A cryptic three-way translocation t(10;19;11)(p12.31;q13.31;q23.3) with a derivative Y-chromosome in an infant with acute myeloblastic leukemia (M5b).

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant transformation of hematopoietic precursors to a pathogenic cell clone. Chromosomal band 11q23 harboring MLL (=mixed lineage leukemia) gene is known to be involved in rearrangements with variety of genes as activating partners of MLL in different AML subtypes. Overall, an unfavorable prognosis is associated with MLL abnormalities. Here we investigated an 11-month-old male presenting with hyperleukocytosis being diagnosed with AML subtype FAB-M5b. In banding cytogenetics a der(19)t(19;?)(q13.3;?) and del(Y)(q11.23) were found as sole aberrations. Molecular cytogenetics revealed that the MLL gene was disrupted and even partially lost due to a t(10;19;11)(p12.31;q13.31;q23.3), an MLL/MLLT10 fusion appeared, and the der(Y) was an asymmetric inverted duplication with breakpoints in Yp11.2 and Yq11.23. The patient got hematopoietic stem cell transplantation from his haploidentical mother. Still three months afterwards 15% of blasts were detected in bone marrow and later the patient was lost during follow-up. The present case highlights the necessity to exclude MLL rearrangements, even when there seems to be no actual hint from banding cytogenetics.

Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience.

Severe combined immunodeficiency (SCID), including the 'variant' Omenn syndrome (OS), represent a heterogeneous group of monogenic disorders characterized by defect in differentiation of T- and/or B lymphocytes and susceptibility to infections since birth. In the period of 25 years, between January 1986 and December 2010, a total of 21 patients (15 SCID, 6 OS) were diagnosed in Mother & Child Health Institute of Serbia, a tertiary-care teaching University hospital and a national referral center for patients affected with primary immunodeficiency (PID). The diagnoses were based on anamnestic data, clinical findings, and immunological and genetic analysis. The median age at the onset of the first infection was the 2nd month of life. Seven (33 %) patients had positive family history for SCID. Out of five male infants with T-B+NK- SCID phenotype, mutation analysis revealed interleukin-2 (common) gamma-chain receptor (IL2RG) mutations in 3 with positive X-linked family history, and Janus-kinase (JAK)-3 gene defects in the other two. Six patients had T-B-NK+ SCID phenotype and further 6 features of OS, 11 of which had recombinase-activating gene (RAG1or RAG2) and 1 Artemis gene mutations. One child with T+B+NK+ SCID phenotype as well had proven RAG mutation. One child each with T-B+NK+ SCID phenotype, CD8 lymphopenia and unknown phenotype remained without known underlying genetic defect. Of the eight patients who underwent hematopoetic stem cell transplant (HSCT) 5 survived, the other 13 died between 2 days and 12 months after diagnosis was made. Early diagnosis of SCID, before onset of severe infections, offers possibility for HSCT and cure. Education of primary-care pediatricians, in particular including awareness of the risk of using live vaccines and non-irradiated blood products, should improve prognosis of SCID in our setting.

[Biphenotypic acute leukaemia: case reports of two paediatric patients].

INTRODUCTION: Biphenotypic acute leukaemia is an uncommon type of leukaemia whose blasts co-express myeloid and B-or T-lymphoid antigens. CASE REPORT: We describe two cases of paediatric patients with biphenotypic acute leukaemia. A four-year-old female patient was found to have myeloid and B-lymphoid associated antigens in the same blast cells. Cytogenetic analysis showed a Philadelphia (Ph) positivity t (9;22) (q34;q1l1 with rearrangements of M.bcr-Abl (p210). She was treated with combined acute myeloid leukaemia/acute lymphoblastic leukaemia induction therapy followed by autologous stem cell transplantation. The patient died due to the complications of stem cell transplantation procedure. Another patient was a 20-month-old girl with myeloid and T-lymphoid associated antigens in the blast cells and with normal karyotype. She received acute myeloid leukaemia induction therapy. She has never achieved remission. DISCUSSION: Immunophenotype is essential to establish the diagnosis of biphenotypic acute leukaemia according to the scoring system adopted by the European Group of Immunological Classification of Leukaemia. There is no agreement about uniformity in treatment for the patients with this type of leukaemia. Biphenotypic acute leukaemia is a high risk leukaemia which requires a more intensive treatment. CONCLUSION: Therapy for every patient with biphenotypic acute leukaemia should depend on their immunophenotype and gene rearrangement profiles.

A complex rearrangement involving cryptic deletion of ETV6 and CDKN1B genes in a case of childhood acute lymphoblastic leukemia.

We report on a case of childhood B-cell lineage acute lymphoblastic leukemia (ALL). Conventional cytogenetic analysis at diagnosis showed the karyotype: 47,XY,add(3)(q?),-12,+2mar[4]/46,XY[18]. Fluorescence in situ hybridization (FISH) revealed a complex rearrangement: 47,XY,der(3)(3pter->3q29::12q13->12q24.33::12p13.31->12p13.2::12q24.33->12qter),der(12)(12pter->12p13.31::12p12.3->12q12::3q29->3qter),+del(21)(q?). The derivative chromosome 3 arose likely from multiple events due to clonal evolution. After insertion of the segment of the short arm of the chromosome 12 to the distal part of the long arm of chromosome 12 [ins(12)(q24.33p13.31p13.2)], a translocation occurred between chromosome 3 and derivative chromosome 12. Additional FISH results disclosed two heterozygous deletions flanking the translocated region on both 12p13.2 approximately p12.3 and 12q12 approximately q13.13. The deleted segment on 12p contains several genes, among the tumor suppressor genes ETV6 and CDKN1B, which are frequently involved in 12p abnormalities in childhood ALL. Thus, the present study documents the loss of both ETV6 and CDKN1B genes accompanying the occurrence of a complex rearrangement involving chromosomes 3 and 12 in a case of childhood ALL.

Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings.

UNLABELLED: We report different immunological phenotypes in three siblings from consanguineous family with recombinase-activating gene 1 (RAG1) gene mutations. Null mutations of RAG genes result in severe combined immunodeficiency (SCID) with absent T and B cells. Hypomorphic mutations with retained activity of RAG genes may lead to a 'leaky' SCID with some features of Omenn syndrome (OS) or typical OS. In our three patients, homozygous, hypomorphic RAG1 gene mutation (g.368-369delAA) was detected. Two patients presented with T-B-SCID phenotype while the youngest patient developed T+B+NK+SCID phenotype with expansion of autologous T-cell receptor (TCR) gammadelta-positive T cells, increased immunoglobulin levels and retained ability for antibody production. Similar to originally reported patients with this newly recognized immune phenotype, our patient developed disseminated cytomegalovirus (CMV) infection and autoimmune cytopenia. CONCLUSION: In infants with disseminated cytomegalovirus infection and autoimmune cytopenia, even if basic immunologic investigation appears normal, RAG1 immunodeficiency should be considered.

Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis.

We report on an association of idiopathic CD4+ lymphocytopenia (ICL) and juvenile laryngeal papillomatosis (JLP) in a pediatric-aged patient. Because of a past medical history of recurrent lung infections and severe chickenpox in infancy, immunologic investigations were done at age 6 years. On several occasions, a CD4+lymphocyte count of <300 cells/mm3 was detected, supporting the diagnosis of ICL. During follow-up, both medical (interferon-alpha) and surgical treatments of JLP were only partially efficient. Our patient developed disseminated infection with Mycobacterium avium and died at 10 years of age. Human papillomavirus is an important pathogen in pediatric and adult patients with ICL. In pediatric patients with JLP who develop other unusually severe viral or opportunistic infections, immunological investigations should be considered.

Long-term follow-up and prognosis of chronic granulomatous disease in Yugoslavia: is there a role for early bone marrow transplantation?

We report the long-term follow-up of 12 pediatric-aged patients with chronic granulomatous disease (CGD). The mean age at the onset of infections was 5 months with a median delay in diagnosis of 2.5 years. Bacille Calmette-Guérin lymphadenitis was the most common presenting infection (6) followed by suppurative lymphadenitis (4), liver abscess (1), or Salmonella sepsis (1). Prophylaxis with cotrimoxazole was recommended to all patients. During the mean follow-up of 10 years (range, 4-23 years) pneumonitis was the most prevalent infection (91%) followed by lymphadenitis (83%), aphtous stomatitis (58%), and liver abscesses (25%). Seven (58%) patients developed chronic lung disease due to grossly delayed diagnosis (3) or poor compliance with antimicrobial prophylaxis (4). Five (41%) patients died during the second decade of life of aspergillosis (3) or chronic lung disease (2). Probability of survival into the third decade of life was estimated to be only 19%. We argue that HLA-identical bone marrow transplantation (BMT), if possible, should be attempted at early age because of significant morbidity and mortality in adolescence. BMT also should be considered in patients who suffer severe infections despite antimicrobial prophylaxis or patients with evidence of chronic lung disease. Possibility of elective BMT from unrelated donors remains to be carefully evaluated.