A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

Natural history of infants with vitamin D deficiency in Hong Kong.

BACKGROUND AND OBJECTIVES: The usual recommended intake of vitamin D for healthy infants is 400 international unit (IU) daily. However, a high dose of vitamin D at 2000-3000 IU daily is needed for those with vitamin D deficiency (VDD). This study aimed to assess the natural history of a group of healthy infants with VDD and the associated factors for persistent VDD. METHODS AND STUDY DESIGN: Healthy infants detected to have VDD (25OHD <25 nmol/L) in a population study were followed, and their demographics and clinical data were collected. RESULTS: One hundred and thirty-one subjects (boys = 66%) were included. Their first serum 25OHD was taken at a median age of 87.5 days. None were treated with high-dose vitamin D supplements, but some have been given vitamin D at 400 IU daily. They were assessed again at the median age of 252.5 days when 15 remained to have VDD and 26 were in the insufficient range (25 - 49.9nmol/L). All persistent VDD children were on exclusive breastfeeding. Exclusive breastfeeding and no vitamin D supplementation were significant risk factors for persistent vitamin D insufficiency (<50nmol/L). CONCLUSIONS: Persistent VDD is common among infants exclusively breastfeeding and those who did not receive vitamin D supplementation.

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.

Carboplatin-induced renal salt-wasting syndrome in pediatric patients with intracranial germ cell tumors and concomitant diabetes insipidus.

We report a case series of 14 children with intracranial germ cell tumor and concomitant central diabetes insipidus, who developed hyponatremia secondary to renal salt-wasting syndrome (RSWS) following the administration of carboplatin. Clinicians prescribing platinum-based chemotherapy for this group of patients should be alert to the risk of RSWS. Regular monitoring should be performed as hyponatremia can be asymptomatic until it is severe.

Bone microarchitectural alterations in boys with Duchenne muscular dystrophy on long-term glucocorticoid treatment.

INTRODUCTION: Osteoporosis is a major health issue in boys with Duchenne muscular dystrophy (DMD). Data on the specific bone deficits and microarchitectural alterations in children with DMD were limited. This study aimed to assess the bone microarchitectural alterations in boys with DMD on long-term glucocorticoid using high-resolution peripheral quantitative computed tomography (HR-pQCT). MATERIALS AND METHODS: This was a cross-sectional, case-control study. Boys with DMD older than 5 years with no prior history of symptomatic fracture and had been on long-term glucocorticoid treatment were recruited from a single tertiary centre. For each participant, three gender- and age-matched controls were selected randomly from an existing HR-pQCT database of healthy individuals. RESULTS: Nine boys with DMD at a median age of 9.3 years were included. Three were found to have asymptomatic vertebral compression fracture. The HR-pQCT findings of these nine boys were compared with 27 healthy controls. Trabecular microstructure indices at the distal radius were significantly lower but the cortical vBMD was significantly higher in the DMD boys when compared with healthy controls. CONCLUSION: Lower microarchitectural measurement of trabecular bones, but higher cortical vBMD, was observed in DMD boys on long-term oral glucocorticoid. The results from this study provide preliminary, yet important insights into the bone microarchitecture of this group of patients.

Does obesity persist from childhood to adolescence? A 4-year prospective cohort study of chinese students in Hong Kong.

BACKGROUND: Little is known about the progression of obesity from childhood to adolescence. This study aimed to longitudinally examine the obesity status in a cohort of children across their childhood and adolescence, and to identify the factors associated with persistent obesity. METHODS: The study used data from School Physical Fitness Award Scheme (SPFAS), a population-based programme in Hong Kong primary and secondary schools. Students were included if they participated in the SPFAS in both 2014 (Primary 1 and 2) and 2018 (Primary 5 and 6). Their anthropometric and physical fitness parameters were analyzed. RESULTS: A total of 18,863 students were included. The baseline prevalence of obesity was 5.7 %. After 4 years, the prevalence increased to 6.7 %. Among those with obesity at baseline, 35.3 % remained obese after 4 years. The addition of baseline physical fitness level did not improve the prediction for persistent obesity. CONCLUSIONS: One-third of obese students in junior primary school remained to be obese into adolescence. Their baseline physical fitness level did not improve the predictive value for future obesity. Further studies should investigate the prognostic factors that may influence the natural course of childhood obesity.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

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.

Outcome of Chinese children with craniopharyngioma: a 20-year population-based study by the Hong Kong Pediatric Hematology/Oncology Study Group.

PURPOSE: Craniopharyngioma is a rare low-grade neoplasm in children. Tumor progression occurs frequently, and survivors are at risk of long-term disease and treatment-related morbidities. We reviewed the population-based experience of managing pediatric craniopharyngioma in Hong Kong. METHODS: The Hong Kong Pediatric Hematology/Oncology Study Group database was interrogated for patients with craniopharyngioma younger than 18 years between 1999 and 2018. Patient demographics, clinical characteristics, outcomes, and long-term morbidities were summarized. RESULTS: Twenty-eight patients with craniopharyngioma were included (approximate incidence of 1.1 per 1,000,000 individuals). The treatment approaches were heterogeneous and included surgery only, surgery with adjuvant radiation, and surgery with intracystic interferon. With a median follow-up of 6.1 years, 12 (43%) patients experienced disease progression, and 3 patients died of progression, postoperative complication, and gastrointestinal bleeding. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 56.8% (± 10.0%) and 92.0% (± 5.4%), respectively. The 10-year PFS and OS rates were 37.3% (± 11.4) and 92.0% (± 5.4%), respectively. Patients receiving treatment in a high-volume center had significantly better outcomes than did those treated at other centers (PFS, p = 0.007; OS, p = 0.029). Period of diagnosis, sex, age at diagnosis, greatest tumor dimension, extent of resection, and radiotherapy use did not significantly affect patient survival. Long-term visual impairment (60%) and endocrinopathies (92%) were common. CONCLUSION: Prognosis of pediatric craniopharyngioma in Hong Kong compares unfavorably with published reports. Centralization and standardization of treatment may prove valuable in mitigating patient outcomes.

Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations.

BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2). RESULTS: HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A = 7, HNF4A = 5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8 years. None had developed diabetes mellitus at a median age of 7.0 years. CONCLUSIONS: Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan.

Osteogenesis Imperfecta Type I Caused by COL1A1 Deletions.

Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufficiency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual cause­heterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and confirmed by quantitative PCR. Array comparative genomic hybridization in DNA of the index patient in each family showed that deletion size varied from 18.5 kb to 2.23 Mb between families, encompassing between 1 and 47 genes (COL1A1 included). The skeletal phenotype of the affected individuals was similar to that of patients with haploinsufficiency caused by COL1A1 stop or frameshift mutations. However, one individual with a deletion that included also DLX3 and DLX4 had tooth discoloration and bone fragility. Three individuals from 2 families had deletions that included also CACNA1G, and these individuals had learning disabilities. These features are not usually observed in COL1A1 haploinsufficiency, but are in accordance with previously described individuals in whom deletions included the same genes. In summary, we found deletions of COL1A1 in 5 out of 161 families (3 %) with OI type I that were evaluated. Deletions encompassing not only COL1A1 but also neighboring genes can lead to contiguous gene syndromes that may include dental involvement and learning disability.

A Narrative Review on Diabetic Ketoacidosis in Children.

BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening complication in children with diabetes mellitus. There are considerable differences in the management approaches for DKA between different countries. One of the main areas of differences between guidelines is the administration of fluid, with most guidelines adopting a restrictive approach. This is based on the concern over cerebral oedema, a lethal sequela allegedly to be caused by excessive fluid administration. However, in recent years, new clinical studies suggest that there is no causal relationship between intravenous fluid therapy and DKA-related cerebral injury. The British Society of Paediatric Endocrinology updated its guideline in 2020 to adopt a more permissive approach to fluid administration, which has sparked controversy among some paediatricians. OBJECTIVES: The purpose of this article is to provide a narrative review on the management of DKA. METHODS: A PubMed search was performed with clinical queries using the key term "diabetic ketoacidosis". The search strategy included randomized controlled trials, clinical trials, meta-analyses, observational studies, guidelines, and reviews. The search was restricted to English literature and the age range of 18 years and younger. Moreover, we reviewed and compared major guidelines. CONCLUSION: The management of DKA involves early recognition, accurate diagnosis, meticulous fluid and insulin treatment with close monitoring of blood glucose, ketones, electrolytes, renal function, and neurological status. There is still limited clinical evidence to support either a restrictive or permissive approach in the fluid management of paediatric DKA patients. Clinicians should exercise caution when applying different guidelines in their clinical practice, considering the specific circumstances of individual paediatric patients.

The acceptability and clinical impact of using polygenic scores for risk-estimation of common cancers in primary care: a systematic review.

BACKGROUND: Polygenic scores (PGS) have been developed for cancer risk-estimation and show potential as tools to prompt earlier referral for high-risk individuals and aid risk-stratification within cancer screening programmes. This review explores the potential for using PGS to identify individuals at risk of the most common cancers seen in primary care. METHODS: Two electronic databases were searched up until November 2023 to identify quantitative, qualitative, and mixed methods studies that reported on the acceptability and clinical impact of using PGS to identify individuals at highest risk of breast, prostate, colorectal and lung cancer in primary care. The Mixed Methods Appraisal Tool (MMAT) was used to assess the quality of included studies and a narrative synthesis was used to analyse data. RESULTS: A total of 190 papers were identified, 18 of which were eligible for inclusion. A cancer risk-assessment tool incorporating PGS was acceptable to the general practice population and their healthcare providers but major challenges to implementation were identified, including lack of evidence for PGS in non-European ancestry and a need for healthcare provider education in genomic medicine. A PGS cancer risk-assessment had relatively limited impact on psychosocial outcomes and health behaviours. However, for prostate cancer, potential applications for its use in primary care were shown. CONCLUSIONS: Cancer risk assessment incorporating PGS in primary care is acceptable to patients and healthcare providers but there is a paucity of research exploring clinical impact. Few studies were identified, and more research is required before clinical implementation of PGS can be recommended.

Association of vitamin D-binding protein polymorphisms and serum 25(OH)D concentration varies among Chinese healthy infants of different VDR-FokI genotypes: A multi-centre cross-sectional study.

Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2-12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.

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.

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.

Two Girls With Adrenal Insufficiency and Failing Gonads.

Congenital lipoid adrenal hyperplasia (CLAH) is a rare cause of adrenal insufficiency caused by mutations in the steroidogenic acute regulatory (StAR) gene. Patients classically present with adrenal crisis in early infancy and female external genitalia irrespective of chromosomal sex. We report 2 Chinese patients with normal female external genitalia presenting with salt wasting in the neonatal period. However, the diagnosis of CLAH was made only during pubertal years when they developed hypergonadotropic hypogonadism. One of them was subsequently found to have a 46XY karyotype and gonadectomy was performed at age 15 years. The other patient developed gonadal insufficiency and polycystic ovaries after menarche with hemorrhage into ovarian cysts requiring cystectomy. These 2 cases illustrate the importance of recognizing atypical features in neonates presenting with adrenal crisis. In managing the newborn with adrenal insufficiency and female-appearing external genitalia, the possibility of sex reversal and diagnosis of CLAH should be considered. Accurate delineation of internal pelvic organs using reliable imaging modalities or even laparoscopy, together with careful interpretation of clinical and laboratory findings, are crucial to accurate diagnosis and subsequent management.

Obesity in children and adolescents: Overview of the diagnosis and management.

Childhood obesity is one of the biggest public health challenges globally. It is associated with various adverse health consequences throughout life. Prevention and early intervention represent the most reasonable and cost-effective approaches. Considerable progress has been achieved in the management of obesity in children and adolescents; yet, implementation in the real world remains a challenge. This article aimed to present an overview of the diagnosis and management of obesity in children and adolescents.

Bone Health Status of Children with Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a group of rare, inherited neuromuscular disorders. Bone health is often a neglected issue in children with SMA. This study aimed to evaluate the bone health status of children with SMA in Hong Kong. METHODS: This retrospective study included children with SMA who were managed in the Neuromuscular Disorder Clinics of 2 quaternary centers in Hong Kong. Bone health status was assessed by fracture history, bone mineral density (BMD) measured by dual energy X-ray absorptiometry, and serum 25-hydroxy-vitamin D (25[OH]D) level. RESULTS: Thirty-two children were included (males, 12). The median age was 10.8 years. BMD assessments were performed in 17 patients (SMA type 1=2, type 2=8, type 3=7). Low BMD was observed in 16 out of 17 patients. Four had a history of long bone fractures and were started on bisphosphonates. SMA types, age at last visit, sex, ambulation, and 25(OH)D level were not associated with fracture history or BMD Z-scores. Only one fulfilled the 2019 International Society for Clinical Densitometry (ISCD) pediatric definition of osteoporosis, with both low BMD and a history of clinically significant fracture. CONCLUSIONS: Children with SMA on disease-modifying treatments commonly had Low BMD and a history of fractures, but osteoporosis was uncommon according to the 2019 ISCD pediatric definition. A special definition of osteoporosis may be needed for this high-risk group.