Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients.

BACKGROUND: Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010-2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. RESULTS: There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. CONCLUSIONS: Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients.

BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of ß-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. METHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019. RESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. CONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.

The Effects of the Face Mask on the Skin Underneath: A Prospective Survey During the COVID-19 Pandemic.

PURPOSE: The study aimed to explore the prevalence and possible risk factors to prevent the face mask related adverse skin reactions during the ongoing COVID-19 after a recommendation of face mask wearing for public use in Thailand. RESULTS: The prevalence of face mask related adverse skin reactions was 454 cases (54.5%), of which acne was the most frequent (399; 39.9%), followed by rashes on the face (154; 18.4%), and itch symptoms (130; 15.6%). Wearing a surgical mask showed a higher risk of adverse skin reaction compared to a cloth mask, OR (95% CI) = 1.54 (1.16-2.06). A duration of face mask wearing of more than 4 hours/day and the reuse of face masks increased the risk of adverse skin reactions compared to changing the mask every day, adjusted OR(95% CI) = 1.96 (1.29-2.98), and 1.5 (1.11-2.02). CONCLUSION: Suggestions were made for wearing a cloth mask in non-health care workers (HCW) to decrease the risk of face mask related adverse skin reactions. This suggestion could potentially help in decreasing the demand of surgical masks which should be reserved for the HCW population during the ongoing COVID-19 pandemic.

Growth charts for Thai children with Prader-Willi syndrome aged 0-18 years.

BACKGROUND: Prader-Willi syndrome (PWS) is a multisystem genetic disorder, which has a typical eating behavior and growth pattern. In the infancy period, children with PWS have low body weight followed by hyperphagia in later childhood. Disease-specific growth charts have been recommended for monitoring PWS patients. Previous literature demonstrated growth differences among individuals with PWS of different ethnicity. METHODS: A retrospective multicenter study was performed in PWS patients from different areas of Thailand included collaboration with the Thai PWS support group during 2000-2017. Baseline characteristics and anthropometric data were reviewed. Both growth hormone and non-growth hormone received patients were included, but the data after receiving GH were excluded before curve construction. Growth charts for Thai PWS compared to the 50th normative centile were constructed using Generalized Least Squares (GLS) methods. Curve smoothing was performed by Fractional Polynomials and Exponential Transformation. RESULT: One hundred and thirteen patients with genetically confirmed PWS (55 males and 58 females) were enrolled. Fifty percent of patients were diagnosed less than 6 months of age. We developed growth charts for non-growth hormone treated Thai children with PWS aged between 0 and 18 years. A growth pattern was similar to other ethnicities while there were some differences. Mean birth weight of PWS patients was less than that of typical newborns. Mean adult height at 18 years of age in Thai children with PWS was lower than that in American children, but taller than Japanese. Mean weight of Thai PWS males at 18 years of age was more than those from other countries. CONCLUSION: This study is the first to document PWS-specific growth charts in Southeast Asian population. These growth charts will be useful in improving the quality of patient care and in evaluating the impact of growth hormone treatment in the future.

Iliac Artery Aneurysms in Menkes Disease: A Case Report.

Background: Menkes disease is a disorder of copper transportation that results in multi-systems involvement including neurological deterioration, seizure, dysmorphic facies and kinky hair. The authors report a case of Menkes disease that was complicated with bilateral iliac artery aneurysms. Case Report: A 6-month-old Thai male infant presented with seizure, global delayed development, hypotonia and sparse, short, lightly pigmented and kinky hair. Light microscopic hair analysis showed pili torti. His serum copper and ceruloplasmin levels were low and were compatible with Menkes disease. Radiological finding from magnetic resonance angiography (MRA) revealed irregular tortuosity of abdominal aorta, a large right internal iliac artery aneurysm and a small left common iliac artery aneurysm. Genetic counseling and supportive treatment were provided for this patient. Conclusion: Iliac aneurysms are a serious complication of patients with Menkes disease. Careful investigation with computed tomographic angiography (CTA) or MRA is helpful in those patients.

Assessment of Chromosome 22q11.2 Deletion in Patients with Isolated Cleft Palate: A Systematic Review of Prospective Studies.

Background: The prevalence of 22q11.2 deletion in patients presenting with isolated cleft palate has not been systematically assessed. Objective: To assess the evidence in the literature for the prevalence of 22q11.2 deletion in patients who were presenting with isolated cleft palate. Material and Method: A systematic literature search was conducted through PubMed between 1992 and June 2016 using search terms of 22q11.2 deletion OR 22q11 deletion AND cleft palate. Results: Of the six prospective studies reported, 328 patients with isolated cleft palate had been screened with FISH (Fluorescence In Situ Hybridization) test for 22q11.2 deletion. Among the 328 patients, there was one (0.3%) patient with positive FISH test for 22q11.2 deletion. This patient was clinically assessed and did not have an associated malformation or clinically recognized syndrome. Conclusion: The prevalence of 22q11.2 deletion among patients with isolated cleft palate is rather low. Of more than 400 genetic disorders involving occurrences of isolated cleft palate, FISH testing for 22q11.2 deletion in a patient with isolated cleft palate is recommended on clinical suspicion of additional clinical presentations of 22q11.2 deletion syndrome such as conotruncal congenital heart diseases, dysmorphic facies, velopharyngeal insufficiencies, immune deficiencies, hypoparathyroidisms, and neuropsychiatric disorders.

Birth Prevalence of Chromosome 22q11.2 Deletion Syndrome: A Systematic Review of Population-Based Studies.

Background: A birth prevalence of chromosome 22q11.2 deletion syndrome among population-based reports has been documented to vary, however, a systematic assessment is lacking. Objective: To assess the evidence in the literature for the birth prevalence of chromosome 22q11.2 deletion syndrome. Material and Method: A systematic literature search was conducted through PubMed between 1992 and June 2016 using search terms of 22q11.2 deletion OR 22q11 deletion and prevalence. Results: Of the six studies reported, there were 156 patients with 22q11.2 deletion syndrome found in total study populations of 1,111,336 live births. According to countries, the birth prevalence of this deletion syndrome (95% confidence interval) from United States, Belgium, Sweden, United Kingdom, France, and Singapore were 1.68 (1.22-2.26), 1.56 (1.33-1.72), 1.36 (0.91-2.08), 1.30 (0.45-2.15), 1.03 (0.53-2.23), and 1.02 per 10,000 live births, respectively. Estimates of minimum prevalence rates on the basis of the presence of this syndrome in cohorts of patients with cardiovascular malformations were from one in 4,000 to one in 7,092 live births. Conclusion: This systematic review indicates that the 22q11.2 deletion syndrome is rather common. The findings can help physicians, health care planners and other health professionals to plan and manage better care of these patients.

Prevalence and type of associated syndromes in patients with cleft lip and cleft palate who received the treatment in Tawanchai Center until 4-5 years of age.

BACKGROUND: Understanding the genetic etiologies of cleft lip and palate (CLP) is important for improved prevention, treatment, and prognosis for patients affected by CLP. OBJECTIVE: To report the prevalence and the type of associated syndromes in Northeastern Thai patients with CLP. MATERIAL AND METHOD: A retrospective study of123 cleft lip/palate children aged 4-5 years was carried out at the Tawanchai Cleft Centel; Khon Kaen University during the period from October to December 2011. Data were collected by reviewing the patient 's medical records. RESULTS: Seventeen (14%) of the 123 children had multiple malformations and five (4%) of these children had associated syndromes. Syndromes were identified in 5 (29%) of the 17 children who had associated malformations. The syndromes were Apert, Cleft lip/palate-ectodermal dysplasia, Kabuki, Oculo-Auriculo-Vertebral Spectrum, and Velocardiofacial syndrome. CONCLUSION: Recognition of the associated syndrome in a patient with CLP is essential to assess the problem of the patient, provide necessaty treatment and the appropriate methodology of prevention.

Incidence of hepatocellular carcinoma in children in Khon Kaen before and after national hepatitis B vaccine program.

BACKGROUND: Hepatitis B virus infection is one of the most important risk factors for hepatocellular carcinoma. Hepatitis B vaccination has been obligatory in the Expanded Program on Immunization (EPI) in Khon Kaen since 1990. OBJECTIVE: To compare the incidence of hepatocellular carcinoma in children in Khon Kaen province before and after the introduction of national hepatitis B vaccination program. METHODS: Cases of liver tumors in children under 18, diagnosed during 1985-2007, were retrieved from the population-based cancer registry of Khon Kaen. Patients were divided into 2 groups, vaccinated and non-vaccinated with hepatitis B vaccine regarding the year of birth before or after 1990. Patients with diagnosis of liver cancer from any basis of diagnosis in population-based registration, except hepatoblastoma, were included. Patients without verified histology were assumed as having hepatocellular carcinoma if the age at diagnosis was over 10. Age-standardized incidence rates (ASRs) were analyzed and expressed as numbers per 1,000,000 population. RESULTS: Fifteen patients aged 13 to 18 years were included in this study. The mean and median ages at diagnosis were 15.7 and 15 years respectively. Four children had a verified histology (age 14 to 18 years, median and mean = 16). The remaining 11 patients were diagnosed based on history and physical examination, radiology and death certificate, at the aged of 13 to 18 years. The ASRs for liver cancer in children over 10 years of age of non-vaccinated and vaccinated children were 0.88 and 0.07 per million respectively (p = 0.039). When calculated by including children at or older the 5 years of age, the ASRs for non-vaccinated and vaccinated cases were 0.97 and 0.24 per million respectively (p = 0.007). CONCLUSIONS: The incidence of hepatocellular carcinoma is significantly lower in Thai children who receive hepatitis B vaccine at birth.