Triallelic and epigenetic-like inheritance in human disorders of telomerase.

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.

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.

Audit of pediatric hematology-oncology outpatients in Kuala Lumpur.

The aims of this study were to determine the types of cancers and hematological disorders in patients attending a pediatric hematology-oncology clinic. This was a prospective study at the Pediatric Institute, General Hospital Kuala Lumpur, Malaysia from June 2005-November 2006. During the 18-month study, 803 patients attended the clinic, 730 had oncological problems and 73 had hematological problems. The age range was from 2 months to 28 years (median 6 years). The patients were Malay (66%), Chinese (23%), Indian (10%) and other races (1%). Of the oncological patients, 51% had either leukemia (n=293) or lymphoma (n=77). The other most common diagnoses were retinoblastoma, followed by Wilm's tumor and germ cell tumors. Six patients (0.8%) developed a second malignant neoplasm. Of the hematological patients, 60% had platelet disorders, most commonly chronic immune thrombocytopenic purpura. Twenty-four per cent had bone marrow failure and 16% had red cell disorders.

TEL-AML1 frequency in multi-ethnic Malaysian pediatric acute lymphoblastic leukemia.

Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.

Heterogeneous t(4;11) fusion transcripts in two infants with acute lymphoblastic leukemia.

An RT-PCR assay detected the t(4;11) translocation in two infants with acute lymphoblastic leukemia (ALL). Case P76 was a 10-month-old, female infant, who presented with a WBC of 137.4 x 10(9)/l and a pre-pre-B ALL immunophenotype. Case P120 was a 6-month-old female infant, with a WBC > 615 x 10(9)/l and a pre-pre-B ALL immunophenotype. RT-PCR of cDNA from both these cases generated a 656 bp and a 542 bp respectively, which sequencing confirmed as t(4;11) fusion transcripts. The primers and conditions selected for this assay are compatible with a one-step multiplex PCR for the main translocations in childhood ALL.

Pediatric cancer deaths: curative or palliative?

AIMS: The aims of this study were to review the deaths of Malaysian pediatric oncology patients in order to determine the major causes and the proportion of patients who received palliative care. SUBJECTS AND METHODS: This was a retrospective review from 2001-2007 of deaths at the Pediatric Institute, General Hospital Kuala Lumpur. Clinical data such as age, gender, disease, cause, and place of death were collected. The patients were divided into two groups: those who received palliative care and those who received curative treatment. RESULTS: Two hundred forty-seven patients were included. There were 148 males and 99 females. The age ranged from 2 months to 22 years (median, 4 years). One hundred thirty cases (53%) were still in the curative phase of treatment at the time of death. The most common cause of death was septicemia (62%), followed by hemorrhage (18%) and underlying cancer (14%). One hundred seventeen cases (47%) were in the palliative phase at the time of death. All palliative care deaths occurred in the oncology ward with one exception. CONCLUSION: Nearly half of all inpatient pediatric cancer deaths were palliative in nature. Septicemia and hemorrhage were the major causes of death in the others.