Latent class analysis of structured histopathology in prognosticating surgical outcomes of chronic rhinosinusitis with nasal polyps in Singapore.

BACKGROUND: Structured histopathology profiling is recommended when reporting chronic rhinosinusitis with nasal polyp (CRSwNP) tissue. The objective of this study is to identify features in structured histopathology that predict outcome after functional endoscopic sinus surgery (FESS) in a cohort of CRSwNP patients from Singapore. METHODS: Latent class analysis was performed on structured histopathology reports of 126 CRSwNP patients who had undergone FESS. Outcome measures were polyp recurrence, need for systemic corticosteroids, revision surgery or biologics, and disease control at 2 years post-FESS. RESULTS: Three classes were identified. Class 1 was characterised by mild, predominantly lymphoplasmacytic inflammation. Class 2 comprised of 100 eosinophils/HPF, hyperplastic seromucinous glands, mucosal ulceration and mucin containing eosinophil aggregates and Charcot-Leyden crystals. Classes 2 and 3 were significantly associated with uncontrolled disease at 2 years post-FESS. Class 3 was additionally associated with the need for systemic corticosteroids. CONCLUSIONS: Eosinophil count, degree of inflammation, predominant inflammatory type, hyperplastic seromucinous glands, mucosal ulceration and mucin containing eosinophil aggregates and Charcot-Leyden crystals predicted need for systemic corticosteroids and uncontrolled disease at 2 years post-FESS. The presence of >100 eosinophils/HPF should be reported, as this subset of tissue eosinophilia was associated with less favourable outcomes after FESS.

COVID-19 vaccination for children in Malaysia - A position statement by the College of Paediatrics, Academy of Medicine of Malaysia.

The availability of COVID-19 vaccines and mass vaccination programmes in adults have significantly reduced the case attack rates and disease burden. COVID-19 vaccination successfully decreases the population at risk of infection, allowing for the safer re-opening of economies and reducing the pandemic's crippling impact on healthcare systems. However, the rapidly mutating severe acute respiratory syndrome-coronavirus-2 poses challenges in diminishing vaccine-induced immunity and vaccinating a significant proportion of adults to achieve herd immunity. These challenges necessitated adolescent vaccination. With the recent emergence of the highly transmissible Omicron variant and the increasing COVID-19 hospitalisation rates of children below 12 years old, many countries opted to also vaccinate younger children. Phase II/III clinical trials and real-world experience demonstrate that COVID-19 vaccinations are effective and safe for younger children and adolescents. Before Malaysia introduced its national COVID-19 vaccination programme for children 5-11 years old (which ran between March and June 2022), an expert advisory statement was issued by the College of Paediatrics, Academy of Medicine of Malaysia, to highlight the benefits and importance of vaccinating children. The advisory statement included clarifications about vaccine-related side effects such as post-vaccination myocarditis and allergic reactions to encourage informed decision making by healthcare providers and parents. This paper, which was prepared based on the critical appraisal of the current evidence, evaluation of the international experiences and the positive impact of COVID-19 vaccination in children, collectively sums up the rationale to support and ensure the success of the nationwide vaccination programme for children. Hence, the College recommends COVID-19 vaccination for children in Malaysia.

Crouzon syndrome: Genetic and intervention review.

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.

Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing.

Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations.

Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency.

Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations.

Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients.

BACKGROUND: Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations. METHODS: We have collected and reviewed our own and published data on tropical dRTA to provide a comprehensive series of clinical and epidemiological studies in 78 patients. RESULTS: Eight responsible SLC4A1 mutations have been described so far, four of them affecting multiple unrelated families. With the exception of the mutation causing South-East Asian ovalocytosis (SAO), none of these mutations has been reported outside the tropics, where dRTA caused by SLC4A1 mutations is much rarer and almost always dominant, resulting from mutations that are quite different from those found in the tropics. SLC4A1 mutations, including those causing dRTA, may cause morphological red cell changes, often with excess haemolysis. In dRTA, these red cell changes are usually clinically recessive and not present in heterozygotes. The high tropical prevalence of dRTA caused by SLC4A1 mutations is currently unexplained. CONCLUSION: A hypothesis suggesting that changes in red cell metabolism caused by these mutations might protect against malaria is put forward to explain the phenomenon, and a possible mechanism for this effect is proposed.

Neonatal intrahepatic cholestasis caused by citrin deficiency in two Malaysian siblings: outcome at one year of life.

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.

Partial deletion 9p syndrome in Malaysian children.

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.

Clinical and pathologic differences between BRCA1-, BRCA2-, and non-BRCA-associated breast cancers in a multiracial developing country.

BACKGROUND: 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. METHODS: We conducted a retrospective review of the medical records of 152 women with breast cancer who underwent genetic testing for BRCA mutations. The patients self-reported ethnicity, age at onset, and clinical stage at diagnosis and tumor pathology were reviewed. RESULTS: A total of 31 patients carried germline deleterious mutations (16 BRCA1, 15 BRCA2). We found that tumors in BRCA1 carriers were more likely to be estrogen receptor (ER)-negative and progesterone receptor (PR)-negative. HER2 was more likely to be negative in both BRCA1 and BRCA2 subjects compared with non-BRCA subjects. We found a strong association between triple-negative status and BRCA1 carriers. In addition, tumors in BRCA1 carriers were more likely to be higher grade than those in BRCA2 and non-BRCA carriers; but the difference was not statistically significant. CONCLUSIONS: These results suggest that tumors associated with BRCA1 mutations are distinct from those of BRCA2-associated and non-BRCA-associated breast cancers, and that the tumors associated with BRCA2 mutations are similar to the non-BRCA-associated breast cancers. Further studies are required to determine if the prognosis is different in each of these groups and the best management strategy for each group.

MECP2 mutations in Malaysian Rett syndrome patients.

INTRODUCTION: Rett syndrome (RS) is a severe neurodevelopmental disorder characterised by normal neurological development followed by progressive developmental regression. The X-linked dominant inheritance of RS has been mapped to the gene that encodes the methyl-CpG-binding protein-2 (MECP2) at Xq28. In the present study, denaturing high-performance liquid chromatography (DHPLC) was used to detect mutations in the MECP2 gene in 20 Malaysian RS patients. METHODS: Polymerase chain reaction (PCR) was carried out to amplify the MECP2 coding exons 2, 3, and 4 in a total of eight reactions (exons 2, 3a, 3b, 4a, 4b, 4c, 4d and 4e). Subsequently, PCR products were analysed by DHPLC. RESULTS: Mutations in the MECP2 gene were detected in 13 of the 20 (65 percent) RS patients. 11 patients had mutations in exons 3b and 4a and six patients had mutations in exon 4c. These mutations were mainly concentrated in the methyl-CpG-binding domain and the transcriptional-repression domain. CONCLUSION: Through the use of post-PCR high-performance liquid chromatography, 65 percent of 20 RS patients were found to have mutation(s) in the MECP2.

Congenital disorder of glycosylation type Ia in a Malaysian family: clinical outcome and description of a novel PMM2 mutation.

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.

Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer.

INTRODUCTION: The cost of genetic testing and the limited knowledge about the BRCA1 and BRCA2 genes in different ethnic groups has limited its availability in medium- and low-resource countries, including Malaysia. In addition, the applicability of many risk-assessment tools, such as the Manchester Scoring System and BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) which were developed based on mutation rates observed primarily in Caucasian populations using data from multiplex families, and in populations where the rate of breast cancer is higher, has not been widely tested in Asia or in Asians living elsewhere. Here, we report the results of genetic testing for mutations in the BRCA1 or BRCA2 genes in a series of families with breast cancer in the multi-ethnic population (Malay, Chinese and Indian) of Malaysia. METHOD: A total of 187 breast cancer patients with either early-onset breast cancer (at age

A population-based study of birth defects in Malaysia.

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.

The spectrum of beta-globin gene mutations in children with beta-thalassaemia major from Kota Kinabalu, Sabah, Malaysia.

INTRODUCTION: 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. METHODS: To confirm the observation that this large deletion is the commonest beta-globin gene mutation among the Kadazandusun and other indigenous populations in Sabah, Malaysia, we performed polymerase chain reaction (PCR) analysis of the beta-globin gene in ten children with beta-thalassaemia major attending the Thalassaemia Centre, Queen Elizabeth Hospital, the major paediatric referral centre in Kota Kinabalu, Sabah. RESULTS: The 45 kb deletion was confirmed to be the commonest mutation found in the Kadazandusun, Bajau and Murut populations, whereby it was detected in 19 out of the 20 (95 percent) alleles analysed. The other mutation was due to an IVS-1 position 1 G > T mutation. CONCLUSION: This finding confirmed the deletion in the homozygous state was associated with a severe phenotype. The reason for the predominance of this mutation in Kota Kinabalu is most likely to be due to founder effects and possibly intermarriages between the various ethnic groups. Prenatal diagnosis using PCR for this common mutation is feasible in this community. Medical workers and scientists at molecular diagnostic centres serving large South East Asian populations should incorporate a diagnostic strategy for this deletion in the appropriate population. Future studies on these indigenous ethnic groups in other areas and other groups in Sabah are required.

Combine-ARMS: a rapid and cost-effective protocol for molecular characterization of beta-thalassemia in Malaysia.

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.

Acampomelic campomelic dysplasia with SOX9 mutation.

Acampomelic campomelic dysplasia is a rare clinical variant of the more commonly encountered campomelic dysplasia (CMD1), characterized by absence of long bone curvature (acampomelia). We present a patient with acampomelic CMD1 with a de novo SOX9 missense mutation and report his clinical course to age one year, thereby contributing to genotype-phenotype correlation in CMD1. 2000.

A child with hemimegalencephaly, hemihypertrophy, macrocephaly, cutaneous vascular malformation, psychomotor retardation and intestinal lymphangiectasia--a diagnostic dilemma.

Although the clinical delineation of the majority of overgrowth syndromes is straightforward, we believe there is a subset of patients with overlapping features from a number of overgrowth syndromes. We report a patient with hemimegalencephaly, hemihypertrophy, macrocephaly, vascular lesions, psychomotor retardation and intestinal lymphangiectasia. The clinical history and findings posed a diagnostic dilemma as the features overlapped between several conditions, namely macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC), Klippel-Trenaunay-Weber syndrome (KTWS), Proteus syndrome and a provisional unique syndrome described by Reardon et al. (1996, Am J Med Genet 66:144-149). We anticipate that only when the molecular basis is delineated will it become clear whether these disorders are separate entities or merely differing ends of the same spectrum.

A single, large deletion accounts for all the beta-globin gene mutations in twenty families from Sabah (North Borneo), Malaysia. Mutation in brief no. 240. Online.

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.