体脱氧核糖核酸（ｍｔＤＮＡ）均呈突变。虽然这些成员长期生活在不同国家和环境，却有类似的临床或实验室改变。结论从本家族ＡＲＭＤ发病情况看，ＡＲＭＤ发病机制上可能存在遗传因素     

The myelodysplastic syndromes: different evolution patterns based on sequential morphological and cytogenetic investigations

Serial morphological and cytogenetic investigations were performed in 46 patients with the myelodysplastic syndrome (MDS). Twenty-one patients (45.5%) progressed to AML (greater than 30% blasts in bone marrow smears). Based on sequential determinations of percentages of bone marrow blasts, three patterns of evolution were observed in MDS. Patients with evolution pattern A (48%) had an apparently stable disease with minimal or no increase in bone marrow blasts. Exceptionally they developed new or additional chromosomal anomalies during the course of their disease. Cases in this group, who showed no abnormal localization of immature myeloid precursors (ALIP) at time of diagnosis experienced prolonged survival (median: 43 months), while ALIP positive patients had shorter survival times (median: 14 months), with high probability of early death from infections and/or bleeding problems. Patients with evolution pattern B (28%) initially had a morphologically stable disease, comparable to cases with evolution pattern A, but showed an abrupt shift from MDS to AML. Most of these patients (82%) were ALIP positive and a substantial proportion (46%) showed karyotype anomalies at diagnosis. The abrupt shift to AML in these patients was frequently (61.5%) associated with additional cytogenetic anomalies. Patients with evolution pattern C (24%) showed a gradual increase in bone marrow blasts. The majority of these cases (8/11) ultimately developed acute myeloid leukaemia (gradual progression to AML), whereas some patients (3/11) died from infections and/or haemorrhagic complications before they had reached the level of clinical AML. All of these patients were ALIP positive at diagnosis and no additional cytogenetic alterations occurred during evolution. Acquisition of new karyotypic anomalies during the course of MDS was almost invariably associated with abrupt shift to AML. From this retrospective study we conclude that evolution in MDS shows two important aspects, which seem to be preponderant in determining the course and outcome of the disease: one is the proliferative capacity and resulting growth advantage of the neoplastic clone over normal haematopoiesis, as measured by increasing percentages of bone marrow blasts in sequential aspirates; the other one is instability of the clone. Unstable clones have a high propensity to further intraclonal changes; they are expressed morphologically by the abrupt increase in bone marrow blasts and cytogenetically by the acquisition of new or additional karyotype anomalies.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chromosomal studies after bone marrow transplantation for leukaemia in children

Chromosomal studies were performed on 114 blood samples and 117 bone marrow samples, taken systematically over a period of 4 months after bone marrow transplantation (BMT) in 42 children grafted for acute lymphoblastic leukaemia (ALL) (n = 20), acute myeloid leukaemia (AML) (n = 16), non-Hodgkin's lymphoma (NHL) (n = 2) and myelodysplastic syndrome (MDS) (n = 4). In some cases, follow-up investigations were performed. In the first 4 months following BMT, mixed chimerism was frequently observed in blood of AML (25%), ALL (30%), NHL (100%) cases and in bone marrow samples of ALL (35%). The presence and relative number of a patient's own metaphases found shortly after transplantation was not related to leukaemia relapse and probably represents residual non-malignant haematopoietic precursor cells of the host. In only one child grafted for MDS with 45,XY, -7 karyotype was the marker clone still detectable in bone marrow at day +437 post-BMT. This patient shows no recurrence of the MDS and has a sustained haematological recovery at the time of writing, i.e. 4.5 years post-BMT. In 11 other patients, various structural chromosomal abnormalities (not related to the original leukaemia) were found in both peripheral blood and bone marrow. In three different patients structural anomalies were also found in bone marrow and blood samples from donor-derived cells. This indicates that, besides irradiation, there are other as yet unidentified factors (e.g. drugs), which are capable of inducing chromosomal anomalies in the post-BMT period.     

Affected siblings with Alzheimer's disease had missense mutation of codon 717 in amyloid precursor protein gene]

Using reverse genetic techniques, the gene responsible for familial Alzheimer's disease (FAD) is one of the clues to identify the pathogenesis of Alzheimer's disease (AD). Recently a missense mutation in the APP (amyloid precursor protein) gene (generally this mutation was called APP717) was detected in 2 Caucasian AD families and the same mutation was found in 3 Japanese AD families. We experienced brother's cases who were diagnosed as AD. Both of them and one normal person of the next generation had APP717. The first symptom of the elder brother (case 1) was forgetfulness at 52 years old, then dementia was advanced. In his clinical course there were characteristic findings such as the mirror sign, pseudodialog and jargon which has been rarely described in the Japanese literature. Finally he died of pneumonia at 57 years old. He was diagnosed as AD pathologically and physical findings of brain CT, SPECT (single photon emission computed tomography) and EEG supported this diagnosis clinically. The first symptom of the younger brother (case 2) was also forgetfulness at 45 years old, then severe dementia was advanced, at last he died of pneumonia at age 53 old. On the other hand the mother of the brothers died of severe dementia, so it was suspected that brothers died of severe dementia, so it was suspected that she had had AD. The clinical courses and pathological findings were thought to be typical of AD, namely there were no significant differences in comparison with other cases of FAD and sporadic AD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG-A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow-up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.     

Follow-up by cytogenetic and fluorescence in situ hybridization analysis of allogeneic bone marrow transplantation in two children with Fanconi's anaemia in transformation

Results of bone marrow transplantation (BMT) in patients with Fanconi's anaemia (FA) in transformation are very poor and only a few cases with favourable outcome have been reported. We present the follow-up of two FA-myelodysplastic syndrome (MDS) patients with monosomy 7 and complex karyotype implicating chromosome 1. Both relapsed with acute myeloid leukaemia (AML) following an allogeneic BMT from an HLA-identical brother. The patients showed clonal cytogenetic evolution coinciding with the leukaemic transformation. In one patient, fluorescence in situ hybridization using X and Y chromosome probes detected an increase of host cells before clinical relapse. Both patients received a successful second allogeneic BMT from the same donor using a more intensive treatment regimen and remain in clinical and cytogenetic remission more than 3 years later.     

Follicular lymphoma in two brothers]

Two brothers, whose parents had a history of exposure to atomic bomb radiation, developed non-Hodgkin's lymphoma. The younger brother, a 48-year-old man, was diagnosed as having follicular small-cleaved cell lymphoma in October, 1996. He had extranodal lymphoma involvement of the right kidney, bone marrow and skin, in addition to generalized lymphadenopathy. He was treated with intermittent COP chemotherapy, and good control of the lymphoma was obtained. The elder brother, aged 50 years, was diagnosed as having follicular mixed cell lymphoma in May, 1998. He also had extranodal lymphoma involvement of the right parotid gland and bone marrow, as well as generalized lymphadenopathy. After one course of CHOP chemotherapy, he developed paresis of the lower legs and was found to have a mass at the Th5-6 vertebrae by CT scan. After four courses of CHOP chemotherapy followed by ESHAP chemotherapy and radiotherapy, he achieved complete remission, and has since been well. Follicular lymphoma occurring among siblings is rare. Further cytogenetic and molecular studies may provide a better understanding of its etiology.     

Myelodysplastic syndrome with eosinophilia in bone marrow

Summary. Clinical features were investigated in 114 patients with de novo myelodysplastic syndrome (MDS) diagnosed over the past 10 years, and eight cases (7%) were complicated with eosinophilia in the bone marrow. Two patients had refractory anaemia (RA), five had RA with excess of blasts (RAEB), and one had RAEB in transformation. Their bone marrow cells exhibited trilineage dysplasia and morphological abnormalities in eosinophils. Cytogenetics revealed major karyotype abnormalities (MAKA) in five patients. Survival durations were significantly shorter than those of other MDS patients. Our study suggests that marrow eosinophilia in MDS is strongly related to the coexistence of MAKA.     

Myelodysplastic syndromes in two young brothers]

Myelodysplastic syndromes that occurred in two young brothers are reported. A 19-year-old man was admitted to Kobe City General Hospital in May 1990 because of fever and nasal bleeding. On admission his hemoglobin was 5.5 g/dl, platelet count 1.5 x 10(4)/microliters and white cell count 1,700/microliters with 18% neutrophils and 80% lymphocytes. Bone marrow aspirate showed dysplastic features of trilineage blood cells with 4.8% myeloblasts. A diagnosis of refractory anemia was made. His younger brother, a 17-year-old man was examined in May 1990 because of increasing fatigability of 2 years' duration. His hemoglobin was 8.7 g/dl, platelet count 2.1 x 10(4)/microliters and white cell count 2,800/microliters. Bone marrow aspirate revealed morphological abnormalities in three lineages with 5.2% myeloblasts. He was diagnosed as having refractory anemia with excess of blasts. Their parent are consanguineous. The onset at a young age, reduced CD4 lymphocytes and similarity of dyshematopoietic findings suggests the presence of common genetic disorder in the pluripotent hematopoietic stem cells.     

Primary splenic lymphoma with hypoplastic bone marrow

A 44-year-old man was admitted because of persistent fever and pancytopenia. Because his bone marrow was hypoplastic and the karyotype of his marrow cells was normal, he was given a diagnosis of aplastic anemia, and treated with glucocorticoids and granulocyte colony-stimulating factor. Splenomegaly was later found and a splenectomy performed: pathological findings on resected tissue specimens disclosed non-Hodgkin's lymphoma, B-cell diffuse large. The patient was transferred to our hospital, where a bone marrow biopsy revealed lymphoma cells infiltrating his hypoplastic marrow. Complex chromosomal abnormalities were detected in marrow cells, but no lymphadenopathy was observed. A diagnosis of primary splenic lymphoma with infiltration of lymphoma cells into bone marrow was made, and chemotherapy was accordingly started. After multiple cycles of chemotherapy, the patient's marrow recovered to a normal state and his karyotype abnormalities disappeared. Six months later, pancytopenia reappeared and lymphoma cells were again detected in the patient's bone marrow. We reasoned that the hypoplastic state of his bone marrow was associated with the lymphoma, and that cytokines, including interferon-gamma, may have been responsible for this association.     

Clinical features of atypical refractory anemia (RA)

Twenty-three patients with bicytopenia or pancytopenia were retrospectively studied. The patients with underlying disorders, blast count of more than 5% on bone marrow (BM) aspirate, blast count of more than 1% on peripheral blood or ringed sideroblast count of more than 15% on BM aspirate were excluded. According to Yoshida's criteria, 23 patients were classified into 6 subtypes [AA (aplastic anemia)1: typical AA, AA2: atypical AA, MDS (myelodysplastic syndrome)3: typical RA (refractory anemia, MDS4-6: atypical RA], and AA1 7 cases; AA2 2 cases; MDS3 5 cases; MDS4 1 case; MDS5 2 cases; MDS6 6 cases. To clarify the clinical features of atypical RA group (MDS4-6), we investigated ferrokinetics, RBC life span, karyotype, serum Epo (erythropoietin) concentration, response to therapy and prognosis. Results were as follows: 1) all three RA patients who were younger than 30 years old were included in atypical RA group, 2) in ferrokinetics study PID (plasma iron disappearance time) values of MDS4 and MDS6 patients ranged between those of AA1 and those of MDS3 patients (5 of 7 patients), 3) two cases who developed leukemia belonged to typical RA group, 4) patients with atypical RA showed response to therapy and their prognosis were better than those with typical RA. These observations suggest that atypical RA have different clinical features from typical RA.     

The route to development of myelodysplastic syndrome/acute myeloid leukaemia in Shwachman-Diamond syndrome: the role of ageing, karyotype instability, and acquired chromosome anomalies

An investigation of 22 new patients with Shwachman-Diamond syndrome (SDS) and the follow-up of 14 previously reported cases showed that (i) clonal chromosome changes of chromosomes 7 and 20 were present in the bone marrow (BM) of 16 out of 36 cases, but if non-clonal changes were taken into account, the frequency of anomalies affecting these chromosomes was 20/36: a specific SDS karyotype instability was thus confirmed; (ii) the recurrent isochromosome i(7)(q10) did not include short arm material, whereas it retained two arrays of D7Z1 alphoid sequences; (iii) the deletion del(20)(q11) involved the minimal region of deletion typical of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML); (iv) only one patient developed MDS, during the rapid expansion of a BM clone with a chromosome 7 carrying additional material on the short arms; (v) the acquisition of BM clonal chromosome anomalies was age-related. We conclude that karyotype instability is part of the natural history of SDS through a specific mutator effect, linked to lacking SBDS protein, with consequent clonal anomalies of chromosomes 7 and 20 in BM, which may eventually promote MDS/AML with the patients' ageing.     

Factor XIII Deficiency in Siblings: Importance of Prophylactic Replacement

Factor XIII deficiency, an autosomal recessive trait, can result in serious bleeding manifestation. This case report presents two brothers with Factor XIII deficiency. Though the younger sibling had been screened and diagnosed prophylactic replacement therapy had not been initiated unlike the elder brother. He presented with intracranial haemorrhage needing surgical evacuation while the elder brother remained symptom free on regular prophylactic replacement of FFP.     

Immune-mediated complications in patients with myelodysplastic syndromes – clinical and cytogenetic features

Abstract: It has been recognized in recent years that some patients with myelodysplastic syndromes (MDS) develop immune-mediated complications (IMC), but little is known about the correlations to MDS-specific disease features. In a retrospective study of 82 MDS patients, we identified 10 (12%) with IMC (group A) and compared them to the remaining 72 cases (group B). Group A consisted of 5 patients with biopsy-verified skin vasculitis and 1 case each with temporal arteritis/polymyalgia rheumatica, necrotising panniculitis, Hashimoto's thyroiditis, autoimmune thrombocytopenia, and Sweet's syndrome. Survival times, sex ratio and distribution of MDS subtypes were similar in the two groups. The patients in group A were younger than those in group B (median 66 vs. 76 years, p<0.01). Four patients (40%) in group A had a history of previous genotoxic therapy for malignant disorders. The bone marrow karyotype was evaluated in 62 patients. Clonal chromosomal abnormalities were found more frequently in Group A than in group B (8/9 vs. 26/53, p = 0.03), and complex karyotypes, i.e., three or more aberrations, were also observed to be more common in group A (3/9 vs. 8/53). The results indicate that IMC preferentially develop in patients with secondary MDS, in younger MDS cases, and in patients with cytogenetic abnormalities.