Antonio Acquaviva

Effect of steroid and high-dose immunoglobulin therapy on opsoclonus-myoclonus syndrome occurring in neuroblastoma.

The authors describe a case of an 8-month-old boy with opsoclonus-myoclonus syndrome (OMS) and coincident unresectable neuroblastoma (NB). He achieved a complete remission for NB after 6 courses of standard-dose chemotherapy without significant neurological improvement despite the use of steroids and high-dose immunoglobulin (HIG), administered separately. Only the combined treatment withthese two drugs induced a complete disappearance of neurological symptoms. On the basis of this experience, the authors suggest the association of steroids plus HIG for the treatment of OMS in patients not responsive to conventional first line therapy with steroids.

Plasmapheresis in a child affected by acute disseminated encephalomyelitis

We describe an eight year old girl with acute relapsing disseminated encephalomyelitis (ADEM) who began to improve concomitantly with plasmapheresis therapy. The patient had previously undergone high-dose intravenous methylprednisolone, intravenous immunoglobulins and Interferon beta-1b treatment which did not control the clinical course of the disease. The long term follow-up suggests that plasmapheresis is effective in this disorder and may give better results than steroids or IVIG.

Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia

We report the case of a child with clinical and haematological features indicative of juvenile myelomonocytic leukaemia (JMML). The patient showed dysmorphic features: high forehead, bilateral epicanthal folds, long eyebrows, low nasal bridge and slightly low‐set ears. A 38G>A (G13D) mutation in exon 1 of the NRAS gene was first demonstrated on peripheral blood cells, and then confirmed on granulocyte‐macrophage colony‐forming units. The same mutation was also found in buccal swab, hair bulbs, endothelial cells, skin fibroblasts. This case suggests for the first time that constitutional mutations of NRAS may be responsible for development of a myeloproliferative/myelodysplastic disorder in children.

Genomic differences between retinoma and retinoblastoma

Introduction. Genomic copy number changes are involved in the multi-step process transforming normal retina in retinoblastoma after RB1 mutational events. Previous studies on retinoblastoma samples led to a multi-step model in which after two successive RB1 mutations, further genomic changes accompany malignancy: 1q32.1 gain is followed by 6p22 gain, that in turn is followed by 16q22 loss and 2p24.1 gain. Retinoma is a benign variant of retinoblastoma that was initially considered a tumor regression, but recent evidences suggest that it rather represents a pre-malignant lesion. Genetic studies on retinoma tissue have rarely been performed. Materials and methods. We investigated by Real-Time qPCR, copy number changes of candidate genes located within the 4 hot-spot regions (MDM4 at 1q32.1, MYCN at 2p24.1, E2F3 at 6p22 and CDH11 at 16q22) in retina, retinoma and retinoblastoma tissues from two different patients. Results. Our results demonstrated that some copy number changes thought to belong to early (MDM4 gain) or late stage (MYCN and E2F3 gain) of retinoblastoma are already present in retinoma at the same (for MDM4) or at lower (for MYCN and E2F3) copy number variation respect to retinoblastoma. CDH11 copy number is not altered in the two retinoma samples, but gain is present in one of the two retinoblastomas. Discussion. Our results suggest that MDM4 gain may be involved in the early transition from normal retina to retinoma, while MYCN and E2F3 progressive gain may represent driving factors of tumor progression. These results also confirm the pre-malignant nature of retinoma.

Array comparative genomic hybridization in retinoma and retinoblastoma tissues

In retinoblastoma, two RB1 mutations are necessary for tumor development. Recurrent genomic rearrangements may represent subsequent events required for retinoblastoma progression. Array‐comparative genomic hybridization was carried out in 18 eye samples, 10 from bilateral and eight from unilateral retinoblastoma patients. Two unilateral cases also showed areas of retinoma. The most frequent imbalance in retinoblastomas was 6p gain (40%), followed by gains at 1q12‐q25.3, 2p24.3‐p24.2, 9q22.2, and 9q33.1 and losses at 11q24.3, 13q13.2‐q22.3, and 16q12.1‐q21. Bilateral cases showed a lower number of imbalances than unilateral cases (P = 0.002). Unilateral cases were divided into low‐level (≤4) and high‐level (÷7) chromosomal instability groups. The first group presented with younger age at diagnosis (mean 511 days) compared with the second group (mean 1606 days). In one retinoma case ophthalmoscopically diagnosed as a benign lesion no rearrangements were detected, whereas the adjacent retinoblastoma displayed seven aberrations. The other retinoma case identified by retrospective histopathological examination shared three rearrangements with the adjacent retinoblastoma. Two other gene‐free rearrangements were retinoma specific. One rearrangement, dup5p, was retinoblastoma specific and included the SKP2 gene. Genomic profiling indicated that the first retinoma was a pretumoral lesion, whereas the other represents a subclone of cells bearing ‘benign’ rearrangements overwhelmed by another subclone presenting aberrations with higher ‘oncogenic’ potential. In summary, the present study shows that bilateral and unilateral retinoblastoma have different chromosomal instability that correlates with the age of tumor onset in unilateral cases. This is the first report of genomic profiling in retinoma tissue, shedding light on the different nature of lesions named ‘retinoma’. (Cancer Sci 2009; 100: 465–471)

Mortality from second tumour among long-term survivors of retinoblastoma: a retrospective analysis of the Italian retinoblastoma registry

Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00–12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38–21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20–20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38–38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55–10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74–16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90–753.20) and soft tissue (SMR 453.00, 95% CI 203.50–1008.40), small intestine (SMR 1375.50, 95% CI 344.00–5499.70), nasal cavity (SMR 13.71, 95% CI 1.93–97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2–127.55)

Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations

AbstractRetinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splice-site mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH

AbstractWe describe three patients with retinoblastoma, dysmorphic features and developmental delay. Patients 1 and 2 have high and broad forehead, deeply grooved philtrum, thick anteverted lobes and thick helix. Patient 1 also has dolicocephaly, sacral pit/dimple and toe crowding; patient 2 shows intrauterine growth retardation and short fifth toe. Both patients have partial agenesis of corpus callosum. Patient 3 has growth retardation, microcephaly, thick lower lip and micrognathia. Using array-comparative genomic hybridization (CGH), we identified a 13q14 de novo deletion in patients 1 and 2, while patient 3 had a 7q11.21 maternally inherited deletion, probably not related to the disease. Our results confirm that a distinct facial phenotype is related to a 13q14 deletion. Patients with retinoblastoma and malformations without a peculiar facial phenotype may have a different deletion syndrome or a casual association of mental retardation and retinoblastoma. Using array-CGH, we defined a critical region for mental retardation and dysmorphic features. We compared this deletion with a smaller one in a patient with retinoblastoma (case 4) and identified two distinct critical regions, containing 30 genes. Four genes appear to be good functional candidates for the neurological phenotype: NUFIP1 (nuclear fragile X mental retardation protein 1), HTR2A (serotonin receptor 2A), PCDH8 (prothocaderin 8) and PCDH17 (prothocaderin 17).

Non-Hodgkin lymphoma in a child presenting with acute paraplegia: a case report.

Spinal cord compression is a rare presentation of non-Hodgkin lymphoma. Extradural location at onset is a rare but devastating event in pediatric oncology. The authors describe a girl with acute spinal cord compression due to epidural non-Hodgkin lymphoma, emphasizing the encouraging perspective for a complete recovery in children with this condition. A 5-year-old girl presented with pain followed by progressive hyposthenia and paraplegia after a trauma. CT scan and MRI showed homogeneous tissue extending from T2 to L4, occupying the entire vertebral canal and extending to the para- and peri-vertebral soft parts. Emergency surgical debulking was carried out through T6-L1 laminectomy. The patient began chemotherapy (LMB 89 Protocol) and the tumor quickly disappeared. The patient is maintaining a complete remission 42 months after diagnosis. Significant results may be obtained with the chemotherapy treatment of epidural non-Hodgkin lymphoma when the disease is promptly diagnosed. Considering the effectiveness of chemotherapy, the authors believe that a neuro-surgical approach should be employed only when rapid worsening of symptoms is observed or for diagnostic purpose.

HYPEREOSINOPHILIC SYNDROME IN CHILDHOOD: Clinical and Molecular Features of Two Cases

Hypereosinophilic syndrome (HES) represents a heterogeneous group of diseases, some of which are being clarified by recent advances in molecular genetics. It is very rare in children. Uncertainties in classification and lack of prospective studies make therapeutic decisions difficult. The authors report two cases of HES in which steroid therapy was effective.