Retinoblastoma and mosaic 13q deletion: a case report

Background Patients with 13q-syndrome are at risk of retinoblastoma when the RB1 gene, located in the chromosomal band 13q14.2, is deleted. This syndrome is frequently associated with congenital malformations and developmental delay, although these signs could be mild. Mosaic 13q-deletion patients have been previously reported in the literature; their phenotype is variable, and they may not be recognized. Case presentation Retinoblastoma diagnosed in a child with 13q-mosaicism confirmed in blood, oral mucosa, healthy retina and retinoblastoma. A second RB1 hit is present exclusively in the retinoblastoma sample (RB1 c.958C>T p.Arg320Ter). Other detected molecular events in retinoblastoma are 6p12.3pter gain and 6q25.3qter loss. Clinical examination is unremarkable except for clinodactyly of the right fifth finger. Discussion and conclusions We describe a case of mosaic 13q deletion syndrome affected by retinoblastoma. Molecular data obtained from the tumor analysis are similar to previous data available about this malignancy. High clinical suspicion is essential for an adequate diagnosis of mosaic cases.

Deletion of 4.4 Mb at 2q33.2q33.3 May Cause Growth Deficiency in a Patient with Mental Retardation, Facial Dysmorphic Features and Speech Delay

A patient with a rare interstitial deletion of chromosomal band 2q33.2q33.3 is described. The clinical features resembled the 2q33.1 microdeletion syndrome (Glass syndrome), including mental retardation, facial dysmorphism, high-arched narrow palate, growth deficiency, and speech delay. The chromosomal aberration was characterized by whole genome BAC aCGH. A comparison of the current patient and Glass syndrome features revealed that this case displayed a relatively mild phenotype. Overall, it is suggested that the deleted region of 2q33 causative for Glass syndrome may be larger than initially suggested.

A NUP98-NSD1 Fusion Gene Can Be Detected in a Small Subset of Adult AML Patients with Normal Karyotype

Abstract 2531 Introduction: Fusion genes can be detected in approximately 30–35% of all AML cases and usually are the result of a cytogenetically detectable chromosomal rearrangement. Very recently, a novel fusion gene has been described in AML with normal karyotype (Hollink et al, Blood, 2011). This cryptic fusion involves nucleophosmin 98kD (NUP98) in chromosomal band 11p15 and the non homeobox gene NSD1 in chromosomal band 5q35. NUP98-NSD1 has been described in this single study with a frequency of 16.1% in pediatric and 2.3% in adult AML patients with distinct characteristics (e.g. mutual exclusivity with NPM1) and dismal prognosis. Aim: The aim of this study was to further evaluate NUP98-NSD1 rearrangements in adult AML with normal karyotype (NK) for frequency, association with other mutations and impact on outcome. Patients and Methods: Screening for NUP98-NSD1 fusion gene was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) in a total cohort of 148 de novo AML patients with NK and NPM1 wildtype status. The NUP98-NSD1 positive cases were verified by direct Sanger Sequencing of the PCR products. The cohort was composed of 84 males and 64 females. Median age was 55.4 years (range: 15.7 to 85.8 years). Further mutation analysis was available in subcohorts: FLT3-ITD (n=32 mut/117 screened), CEBPA (n=22 mut/124 screened), MLL-PTD (n=32 mut/117 screened) and RUNX1 (n=26 mut/83 screened). Results: In total, in 8/148 (5.4%) patients a NUP98-NDS1 fusion transcript was detected. NUP98-NDS1-positive cases had significantly higher platelet counts (median 221 vs 87 × 10e9/L; p=0.001). Patients with NUP98-NDS1 were younger than the NUP98-NDS1-negative patients (median: 43.5 years vs 55.4 years, p=0.067). Sex (5 male vs. 3 female), white blood cell count and hemoglobin levels at diagnosis were not different compared to NUP98-NDS1-negative cases. Cytomorphology revealed AML with minimal differential differentiation (n=4), with maturation (n=1), and myelomonocytic AML (n=3). In 3 NUP98-NDS1-positive cases immunophenotyping data was available and all 3 cases aberrantly expressed CD7. NUP98-NDS1-positive cases have a higher frequency of FLT3-ITD compared to NUP98-NDS1-negative cases (5/8, 62.5% vs. 27/140, 19.3%; p=0.015) and were mutually exclusive of CEBPA and RUNX1 mutations. With respect to survival the NUP98-NDS1-positive cases had a worse event free survival compared to NUP98-NDS1-negative cases (median 5.1 months vs. 25.2 months; p=0.054). Conclusions: A NUP98-NSD1 fusion transcript was detected in 5.4% of normal karyotype adult AML patients without NPM1 mutation. NUP98-NSD1-positive cases are characterized by younger age, high coincidence of FLT3-ITD, aberrant expression of CD7, relatively high platelet counts, and a short event free survival. Thus NUP98-NSD1 translocations seem to define a new subgroup of NK-AML. Importantly, in this prognostically adverse and so far cytogenetically undetectable group close and sensitive PCR based monitoring for minimal residual disease is available. Thus, this data suggests to perform PCR based screening for NUP98-NSD1 in AML with normal karyotype that lack NPM1 and CEBPA mutations. Disclosures: Fasan: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.