Spectrum of germ-line RB1 gene mutations in Malaysian patients with retinoblastoma.

PURPOSE: The availability of molecular genetic testing for retinoblastoma (RB) in Malaysia has enabled patients with a heritable predisposition to the disease to be identified, which thus improves the clinical management of these patients and their families. In this paper, we presented our strategy for performing molecular genetic testing of the RB1 gene and the findings from our first 2 years of starting this service. METHODS: The peripheral blood of 19 RB probands, including seven bilateral and 12 unilateral cases, was obtained, and genomic DNA was extracted. Analysis of the RB1 exons and the promoter region was conducted first using PCR and direct sequencing. Next, multiplex ligation-dependent probe amplification (MLPA) analysis was performed for patients whom the first results were negative. For patients whom either the first or second method results were positive, parental samples were analyzed to determine the origin of the mutation. RESULTS: Ten RB1 mutations were identified in ten (52.6%) of the 19 probands (seven bilateral and three unilateral cases), of which 30.0% (3/10) was identified with MLPA. The detection rates in the bilateral and unilateral cases were 100.0% (7/7) and 25.0% (3/12), respectively. Three new RB1 mutations were discovered, two in patients with bilateral RB and one in patient with unilateral RB. Interestingly, all mutations detected with the PCR-sequencing method were predicted to create a premature stop codon. Eight mutations were proven to be de novo while one mutation was inherited from the mother in a family with a positive history of RB. CONCLUSIONS: Our results confirmed the heterogeneous nature of RB1 mutations and the predominantly de novo origin. The high prevalence of pathogenic truncating mutations was evident among local patients with RB. The combination of PCR sequencing and MLPA is recommended for sensitive identification of heritable RB cases.

Late presentation of retinoblastoma in Malaysia.

AIMS: The aims of this study were to review the presenting features, treatment and outcome for Malaysian children with retinoblastoma currently. SUBJECTS AND METHODS: This was a prospective study, conducted at the General Hospital Kuala Lumpur from August 2001 until October 2007. Clinical data were collected at presentation and follow-up. RESULTS: One hundred five children were diagnosed to have retinoblastoma. There were 55 males and 50 females, ranging in age from 1 month to 14 years (median 20 months). Seventy-six children were Malay in ethnic origin (73%), 14 Chinese (13%), 12 Indian (11%), and other races (3%). Sixty-four children presented with leukocoria (61%), followed by 23 with proptosis (22%), 13 with squint (12%), and 3 with orbital cellulitis (3%). Thirty-three children (31%) deferred treatment for 6 months or more. Overall, 56 children had extraocular disease (55%), 52 at presentation, 4 later. Seventy-one children (68%) underwent primary enucleation, 76 received chemotherapy (72%), and 23 radiotherapy (22%). Fifty-seven children are alive (54%), of whom 3 are blind (5%). Twenty-seven children were lost to follow-up (26%) and 21 have died (20%). CONCLUSION: Retinoblastoma in Malaysia is still characterized by predominantly extraocular disease due to late presentation and high rates of abandonment.

Presentation of retinoblastoma patients in Malaysia.

BACKGROUND: Retinoblastoma is a rare type of cancer that usually develops in early childhood. If left untreated it can cause blindness and even death. The aim of this study is to determine sociodemographic and clinical features of retinoblastoma patients and also to determine the treatment pattern and outcome in Malaysia. MATERIALS AND METHODS: Data for this study were retrieved from the Retinoblastoma Registry of the National Eye Database (NED) in Malaysia. Hospital Kuala Lumpur, Hospital Umum Kuching, Sarawak and Hospital Queen Elizabeth, Kota Kinabalu were the major source data providers for this study. Data collected in the registry cover demography, clinical presentation, modes of treatment, outcomes and complications. RESULTS: The study group consisted of 119 patients (162 eyes) diagnosed with retinoblastoma between 2004 and 2012. There were 68 male (57.1%) and 51 (42.9%) female. The median age at presentation was 22 months. A majority of patients were Malays (54.6%), followed by Chinese (18, 5%), Indians (8.4%), and indigenous races (15.9%). Seventy six (63.8%) patients had unilateral involvement whereas 43 patients had bilateral disease (36.1%). It was found that most children presented with leukocoria (110 patients), followed by strabismus (19), and protopsis (12). Among the 76 with unilateral involvement (76 eyes), enucleation was performed for a majority (79%). More than half of these patients had extraocular extension. Of the 40 who received chemotherapy, 95% were given drugs systemically. Furthermore, in 43 patients with bilateral involvement (86 eyes), 35 (41%) eyes were enucleated and 17 (49%) showed extraocular extension. Seventy-two percent of these patients received systemic chemotherapy. The patients were followed up 1 year after diagnosis, whereby 66 were found to be alive and 4 dead. Sixteen patients defaulted treatment and were lost to follow-up, whereas follow-up data were not available in 33 patients. CONCLUSIONS: Patients with retinoblastoma in this middle-income Asian setting are presenting at late stages. As a result, a high proportion of patients warrant aggressive management such as enucleation. We also showed that a high number of patients default follow-up. Therefore, reduction in refusal or delay to initial treatment, and follow-up should be emphasized in order to improve the survival rates of retinoblastoma in this part of the world.

Chemoreduction for intraocular retinoblastoma in Malaysia.

In the last decade, chemotherapy in combination with focal therapy (chemoreduction) has been increasingly used in intraocular retinoblastoma to avoid enucleation and radiotherapy. The aim of this study was to assess the feasibility and outcome of chemoreduction in Malaysian children with retinoblastoma. This was a prospective study from August 2001 to January 2006. Twenty children (25 eyes) were given 4 cycles of chemoreduction, after which the response was assessed. Fourteen eyes showed a complete response, 10 eyes showed a partial response, and 1 eye had progressive disease. Twelve eyes developed progressive disease later, 9 after an initial complete response and 3 after a partial response. Overall, progressive disease occurred in 52%. There were 2 treatment failures, in Reese-Elsworth groups 3 and 4. Both eyes required enucleation. One eye in group 5 required second line chemotherapy to achieve a complete response. No eyes were irradiated. Five children (25%) defaulted follow-up, one of whom returned with disseminated disease. In conclusion, 4 cycles of chemoreduction achieved a durable complete response in only 12% of eyes. Chemoreduction is feasible in Malaysia but requires good patient compliance and close follow-up.