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Severe acute respiratory syndrome (SARS) is a newly discovered infectious disease caused by a novel coronavirus. During the community outbreak in Hong Kong, 5 liveborn infants were born to pregnant women with SARS. A systematic search for perinatal transmission of the SARS-associated coronavirus, including serial reverse transcriptase-polymerase chain reaction assays, viral cultures, and paired serologic titers, failed to detect the virus in any of the infants. In addition, none of the infants developed clinical, radiologic, hematologic, or biochemical evidence suggestive of SARS. One preterm infant developed jejunal perforation and another developed necrotizing enterocolitis with ileal perforation shortly after birth. This case series is the first report to describe the clinical course of the first cohort of liveborn infants born to pregnant women with SARS. [ABSTRACT FROM AUTHOR]

A three-year-old Chinese girl presented with hyperammonemia was diagnosed biochemically and genetically (heterozygous for a novel likely pathogenic missense variant c.476T>A) as having ornithine transcarbamylase (OTC) deficiency, a rare X-linked recessive urea cycle disorders. Extensive family genetic screening eventually revealed paternal gonadosomatic mosaicism., Competing Interests: The authors declare no conflicts of interest regarding the publication of this article., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination., Methods: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed., Results: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval [CI], 11.67-29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12-9.51) and 21.22 (95% CI, 13.78-32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38-12.53) and 37.32 (95% CI, 26.98-51.25) per 100 000 persons vaccinated., Conclusions: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose., Competing Interests: Potential conflict of interest. C. C. has received grants outside of the submitted work from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grants Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, and Amgen; and a personal fee from Primevigilance Ltd. A. S. Y. L. received grants outside of the submitted work from the Health and Medical Research Fund, Food and Health Bureau of the Hong Kong Government Special Administrative Region. M. Y. N. has received funding/education grants from the Food and Health Bureau of the Hong Kong Government, Radiological Society of North America, GE, Lode, Arterys, Bayer, Circle Cardiovascular Imaging and TeraRecon; honoraria for education activities from Boehringer Ingelheim; reports the following leadership roles: Vice Chair of the Education Committee for Society of Cardiovascular Magnetic Resonance and Member of the Corporate Relations Committee for Society of Cardiovascular Computed Tomography. G. C. F. C. is the CMO of Xellera and advisor of Pangenia. Y. L. L. received Government funding for COVID-19 Vaccinations in Adolescents (COVA) and is the Chairman of the Scientific Committee on Vaccine Preventable Diseases, Centre for Health Protection, HKSAR. I. W. has received research funding outside of the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Hong Kong Research Grants Council, Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, and National Health and Medical Research Council in Australia (Research grants on pharmacoepidemiology to The University of Hong Kong outside of the submitted work); consultancy fee for advising IQVIA on pharmacoepidemiology studies outside of the submitted work; payment for expert testimony from Appeal Court in Hong Kong (expert report on effects of cannabis outside of the submitted work); and speaker fees from Janssen and Medicine in the previous 3 years; reports the following leadership roles: Member of Pharmacy and Poisons Board (this is the regulatory agency in pharmaceutical product licensing), Member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization (advise the Hong Kong Government on safety of COVID-19 vaccines), and Member of the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government (advise the Hong Kong Government on the emergency use of COVID-19 vaccines). He is also an independent nonexecutive director of Jacobson Medical in Hong Kong (salaried). P. I. has received grants outside of the submitted work from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grants Council, and Hong Kong Jockey Club Charities Trust. M. T. Y. L. reports receiving Honorarium for a talk on ADHD. W. K. C. N. reports personal honoraria for Guerbet online lecture on pediatric cardiac imaging; holds 100 shares in Moderna stock, 50 shares in Biotech stock since April, owned 100 shares in Pfizer stock from July 2020 to January 2021. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Citrin deficiency is one of the most common inborn errors of metabolism in East Asians, which may manifest as neonatal cholestasis, failure to thrive and dyslipidaemia, or recurrent hyperammonaemic encephalopathy. Its molecular diagnosis requires confirmation of the presence of biallelic pathogenic variants in SLC25A13 gene by sequencing, and analysis for a common insertion IVS16ins3kb. However, patients with compatible biochemical features but only one monoallelic pathogenic variant have remained a diagnostic challenge. Here we report the development, validation and application of a multiplex ligation-dependent probe amplification (MLPA) assay using an in-house oligonucleotide probemix and a customised Coffalyer.NET worksheet for detection of exonic copy number variations in SLC25A13. With this MLPA assay, we successfully identified the presence of a heterozygous exonic deletion in SLC25A13 in three of 15 (20%) unrelated individuals with only one monoallelic pathogenic variant detected using conventional methods. Three exonic deletions, two novel involving exon 14 and one reported involving exon 5, were subsequently confirmed with Sanger sequencing. In summary, we developed, evaluated, and demonstrated the clinical utility of an in-house MLPA assay to look for exonic deletions in SLC25A13 in patients with citrin deficiency. With the discovery of novel deletions, MLPA should be considered a test of choice for molecular diagnosis of citrin deficiency when the sequencing result is inconclusive., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objectives: Meningitis in neonates and young infants leads to significant morbidity and mortality worldwide. This study aimed to investigate pathogens, antibiotic resistance and secular change of incidence in Hong Kong., Methods: A retrospective search was performed on meningitis in neonates and infants aged <3 months in three Hong Kong public hospitals from 2004 to 2019. Medical charts were reviewed, with focus on the identification and antibiotic resistance of the pathogens., Results: A total of 200 cases of meningitis were identified (67% were bacterial). Group B Streptococcus (GBS) and Escherichia coli (E. coli) were the commonest bacterial pathogens. The annual rates of early-onset GBS meningitis decreased after the implementation of universal GBS screening and intrapartum antibiotic prophylaxis (IAP) in 2012, while that of late-onset GBS meningitis remained similar. A significant portion of E. coli isolates were resistant to ampicillin and/or gentamicin., Conclusion: GBS and E. coli were the most common bacteria for meningitis in this age group. The annual rate of bacterial meningitis in Hong Kong has declined in recent years, which has been attributed to the decline in early-onset GBS meningitis due to universal GBS screening and IAP. Antimicrobial-resistant bacterial strains that cause meningitis require further clinical and public health attention., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Familial hCG syndrome is a rare and benign cause of elevated serum beta human chorionic gonadotropin (hCG). We present here a case of familial hCG syndrome diagnosed in a Hong Kong Chinese family, which we believe to be the first reported in Chinese. A 38-year-old woman presented with incidental finding of persistently elevated hCG, analytically confirmed both in urine and blood. Extensive radiological and biochemical work-up were performed but were negative for pregnancy and malignancy. Testing of another asymptomatic family member revealed unexplained elevation of serum hCG, confirming the diagnosis of familial hCG syndrome. Knowledge and awareness of this entity among clinicians are important to avoid unnecessary investigations and treatment in affected families., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hung LY et al.)

Objectives: To compare the clinical and laboratory features of severe acute respiratory syndrome 2003 (SARS) and coronavirus disease 2019 (COVID-19) in 2 Chinese pediatric cohorts, given that the causative pathogens and are biologically similar., Study Design: This is a cross-sectional study reviewing pediatric patients with SARS (n = 43) and COVID-19 (n = 244) who were admitted to the Princess Margaret Hospital in Hong Kong and Wuhan Children's Hospital in Wuhan, respectively. Demographics, hospital length of stay, and clinical and laboratory features were compared., Results: Overall, 97.7% of patients with SARS and 85.2% of patients with COVID-19 had epidemiologic associations with known cases. Significantly more patients with SARS developed fever, chills, myalgia, malaise, coryza, sore throat, sputum production, nausea, headache, and dizziness than patients with COVID-19. No patients with SARS were asymptomatic at the time of admission, whereas 29.1% and 20.9% of patients with COVID-19 were asymptomatic on admission and throughout their hospital stay, respectively. More patients with SARS required oxygen supplementation than patients with COVID-19 (18.6 vs 4.7%; P = .004). Only 1.6% of patients with COVID-19 and 2.3% of patients with SARS required mechanical ventilation. Leukopenia (37.2% vs 18.6%; P = .008), lymphopenia (95.4% vs 32.6%; P < .01), and thrombocytopenia (41.9% vs 3.8%; P < .001) were significantly more common in patients with SARS than in patients with COVID-19. The duration between positive and negative nasopharyngeal aspirate and the length in hospital stay were similar in patients with COVID-19, regardless of whether they were asymptomatic or symptomatic, suggesting a similar duration of viral shedding., Conclusions: Children with COVID-19 were less symptomatic and had more favorable hematologic findings than children with SARS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since the emergence of a cluster of viral pneumonia cases in Wuhan, Hubei Province, People's Republic of China, at the end of December 2019, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus also known as "coronavirus disease 2019 (COVID-19)," as of 7 April 2020, more than 1,214,466 cases of COVID-19 have been reported in more than 200 countries and territories, resulting in more than 67,767 deaths. The disease was recognized by World Health Organization (WHO) as a pandemic on 11 March 2020. Published reports of adult patients with COVID-19 infection described symptoms including fever, cough, fatigue, sputum production, headache, dyspnea and diarrhea. Children usually showed milder respiratory symptoms or were asymptomatic, while loss of taste or sensation of smell were seldom reported. In this paper, we report three cases of pediatric patients with COVID-19 infection who presented with anosmia and/or ageusia.

Haematological and immunological data of children with COVID-19 infection is lacking. Between 21st January and 20th March 2020, 244 children who were confirmed to have COVID-19 infection and admitted to the Wuhan Children's Hospital, China were retrospectively reviewed. 193 children were considered as symptomatic, which was defined as having either the presence of clinical symptoms or the presence of CT thorax abnormalities. Their haematological and immunological profiles, including complete blood counts, lymphocyte subsets (T, B and NK cell counts), immunoglobulin (Ig) profiles (IgG, IgA and IgM) and cytokine profiles were analysed and compared between the symptomatic and asymptomatic groups. The median values and the interquartile ranges were calculated. Comparison was made using the Mann-Whitney U test. Children with symptomatic COVID-19 infection had significantly lower haemoglobin levels, but higher absolute lymphocyte and monocyte counts, IgG and IgA levels, as well as interleukin 6 (IL-6), IL-10, tumour necrosis factor alpha and interferon gamma levels. The obtained data will be utilized for further studies in comparing children and adults with COVID-19 infections in other parts of the world and with different severity ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Authors.)

Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation., (© Endocrine Society 2019.)

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.

Objective: This study aimed at investigating the association of serum vitamin D (25(OH)D) and anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) as well as non-PCOS healthy ovulatory women and the possible confounding effects of adiposity and androgen., Method: This was a cross-sectional study conducted on serum samples collected from 451 women diagnosed with PCOS as well as 244 age-matched healthy ovulatory women in a tertiary gynaecology out-patient clinic and a family planning clinic., Results: Serum 25(OH)D level was significantly higher in women recruited during summer and autumn than those recruited in winter and spring. Both serum 25(OH)D and AMH levels peaked during summer in women with PCOS. In ovulatory women, only serum 25(OH)D but not AMH level showed such seasonal variation. Serum 25(OH)D level in women with PCOS significantly correlated positively with AMH, AMH/antral follicle count (AFC) ratio, serum total testosterone, sex-hormone-binding globulin and quantitative insulin-sensitivity check index and inversely with body mass index (BMI), insulin, triglycerides and homeostatic model assessment of insulin resistance. After controlling for BMI, 25(OH)D level remained significantly correlated positively with serum AMH, AMH/AFC and total testosterone, and inversely with triglycerides. 25(OH)D level was an independent predictor of serum AMH level after controlling for age, BMI and free androgen index in women with PCOS., Conclusion: Serum 25(OH)D level is an independent factor significantly associated with AMH level in women with PCOS but not in ovulatory women., (© 2018 John Wiley & Sons Ltd.)

Introduction: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM., Methods: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling., Results: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years., Conclusion: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Introduction: There is a pressing need to identify diagnostic testing for Cushing's syndrome that can be achieved with ease and at low cost. This study aimed to explore the usefulness of late-night and post-overnight 1-mg dexamethasone suppression salivary cortisone, as measured by liquid chromatography-tandem mass spectrometry, for investigation of hypercortisolism., Methods: Salivary cortisone data of subjects were investigated according to a pre-specified protocol. Subjects were classified as having 'hypercortisolism' or 'eucortisolism' on the basis of histological or biochemical criteria. Receiver operating characteristic curves were drawn to identify the cut-off values and study their performance characteristics. We measured 24-hour urinary free cortisol; late-night salivary cortisol and cortisone; and post-overnight 1-mg dexamethasone suppression serum cortisol, and salivary cortisol and cortisone. Saliva and urine samples were assayed by liquid chromatography-tandem mass spectrometry., Results: In this study, 21 subjects were classified as having hypercortisolism and 78 as having eucortisolism. A late-night salivary cortisone cut-off of 13.50 nmol/L had a sensitivity of 94.7% and a specificity of 87.2%. After taking 1-mg dexamethasone the night before, a salivary cortisol cut-off of 0.85 nmol/L had a sensitivity of 76.2% and a specificity of 96.2%; a salivary cortisone cut-off of 7.45 nmol/L had a sensitivity of 85.7% and a specificity of 94.9%, while a salivary cortisone cut-off of 3.25 nmol/L had a sensitivity of 95.2% and a specificity of 79.5%. Many salivary cortisol samples were below the detection limit of liquid chromatography-tandem mass spectrometry. In comparison with salivary cortisol, salivary cortisone had a better correlation with total serum cortisol and better diagnostic performance following dexamethasone suppression., Conclusions: Both late-night and post-overnight dexamethasone suppression salivary cortisone levels are of diagnostic value in the investigation of hypercortisolism.

Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A > C, named TPMT*41, together with the more common variant *3C c.719A > G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A > C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity.

Context: Basal and poststimulation salivary cortisol and cortisone levels can be useful in the diagnosis of adrenal insufficiency. However, little is known about the optimal cutoffs and performance characteristics of these tests., Objective: To derive the cutoff values and study the performance characteristics of salivary cortisol and salivary cortisone in the diagnosis of adrenal insufficiency., Design and Setting: Prospective study in a regional hospital in Hong Kong from January 2014 to September 2015., Participants: Fifty-six Chinese healthy volunteers and 171 patients suspected of having adrenal insufficiency., Main Outcome Measures: All participants underwent low-dose short Synacthen test (LDSST) with intravenous injection of 1 μg of tetracosactide (Synacthen 1-24). Serum cortisol, salivary cortisol and cortisone levels were measured at baseline and 30 and 60 minutes afterward., Results: Using the reference cutoff (mean - 2 standard deviations of post-LDSST peak serum cortisol) derived from healthy volunteers as the gold standard, receiver operating characteristic analysis of patients' data revealed that both post-LDSST peak salivary cortisol and cortisone performed better than basal tests. The most optimal cutoff values for serum cortisol as measured by immunoassay and for salivary cortisol and salivary cortisone as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were 376, 8.6, and 33.5 nmol/L, respectively, for post-LDSST peak values, and 170, 1.7, and 12.5 nmol/L, respectively, for basal values., Conclusions: We established method-specific reference cutoffs for serum cortisol, salivary cortisol, and salivary cortisone during LDSST. Both post-LDSST peak salivary cortisol and cortisone performed well as diagnostic tests for adrenal insufficiency. Their measurements by LC-MS/MS can alleviate problems associated with serum cortisol immunoassays.

Subamniotic hemorrhage results from rupture of chorionic vessels near the cord insertion. In the literature, it has never been a major cause for severe intrapartum complications. We report the first case of acute massive subamniotic hemorrhage intrapartum resulting in severe perinatal asphyxia.

Objective: Disorders of sex development are due to congenital defects in chromosomal, gonadal, or anatomical sex development. The objective of this study was to determine the aetiology of this group of disorders in the Hong Kong Chinese population., Setting: Five public hospitals in Hong Kong., Patients: Patients with 46,XY disorders of sex development under the care of paediatric endocrinologists between July 2009 and June 2011., Main Outcome Measures: Measurement of serum gonadotropins, adrenal and testicular hormones, and urinary steroid profiling. Mutational analysis of genes involved in sexual differentiation by direct DNA sequencing and multiplex ligation-dependent probe amplification., Results: Overall, 64 patients were recruited for the study. Their age at presentation ranged from birth to 17 years. The majority presented with ambiguous external genitalia including micropenis and severe hypospadias. A few presented with delayed puberty and primary amenorrhea. Baseline and post-human chorionic gonadotropin-stimulated testosterone and dihydrotestosterone levels were not discriminatory in patients with or without AR gene mutations. Of the patients, 22 had a confirmed genetic disease, with 11 having 5α-reductase 2 deficiency, seven with androgen insensitivity syndrome, one each with cholesterol side-chain cleavage enzyme deficiency, Frasier syndrome, NR5A1-related sex reversal, and persistent Müllerian duct syndrome., Conclusions: Our findings suggest that 5α-reductase 2 deficiency and androgen insensitivity syndrome are possibly the two most common causes of 46,XY disorders of sex development in the Hong Kong Chinese population. Since hormonal findings can be unreliable, mutational analysis of the SRD5A2 and AR genes should be considered the first-line tests for these patients.

Both lipoprotein glomerulopathy (LPG) and fibrillary glomerulonephritis (FGN) are rare causes of end-stage renal disease (ESRD), and the literature concerning the outcome of kidney transplant in patients with LPG or FGN is scarce. We report a patient who suffered from ESRD with coexisting FGN and LPG and received deceased kidney transplant >10 years ago did not reveal any clinical features of disease recurrence during follow-up. Our case shows that the prognosis of patients with LPG component who received kidney transplant can be good. Kidney transplantation remains a viable therapeutic option for patients with ESRD secondary to FGN with LPG.

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 5β-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., (© 2013 American Association for Clinical Chemistry.)

Background: Deficiency in any one of the steroidogenic enzymes may result in congenital adrenal hyperplasia (CAH) and disorders of sex development (DSD). Urinary steroid profiling (USP) can quantify metabolites of all relevant steroids simultaneously in a single analysis and has established clinical applications in the investigation and diagnosis in these disorders., Patients and Methods: A retrospective review was performed on all the samples sent to the Chemical Pathology Laboratory, Queen Elizabeth Hospital, Hong Kong, for the investigation of suspected disorders in steroid metabolism by USP between 2003 and 2011., Results: 432 patients had urine samples sent to our laboratory for USP for the investigation of CAH and DSD in the review period. USP showed diagnostic pattern of 21-hydroxylase deficiency (n=21), 5α-reductase 2 deficiency (n=12), 17α-hydroxylase deficiency (n=3), isolated 17,20-lyase deficiency (n=1), 11β-hydroxylase deficiency (n=1) and P450 oxidoreductase deficiency (n=1)., Conclusions: 21-hydroxylase deficiency is the most common form of CAH while 5α-reductase 2 deficiency is the most common cause of 46,XY DSD in our population. USP is a useful tool in the investigation and diagnosis of CAH and DSD due to different steroidogenesis defects and should be included as a first-line endocrine investigation in this group of patients., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Capecitabine is an orally administered pro-drug of 5-fluorouracil that confers superior disease-free survival and presumably has a more favourable side-effect profile. Here we report on a patient who developed acute necrotising pancreatitis and very high triglyceride levels as well as hand-foot syndrome after receiving capecitabine for colonic cancer. Increased awareness of this potential side-effect and close monitoring of lipid levels may be warranted, especially in patients who have other conditions predisposing them to severe secondary hyperlipidaemia when using this drug.

We report on an adult patient with citrin deficiency in Hong Kong, in whom a novel mutation was identified. The patient presented with recurrent hyperammonaemic encephalopathy due to impairment of the liver urea cycle enzyme argininosuccinate synthetase. This autosomal recessive condition is also characterised by interesting food preferences, notably aversion to carbohydrates and craving for protein-rich and/or lipid-rich foods, as well as neuropsychiatric symptoms. Plasma amino acid analysis is very useful in revealing urea cycle disorders, and mutational analysis of the SLC25A13 gene can confirm the diagnosis.

Background: Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder due to mutation in the CYP21A2 gene., Objective: To elucidate the genetic basis of 21-hydroxylase-deficient CAH in Hong Kong Chinese patients., Patients and Methods: Mutational analysis of the CYP21A2 gene was performed on 35 Hong Kong Chinese patients with 21OHD using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA)., Results: The genetic findings of 21 male and 14 female patients are the following: c.293-13A/C>G (intron 2 splice site; 20 alleles), p.I172N (13), p.R356W (7), p.Q318X (4). A total of 20 mutant alleles contained gross deletion/conversion of all or part of the CYP21A2 gene. A novel mutation, c.1367delA (p.D456fs), was detected in one patient. One patient had only a heterozygous mutation detected. Out of 35 patients, 16 would have been incorrectly genotyped if either DNA sequencing or MLPA alone was used for molecular analysis., Conclusions: The frequency of various mutations in the studied patients differs from those reported in other Asian populations. Gross deletion/conversion accounts for nearly one-third of the genetic defects. Therefore, laboratories must include methods for detecting point mutations as well as gross deletions/conversions to avoid misinterpretation of genotype. Genotyping has increasingly been proven to be a useful tool for supplementing, if not replacing, hormonal profiling for the diagnosis of 21OHD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a very rare inherited lysosomal storage disease. We evaluated the efficacy and safety of weekly infusions of recombinant human arylsulfatase B as enzyme replacement therapy for two patients in whom this condition was advanced. The primary outcome variables were the distance walked in a 6-minute walk test, forced vital capacity, and ejection fraction. The secondary outcome variables were the number of stairs climbed in a 3-minute stair climbing test, joint mobility, urinary glycosaminoglycan excretion, auto-continuous positive airway pressure study and liver size. After 24 weeks of treatment, patient A walked 40 m (36%) and patient B walked 66 m (58%) more in the walk test than at baseline. After 48 weeks, in patient A the corresponding improvements were 142 m (129%) in the walk test and 33 stairs (60%) in the 3-minute stair climbing test, and in patient B the respective improvements were 198 m (174%) and 77 stairs (140%). There was a significant decline in urinary glycosaminoglycan excretion and improvement in range of motion of joints in both patients. The auto-continuous positive airway pressure study revealed improvements in patient A, while other efficacy variables remained static. There were no drug-related adverse events or allergic reactions reported during and after the infusions of recombinant human arylsulfatase B. Recombinant human arylsulfatase B significantly improves endurance and reduces urinary glycosaminoglycan excretion. The drug is generally safe and well tolerated.

Aim: The upper reference limit of thyroid-stimulating hormone (TSH) is critical for defining patients with subclinical hypothyroidism, a condition which carries a higher risk of progression to overt hypothyroidism and adverse cardiovascular events. Yet, there is a lack of consensus on its absolute value, and data in non-pregnant adult Chinese are lacking., Methods: Apparently healthy and drug-free local adult Chinese were recruited by completing health questionnaires. Their serum samples were tested for TSH, free thyroxine (FT4), thyroglobulin antibody and thyroid peroxidase antibody levels. After excluding subjects with thyroid antibodies, the TSH level was log-transformed, and the reference limits were defined as mean ± 1.96SD. The 2.5th and 97.5th percentiles of FT4 were also calculated., Results: Serum samples from 212 subjects were used in this study. 51 subjects were seropositive to thyroglobulin antibody, 31 were seropositive to thyroid peroxidase antibody, and 27 were seropositive to both. The reference intervals after excluding subjects seropositive to thyroid antibodies were: TSH: 0.68-3.70 mIU/l; FT4: 13.5-21.3 pmol/l (male) and 12.6-19.7 pmol/l (female). Including subjects with thyroid antibodies only minimally changed the reference intervals of these hormones., Conclusion: The authors have set up the reference interval of TSH for the local population, and their findings also suggest that the importance of excluding subjects with thyroid antibodies in the reference population should not be overemphasised. Moreover, the international authorities should consider recommending percentile-equivalent action limits instead of an absolute cut-off on TSH for categorisation of different types of thyroid dysfunction.

Background: Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area., Methods: The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed., Results: Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births., Conclusions: Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.

A Chinese adolescent girl presented with secondary amenorrhea. During follow-up, she gradually developed Cushingoid features and virilization. After a series of endocrine investigations, including urinary steroid profiling, a diagnosis of adrenocortical carcinoma was made. The treatment and prognosis of the disease are discussed.

Cytochrome P450 oxidoreductase deficiency is a recently established autosomal recessive disease characterised by ambiguous genitalia, impaired steroidogenesis, and skeletal malformations, referred to as Antley-Bixler syndrome. Clinical manifestations in affected patients are highly variable. We report on a girl with P450 oxidoreductase deficiency who presented with virilisation at birth. There was transient maternal virilisation during pregnancy as well. She was initially diagnosed with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and/or aromatase deficiency. At 1 year of age, skeletal abnormalities suggestive of Antley-Bixler syndrome were detected. Molecular analysis of the fibroblast growth factor receptor 2 (FGFR2) gene was normal but POR gene analysis showed that she was homozygous for an R457H missense mutation. The diagnosis, P450 oxidoreductase deficiency, was confirmed. Results of her endocrine studies and urinary steroid profiling are also presented.

It has been suggested that urinary steroid profiling may be used to provide information aiding the diagnosis and monitoring of adrenocortical carcinoma. Nonetheless, the abnormal patterns suggestive of adrenal malignancy are not well defined. We retrospectively studied the urinary steroid profiles of five patients with adrenocortical carcinoma at presentation and at follow-up, and compared these results with those from 76 patients with benign adrenocortical adenoma and 172 healthy controls. Three abnormal patterns of urinary steroid excretion were identified in patients with adrenocortical carcinoma at presentation and/or follow-up of residual disease: (1) hypersecretion in multiple steroid axes; (2) excretion of unusual metabolites, notably 5-pregnene-3alpha,16alpha,20alpha-triol, 5-pregnene-3beta,16alpha,20alpha-triol, and neonatal steroid metabolites in the post-neonatal period; (3) increase of tetrahydro-11-deoxycortisol relative to total cortisol metabolites. These preliminary findings offer ways in which urinary steroid profiling performed using gas chromatography-mass spectrometry can be helpful in the diagnosis and monitoring of adrenocortical carcinoma.

Withdrawal of the support for the REMEDi HS drug profiling system has necessitated its replacement within our laboratories with an alternative broad toxicological screening technique. To this end, a novel method, based on ultra-performance liquid chromatography (UPLC) and time-of-flight (TOF) mass spectrometry, was developed for the routine analysis of urine samples. Identification was achieved by comparison of acquired data to libraries containing more than 300 common drugs and metabolites, and was based on a combination of retention time, exact mass and fragmentation patterns. Validation data for the method is presented and comprised an evaluation of the following parameters: precision; transferability of the methodology between the six collaborating laboratories; specificity; extraction recovery and stability of processed samples; matrix effects and sensitivity. This paper presents the benefits of supplementary fragmentation data with particular regard to increasing specificity and confidence of identification and its usefulness with overdosed samples. The utility of the method was assessed by the parallel analysis of 30 authentic urine samples using the REMEDi HS and UPLC-TOF. The latter provided enhanced detection, leading to the identification of twice as many drugs. Furthermore it did not miss any compounds that were identified by REMEDi HS. The UPLC-TOF findings were further verified by a combination of data from three other conventional screening techniques, i.e., GC-MS, HPLC-DAD and UPLC-MS/MS.

Objective: Elevated serum levels of homocysteine have been shown to be associated with schizophrenia in some studies, but the evidence is still limited and mixed. The aim of the present study was therefore to evaluate the serum homocysteine level in Chinese in schizophrenia patients and assess its association with clinical phenotypes of the disease., Method: A total of 250 inpatients and 250 healthy controls were identified at Kowloon Hospital and the Red Cross Blood Donation Centre, respectively. Each subject was evaluated with a structured diagnostic interview. Demographic data were collected and blood was analysed for homocysteine level. The Positive and Negative Syndrome Scale was used to grade clinical symptoms of schizophrenia. Confounding factors affecting homocysteine levels were controlled by strict exclusion criteria or statistical methods., Results: Serum homocysteine level was elevated in Chinese schizophrenia patients. Both male (mean, 12.26 micromol L(-1); control, 11.40 micromol L(-1), p = 0.026) and female (mean, 9.61 micromol L(-1); control, 8.33 micromol L(-1), p < 0.001) patients had a higher serum homocysteine level than the healthy controls, and these differences persisted after controlling for age. There was no significant association between serum homocysteine level and duration of illness, clinical symptoms or age of onset of schizophrenia., Conclusion: The serum homocysteine levels were elevated in both male and female Chinese schizophrenia patients. The levels were not apparently related to other clinical parameters.

5Alpha-reductase 2 deficiency is an autosomal recessive disorder characterised by lack of masculinisation in XY individuals due to failure to convert testosterone to dihydrotestosterone, the bioactive androgen. Traditionally, the testosterone-to-dihydrotestosterone ratio is used to diagnose this condition but interpreting these results is not always straightforward, thus they may be inconclusive. On the contrary, urinary steroid profiling unambiguously demonstrates a significantly reduced excretion of 5alpha-reduced steroid metabolites compared to their 5beta counterparts. This analytical technique can also simultaneously confirm or rule out other causes of ambiguous genitalia due to steroidogenic defects. Making a DNA-based diagnosis by studying the SRD5A2 gene has become increasingly popular. Here, we report six Chinese patients from different families who were all diagnosed with 5alpha-reductase 2 deficiency based on urinary steroid profile findings and mutational analysis of the SRD5A2 gene. R227Q was the most commonly identified mutation in these patients. Management of sexual development disorders is also discussed.

Lipoprotein glomerulopathy is a rare kidney disease in which lipoprotein thrombi are seen in the glomerular capillaries. Most of these patients are found in Japan and East Asian countries. The presenting symptoms include proteinuria, an abnormal plasma lipoprotein profile that resembles type III hyperlipoproteinaemia, and a marked increase in serum apolipoprotein E concentration. Previous studies have suggested that lipoprotein glomerulopathy might be related to APOE gene mutation. No effective therapeutic regimen has been established for lipoprotein glomerulopathy. We report the first case of biopsy-proven lipoprotein glomerulopathy in Hong Kong in a patient who presented with nephrotic syndrome and dyslipidaemia. DNA analysis revealed apolipoprotein E Kyoto together with a novel apolipoprotein E mutation, apolipoprotein E (Asp230Tyr) Hong Kong. There was significant improvement in the clinical parameters and resolution of symptoms after the introduction of statins. Further studies will be needed to clarify the role of apolipoprotein E Hong Kong and its interaction with apolipoprotein E Kyoto in the pathogenesis of lipoprotein glomerulopathy.

Background: Urinary steroid profiling by GC or GC-MS are established clinical tools to complement other biochemical tests in the diagnosis and investigation of a wide range of adrenocortical disorders, but normative data on adults using the more specific GC-MS are lacking. Our objective was to set up the reference intervals of commonly detected urinary steroid metabolites as well as marker metabolites seen in disease states., Method: Apparently healthy adult Chinese males and females were recruited by completing health questionnaires. A 24-h urine specimen was collected from all the participants for urinary steroid profiling by GC-MS in cyclic scan mode. The analyzer was calibrated by using authentic steroid standards. Statistical methods recommended by the National Committee for Clinical Laboratory Standards were followed for setting up the reference intervals of various steroid metabolites. After outliers were excluded, the data were tested for the necessity to partition into sex-, menopausal status- and age-specific reference intervals., Results: 83 males and 89 females were recruited for the study. Necessity to partition into sex-specific reference intervals was demonstrated for almost all steroid metabolites. Menopausal status and age also had a significant impact on steroid metabolite excretion, making separate reference intervals necessary., Conclusions: We have set up the normative data on the levels of urinary steroid metabolite excretion in Chinese adults for future reference in patient management and research in steroid metabolism.

Aims: To evaluate the efficacy and safety of a tacrolimus-based immunosuppressive regimen with and without induction therapy using daclizumab in first cadaveric renal transplant recipients., Methods: Since January 2001, we studied the effect of daclizumab in a non-randomized and prospective study of 36 sequential first cadaveric renal transplant recipients. They were compared with a historical control group of 21 sequential first cadaveric renal transplant recipients without induction therapy. All patients received tacrolimus, azathioprine and corticosteroids as concomitant immunosuppressive therapy. Daclizumab was given at 1 mg/kg infusion 2 h before transplantation and then every 14 days for four more doses. Outcomes measured included incidence of acute rejection, patient survival, graft survival, annualized change in creatinine clearance (CrCl), cardiovascular risk profile, infection and malignancy., Results: Fewer biopsy proven acute rejections were observed in the induction treatment group: 11.1% (4/36) versus 19% (4/21) but the rejection free survival was similar (P = 0.37). The patient survival and graft survival were comparable. The renal function was similar in both groups. There were also no significant difference in infection, malignancy and cardiovascular risk profile in both groups., Conclusion: Adding daclizumab to a tacrolimus-based therapy is safe but cannot further improve clinical efficacy.

Aim: Setting up reference intervals from the local service populations is one of the major responsibilities of clinical laboratories. Yet, this task is difficult to achieve because it is costly and time consuming when compared with validating reference intervals from assay manufacturers., Methods: Following the recommendations of the International Federation of Clinical Chemistry, healthy local Chinese adults were recruited to set up reference intervals for common serum analytes. Statistical methods recommended by the National Committee for Clinical Laboratory Standards were used for defining the reference limits., Results: Data from 335 subjects were analysed. The reference intervals set up were broadly similar to those provided by the assay manufacturer, except for sodium and potassium. Glomerular filtration rate was estimated by the modification of diet in renal disease equation, with or without modification for Chinese. Body mass index had a significant impact on serum urate and alanine aminotransferase levels., Conclusion: Reference intervals of common serum analytes have been set up for the local Chinese population. A good example of quality laboratory service has also been set up to provide clinicians with reliable reference intervals that they can confidently rely on for the diagnosis and management of patients.

Dried blood spot (DBS) sampling and high-performance liquid chromatography tandem-mass spectrometry have been developed in monitoring tacrolimus levels. Our center favors the use of limited sampling strategy and abbreviated formula to estimate the area under concentration-time curve (AUC(0-12)). However, it is inconvenient for patients because they have to wait in the center for blood sampling. We investigated the application of DBS method in tacrolimus level monitoring using limited sampling strategy and abbreviated AUC estimation approach. Duplicate venous samples were obtained at each time point (C(0), C(2), and C(4)). To determine the stability of blood samples, one venous sample was sent to our laboratory immediately. The other duplicate venous samples, together with simultaneous fingerprick blood samples, were sent to the University of Maastricht in the Netherlands. Thirty six patients were recruited and 108 sets of blood samples were collected. There was a highly significant relationship between AUC(0-12), estimated from venous blood samples, and fingerprick blood samples (r(2) = 0.96, P < 0.0001). Moreover, there was an excellent correlation between whole blood venous tacrolimus levels in the two centers (r(2) = 0.97; P < 0.0001). The blood samples were stable after long-distance transport. DBS sampling can be used in centers using limited sampling and abbreviated AUC(0-12) strategy as drug monitoring.

Cryoglobulins are immunoglobulins that precipitate in the serum upon cooling to below core body temperature and re-dissolve at higher temperatures. Cryoglobulinaemia may be life-threatening. The three types of cryoglobulinaemia are associated with a wide spectrum of haematological, autoimmune, and chronic infectious diseases, especially hepatitis C infection. Our laboratory has received 378 requests for cryoglobulin testing over the past 5 years, with a detection rate of 4.8% in the 271 patients involved. Twelve per cent of the specimens were not processed due to being at an inappropriate temperature on arrival at the laboratory. Clinicians should be aware of temperature requirements when requesting cryoglobulin testing in suspected cases, and for all relevant protein tests in patients with cryoglobulinaemia. Handling specimens at inappropriate temperatures in the pre-analytical and analytical phases of the investigation might lead to cryoprecipitation and therefore false-negative results. The potential pitfalls encountered with specimen handling, analysis, and result interpretation are discussed in detail.

We report on three Chinese neonates with carnitine-acylcarnitine translocase deficiency. They presented within the first 48 hours of life. Two neonates were found in cardiac arrest; one of them survived after resuscitation. The third neonate suddenly developed cardiorespiratory insufficiency and succumbed eventually. The clustering of three cases in 5 years suggests that carnitine-acylcarnitine translocase deficiency is not rare in our Chinese population. We advocate that investigation for metabolic diseases including carnitine-acylcarnitine translocase deficiency should be performed in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period. Non-ketotic hypoglycaemia is an early clue. The mainstay of initial treatment is glucose infusion at a rate greater than 7 mg/kg/minute, which inhibits beta-oxidation of fatty acids (the defective enzymatic steps in carnitine-acylcarnitine translocase deficiency) and thus prevents the accumulation of toxic long-chain acylcarnitines.