Detection of cytogenetics abnormalities in chronic lymphocytic leukemia using FISH technique and their prognostic impact.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is a clonal lymphoproliferative disorder characterized by progressive accumulation of morphologically and immunophenotypically mature lymphocytes. Characterization of genomic aberrations may help to understand the pathogenesis of CLL and may give prognostic information independent from conventional clinical markers for a risk-adapted management of CLL patients. AIM: The aim of the present study is to determine the most common cytogenetics abnormalities between patients with CLL and its prognostic impact. PATIENTS AND METHODS: The present study was carried out on 20 adult patients presented with chronic lymphocytic leukemia. The patients were diagnosed on the basis of standard clinical (lymph node involvement and/or hepatosplenomegaly), hematological and immunophenotypic criteria for diagnosis of B-CLL. All cases were studied at the time of their diagnosis. FISH technique was successfully performed on PB samples using CLL LSI probes for ATM (11q22) / GLI (12q13) and 13q14/ p53 (17p13). RESULTS: For comparative statistical studies, the patients were divided into group I (patients with favorable outcome) and group II (patients with unfavorable outcome). All patients showed one or more cytogenetic abnormality with the prevalence of p53 in 16 patients out of 20 that perfectly correlated with the poor outcome of the patients. This is followed by deletion in the 13q14 and to a lesser extent deletion in ATM gene, but no one has exhibited amplification in the 12q13 locus. CONCLUSION: p53 deletion as a sole abnormality has a higher prognostic power than other cytogenetics abnormalities. The cytogenetics study using FISH panel for CLL patients in a complementary fashion to the other clinical and laboratory findings may overcome the pitfalls in the diagnosis and may also assess the assignment of therapeutic protocols for CLL patients according to the results of their cytogenetic analysis at the time of diagnosis. KEYWORDS: FISH, chronic lymphocytic leukemia, CLL, p53, cytogenetics, Egypt.

Holoprosencephaly spectrum among Egyptian patients: clinical and cytogenetic study.

We report 24 patients with holoprosencephaly (HPE) spectrum screened for Del 7q36 and subtelomere 13q. They were divided according to the type of HPE into: 6 alobar, 15 semilobar, 1 lobar and 2 middle interhemispheric variant (MIH). All patients presented with global developmental delay. Microcephaly was in 83.3% and midfacial developmental defects were in the form of; cyclopia, arrhinia and agnathia in 2 patients (8.3%), premaxillary agenesis in 2 patients (8.3%), cleft lip and palate in 7 patients (29.2%), hypotelorism in 8 patients (33.3%) and hypertelorism in 9 patients (37.5%). The neurological deficits were as follows: abnormal tone and spasticity were present in all of them with exceptional of a single patient with MIH who presented with hypotonia and was able to walk independently at the age of 3 years, athetoid and/or dystonic movements of limbs in 22 patients, seizures in twelve patients (50%) and abnormal EEG in 15 patients (62.5%). Poor temperature regulation was found in 50% of patients and diabetes insipidus was documented in 3 patients (12.5%). The MRI showed complete or partial fusion of basal ganglia and thalami in 21 patients (87.5%) and 19 patients (79.2%) respectively, fused mesencephalon in 8 patients (33.3%), incomplete separation of mesencephalon from diencephalon in 4 patients (16.7%), dorsal cyst in 10 patients (41.7%), abnormal gyral pattern anteriorly in 15 patients (62.5%), anterior located sylvian fissures in 22 patients (99.7%), complete or partial agenesis of the corpus callosum (ACC) in all patients and Dandy-Walker malformation (DWM) in three patients (12.5%). A small occipital cephalocele was detected clinically and radiological as atretic type in MIH patient. Karyotype analysis demonstrated 47, XY+13 in a patient with alobar holoprosencephaly, 46, XY,t(12;13) (q13q24.1;q14q33) in a semilobar case associated with DWM, 46, XY, del(13)(q34) in one semilobar case and three cases had del 7q36 using FISH technique in two semilobar cases and one lobar case. Conclusion: This study highlights the clinical spectrum in patients with HPE and report a case of HPE and DWM associated with t(12;13). Neuroimaging delineated the pathogenesis underlying developmental defects in HPE. Accurate molecular diagnosis is crucial for further understanding of the pathogenesis of HPE.

Distal 11q monosomy syndrome: a report of two Egyptian sibs with normal parental karyotypes confirmed by molecular cytogenetics.

Jacobsen syndrome is a rare disorder, caused by segmental monosomy for the distal end of the long arm of chromosome 11 with variable phenotypic expressivity. We report on the first male (6 years old) and female (3 years old) sibs with clinical and cytogenetics characterization of Jacobsen syndrome. Their karyotypes showed deletion 11q23.3-qter. Patients presented with growth and psychomotor retardation, facial dysmorphism, eye anomalies, and congenital heart disease (variable degrees of septal defect). Family history revealed a clinically similar brother, who died at 2 months old from cardiac anomalies in the form of single ventricle without being subjected to further investigations. Chromosomal analysis of the parents was normal. Karyotyping for the 2 patients and their parents was confirmed by fluorescence in situ hybridization analysis (FISH) using whole chromosome painting probes for 11 (WCP 11). Relevant investigations for both sibs showed mild thrombocytopenia with normal platelets morphology and striking periventricular demyelination on neuroimaging. Inguinal small testicles as well as focal epileptiform dysfunction were recorded in the male patient only. Abdominal ultrasound, hearing test, and DEXA scan were normal in both patients. Due to of the presence of apparently 3 affected offspring and normal parental karyotypes, an inherited predisposition was highly suspected. The large size of the distal deleted 11q segment in our patients support the recent hypothesis, that Jacobsen syndrome is a chromosomal deletion syndrome with genetic predisposition, due to expansion of p(CCG)n trinucleotide in the folate-sensitive fragile site FRA11B, at breakpoint 11q23.3. In conclusion, identification and further delineation of more similar patients will contribute to understanding the genetic basis of the 11q phenotype.

Phenotypic variability in Micro syndrome: report of new cases.

The authors describe seven Egyptian patients (5 males and two females) with microcephaly, mild microphthalmia, microcornea, congenital cataracts and hypogenitalism (only in males). These features (after excluding possible non-genetic causes) are consistent with the diagnosis of Micro syndrome. Clinical, neurological, ophthalmologic examinations and brain imaging and electrophysiological studies were performed in all patients. Three cases had characteristic facial features consistent with those originally described in the Micro syndrome whilst the rest of the cases had clearly different facies to that of the original patients of Micro syndrome but similar to those described in Martsolf syndrome. The patients had a variable degree of brain atrophy but hypogenesis of the corpus callosum was evident only in five patients. Abnormal gyral pattern, small cerebellum, vermian hypoplasia and delayed myelination were additional imaging findings in 3 cases. All patients had delayed visual evoked potential but normal electroretinogram. The frequently-reported parental consanguinity emphasizes the major role of the single gene inheritance. Mutation analysis for two patients showed homozygous nonsense mutation of RAB3GAP1 in one while the other showed no evidence of linkage to either RAB3GAP1 or RAB2GAP2. Based on these cases and review of the literature, RAB3GAP genes dysregulation may result in a spectrum of phenotypes that range from Micro syndrome to Martsolf syndrome.