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.

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.

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.

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.

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.

A Chinese girl with delayed puberty due to 17α-hydroxylase deficiency: the diagnosis, treatment and monitoring approach.

Summary: 17α-hydroxylase deficiency (17α-OHD) is a rare form of congenital adrenal hyperplasia. We report the case of a teenage girl with 17α-OHD who presented with delayed puberty, hypergonadotropic hypogonadism and hypertension. We illustrate the clinical approach in workup, the subsequent management and monitoring of this rare condition. Learning points: 17α-hydroxylase deficiency (17α-OHD) should be considered as a rare yet important differential diagnosis of girls with delayed puberty and elevated gonadotropins. Urine steroid profile, plasma aldosterone and renin levels should be assessed in adolescent girls with hypergonadotropic hypogonadism, after the exclusion of more common conditions, e.g. Turner syndrome. Inhibiting deoxycorticosterone (DOC) release by partial glucocorticoid replacement, counteracting DOC's mineralocorticoid effects by antagonists (such as eplerenone or spironolactone) as well as sex hormone replacements constitute the major backbone in the management of 17α-OHD.

Fibrodysplasia ossificans progressiva in Hong Kong-A case report series.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare condition. The diagnosis could be challenging due to its rarity and non-specific presenting symptoms. However, early diagnosis and appropriate management help in preserving patients' function and quality of life. Herein, we report the diagnostic journeys and clinical courses of 8 patients with FOP in Hong Kong and illustrate the challenges involved.

Rare manifestation of hyperreactio luteinalis: when both the mother and baby girl are virilised.

Hyperreactio luteinalis is a benign, pregnancy-related condition with cystic enlargement of the ovaries and elevated androgen. However, only one-third of patients manifest as maternal virilisation and rarely does it cause fetal virilisation. Here, we report a virilised baby girl born to a virilised mother because of hyperreactio luteinalis. This case illustrates our management to maternal and fetal virilisation.

Thirty-Minute Post-load Glucose Could Be a Useful Screening Measure for Abnormal Oral Glucose Tolerance Test Response in Adolescents with Obesity.

Background: With the growing obesity epidemic, subjecting every child with obesity to a 2-hour oral glucose tolerance test (OGTT) is impractical. Instead, 30-minute plasma glucose (PG), which reflects the acute phase of insulin secretion, might be a useful measure in the initial assessment of such individuals. Our study aimed to evaluate the optimal cutoff of 30-minute PG in predicting abnormal OGTT response and to compare the predictive value of this cutoff with that of the previously reported values from a combination of non-fasting parameters. Methods: For this study, 332 overweight or obese pediatric individuals who had undergone the OGTT under the Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong, from 2012 to 2018 were included. The optimal cutoff of 30-minute PG for prediction of abnormal OGTT response was determined using a receiver operating characteristics curve, and the positive predictive value (PPV) was evaluated. Results: There were 180 males (54.2%) and the mean age of the included individuals was 15.4±2.3 years. A 30-minute PG ≥9.2 mmol/L predicts abnormal OGTT response with the best combination of sensitivity and specificity. The PPV for abnormal OGTT response at this cutoff was 45%. Addition of this 30-minute PG cutoff to non-fasting parameters, including glycated hemoglobin, abnormal alanine transaminase, and family history of diabetes, resulted in an improved PPV of 70% for abnormal OGTT response. Conclusion: Addition of 30-minute PG to non-fasting parameters improved the clinical utility in identifying high-risk individuals for abnormal OGTT response.

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.

Successful transition from insulin to sulphonylurea in a child with neonatal diabetes mellitus diagnosed beyond six months of age due to C42R mutation in the KCNJ11 gene.

Neonatal diabetes mellitus is a rare monogenic condition affecting 1 in 100,000-300,000 live births. Mutations in the subunits of ATP-sensitive potassium (KATP) channels, which are the central gatekeepers of electrical activity, are the common cause of this condition, thereby reducing insulin secretion in the pancreatic beta cells. Most cases are diagnosed before 6 mo of age. The development of this condition in the latter half of the first year of life is rare; hence, testing in older infants is not routinely performed. Here, we describe the case of a patient who presented with neonatal diabetes mellitus and diabetic ketoacidosis at 10 mo of age. All the pancreatic autoantibodies were undetectable, prompting us to pursue genetic testing. At 13 yr of age, a heterozygous missense variant, C42R, was identified in the KCNJ11 gene by exome sequencing. Subsequently, sulfonylurea was initiated, and insulin therapy was discontinued that resulted in improved blood glucose control and increased C-peptide levels. Given the potential benefit of switching to oral medication, genetic testing should be extended to all infants diagnosed with antibody-negative diabetes before 1 yr of age.

Dental phenotype in an adolescent with osteogenesis imperfecta type XII.

Mutation in SP7, encoding the osteoblast-specific transcription factor SP7 (also known as osterix), has been described to cause osteogenesis imperfecta (OI) type XII. However, the exact dental phenotype has not been well described. We report the detailed dental manifestation of a boy known to have OI type XII, presented with impacted dentition, necessitating combined oral and maxillofacial surgical and orthodontic treatment. This case also highlighted the need of multidisciplinary team assessment in this group of children.

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.

Who should return for an oral glucose tolerance test? A proposed clinical pathway based on retrospective analysis of 332 children.

OBJECTIVES: Fasting plasma glucose or oral glucose tolerance test (OGTT) is the traditional diagnostic tool for type 2 diabetes (T2DM). However, fasting is required and implementation in all overweight/obese subjects is not practical. This study aimed to formulate a clinical pathway to stratify subjects according to their risk of abnormal OGTT. METHODS: This retrospective study included patients with overweight or obesity who had undergone OGTT in a tertiary paediatric unit from 2012 to 2018. The optimal haemoglobin A1c (HbA1c) cutoff that predicts abnormal OGTT was evaluated. Other non-fasting parameters, in combination with this HbA1c cutoff, were also explored as predictors of abnormal OGTT. RESULTS: Three hundred and thirty-two patients (boys: 54.2%, Chinese: 97.3%) were included for analysis, of which, 272 (81.9%) patients had normal OGTT while 60 (18.0%) patients had abnormal OGTT (prediabetes or T2DM). Optimal HbA1c predicting abnormal OGTT was 5.5% (AUC 0.71; sensitivity of 66.7% and specificity of 71%). When HbA1c≥5.5% was combined with positive family history and abnormal alanine transaminase (ALT) level, the positive predictive value for abnormal OGTT was increased from 33.6 to 61.6%. CONCLUSIONS: HbA1c, family history of T2DM and ALT level could be used to derive a clinical pathway to stratify children who have high risk of abnormal OGTT.

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.

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.

Vaginal Bleeding in an Infant with Extreme Prematurity.

BACKGROUND: Minipuberty of infancy refers to the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during the first few months of life. Studies have documented a more exaggerated and prolonged gonadotropin surge in preterm infants compared with term infants. We present a case of minipuberty presenting with vaginal bleeding at the corrected age of 3 months of life. Case Presentation. A former 23 + 6-week infant presented with intermittent vaginal bleeding in the diaper at the corrected age of 3 months. Physical exam showed bilateral breast buds of 0.5 cm-1 cm with no signs of pubarche. Investigations showed pubertal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol. As she was impressed to have exaggerated minipuberty due to extreme prematurity, no intervention was given. Repeated hormonal workup at the corrected age of 8 months showed decreasing trend of gonadotropin and estradiol levels. Vaginal bleeding resolved, and breast buds also regressed clinically. CONCLUSION: Our case illustrated that the robust surge of gonadotropin in an ex-premature infant can in fact result in endometrial maturation and present as vaginal bleeding. Though the mechanism of this alteration in the HPG axis in prematurity is not clearly understood, pediatricians should be aware of the benign and self-limiting nature of this phenomenon and avoid unnecessary intervention.

Coexistence of paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p hyperinsulinism.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner. CASE PRESENTATION: A large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic ABCC8:c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI. CONCLUSIONS: This case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.

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.