A 56-year-old man was presented to the emergency department of our institution in June 2023 and has had been followed up in our medical clinic for 1 year prior to his current hospital admission. He had been diagnosed with frequent symptomatic premature ventricular complexes with an ectopic burden of 8.2% on extended ambulatory rhythm monitoring. There were also multiple recorded episodes of non-sustained ventricular tachycardia. Beta-blocker was initiated and uptitrated according to clinical symptoms. His family history was remarkable for the sudden cardiac death of his father at the age of 64 years. Subsequent transthoracic echocardiogram of the patient revealed a global hypokinetic left ventricle with a biplane-measured left ventricular ejection fraction (LVEF) of 45%. There was mild left atrial enlargement with a two-dimensional area of 25.7 cm² but no other structural abnormalities. Computed tomography coronary angiogram showed mild to moderate coronary artery disease in three vessels and guideline-directed medical treatment was initiated. Cardiac magnetic resonance imaging (CMR) was scheduled to assess cardiac structures and function, as well as tissue characterisation for features of non-ischaemic cardiomyopathy. He had been scheduled to undergo catheter ablation for frequent symptomatic premature ventricular complexes.

The patient presented to our emergency department with out-of-hospital cardiac arrest. He had been found collapsed adjacent to a swimming pool and a bystander had initiated cardiopulmonary resuscitation. Spontaneous circulation was restored shortly after a single defibrillation delivered by an automated external defibrillator and he was transferred to our hospital immediately. On arrival at the emergency department, he was hemodynamically stable with a Glasgow Coma Scale score of 15. High-sensitive troponin I level was elevated at 44.9 ng/L. Electrocardiogram showed sinus rhythm of 71 beats/min with occasional premature ventricular complexes. There was no ST-segment elevation or significant conduction abnormalities. Bedside echocardiogram showed a similar biplane-measured LVEF of 43% with global hypokinesia. Urgent coronary angiogram showed non-occlusive moderate to severe coronary artery disease in three vessels. Given his current presentation, together with angiographic progression in coronary artery disease, complete revascularisation was performed uneventfully. He was then transferred to our cardiac care unit postoperatively for close monitoring. Inpatient CMR revealed a non-dilated left ventricle with mildly reduced LVEF of 43% with global hypokinesia. There was multifocal patchy mid-wall and subepicardial late gadolinium enhancement (LGE) at the mid-ventricular anterior, anteroseptal and anterolateral walls, as well as basal to mid-ventricular inferior and inferolateral walls (Fig 1). There was no evidence of myocardial infarct. Parametric mapping showed a mild increase in myocardial T1 with values up to 1067 ms to 1080 ms (native T1 values in healthy subjects obtained in our Aera 1.5T magnetic resonance imaging scanner [Siemens, Munich, Germany] is 996±26 ms for males), suggestive of mild diffuse interstitial fibrosis (Fig 2). Prior to hospital discharge, a transvenous implantable cardioverter defibrillator (ICD) was implanted for secondary prevention. Subsequent genetic testing identified a heterozygous pathogenic truncating variant NM_001458.5(FLNC):c.3279del p.(Gly1094Alafs^*4) in the filamin-C gene. The final clinical diagnosis was sudden cardiac arrest secondary to filamin-C variant–associated cardiomyopathy in a patient with non-dilated left ventricular cardiomyopathy (NDLVC) and mid-range ejection fraction.

The filamin-C gene encodes the filamin-C protein that plays essential roles in the sarcomere stability in cardiac muscles. Filamin-C variants have been increasingly recognised as an important cause of cardiomyopathy. It has been identified in approximately 3% to 4% of patients with dilated cardiomyopathy and commonly presents in early-to-mid adulthood with high arrhythmic risks.1

According to the 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure,2 primary prevention ICD is indicated in patients with symptomatic heart failure with an LVEF of lower than 35% despite optimal medical treatment and a reasonable quality of life. Such recommendation is supported by numerous landmark trials including MADIT (Multicenter Automatic Defibrillator Implantation Trial),3 DEFINITE (DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation),4 and SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial).5 In addition, several additional clinical risk factors should also be considered in sudden cardiac death risk assessment, especially in patients with non-ischaemic cardiomyopathy.2 These risk factors include significant LGE on CMR, younger age, and specific genotypes. Nonetheless these recommendations are ambiguous, and the guideline has not defined, for example, the burden of LGE and variant mechanisms in several high-risk genes that would warrant ICD implantation. Moreover, there are limited recommendations for primary prevention ICD in patients with heart failure with mid-range or preserved ejection fraction.

In the updated 2023 ESC Guidelines for the management of cardiomyopathies,6 a new entity of NDLVC is introduced. An algorithm for consideration of primary prevention ICD similar to that for patients with dilated cardiomyopathy is recommended in this patient population. Patient genotype and imaging features on CMR have been proposed in the early sudden cardiac death risk assessment for patients with NDLVC. A previous study has demonstrated a higher rate of malignant arrhythmic events in patients who are genotype-positive, compared with their genotype-negative counterparts.7 Such association has been observed irrespective of LVEF. Variants in certain genes including lamin A/C, phospholamban, filamin-C, RNA-binding motif protein 20, desmoplakin and plakophilin-2 are associated with a high risk of malignant ventricular arrhythmias and sudden cardiac death. Apart from genotype information, the presence and distribution of LGE on CMR, such as a ring-like pattern of LGE, has also been shown to be a strong risk marker for ventricular arrhythmias.8 Hence, based on the current ESC Guidelines,6 primary prevention ICD should be considered in patients with NDLVC and high-risk genotype and in the presence of additional risk factors such as syncope and LGE on CMR, irrespective of LVEF.

Our case highlights the need to incorporate a patient’s genotype and imaging features on CMR into the personalised risk assessment for sudden cardiac death in patients with NDLVC. This will facilitate a more comprehensive and informative discussion about the indication for primary prevention ICD and improve the clinical outcome for patients with cardiomyopathy.

Concept or design: KWC Lun, DPH Lee.
Acquisition of data: All authors.
Analysis or interpretation of data: KWC Lun, DPH Lee.
Drafting of the manuscript: KWC Lun, DPH Lee.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided consent for all treatments and procedures, and consent for publication of the case report.

1. Agarwal R, Paulo JA, Toepfer CN, et al. Filamin C cardiomyopathy variants cause protein and lysosome accumulation. Circ Res 2021;129:751-66. Crossref

2. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726. Crossref

3. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83. Crossref

4. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-8. Crossref

5. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37. Crossref

6. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023;44:3503-626. Crossref

7. Escobar-Lopez L, Ochoa JP, Mirelis JG, et al. Association of genetic variants with outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2021;78:1682-99. Crossref

8. Meier C, Eisenblätter M, Gielen S. Myocardial late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR)—an important risk marker for cardiac disease. J Cardiovasc Dev Dis 2024;11:40. Crossref

Etomidate is a non-barbiturate intravenous anaesthetic agent commonly used in emergency and critical care settings, due to its rapid onset, short duration of action, and minimal cardiorespiratory suppression. Adrenal suppression is a known side-effect. From April to May 2024, three adolescents presented to the paediatric departments of local hospitals with adrenal insufficiency due to etomidate inhalation via electronic cigarette (e-cigarette) vaping, a novel form of drug misuse emerging in Hong Kong.

In Case 1, a 17-year-old male with attention deficit hyperactivity disorder was admitted with ketamine cystitis. He had mild hypokalaemia, hypertension (137/84 mm Hg), and a positive urine toxicology screen by liquid chromatography–tandem mass spectrometry for cocaine, ketamine, and etomidate (Table). He reported daily vaping of ‘space oil’ via e-cigarettes for 4 months. Adrenal insufficiency was diagnosed based on elevated adrenocorticotropic hormone (ACTH) and a suboptimal response in a low-dose short Synacthen test. In Case 2, a 16-year-old male with autistic spectrum disorder presented with confusion, insomnia, and unsteady gait after vaping ‘space oil’ weekly for 1 month. Blood pressure and electrolytes were normal. Urine toxicology revealed etomidate and its analogue propoxate. Adrenal insufficiency was confirmed. In Case 3, a 15-year-old male with substance abuse–induced psychosis presented with emotional instability under drug effects. He reported vaping ‘space oil’ via e-cigarettes weekly for several months. Blood pressure and electrolytes were normal. Partial adrenal insufficiency was diagnosed with borderline results in the low-dose short Synacthen test. Two patients (Cases 1 and 2) required regular hydrocortisone replacement. In Case 1, repeated testing 5 months after cessation of etomidate revealed persistent adrenal insufficiency, likely due to second-hand smoke exposure from peers who used etomidate. For Cases 2 and 3, follow-up tests were planned after etomidate cessation. All patients received psychiatric follow-up.

This is the first local paediatric report of adrenal insufficiency associated with etomidate misuse via e-cigarettes. Since its clinical introduction 40 years ago, recreational use via the intravenous route has been rare.1 Nonetheless, its misuse as ‘space oil’ via e-cigarette vaping has surged in Hong Kong and Mainland China since 2023. e-Cigarette use is relatively common among adolescents, with a local survey reporting that 5.3% of secondary school students have had experience with e-cigarettes.2 From May to December 2024, the Hong Kong Poison Control Centre recorded 45 cases of ‘space oil’ misuse presenting to Hospital Authority emergency departments, with a median patient age of 17 years.3 Our cases also illustrate that psychiatric co-morbidities and polysubstance misuse are not uncommon among adolescent etomidate users.

Knowledge about the pharmacology of inhaled etomidate is limited since historical studies have focused on its properties in the context of a single intravenous bolus or short-duration infusion,4 while inhalation may involve higher doses and prolonged use. Known toxicities include decreased consciousness, nausea, vomiting, myoclonus, and adrenal insufficiency. Respiratory suppression or bradycardia may develop in overdose. Long-term neurological and psychological effects, particularly dependence and withdrawal, remain poorly characterised.

Etomidate and its analogues, propoxate/isopropoxate, inhibit 11-beta-hydroxylase, causing adrenal insufficiency with consequent decreased cortisol and aldosterone production, and elevated precursors such as 11-deoxycorticosterone, 11-deoxycortisol, and 17-hydroxyprogesterone (Fig). Accumulation of deoxycorticosterone, the precursor to aldosterone, leads to mineralocorticoid excess. Marked elevation of androstenedione in Case 1 and urinary androgen metabolites in Case 3 suggested androgen excess, consistent with a recently reported local female adult case of hyperandrogenism from etomidate misuse.5

Adrenal suppression from etomidate is dose-dependent and reversible, lasting 6 to 8 hours after a single dose and up to 24 to 48 hours with continuous infusion.4 6 Effects after chronic inhalation are less clear due to the variable drug content of e-cigarettes and inconsistent inhalation routes. Adrenal hyperplasia has been observed on computed tomography examinations among chronic users,5 7 suggesting possible prolonged ACTH stimulation due to ongoing adrenal suppression beyond typical durations in clinical settings.

Etomidate-induced 11-beta-hydroxylase inhibition can resemble congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. In addition to adrenal insufficiency, features of mineralocorticoid excess include hypertension, hypokalaemia, and suppression of endogenous renin and aldosterone, as seen in Case 2. Although mild hypokalaemia was observed in Case 1, severe hypokalaemia has been reported.7 Cases 1 and 3 demonstrated significantly elevated 11-deoxycortisol, while 17-hydroxyprogesterone was normal to mildly elevated, suggesting the former is a more sensitive marker of enzyme inhibition, as it is immediately upstream of the inhibited enzyme (Fig). Urinary steroid profiling can identify abnormal precursor-to-product ratios. A short Synacthen test should be performed to confirm adrenal insufficiency. Cases 2 and 3 demonstrated that ACTH may be normal and cortisol response may be relatively preserved despite circumstantial evidence of 11-beta-hydroxylase inhibition, possibly reflecting less drug exposure or compensation between periods of drug use.

Given the uncertainty of the duration of adrenal suppression, hydrocortisone replacement and/or stress dose precautions should be given for confirmed adrenal insufficiency. Etomidate users should receive counselling on hydrocortisone’s role, as it does not mitigate the full spectrum of etomidate toxicities. After cessation of etomidate, follow-up testing is recommended to document adrenal recovery. Persistently abnormal results should prompt suspicion of ongoing drug use, with non-classic congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency being a rare differential diagnosis. Our cases highlight the challenges of achieving complete cessation of drug misuse due to peer influence and potential dependence. A multidisciplinary approach should be adopted to address the complex medical and psychosocial issues in adolescent etomidate users.

Etomidate and its three analogues—metomidate, propoxate, and isopropoxate—have been listed as dangerous drugs in Hong Kong since February 2025.8 It is expected that more stringent regulations, along with continued law enforcement on illegal drug production and distribution, may help deter etomidate misuse. Public education should also be strengthened to emphasise that substances in e-cigarettes are not harmless, even if they are not traditionally classified as drugs.

Etomidate misuse via e-cigarettes is an emerging public health issue. Clinicians should be alert to the risk of adrenal insufficiency among e-cigarette users, particularly those who present with unexplained hypertension or hypokalaemia. Additional testing, such as toxicology screening, 11-deoxycortisol measurement, and urinary steroid profiling may provide supportive evidence. Further research is warranted to understand the pharmacological properties and long-term effects of etomidate misuse.

Concept or design: All authors.
Acquisition of data: YK Chung, YT Cheung, CSY Chan, CC Wong.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: YK Chung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were managed in accordance with the Declaration of Helsinki and provided informed consent for all treatments, procedures, and publication.

1. Uhm J, Hong S, Han E. The need to monitor emerging issues in etomidate usage: the misuse or abuse potential. Forensic Sci Med Pathol 2024;20:249-60. Crossref

2. Health Bureau, Hong Kong SAR Government. School-based survey on smoking among students in 2022/23. 2023. Available from: https://www.censtatd.gov.hk/wbr/B1130201/B11302012024XX01/att/en/78/School-based%20Survey%20on%20Smoking%20among%20Students%20in%202022-23%20-%20Key%20findings_7.pdf. Accessed 15 Aug 2024.

3. Wong IN, Chan CK, Tse ML. Spread of ‘space oil drug’ (etomidate) abuse in Hong Kong and consequent emergency department presentations. Hong Kong Med J 2025;31:173-4. Crossref

4. Forman SA. Clinical and molecular pharmacology of etomidate. Anesthesiology 2011;114:695-707. Crossref

5. Lau CY, Cheung YT, Han TM, Chung CM, Chong YK, Chen PL. Acquired 11β-hydroxylase deficiency by inhaled etomidate and its analogues: a mimic of congenital adrenal hyperplasia. JCEM Case Rep 2024;2:luae207. Crossref

6. Vinclair M, Broux C, Faure P, et al. Duration of adrenal inhibition following a single dose of etomidate in critically ill patients. Intensive Care Med 2008;34:714-9. Crossref

7. Wu W, Xia C, Gan L, Liao S, Yan Y. Etomidate-induced hypokalemia in electronic cigarette users: two case reports and literature review. Front Endocrinol (Lausanne) 2024;15:1321610. Crossref

8. Hong Kong SAR Government. Dangerous Drugs Ordinance (Amendment of First Schedule) Order 2025. Available from: https://www.elegislation.gov.hk/hk/2025/ln13!en. Accessed 15 Feb 2025.

A 69-year-old female presented to the clinic with a 2-year history of intermittent headaches. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) examination (Fig 1a and b) revealed a space-occupying lesion in the right frontal lobe, suggestive of a meningioma. Preoperatively, the patient experienced a single episode of epilepsy lasting for 2 minutes, relieved by antiepileptic medication.

Cranial surgery was performed based on the preoperative CT localisation. The tumour was completely separated and excised, measuring 4 × 3 × 2 cm³, greyish-yellow in colour, and encapsulated (Fig 1e). The encapsulated surface was rich in blood vessels. Upon opening, the tumour was yellow, and lipid droplet-like fluid was observed on the surface (Fig 1f).

Postoperative pathology indicated a hibernoma. Haematoxylin and eosin staining revealed a complete thin capsule attached to the outside of the tumour that was lobulated. A network of capillaries could be seen inside. Under the microscope, polygonal/round cells with eosinophilic granular cytoplasm were seen. The cell nuclei were round and centrally located. In addition, many small vacuolated brown adipocytes and unilocular adipocytes were seen, with a considerable amount of blood vessels, spindle cells, and collagen fibres infiltrating around the tumour cells (Fig 2).

Immunohistochemistry showed CD34 to be positive in the vessels, and Ki-67 scattered positive with a proportion of <1%. Immunohistochemistry results were as follows: CK (-), S-100 (-), MDM2 (-), CDK4 (-), P53 (-), CD34 (vascular +), CD117 (-), and Ki -67 (+, <1%) [Fig 2].

Postoperative re-examination confirmed complete removal of the tumour, and the patient had no further epileptic seizures. Three years later, cranial MRI follow-up revealed no tumour recurrence (Fig 1c and d).

Hibernomas are rare benign tumours composed of brown adipose tissue.1 They are asymptomatic and slow-growing. Compared with lipomas originating from white adipose tissue, hibernomas are exceedingly rare, with <200 cases reported in the literature.2 These tumours most commonly occur in the proximal axial skeleton, where fetal brown adipose tissue exists and continues into adulthood. They are most frequently found in the interscapular region, upper mediastinum, axilla, retroperitoneum, and neck. According to literature reports, hibernomas are extremely rare in the cranial cavity. In 1972, Vagn-Hansen et al3 reported a case of intracranial hibernoma. Due to medical constraints at the time, detailed case descriptions of CT and MRI images were not available. Therefore, the diagnosis of this patient has significant clinical significance and academic value. The rarity of intracranial hibernomas in clinical diagnosis can easily be overlooked or misdiagnosed as other more common intracranial tumours such as meningiomas. Clinicians and pathologists need to remain highly vigilant for this rare tumour to ensure timely and accurate diagnosis and treatment.

In radiology, differentiation between hibernomas and meningiomas is challenging. Hibernomas typically present as low- to medium-intensity on T1-weighted MRI and high intensity on T2-weighted MRI. Due to their origin from adipose tissue, hibernomas may show signal suppression in the fat-suppressed sequence of MRI. Due to the rich vascular supply inside the tumour, MRI post-contrast enhancement is evident. Also, due to the high fat content of hibernomas, they may appear as low density or iso-density lesions on CT scans.

Meningiomas typically present as iso- to high-intensity on both T1- and T2-weighted MRI and show significant uniform enhancement following contrast administration. Meningiomas often accompany the dural tail sign, an important distinguishing feature in imaging. Furthermore, the density of meningiomas on CT scans is quite uniform, with significant enhancement following contrast administration. Therefore, while there is overlap in imaging between hibernomas and meningiomas, detailed radiological analysis, especially the combination of fat-suppressed sequences and tumour enhancement characteristics, can help distinguish the two and increase diagnostic accuracy.

Pathological diagnosis is the gold standard for confirming hibernomas. Histological features include small multilocular brown adipocytes that have a rich granular cytoplasm and central or eccentric round or oval nuclei. Unlike the single large lipid droplet in white adipocytes, brown adipocytes contain multiple small lipid droplets and abundant mitochondria, giving the cytoplasm a granular appearance. In addition, hibernomas usually have a rich vascular network. Immunohistochemical staining showing vascular CD34 positivity can further confirm the diagnosis. Hibernoma cells have varying degrees of S-100 protein and CD34 expression according to the literature.4 5 Combining these pathological features can effectively distinguish hibernomas from other intracranial tumours such as meningiomas.

The diagnostic process of this case of intracranial hibernoma emphasises the importance of clinicians and pathologists when facing uncommon intracranial tumours. Detailed imaging analysis and pathological examination facilitate accurate differential diagnosis, providing the best treatment plan for patients. More case reports and research are needed to further enrich the understanding and treatment strategies of intracranial hibernomas.

All authors contributed to the concept or design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors declared no conflicts of interest.

The authors thank Dr Yanqing Li and Dr Qinyi Wang from the Department of Pathology at Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine for their expertise and assistance in the diagnosis and analysis of the patient’s condition.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The study was approved by the Ethics Committee of Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, China (Ref No.: 2024-005). The patient was treated in accordance with the Declaration of Helsinki. The patient provided written consent for publication of this case report.

1. Klevos G, Jose J, Pretell-Mazzini J, Conway S. Hibernoma. Am J Orthop (Belle Mead NJ) 2015;44:284-7.

2. Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. Am J Surg Pathol 2001;25:809-14. Crossref

3. Vagn-Hansen PL, Osgård O. Intracranial hibernoma. Report of a case. Acta Pathol Microbiol Scand A 1972;80:145-9. Crossref

4. Vassos N, Lell M, Hohenberger W, Croner RS, Agaimy A. Deep-seated huge hibernoma of soft tissue: a rare differential diagnosis of atypical lipomatous tumor/well differentiated liposarcoma. Int J Clin Exp Pathol 2013;6:2178-84.

5. Suster S, Fisher C. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol 1997;21:195-200. Crossref

Twenty-four–hour pH monitoring is indicated for evaluation of gastroesophageal reflux symptoms in children, as well as part of a preoperative work-up for those who require long-term nasogastric tube feeding or a gastrostomy. Its use is nonetheless restricted by the need to keep a nasal catheter in place for at least 24 hours. This can cause great discomfort and may be poorly tolerated by children, especially those with behavioural issues. Wireless pH monitoring can improve patient satisfaction and the overall sensitivity of diagnosing gastroesophageal reflux (Fig 1). Despite its rising popularity among adults, its use has been limited in children. This report documents the first experience in Hong Kong of a wireless oesophageal pH monitoring system in children with gastrointestinal symptoms and feeding problems.

A 9-year-old girl with good previous health and normal development presented to a surgical clinic in March 2023 with recurrent epigastric pain and heartburn. She was prescribed a proton pump inhibitor without symptom improvement. As her parents were keen to determine the cause of her symptoms, upper endoscopy and a pH study were offered. With consideration of patient comfort and the sensitivity of the test, wireless oesophageal pH monitoring was arranged. Endoscopy under general anaesthetic revealed mild antral gastritis but was otherwise unremarkable. An antral biopsy confirmed mild gastritis without Helicobacter pylori. The oesophagogastric junction (OGJ) was measured as 34 cm from the incisor, and a wireless pH monitoring capsule (Bravo; Medtronic Inc, Minneapolis [MN], United States) was inserted at 30 cm under direct endoscopic visualisation (Fig 2a). Post-insertion endoscopy confirmed secure placement at a satisfactory position (Fig 2b). An X-ray after the procedure further confirmed the good position of the capsule (Fig 2c). pH monitoring lasted 96 hours, with a DeMeester score of 6.8. The girl initially complained of mild chest discomfort and a globus sensation during swallowing on the first 2 days post procedure but this resolved spontaneously after 4 days. The capsule passed spontaneously within 3 weeks of the procedure. The diagnosis of gastritis was made after excluding gastroesophageal reflux by pH monitoring; the patient was prescribed a short course of a proton pump inhibitor that resolved the symptoms.

A 6-year-old girl with known glucose phosphate isomerase deficiency, cerebral ataxia and mild intellectual impairment presented to the same surgical clinic in January 2023. She had feeding problems with failure to thrive and needed supplemental milk feeding via a nasogastric tube. Given her medical background and neurodevelopment, she could not tolerate nasogastric tube insertion during her regular revision and required frequent sedation during the procedure. Owing to the anticipated requirement for long-term tube feeding, her parents were advised of the need for gastrostomy tube insertion and a preoperative pH study. As both the patient and parents could not accept a conventional 24-hour pH study, a wireless oesophageal pH monitoring system was inserted under monitored anaesthetic care. The upper endoscopy was unremarkable with no sign of oesophagitis or gastritis. Bravo was inserted at 25 cm from the incisor (ie, 5 cm from the OGJ). Monitoring continued for 96 hours, with a DeMeester score of 0.7. The capsule passed without any complications within 3 weeks of the procedure. The patient was well and there were no adverse events during the study period. In view of the negative pH study, an anti-reflux procedure was deemed unnecessary and subsequently only a laparoscopic gastrostomy was performed.

A 16-year-old boy with recurrent postprandial heartburn and vomiting presented to the same surgical clinic in March 2024. Medical treatment with proton pump inhibitors elicited no improvement and he was referred for work-up for an anti-reflux procedure. At the time of referral, as capsule pH monitoring was not available locally, a catheter-based 24-hour pH-impedance probe was attempted. Nonetheless the patient could not tolerate the procedure with repeated vomiting and failure of catheter insertion. Given the parents’ wish to have a definitive diagnosis prior to initiating an anti-reflux procedure, pH study was rearranged with the wireless oesophageal pH monitoring system under monitored anaesthesia care. The procedure was well tolerated and the patient was able to complete a 96-hour pH study. The overall DeMeester score was 16.1. During the study period, Day 2 was the patient’s worst day, with acid exposure time at 5.9% and DeMeester score at 22.1. There was significant improvement following resumption of a proton pump inhibitor on Day 3 with acid exposure time at 1% and DeMeester score at 3.5. With the diagnosis of significant gastroesophageal reflux disease confirmed, the parents agreed to proceed with laparoscopic fundoplication.

According to the joint updated guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition in 2018,1 24-hour pH monitoring is indicated in children with persistent symptoms of gastroesophageal reflux disease despite proton pump inhibitor treatment. The aim is to correlate persistent troublesome symptoms with acid gastroesophageal reflux events, clarifying the role of acid reflux and determining the efficacy of acid suppression therapy.1 Twenty-four–hour pH monitoring is also recommended as pre-gastrostomy work-up in children to guide patient selection for a concomitant anti-reflux procedure.2 Nonetheless conventional transnasal catheter pH monitoring, although still widely used, is frequently criticised for causing great patient discomfort, limiting the patient’s mobility during the test and, more importantly, being neither tolerable nor inducing compliance by children with neurodevelopmental and behavioural issues,3 as illustrated by Case 2. Not only is the quality of life of patients jeopardised, the unpleasant experience may also restrict reflux-provoking activities, limiting the accuracy and sensitivity of the test and yielding false lower values, as illustrated by Case 3.

To overcome these difficulties, the wireless oesophageal pH monitoring system uses a capsule attached to the mucosal wall of the oesophagus for pH monitoring (Fig 1). It consists of a 6.0×6.3×26.0 mm³ capsule-based device, equipped with an internal battery and a pH electrode. The device is attached to the distal wall of the oesophagus, approximately 4 to 6 cm from the OGJ, under direct endoscopic visualisation.3 4 It transmits pH data to a mobile phone–sized recorder via radio telemetry, thus obviating the need for a transnasal pH probe. The capsule enables data to be recorded for at least 48 hours and up to 96 hours, with minimal patient discomfort. The capsule detaches from the oesophageal mucosa and is expelled in stools, with spontaneous sloughing of the oesophageal mucosa and uneventful healing, usually over 3 to 7 days. Its clinical use in children has been established in the United Kingdom and the United States, demonstrating a high success rate, with better tolerance than standard transnasal pH monitoring in children with behavioural issues and an improvement in the detection rate of gastroesophageal reflux disease by 16% through extended recording time.3 4 As illustrated by Case 3, not only is the procedure tolerated, the successful extension of study for a duration of 96 hours may result in a higher diagnostic yield and provision of more information, eg, effect of pump on and off (whether patient was on proton pump inhibitor).5 Currently, the wireless pH monitoring system is intended to be used in adults and children from 4 years of age but is contraindicated in those with bleeding diathesis, strictures, severe oesophagitis, varices, obstructions, pacemakers or implantable cardiac defibrillators. In situations where the wireless pH capsule needs to be removed, for instance in patients with severe discomfort or failure of spontaneous passage, cold snare and hot snare (when cold snare is not sufficient) can be applied to safely remove the capsule with only thin superficial oesophageal mucosal tissue.6

To the best of our knowledge, our centre is the first to introduce and report the use of the wireless oesophageal pH monitoring system in children in Hong Kong. The procedure was smooth, with no equipment or technical failure, and all patients could be discharged on the same day of the procedure. Since Case 1 was the first patient at our centre to receive the device, a chest X-ray was taken to double confirm its position. Nonetheless a post-procedure chest X-ray is not routine for the paediatric population since the device position can be confirmed with endoscopy, as in the adult population. All patients tolerated the pH study well except for the complaint of a self-limiting globus sensation in one patient (Case 1). All parents reported no difficulty in utilising the mobile pH recording system. All capsules were expelled from the patients within 3 weeks of the procedure without any complication.

Wireless oesophageal pH monitoring cannot easily diagnose some conditions such as functional belching and rumination syndrome due to the lack of impedance monitoring. Nonetheless these cases highlight that it is well tolerated and feasible in evaluating gastroesophageal reflux symptoms in children and provides a sensible alternative to standard transnasal pH monitoring. In addition, it may result in a higher diagnostic yield and more comprehensive clinical information. As clinicians, we are obliged to keep track of technological advancements and strive to provide holistic and optimal care for children, improve patient satisfaction and shorten their hospital stay.

Both authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Both authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, KKY Wong was not involved in the peer review process. The other author has disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were treated in accordance with the Declaration of Helsinki. Verbal consent was obtained from the patients for the publication of the case reports.

1. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:516-54. Crossref

2. Fung AC, Ooi YN, Hui HM, Mok MK, Chung PH, Wong KK. Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: rethinking of the routine practice. World J Surg 2024;48:739-45. Crossref

3. Rodriguez L, Morley-Fletcher A, Winter H, Timothy B. Evaluation of gastroesophageal reflux disease in children on the autism spectrum: a study evaluating the tolerance and utility of the BRAVO wireless pH monitoring. J Pediatr Gastroenterol Nutr 2022;75:450-4. Crossref

4. Rao NM, Campbell DI, Rao P. Two years’ experience of using the Bravo wireless oesophageal pH monitoring system at a single UK tertiary centre. Acta Paediatr 2017;106:312-5. Crossref

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6. de Hoyos A, Esparza EA, Loredo ML. Cold and hot snare endoscopic techniques for removal of the Bravo pH monitoring capsule. Digestion 2009;79:14-6. Crossref

Two Chinese girls (22 months and 26 months of age [Case 1 and Case 2, respectively]) presented in August 2021 and November 2021 with progressive bowing of the lower limbs since infancy. Neither had any significant family history. Physical examination revealed rachitic deformity, waddling gait, and short stature. Further investigations showed hypophosphataemia, isolated hyperphosphaturia and a high serum alkaline phosphatase (ALP) level with normal serum calcium, 25(OH) vitamin D, and parathyroid hormone levels. Characteristic clinical and radiographical findings suggestive of hypophosphataemic rickets were also evident (Fig). Molecular testing confirmed a diagnosis of X-linked hypophosphataemia (XLH) with heterozygous pathogenic PHEX (phosphate-regulating endopeptidase homologue on the X chromosome) variants detected in both patients [Case 1: c.2104C>T, p.(Arg702); Case 2: (c.1699c>T) (Arg567)]. Neither set of parents was affected. Both girls were commenced on conventional treatment with phosphate solution and alfacalcidol for around 3 months with only fair improvement. They were then started on burosumab at a starting dose of 0.8 mg/kg every 2 weeks, titrated up to 2 mg/kg (20 mg) 4 months later based on fasting serum phosphate level. Despite maximum doses of burosumab, serum phosphate level remained slightly below the normal range for both patients. Nevertheless there was ongoing clinical improvement in ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and healing of rickets in both patients. After burosumab treatment for 24 months, both patients had significant clinical, biochemical, and radiological improvement (Table and Fig). They were followed up by the multidisciplinary team at the Hong Kong Children’s Hospital. No treatment-related adverse reactions or disease-related complications (including skull deformities, dental abscess, and hearing problem) were observed.

X-linked hypophosphataemia is the most common cause of genetic rickets, with a prevalence of 1:20 000 to 1:60 000.1 2 It is caused by mutations in the PHEX gene and results in an increased level of the fibroblast growth factor 23 (FGF-23) hormone. This leads to impaired renal reabsorption of phosphate, low serum 1,25-dihydroxyvitamin D concentration, and reduced intestinal phosphate absorption, and ultimately, chronic hypophosphataemia. Patients typically present in early childhood with signs and symptoms of rickets and osteomalacia, progressive bowing deformities of the lower limbs, bone pain and stunted growth, as in our patients.

X-linked hypophosphataemia is conventionally treated with oral phosphate and active vitamin D analogues but this does not address the underlying pathogenesis and may only partially correct the biochemical derangement and skeletal deformities. Patients often require repeated orthopaedic procedures, eg, hemiepiphysiodesis or even multiple corrective osteotomies to maintain the mechanical axis of the lower limbs. Surgical correction is fraught with technical difficulties due to osteomalacia and there are high rates of recurrence. Moreover, conventional treatment is associated with long-term side-effects such as hyperparathyroidism and nephrocalcinosis.

Burosumab, a monoclonal antibody to FGF-23 for XLH treatment, was approved by the United States Food and Drug Administration3 and the European Medicines Agency4 in 2018. Subsequently, a phase III trial to evaluate 61 children with XLH aged 1 to 12 years for 64 weeks5 and another trial evaluating children with XLH aged 5 to 12 years for 160 weeks6 further supported its safety and effectiveness in terms of improved total Rickets Severity Score and fasting serum phosphate level. These outcomes were also measured in our patients and similar improvements observed. With the approval of burosumab, there has been a paradigm shift in the treatment of XLH in Western countries. Nevertheless conventional treatment continues to be the norm in most parts of our region—partly attributed to the high cost of burosumab, and partly due to the lack of published regional experience with burosumab in the clinical setting.

In our patients, the dose of burosumab was titrated up slowly to the maximum dose based on age-specific fasting phosphate level, as per various clinical practice recommendations.7 8 With the maximum dose, fasting serum phosphate level improved but failed to reach that of the age-specific normal range. Other secondary causes including vitamin D deficiency and hyperparathyroidism were excluded. Nevertheless improvement in other clinical parameters including serum ALP level, the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, growth velocity, and clinical and radiological evidence of rickets healing were observed. We have maintained our two patients on the same dose with ongoing clinical improvements observed. This is consistent with the recently published opinion based on early experience in seven European countries, recommending that a serum phosphate concentration below the age- and sex-specific range may be acceptable and the same maintenance dose continued as improvements in other clinical parameters are maintained.9 This is based largely on expert opinion with no data on the proportion of patients who do not achieve a normalised phosphate level and no comparison of clinical outcomes.

X-linked hypophosphataemia is a rare, genetic multisystem disease. In addition to the skeletal manifestations, around two-thirds of affected individuals have associated dental and periodontal issues, such as spontaneous periapical abscesses, related to poor dentin mineralisation.10 Some patients also have other complications including craniosynostosis and impaired hearing. Consequently, most guidelines recommend a multidisciplinary approach for this group of patients.7 8 Despite treatment with burosumab, some complications cannot be mitigated. Dental abscess, a well-known complication in patients with XLH, has not been consistently shown to be ameliorated by burosumab treatment. In the phase 3 burosumab trial,5 dental abscess was observed at a higher rate in the treatment group than the control arm. This implies that the pathophysiology of dental abscess is not mediated only by the FGF-23 pathway. This highlights the importance of a multidisciplinary approach to the management of XLH, as recommended by recent international clinical practice guidelines7 and regional consensus statements.8 At the Hong Kong Children’s Hospital, this group of patients is seen in the multidisciplinary bone clinic with input from a paediatric endocrinologist, orthopaedic surgeon, geneticist, dental surgeon, radiologist, and case manager (nurse practitioner). This orchestrated, coordinated multidisciplinary care is particularly important to maximise the effect and overall clinical outcome of burosumab treatment that remains remarkably expensive.

To the best of our knowledge, this is the first report of real-world experience of XLH treated with burosumab outside clinical trials in Asia. The target of a normal phosphate level may not be achievable in practice, and treatment response should also be guided by other clinical parameters. Further research into factors that affect the biochemical outcome and the clinical response of groups with different biochemical outcome is needed. A multidisciplinary approach should be adopted in the care of children with XLH.

Concept or design: JYL Tung.
Acquisition of data: JYL Tung.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: JYL Tung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

Preliminary results for these two cases were presented as a poster at the 12th Asia Pacific Paediatric Endocrine Society Biennial Scientific Meeting 2022 (South Korea, 5-8 October 2022).

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were treated in accordance with the Declaration of Helsinki. Consent for all treatments, procedures, and consent for publication was obtained from parents of the patients.

1. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 2009;160:491-7. Crossref

2. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 2016;174:125-36. Crossref

3. United States Food and Drug Administration. FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia. 2018 Apr 17. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-inherited-form-rickets-x-linked-hypophosphatemia. Accessed 28 Oct 2024.

4. European Medicines Agency. EU/3/14/1351—orphan designation for treatment of X-linked hypophosphataemia. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-14-1351. Accessed 28 Oct 2024.

5. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019;393:2416-27. Crossref

6. Linglart A, Imel EA, Whyte MP, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-linked hypophosphatemia. J Clin Endocrinol Metab 2022;107:813-24. Crossref

7. Sandy JL, Simm PJ, Biggin A, et al. Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab. J Paediatr Child Health 2022;58:762-8. Crossref

8. Munns CF, Yoo HW, Jalaludin MY, et al. Asia-Pacific consensus recommendations on X-linked hypophosphatemia: diagnosis, multidisciplinary management, and transition from pediatric to adult care. JBMR Plus 2023;7:e10744. Crossref

9. Mughal MZ, Baroncelli GI, de Lucas-Collantes C, et al. Burosumab for X-linked hypophosphatemia in children and adolescents: opinion based on early experience in seven European countries. Front Endocrinol (Lausanne)2023;13:1034580. Crossref

10. Baroncelli GI, Mora S. X-linked hypophosphatemic rickets: multisystemic disorder in children requiring multidisciplinary management. Front Endocrinol (Lausanne) 2021;12:688309. Crossref