Three strains of Pseudomonas putrefaciens were isolated from routine clinical specimens at the University Hospital, Kuala Lumpur, Malaysia. Their cultural and biochemical characteristic, and antibiotic susceptibilities are presented. Characteristics of diagnostic value were stressed. Two isolates appeared to have played a pathogenic role in chronic otitis media.
In a study of 1,002 consecutive Malaysian male newborns, 48 (4.8%) were found to have undescended testes (UDT). The rate and laterality of the UDT were associated with lower birth weight (P < 0.001) and prematurity (P < 0.001). Boys with UDT were also more likely to have other congenital abnormalities of the external genitalia, the commonest being hydrocele. No correlation between UDT and maternal age, birth order, social class, or mode of delivery was demonstrated in this study. Although 26/34 (76.5%) of UDT achieved full spontaneous descent by 1 year of age, 1.1% of all infants whose testes remained undescended required regular long-term follow-up with surgical referral and correction at an appropriate time. A premature infant with UDT is more likely to achieve full testicular descent at 1 year of age than a term infant.
Study site: University Hospital, Kuala Lumpur, Malaysia (University Malaya Medical Centre)
We report the first two Malaysian children with partial deletion 9p syndrome, a well delineated but rare clinical entity. Both patients had trigonocephaly, arching eyebrows, anteverted nares, long philtrum, abnormal ear lobules, congenital heart lesions and digital anomalies. In addition, the first patient had underdeveloped female genitalia and anterior anus. The second patient had hypocalcaemia and high arched palate and was initially diagnosed with DiGeorge syndrome. Chromosomal analysis revealed a partial deletion at the short arm of chromosome 9. Karyotyping should be performed in patients with craniostenosis and multiple abnormalities as an early syndromic diagnosis confers prognostic, counselling and management implications.
Beta-thalassaemia major is one of the commonest genetic disorders in South East Asia. The strategy for the community control of beta-thalassaemia major requires the characterisation of the spectrum of beta-globin gene mutations in any multi-ethnic population. There is only a single report of mutation analyses of the beta-globin gene in an isolated Kadazandusun community in Kota Belud, Sabah, Malaysia, which showed the presence of a common 45 kb deletion.
The beta-thalassaemia mutations in 20 Malaysian children with beta-thalassaemia major were characterised by using a multi-modal approach, consisting of a slot-blot hybridisation with selected allele-specific oligonucleotides (ASO), followed by reverse dot-blot assay (RDB), amplification refractory mutation system (ARMS) and genomic sequencing. This strategy yielded a 94.4% mutation detection rate. The 6 most common mutations were codons 41/42 (-TTCT), IVS II nt 654(C --> T), IVS I nt 5(G --> C), IVS I nt 1(G -->T), codon 35 (-C) and codon 19 (A --> G), which accounted for 83.3% of all mutations detected. A strategy of initial screening with the above 6 selected ASOs for slot-blot hybridisation followed by RDB assay for the less common Asian mutations would give a mutation identification of 91.7%. Another feasible approach would be to analyse alleles from a particular racial group, by a judicious selection of 4 ASOs common to that particular subpopulation and then supplement this with RDB assay. This could yield a 100% coverage for the Chinese subpopulation in Malaysia. With these strategies, a practical approach has been identified to overcome the pitfalls posed by the molecular heterogeneity of beta-thalassaemia to enable prenatal diagnosis and carrier screening to be carried out. Regional collaborative studies are to be encouraged as an indispensable tool in providing better health care services to our patients.
The finding of a supernumerary or marker chromosome in a karyotype poses difficulty in genetic counselling. The true incidence and significance of this chromosomal aberration is unknown in Malaysia. We report two patients who presented with supernumerary chromosomes in mosaic Turner syndrome.
Birth defects are one of the leading causes of paediatric disability and mortality in developed and developing countries. Data on birth defects from population-based studies originating from developing countries are lacking. One of the objectives of this study was to determine the epidemiology of major birth defects in births during the perinatal period in Kinta district, Perak, Malaysia over a 14-month period, using a population-based birth defect register. There were 253 babies with major birth defects in 17,720 births, giving an incidence of 14.3/1000 births, a birth prevalence of 1 in 70. There were 80 babies with multiple birth defects and 173 with isolated birth defects. The exact syndromic diagnosis of the babies with multiple birth defects could not be identified in 18 (22.5%) babies. The main organ systems involved in the isolated birth defects were cardiovascular (13.8%), cleft lip and palate (11.9%), clubfeet (9.1%), central nervous system (CNS) (including neural tube defects) (7.9%), musculoskeletal (5.5%) and gastrointestinal systems (4.7%), and hydrops fetalis (4.3%). The babies with major birth defects were associated with lower birth weights, premature deliveries, higher Caesarean section rates, prolonged hospitalization and increased specialist care. Among the cohort of babies with major birth defects, the mortality rate was 25.2% during the perinatal period. Mothers with affected babies were associated with advanced maternal age, birth defects themselves or their relatives but not in their other offspring, and significantly higher rates of previous abortions. The consanguinity rate of 2.4% was twice that of the control population. It is concluded that a birth defects register is needed to monitor these developments and future interventional trials are needed to reduce birth defects in Malaysia.
Distal renal tubular acidosis (RTA) and hereditary elliptocytosis (HE) are apparently distinct, genetic conditions. We report a family with 3 children having both hereditary elliptocytosis and distal renal tubular acidosis. The simultaneous occurrence of these two conditions in three siblings could be due to covariations in the same family, although a possible contiguous gene syndrome for distal RTA and HE cannot be excluded. This report emphasises the importance of excluding a renal tubular defect in any child who presents with elliptocytosis and failure to thrive.
We report the occurrence of X-linked lymphoproliferative disease (XLP) in two brothers in a Malaysian family. In this disorder, a primary Epstein-Barr virus (EBV) infection is followed by an abnormal proliferation of transformed B-cells that cannot be controlled by suppressor T-cells, leading to the development of deranged immune function. This results in fatal infectious mononucleosis, acquired hypogammaglobulinaemia, virus-infected haemophagocytic syndrome and non-Hodgkin's lymphoma. The diagnosis should be considered when there is a family history of any male having a fulminant course of infectious mononucleosis, an otherwise benign disease. Early diagnosis is important as bone marrow transplantation is the only curative option in this disorder.
There are few reports of congenital disorders of glycosylation (CDGs) in the Asian population, although they have been reported worldwide. We identified a Malaysian infant female at 2 days of life with CDG type Ia. The diagnosis was suspected on the basis of inverted nipples and abnormal fat distribution. She had cerebellar hypoplasia and developed coagulopathy, hypothyroidism and severe pericardial effusion and died at 7 months of life. The diagnosis was supported by abnormal serum transferrin isoform pattern that showed elevated levels of the disialotransferrin isoform and trace levels of the asialotransferrin isoform. Enzyme testing of peripheral leukocytes showed decreased level of phosphomannomutase (PMM) activity (0.6 nmol/min per mg protein, normal range 1.6-6.2) and a normal level of phosphomannose isomerase activity (19 nmol/min per mg protein, normal range 12-25), indicating a diagnosis of CDG type Ia. Mutation study of the PMM2 gene showed the patient was heterozygous for both the common p.R141H (c.422T>A) mutation and a novel sequence change in exon 7, c.618C>A. The latter change is predicted to result in the replacement of the highly conserved phenylalanine residue at position 206 with a leucine residue (p.F206L) and occurs in the same codon as the previously reported p.F206S mutation. Analysis of 100 control chromosomes has shown that the p.F206L sequence change is not present, making it highly likely that this change is functionally important. To the best of our knowledge, this is the first report of CDG in the Malay population. Prenatal diagnosis was successfully performed in a subsequent pregnancy for this family.
Between January 1984 and December 1994, 30 cases of early neonatal group B streptococcus (GBS) septicaemia were managed in the Neonatal Unit, University Hospital, Kuala Lumpur. Two neonates were outborn and 28 were inborn, giving an average annual incidence of neonatal GBS septicaemia of 0.4/1000 livebirths among inborn babies. In a separate survey over a three-month period, GBS genital carriage rate among 196 parturients was found to be 9.7%. Of the infants with GBS septicaemia, the mean gestational age was 37.5 +/- 3.8 weeks and the mean birthweight was 2540 +/- 716 g. Twelve (40%) were preterm infants and 14 (47%) were low birthweight infants. Male and female infants were almost equally affected. Prolonged rupture of membranes and maternal pyrexia accounted for only 5 (17%) and 3 (10%) of the cases respectively. Twenty-four (80%) neonates had onset of symptoms within 6 hours of life and respiratory symptoms were observed in 24 (80%) of the cases, while meningitis was uncommon. Six (20%) neonates died. Preterm and low birthweight infants had higher mortality than their term counterparts: 42% versus 6% and 36% versus 6% respectively. Of those who died, 4 (67%) required respiratory support right from birth and the mean time of onset of symptoms was 4 hours (range 0 to 21 hours) and the duration of survival was only 28.8 hours (range 12 to 38 hours). As the incidence of neonatal GBS septicaemia was low, mass screening and chemoprophylaxis for GBS were not recommended. All the GBS isolates were sensitive to penicillin and ampicillin, thus one of these antibiotics should be included in the antimicrobial therapy of septic neonates.
In dengue shock syndrome, an acute increase in capillary permeability results in leakage of plasma into the interstitial space. Pleural effusion is commonly seen in dengue shock syndrome. We report three cases of dengue-associated adult respiratory distress syndrome (ARDS) in children, in all of whom dengue haemorrhagic fever, presenting with grade 3 or grade 4 dengue shock syndrome with disseminated intravascular coagulopathy, was confirmed. The criteria for the diagnosis of ARDS were based on the expanded definition of ARDS by Murray et al. Treatment consisted of fluid resuscitation, correction of coagulopathy and mechanical ventilation. All three children had multi-organ impairment, but it was more severe in the two who died. The one survivor was well at discharge.
Crouzon syndrome exhibits considerable phenotypic heterogeneity, in the aetiology of which genetics play an important role. FGFR2 mediates extracellular signals into cells and the mutations in the FGFR2 gene cause this syndrome occurrence. Activated FGFs/FGFR2 signaling disrupts the balance of differentiation, cell proliferation, and apoptosis via its downstream signal pathways. However, very little is known about the cellular and molecular factors leading to severity of this phenotype. Revealing the molecular pathology of craniosynostosis will be a great value for genetic counselling, diagnosis, prognosis and early intervention programs. This mini-review summarizes the fundamental and recent scientific literature on genetic disorder of Crouzon syndrome and presents a graduated strategy for the genetic approach, diagnosis and the management of this complex craniofacial defect.
We report two Malaysian siblings with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The younger sibling, a six-month-old Chinese girl, presented with prolonged neonatal jaundice, and was investigated for biliary atresia. Urine metabolic screen showed the presence of urinary-reducing sugars, and she was treated with a lactose-free formula. NICCD was suspected based on the clinical history, examination and presence of urinary citrulline. Mutation study of the SLC25A13 gene showed the compound heterozygotes, 851del4 and IVS16ins3kb, which confirmed the diagnosis of NICCD in the patient and her three-year-old female sibling, who also had unexplained neonatal cholestasis. Long-term dietary advice, medical surveillance and genetic counselling were provided to the family. The diagnosis of NICCD should be considered in infants with unexplained prolonged jaundice. DNA-based genetic testing of the SLC25A13 gene may be performed to confirm the diagnosis retrospectively. An awareness of this condition may help in early diagnosis using appropriate metabolic and biochemical investigations, thus avoiding invasive investigations in infants with neonatal cholestasis caused by NICCD.
Beta-thalassemia major is one of the commonest genetic disorders in South-East Asia. The spectrum of beta-thalassemia mutations in the various ethnic sub-populations on the island of Borneo is unknown. We studied 20 Dusun children from the East Malaysian state of Sabah (North Borneo) with a severe beta-thalassemia major phenotype, using a combination of Southern analysis, polymerase chain reaction analysis and direct sequencing. We found the children to be homozygous for a large deletion, which has a 5' breakpoint at position -4279 from the cap site of the beta-globin gene (HBB) with the 3' breakpoint located in a L1 family of repetitive sequences at an unknown distance from the beta-globin gene. This was similar to a recent finding of a large deletion causing beta-thalassemia first described in unrelated beta-thalassemia heterozygotes of Filipino descent. This report describes the first 20 families with homozygosity of the deletion causing a severe phenotype. It provides the first information on the molecular epidemiology of beta-thalassemia in Sabah. This finding has implications for the population genetics and preventative strategies for beta-thalassemia major for nearly 300 million individuals in South-East Asia.
Beta-thalassemia major patients have chronic anemia and are dependent on blood transfusions to sustain life. Molecular characterization and prenatal diagnosis of beta3-thalassemia is essential in Malaysia because about 4.5% of the population are heterozygous carriers for beta-thalassemia. The high percentage of compound heterozygosity (47.62%) found in beta-thalassemia major patients in the Thalassaemia Registry, University of Malaya Medical Centre (UMMC), Malaysia, also supports a need for rapid, economical, and sensitive protocols for the detection of beta-thalassemia mutations. Molecular characterization of beta-thalassemia mutations in Malaysia is currently carried out using ARMS, which detects a single beta-thalassemia mutation per PCR reaction. We developed and evaluated Combine amplification refractory mutation system (C-ARMS) techniques for efficient molecular detection of two to three beta-thalassemia mutations in a single PCR reaction. Three C-ARMS protocols were evaluated and established for molecular characterization of common beta-thalassemia mutations in the Malay and Chinese ethnic groups in Malaysia. Two C-ARMS protocols (cd 41-42/IVSII #654 and -29/cd 71-72) detected the beta-thalassemia mutations in 74.98% of the Chinese patients studied. The CARMS for cd 41-42/IVSII #654 detected beta-thalassemia mutations in 72% of the Chinese families. C-ARMS for cd 41-42/IVSI #5/cd 17 allowed detection of beta-thalassemia mutations in 36.53% of beta-thalassemia in the Malay patients. C-ARMS for cd 41-42/IVSI #5/cd 17 detected beta-thalassemia in 45.54% of the Chinese patients. We conclude that C-ARMS with the ability to detect two to three mutations in a single reaction provides more rapid and cost-effective protocols for beta-thalassemia prenatal diagnosis and molecular analysis programs in Malaysia.
Mutations in BRCA1 and BRCA2 confer an increased risk to breast and other cancers, but to date there have only been limited numbers of studies of BRCA1- and BRCA2-associated cancers among Asians. Malaysia is a multiracial country with three main races: Malays, Chinese, Indians. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations in this Asian population.