A case of follow-up of a patient with 22q11.2 distal deletion syndrome and a review of the literature

Microdeletions of chromosome 22q11.2 are one of the most common microdeletions occurring in humans, and is known to be associated with a wide range of highly variable features. These deletions occur within a cluster of low copy repeats (LCRs) in 22q11.2, referred to as LCR22 A-H. DiGeorge (DGS)/velocardiofacial syndrome is the most prevalent form of a 22q11.2 deletions, caused by mainly proximal deletions between LCR22 A and D. As deletions of distal portion to the DGS deleted regions has been extensively studied, the recurrent distal 22q11.2 microdeletions distinct from DGS has been suggested as several clinical entities according to the various in size and position of the deletions on LCRs. We report a case of long-term follow-up of a female diagnosed with a 22q11.2 distal deletion syndrome, identified a deletion of 1.9 Mb at 22q11.21q11.23 (chr22: 21,798,906-23,653,963) using single nucleotide polymorphism array. This region was categorized as distal deletion type of 22q11.2, involving LCR22 D-F. She was born as a preterm, low birth weight to healthy non-consanguineous Korean parents. She showed developmental delay, growth retardation, dysmorphic facial features, and mild skeletal deformities. The patient underwent a growth hormone administration due to growth impairment without catch-up growth. While a height gain was noted, she had become overweight and was subsequently diagnosed with pre-diabetes. Our case could help broaden the genetic and clinical spectrum of 22q11.2 distal deletions.

Chromosomal Microarray Analysis as a First-Tier Clinical Diagnostic Test in Patients With Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies: A Prospective Multicenter Study in Korea

BACKGROUND: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.

The 2016 WHO versus 2008 WHO Criteria for the Diagnosis of Chronic Myelomonocytic Leukemia

The 2016 WHO diagnostic criteria for chronic myelomonocytic leukemia (CMML) require both absolute and relative monocytosis (≥1×10⁹/L and ≥10% of white blood cell counts) in peripheral blood. Moreover, myeloproliferative neoplasm (MPN) features in bone marrow and/or MPN-associated mutations tend to support MPN with monocytosis rather than CMML. We assessed the impact of the 2016 WHO criteria on CMML diagnosis, compared with the 2008 WHO criteria, through a retrospective review of the medical records of 38 CMML patients diagnosed according to the 2008 WHO classification. Application of the 2016 WHO criteria resulted in the exclusion of three (8%) patients who did not fulfill the relative monocytosis criterion and eight (21%) patients with an MPN-associated mutation. These 11 patients formed the 2016 WHO others group; the remaining 27 formed the 2016 WHO CMML group. The significant difference in the platelet count and monocyte percentage between the two groups indicated that the 2016 WHO criteria lead to a more homogenous and improved definition of CMML compared with the 2008 WHO criteria, which may have led to over-diagnosis of CMML. More widespread use of molecular tests and more sophisticated clinical and morphological evaluations are necessary to diagnose CMML accurately.

An Automated Draft Report Generator for Peripheral Blood Smear Examinations Based on Complete Blood Count Parameters

BACKGROUND: Complete blood count (CBC) results play an important role in peripheral blood smear (PBS) examinations. Many descriptions in PBS reports may simply be translated from CBC parameters. We developed a computer program that automatically generates a PBS draft report based on CBC parameters and age- and sex-matched reference ranges. METHODS: The Java programming language was used to develop a computer program that supports a graphical user interface. Four hematology analyzers from three different laboratories were tested: Sysmex XE-5000 (Sysmex, Kobe, Japan), Sysmex XN-9000 (Sysmex), DxH800 (Beckman Coulter, Brea, CA, USA), and ADVIA 2120i (Siemens Healthcare Diagnostics, Eschborn, Germany). Input data files containing 862 CBC results were generated from hematology analyzers, middlewares, or laboratory information systems. The draft reports were compared with the content of input data files. RESULTS: We developed a computer program that reads CBC results from a data file and automatically writes a draft PBS report. Age- and sex-matched reference ranges can be automatically applied. After examining PBS, users can modify the draft report based on microscopic findings. Recommendations such as suggestions for further evaluations are also provided based on morphological findings, and they can be modified by users. The program was compatible with all four hematology analyzers tested. CONCLUSIONS: Our program is expected to reduce the time required to manually incorporate CBC results into PBS reports. Systematic inclusion of CBC results could help improve the reliability and sensitivity of PBS examinations.

Spontaneous Remission in a Teenage Girl with Acquired Pure Red Cell Aplasia / 임상소아혈액종양

Acquired pure red cell aplasia (PRCA) can be induced by various factors such as viral infection, thymoma, connective tissue disease, lymphoma, and adverse drug reactions. PRCA has not been reported in an adolescent in Korea for the past several decades. We recently experienced a case of acquired PRCA in an adolescent. A 14-year-old girl presented with pallor, dizziness, and mild fever. She had isolated normocytic normochromic anemia with reticulocytopenia in the peripheral blood and erythroblastopenia in the bone marrow. She was diagnosed with secondary acquired PRCA presumably induced by Mycoplasma pneumoniae infection during her clinical course, and she experienced spontaneous remission 11 weeks after initial diagnosis. Her clinical and hematologic statuses were normal as far as 20 months after her diagnosis.

Spontaneous Remission in a Teenage Girl with Acquired Pure Red Cell Aplasia / 임상소아혈액종양

Acquired pure red cell aplasia (PRCA) can be induced by various factors such as viral infection, thymoma, connective tissue disease, lymphoma, and adverse drug reactions. PRCA has not been reported in an adolescent in Korea for the past several decades. We recently experienced a case of acquired PRCA in an adolescent. A 14-year-old girl presented with pallor, dizziness, and mild fever. She had isolated normocytic normochromic anemia with reticulocytopenia in the peripheral blood and erythroblastopenia in the bone marrow. She was diagnosed with secondary acquired PRCA presumably induced by Mycoplasma pneumoniae infection during her clinical course, and she experienced spontaneous remission 11 weeks after initial diagnosis. Her clinical and hematologic statuses were normal as far as 20 months after her diagnosis.

A Case of Acquired Transient Vitamin K Deficiency in a Teenage Girl / 임상소아혈액종양

A 13-year old girl visited emergency medical center presenting with nasal bleeding and gross hematuria. She had no growth retardation, nor history of abnormal bleeding. Her initial blood test results showed normal platelet counts, normal liver enzyme level but prolonged prothrombin time and activated partial thromboplastin time. On admission, she showed massive but intermittent bleeding until the 15th hospital day. Evaluation including coagulation factor assay was done and the results were compatible with vitamin K deficiency. She was treated with vitamin K intramuscular injection 7 times and intermittent transfusion of red blood cells, platelets and fresh frozen plasma. After that, all of her blood test results returned to normal levels including coagulation tests concomitent with resolving symptoms. In that there were no proof of underlying diseases that can cause vitamin K deficiency, she was diagnosed as idiopathic transient vitamin K deficiency.

A Case of Acquired Transient Vitamin K Deficiency in a Teenage Girl / 임상소아혈액종양

A 13-year old girl visited emergency medical center presenting with nasal bleeding and gross hematuria. She had no growth retardation, nor history of abnormal bleeding. Her initial blood test results showed normal platelet counts, normal liver enzyme level but prolonged prothrombin time and activated partial thromboplastin time. On admission, she showed massive but intermittent bleeding until the 15th hospital day. Evaluation including coagulation factor assay was done and the results were compatible with vitamin K deficiency. She was treated with vitamin K intramuscular injection 7 times and intermittent transfusion of red blood cells, platelets and fresh frozen plasma. After that, all of her blood test results returned to normal levels including coagulation tests concomitent with resolving symptoms. In that there were no proof of underlying diseases that can cause vitamin K deficiency, she was diagnosed as idiopathic transient vitamin K deficiency.

Significance of Neutrophil Gelatinase-Associated Lipocalin Level as an Acute-Phase Reactant in Patients with Systemic Inflammatory Response Syndrome

BACKGROUND: We investigated the significance of plasma neutrophil gelatinase-associated lipocalin (pNGAL) level as an acute-phase reactant and an index for an increase in serum creatinine (sCr) level in patients with inflammatory diseases. METHODS: A total of 63 patients with systemic inflammatory response syndrome (SIRS) and 149 without SIRS were evaluated, and pNGAL level was determined using a fluorescence immunoassay. sCr levels were measured daily during three days, and the difference between the initial and follow-up sCr levels was defined as a delta sCr value. Serum albumin/sCr ratio (sACR) was calculated. High-sensitivity C-reactive protein (hsCRP) level was determined using a latex turbidometric method. RESULTS: The median pNGAL level in the SIRS group (154 ng/mL) was significantly higher than that in the non-SIRS (86 ng/mL) and control (62 ng/mL) groups (P<0.001, respectively). The area under the ROC curve (AUC) of pNGAL for diagnosing SIRS was 0.725 (95% CI, 0.664-0.781), which was not significantly different from that of hsCRP (0.749; 95% CI, 0.685-0.809; P=0.375). Multivariate regression analyses revealed that log-pNGAL was significantly associated with hsCRP (beta=0.546, P<0.001) and sACR (beta=0.351, P<0.001). The AUC of pNGAL for the positive delta sCr in 48-72 hr was 0.649 (95% CI, 0.542-0.746, P=0.023) in the SIRS group. CONCLUSIONS: pNGAL is comparable to hsCRP as an inflammation-related parameter, and its measurement may provide additional information for a potential increase in sCr during 48-72 hr in patients with SIRS.

Usefulness of Serum IGF-I and IGFBP-3 Levels in Children with Short Stature / 임상검사와정도관리

BACKGROUND: Serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels are known markers of growth hormone (GH) secretion. The clinical utility of serum IGF-I and IGFBP-3 testing, however, remains controversial. The aims of this study were to evaluate the usefulness of IGF-I and IGFBP-3 as indicators of GH secretion through the GH stimulation test and to investigate whether a decrease in serum IGF-I levels in children with short stature, regardless of the cause, can be used as a screening test for short stature. METHODS: A total of 262 children presented with short stature, precocious puberty, or premature thelarche and were grouped into 7 tiers based on the 2007 growth chart. Serum IGF-I and IGFBP-3 levels and GH stimulation were analyzed using an immunoradiometric assay, and the data from 68 children who were below the 3rd percentile for height were used to evaluate the usefulness of IGF-I and IGFBP-3 as markers of GH status. RESULTS: GH deficiency was confirmed by the GH stimulation test in 25 of the 68 children, and 15 (15/25, 60%) and 4 (4/25, 16%) of them showed a decrease in IGF-I and IGFBP-3 levels, respectively. The sensitivity and specificity for predicting GH secretion were 60% and 16%, respectively, for IGF-1 and 41.9% and 97.7%, respectively, for IGFBP-3. Decreased serum IGF-I levels were more frequently observed in children below the 25th percentile than in those in the 25th to 95th percentiles. CONCLUSIONS: IGF-I and IGFBP-3 levels have been used as a screening tool for GH secretion in children with short stature, but based on the results of the GH stimulation test in the current study, the levels of IGF-I and IGFBP-3 might not be useful as markers of GH secretion. Evaluating serum IGF-I levels alone is not a sufficient screening test for children with a short stature.

Klebsiella Pneumoniae Associated Extreme Plasmacytosis / 감염과화학요법

Infection-associated plasmacytosis is not uncommon; however, marked plasmacytosis in both peripheral blood and bone marrow that mimicks plasma cell leukemia is a very rare condition. We encountered a case of extreme plasmacytosis associated with Klebsiella pneumoniae sepsis in an aplastic anemia patient. A 42-year-old man presented with high fever of 5 days' duration. Hematological analysis revealed severe neutropenia and thrombocytopenia; his white blood cell count was 900/mm3, with 26% of plasma and plasmacytoid cells in peripheral blood. Bone marrow biopsy and aspiration showed 25% cellularity with marked plasmacytosis (80%), highly suggestive of plasma cell leukemia. On the eighth hospital day, K. pneumoniae was identified in blood and sputum cultures. Fever improved after switching antibiotics, although his hematological condition worsened. His bone marrow cellularity (plasma cell proportion) progressively decreased: the values were 25% (80%), 10% (26%), 10% (11%), and < 10% (< 4%) on the 8th, 30th, 60th, and 90th hospital day, respectively. His plasmacytosis was extremely severe but was confirmed to be reactive with polyclonality. The present case represents the first report of strong suspicion of K. pneumoniae sepsis-associated marked plasmacytosis in an aplastic anemia patient.

A Novel Translocation Involving RUNX1 and HOXA Gene Clusters in a Case of Acute Myeloid Leukemia with t(7;21)(p15;q22)

Translocations involving chromosome 21q22 are frequently observed in hematologic malignancies including acute myeloid leukemia (AML), most of which have been known to be involved in malignant transformation through transcriptional dysregulation of Runt-related transcription factor 1 (RUNX1) target genes. Nineteen RUNX1 translocational partner genes, at least, have been identified, but not Homeobox A (HOXA) genes so far. We report a novel translocation of RUNX1 into the HOXA gene cluster in a 57-year-old female AML patient who had been diagnosed with myelofibrosis 39 months ahead. G-banding showed 46,XX,t(7;21)(p15;q22). The involvement of RUNX1 and HOXA genes was confirmed by fluorescence in situ hybridization.

Detection Limit of Monoclonal B-Cells Using Multiplex PCR and Laser-Induced Fluorescence Capillary Electrophoresis

BACKGROUND: The identification of monoclonality has been widely used for making diagnoses of lymphoproliferative lesions. Awareness of the sensitivity and detection limit of the technique used would be important for the data to be convincing. METHODS: We investigated the minimum requirement of cells and sensitivity of gel electrophoresis (GE) and laser-induced fluorescence capillary electrophoresis (LFCE) for identifying IgH gene rearrangement using BIOMED-2 protocols. DNA extracted from Raji cells were diluted serially with peripheral blood mononuclear cells (PBMNCs) DNA. DNA from mixtures of diffuse large B-cell lymphoma (DLBCL) and reactive lymph nodes were also serially diluted. RESULTS: For Raji cells, the detection limit was 62 and 16 cell-equivalents for GE and LFCE, respectively. In the condition with PBMNCs mixture, 2.5% and 1.25% of clonal cells was the minimum requirement for GE and LFCE, respectively. In 23% of DLBCL cells in tissue section, the detection limit was 120 and 12 cell-equivalents for GE and LFCE, respectively. In 3.2% of DLBCL cells, that was 1,200 and 120 cell-equivalents for GE and LFCE, respectively. CONCLUSIONS: These results show that LFCE method is more sensitive than GE and the sensitivity of clonality detection can be influenced by the amount of admixed normal lymphoid cells.

A Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Initially Mimicking Cutaneous Lupus Erythematosus / Journal of the Korean Cancer Association, 대한암학회지

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease. The prognosis is poor in most cases with rapid progression despite administering chemotherapy. A 67-year-old man complained of skin rashes on his back and this spread to the trunk, face, arms and thighs, and he was initially diagnosed with cutaneous lupus erythematosus according to the skin biopsy. The skin rashes then became aggravated on a trial of low dose methylprednisolone for 3 months. Repeated skin biopsy revealed a diffuse infiltration of lymphoid cells with medium sized nuclei, positive for CD4 and CD56, negative for Epstein-Barr virus (EBV), indicating a diagnosis of BPDCN. Further workups confirmed stage IVA BPDCN involving the skin, multiple lymph nodes, the peripheral blood and the bone marrow. He was treated with six cycles of combination chemotherapy consisting of ifosphamide, methotrexate, etoposide, prednisolone and L-asparaginase, and he achieved a partial response. Herein we report on a rare case of BPDCN that was initially misinterpreted as cutaneous lupus erythematosus.

Chronic Myelogenous Leukemia with a Variant Philadelphia Translocation: t(11;22)(q25;q11.2) / 대한진단검사의학회지

We report a case of chronic myelogenous leukemia displaying a variant Philadelphia translocation t(11;22)(q25;q11.2). Breakpoint 11q25 has not previously been reported. Reverse transcriptase polymerase chain reaction and fluorescence in-situ hybridization demonstrated the BCR/ABL rearrangement.

Ten-year Experience on Acute Promyelocytic Leukemia at Inha University Hospital

BACKGROUND: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia in its morphology as well as molecular or genetic profiles, conferring a good prognosis owing to the active roles of all-trans-retinoic acid (ATRA) and anthracyclines. METHODS: Patients diagnosed as APL from March 1997 to April 2006 were analyzed on their clinical features, laboratory profiles, methods of treatment including remission induction, consolidation and maintenance, treatment outcomes, and treatment-related morbidity. RESULTS: Chemotherapy naive were all the 12 patients in our study consisting of 3 males and 9 females. All patients showed typical morphologic feature of APL with cytogenetic abnormality, t(15;17), and PML/RAR alpha fusion gene was confirmed in 10 patients by FISH or PCR. The combination of cytarabine with daunorubicin (n=2) or idarubicin (n=9) was used as an induction regimen with concurrent ATRA administration. For consolidation therapy, cytarabine with anthracycline (n=4) or idarubicin monotherapy (n=8) was used with ATRA. Cytogenetic and molecular remissions were documented after induction chemotherapy (n=11) or first consolidation therapy (n=1). Maintenance therapy with ATRA was done in 11 patients. CR was obtained in 12 patients, with median remission duration of 30.5+ months (range 2 to 86+) at a median follow up duration of 33.5+ months (range 4 to 89+). One patient relapsed after completion of maintenance therapy and died of infection during reinduction chemotherapy. CONCLUSION: Herein is the report of ten years' experience of our hospital in the treatment of APL with favorable results as seen by high CR rate and fewer complications.

Double Minutes Containing C-MYC oncogene with a Normal Karyotype in Acute Myelogenous Leukemia: A Case Report / 대한진단검사의학회지

We report a case of a female karyotype that was normal except for double minutes (dmin) in acute myeloid leukemia. Using fluorescence in situ hybridization, the amplification of C-MYC was detected in both interphase and metaphase cells. The patient of the present case had received only limited therapy with cytosine arabinoside, but lived for more than one year. It supports the recent notion that dmin may not necessarily be associated with a poor outcome.

Idiopathic Hyperammonemia: A Rare Complication Following Allogeneic Bone Marrow Transplantation / 대한내과학회지

Idiopathic hyperammonemia is a rare and serious complication of intensive cytoreductive chemotherapy for hematologic malignancies as well as after autologus or allogeneic bone marrow transplantation (BMT). A 42-year-old woman with Philadelphia chromosome positive acute lymphoblastic leukemia was undertaken unrelated BMT. Fourteen days later, the patient developed hallucination, mental confusion, lethargy, incoordination and stupor. Laboratory tests revealed normal serum aminotransferases. The serum ammonia level is moderately increased. Parenteral alimentation was discontinued to lower protein intake and treatment with lactulose, metronidazole, carnitine, and flumazenil was started. Also, hemodialysis was performed. Despite of these appropriate therapies, she died of idiopathic hyperammonenia at twenty-two days after allogeneic BMT.

Balantidium coli in an Asymptomatic Patient: A Case Report / 대한진단검사의학회지

Balantidium coli is widely distributed in hogs, particularly in warm and temperate climates, and in monkeys in the tropics. B. coli is the only pathogenic ciliate and is the largest protozoan parasitizing humans. Some individuals with B. coli infections are totally asymptomatic, whereas others have symptoms of severe dysentery similar to those seen in patients with amebiasis. We report a 5-year-old girl with asymptomatic balantidiasis. The patient was suffering from herpes zoster for several days. She did not have symptoms of dysentery or urinary tract infection. Motile trophozoites of B. coli were observed in the urinary sediment. This is the first report of asymptomatic balantidiasis in Korea.

Tc-99m ciprofloxacin imaging in diagnosis of chronic bacterial prostatitis / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate the value of Tc-99m ciprofloxacin imaging in the differential diagnosis of chronic bacterial prostatitis.</p><p><b>METHODS</b>The study included 4 normal subjects as the negative controls, 2 patients with acute prostatitis or cystourethritis as the positive controls and 59 patients diagnosed as chronic bacterial prostatitis or chronic pelvic pain syndrome by traditional laboratory tests. In every subject, the single photon emission computerized tomography images were obtained 3 h after intravenous injection of Tc-99m Ciprofloxacin. The results of the imaging were compared with those of laboratory tests.</p><p><b>RESULTS</b>On the images, negative uptake was observed in all normal subjects, while strong hot uptake, in the whole prostate of acute prostatitis patients and in the whole urethra of acute cystourethritis patients. In 13 (68%) of 19 patients categorized as chronic bacterial prostatitis by standard laboratory tests, hot uptake with less intensity than that of acute prostatitis was observed in the prostate area around the prostatic urethra. Negative uptake in the prostate was observed in 6 of 19 patients (32%) categorized as chronic bacterial prostatitis. Interestingly, hot uptake in the prostate was exhibited in 28 (70%) of the 40 patients categorized as chronic pelvic pain syndrome.</p><p><b>CONCLUSION</b>Tc-99m ciprofloxacin imaging is helpful in the differential diagnosis of prostatitis syndrome.</p>