Expanded Newborn Screening for Inborn Errors of Metabolism in Hong Kong: Results and Outcome of a 7 Year Journey.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

Review on the screening of urine glucose for early diagnosis of type 2 diabetes mellitus in school children and adolescents with obesity in Hong Kong.

OBJECTIVES: Obesity and type 2 diabetes mellitus (T2DM) are growing health concerns. Since 2005, Student Health Service (SHS) and Hong Kong Paediatric Society formulated a protocol on urine glucose screening (UGS) for early diagnosis of T2DM in students with obesity in Hong Kong. This study reviews students with T2DM captured by this screening program and compare the data with the Hong Kong Children Diabetes Registry (HKCDR) database, to see if the UGS program facilitates early diagnosis of T2DM. METHODS: Students between the ages of 10-18 years old with age- and sex-specific body mass index (BMI) >97th percentile who attended SHS between the school years from 2005/06 to 2017/18 were recruited for UGS. Those tested positive for random urine glucose underwent diagnostic testing for T2DM according to ADA guidelines. Demographic data and investigatory results from UGS and HKCDR within the same time period were compared. RESULTS: A total of 216,526 students completed UGS in the said period; 415 (0.19 %) students were tested positive for urine glucose of which 121 students were diagnosed with T2DM. UGS picked up 23 % of the newly diagnosed T2DM cases. When compared to the HKCDR database, students diagnosed via UGS were significantly younger, less obese, and had fewer diabetic related complications. The negative predictive value of UGS is high and can effectively rule out T2DM. CONCLUSIONS: Urine glucose screening is an inexpensive and simple test that allows for early diagnosis of T2DM among obese school students. Other methods including POCT HbA1c can be explored to improve program effectiveness.

Diabetic ketoacidosis in children with new-onset type 1 diabetes mellitus: demographics, risk factors and outcome: an 11 year review in Hong Kong.

OBJECTIVES: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D). The aim of this study is to analyze the incidence, clinical characteristics, management and outcome of children presenting with DKA in new-onset T1D from 2008 to 2018 in Hong Kong. METHODS: Data was extracted from the Hong Kong Childhood Diabetes Registry. All subjects less than 18 years with newly diagnosed T1D from 1 January 2008 to 31 December 2018 managed in the public hospitals were included. Information on demographics, laboratory parameters, DKA-related complications and management were analyzed. RESULTS: In the study period, there were 556 children with newly diagnosed T1D in our registry and 43.3% presented with DKA. The crude incidence rate of new-onset T1D with DKA was 1.79 per 100,000 persons/year (CI: 1.56-2.04). Subjects presenting with DKA were younger (9.5 ± 4.5 vs. 10.5 ± 4.4, p=0.01) and had shorter duration of symptoms (4.2 ± 5.9 days vs. 10.6 ± 17.1 days, p<0.01). Regarding management, up to 12.4% were given insulin boluses and 82.6% were started on insulin infusion 1 h after fluid resuscitation. The rate of cerebral edema was 0.8% and there was no mortality. CONCLUSIONS: Younger age and shorter duration of symptoms were associated with DKA in new-onset T1D. Despite availability of international guidelines, there was inconsistency in acute DKA management. These call for a need to raise public awareness on childhood diabetes as well as standardization of practice in management of pediatric DKA in Hong Kong.

Incidence and clinical characteristics of pediatric-onset type 2 diabetes in Hong Kong: The Hong Kong childhood diabetes registry 2008 to 2017.

OBJECTIVE: With increasing prevalence of childhood obesity worldwide, the incidence of pediatric-onset type 2 diabetes (T2D) is also increasing in many countries. We aim to analyze the time trend and incidence of T2D in children in Hong Kong from 2008 to 2017, and to characterize clinical characteristics at diagnosis. METHODS: Data were retrieved from the Hong Kong Childhood Diabetes Registry. All children with T2D diagnosed at the age of less than 18 years from January 1, 2008 to December 31, 2017 and managed in the public health care system were included in this study. RESULTS: In the incident years of 2008-2017 period, 391 children were diagnosed with T2D. The crude incidence rate was 3.42 per 100,000 persons/year [95% confidence interval (CI) 3.08-3.76], which was much higher than that in last registry of 1.27 per 100,000 persons/year in 1997-2007 (P < 0.001).Most children (76%) were asymptomatic and were diagnosed by routine screening. At presentation, a significant proportion presented with co-morbidities including fatty liver (37.9%), dyslipidaemia (35.3%), hypertension (22.5%), and microalbuminuria (12.8%). CONCLUSIONS: The incidence of T2D in children has increased significantly in Hong Kong. Most of them were asymptomatic and picked up on routine health screening. Yet, comorbidities were commonly identified at diagnosis.

Increasing incidence of type 1 diabetes among Hong Kong children and adolescents: The Hong Kong Childhood Diabetes Registry 2008 to 2017.

OBJECTIVE: The incidence of childhood-onset type 1 diabetes (T1D) has been reported to be rising but there is also evidence that it has been attenuated in recent years. We described the time trends and the incidence of T1D in children in Hong Kong from 2008 to 2017 and compared with the previous local registry in 1997 to 2007. METHODS: Data were extracted from the Hong Kong Childhood Diabetes Registry, which was established in 2016. It consists of a retrospective registry (including all childhood diabetes diagnosed in 2008 to 2015) and a prospective registry (including all T1D children diagnosed from 2016 onwards). All T1D children diagnosed at the age of less than 18 years from 1 January 2008 to 31 December 2017 and managed in the public system were included in this study. RESULTS: For the incident years in the 2008 to 2017 period, a total of 498 children with T1D was identified. The crude incidence rate was 4.3 per 100 000 person/year (95% confidence interval 3.96-4.72), which was much higher than the last registry of 2.2 per 100 000 persons/year. Using general linear model, the increment is statistically significant (P = .02). When compared to the last registry, the rate of increment had attenuated, with annual increment in crude incidence in the two periods for T1D <15 years changing from 4.3% to 3.5% (P = .02). CONCLUSIONS: The incidence of T1D children increased significantly in the past two decades in Hong Kong, but the rate of increase had attenuated in recent years.

Influenza vaccine effectiveness in hospitalised Hong Kong children: Feasibility of estimates from routine surveillance data.

BACKGROUND: Hong Kong has a high burden of influenza hospitalisation. This study estimated influenza vaccine effectiveness in hospitalised Hong Kong children aged 6 months to below 6 years using data potentially obtainable from routine surveillance sources. METHODS: This 'test-negative' case-control study was conducted over two summer and one winter influenza seasons in five public Hong Kong hospitals during 2015 and 2016. Patients admitted for febrile and/or respiratory-associated illnesses who met inclusion criteria were invited to participate. Case-patients were respiratory-associated admissions with nasopharyngeal aspirate or nasopharyngeal swab specimens obtained during the first 48 h of hospitalisation that tested positive for influenza A or B, whereas control-patients were those with specimens that tested negative for both influenza A and B. Reliability of a routinely collected influenza immunisation status form was evaluated. Vaccine effectiveness for administration of full or partial series of influenza vaccination was calculated as 1 minus the odds ratio for influenza vaccination history for case-patients versus control-patients. RESULTS: 2900 eligible subjects had influenza vaccination status available. A simple record form, designed to collect upon admission information on influenza vaccination status, was found to be reliable when compared to confirmed vaccination status from immunisation records and guardians' self-reports. Influenza vaccine effectiveness for preventing influenza A or B hospitalisation in children aged from 6 months to below 6 years during the period June 2015 to November 2016 was 68% (95% confidence interval [CI]: 55%, 77%) from unconditional analyses and 64% (95% CI: 46%, 75%) from conditional analyses. CONCLUSIONS: Seasonal influenza vaccine was effective in preventing hospitalisation from influenza A or B in young Hong Kong children during 2015 and 2016. As influenza vaccination status is not currently routinely recorded, implementation of an influenza immunisation status form in all paediatric wards, and centralising the data in Hong Kong's central computerised database, could provide real-time monitoring of influenza vaccine effectiveness.

Rotavirus vaccine effectiveness in Hong Kong children.

BACKGROUND: Rotavirus is a common infectious cause of childhood hospitalisation in Hong Kong. Rotavirus vaccines have been used in the private sector since licensure in 2006 but have not been incorporated in the government's universal Childhood Immunisation Programme. This study aimed to evaluate rotavirus vaccine effectiveness against hospitalisation. METHODS: This case-control study was conducted in the 2014/2015 rotavirus season in six public hospitals. Hospitalised acute gastroenteritis patients meeting inclusion criteria were recruited and copies of their immunisation records were collected. Case-patients were defined as enrolled subjects with stool specimens obtained in the first 48h of hospitalisation that tested positive for rotavirus, whereas control-patients were those with stool specimens obtained in the first 48h of hospitalisation testing negative for rotavirus. Vaccine effectiveness for administration of at least one dose of either Rotarix(®) (GlaxoSmithKline Biologicals) or RotaTeq(®) (Merck Research Laboratories) was calculated as 1 minus the odds ratio for rotavirus vaccination history for case-patients versus control-patients. RESULTS: Among the 525 eligible subjects recruited, immunisation records were seen in 404 (77%) subjects. 31% (162/525 and 126/404) tested positive for rotavirus. In the 404 subjects assessed for vaccine effectiveness, 2.4% and 24% received at least 1 dose of either rotavirus vaccine in case- and control-patients respectively. The unmatched vaccine effectiveness against hospitalisation for administration of at least one dose of either rotavirus vaccines was 92% (95% confidence interval [CI]: 75%, 98%). The matched analyses by age only and both age and admission date showed 96% (95% CI: 72%, 100%) and 89% (95% CI: 51%, 97%) protection against rotavirus hospitalisation respectively. CONCLUSIONS: Rotavirus vaccine is highly effective in preventing hospitalisation from rotavirus disease in young Hong Kong children.

Novel large deletion in AVPR2 gene causing copy number variation in a patient with X-linked nephrogenic diabetes insipidus.

BACKGROUND: The diagnosis of cranial and nephrogenic diabetes insipidus (DI) can be clinically challenging. The application of molecular genetic analysis can help in resolving diagnostic difficulties. CASE: A 3 month-old boy presented with recurrent polyuria was admitted to Intensive Care Unit and was treated as DI. The patient also had a strong family history of polyuria affecting his maternal uncles. Molecular genetic analysis using Single Nucleotide Polymorphism (SNP) array detected a large deletion located at Xq28 region and the breakpoint was identified using PCR and Sanger sequencing. An 11,535 bp novel deletion affecting the entire APVR2 gene and the last intron and exon of the ARHGAP4 gene was confirmed. This large deletion is likely due to the 7-bp microhomology sequence at the junctions of both 5' and 3' breakpoints. No disease-causing mutation was identified for AQP2. CONCLUSION: We report a novel deletion in a Chinese patient with congenital nephrogenic DI. We suggested that patients with suspected congenital DI should undergo genetic analysis of AVPR2 and AQP2 genes. A definitive diagnosis can benefit patient by treatment of hydrochlorothiazide and amiloride and avoiding unnecessary investigations.

Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential?

BACKGROUND: 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS: We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS: Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5ß-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS: 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

Hyperinsulinism and hyperammonaemia syndrome due to a novel missense mutation in the allosteric domain of the glutamate dehydrogenase 1 gene.

Congenital hyperinsulinism is one of the causes of persistent hypoglycaemia in neonates and infants. We describe a one-month-old boy with a rare form of congenital hyperinsulinism characterised by hypoglycaemia and hyperammonaemia.