In July 2021, a 1.5-kg baby girl presented with polyhydramnios on antenatal ultrasound scan at 27 weeks that had resolved by 35 weeks. Physical examination showed no dysmorphic features. She was born by caesarean section at 35 weeks due to discordant growth in a dichorionic diamniotic twin pregnancy. She was intubated at birth but resistance was noted during orogastric tube insertion. Chest X-ray revealed coiling of the gastric tube at the upper pouch of the oesophagus with the presence of intestinal gas, which is a classic feature of type C oesophageal atresia (Fig 1). Echocardiogram revealed several cardiac anomalies including a ventricular septal defect, a moderate patent ductus arteriosus, and a large atrial septal defect.

Thoracoscopic repair of oesophageal atresia was scheduled for the next day following stabilisation. The patient was positioned in a semi-prone position with the right chest slightly elevated. She was put on conventional ventilation without single lung ventilation, as per our practice. A camera port was inserted at the 5th intercostal space and two further 5-mm working ports were inserted under direct vision. Pneumothorax of 3 to 4 mm Hg was created using CO₂. The azygous vein was cauterised and divided with monopolar diathermy and the tracheoesophageal fistula readily identified. This was closed by Weck Hem-o-lok (Teleflex; Wayne [PA], United States) and divided (Fig 2). The proximal oesophageal stump was identified and opened with scissors. End-to-end esophago-oesophagostomy was performed using single-layer interrupted 5/0 polydioxanone sutures (Ethicon; Bridgewater [NJ], United States). A 12-Fr chest drain was inserted at the end of the procedure. The operation was uneventful and completed in 145 minutes.

After surgery, the patient was managed in the neonatal intensive care unit according to our usual protocol. On day 1 after surgery she developed sudden profound desaturation with CO₂ retention when the endotracheal tube was secured at 8 cm from the upper lip. Bedside bronchoscopy showed a tracheal pouch (fistula remnant) close to the tip of the endotracheal tube. The tip completely entered the pouch with minimal advancement of the endotracheal tube. The endotracheal tube was then withdrawn to 7.5 cm from the upper lip and no further desaturation was noted.

A contrast swallow study on day 18 after surgery showed an intact anastomosis. The patient was extubated successfully on day 19 after surgery. Bolus feeding via a feeding tube was established after extubation, and oromotor training was commenced. She was transferred back to the referring hospital for management of her cardiac disorders. At 6 weeks after surgery, she had good weight gain with full oral feeding and no clinical gastroesophageal reflux.

The introduction of minimally invasive surgery has undoubtedly revolutionised the treatment of many surgical disorders. The role of minimally invasive surgery in common neonatal procedures such as inguinal hernia repair and pyloromyotomy is well established. However, this operative approach in more complex procedures is still limited by various factors including equipment size, surgical expertise, and perioperative support.

Among all the neonatal operations, repair of oesophageal atresia is one of the most challenging. In addition to the need for meticulous surgical skill, adequate support from a dedicated neonatal intensive care unit and expert paediatric anaesthetists are equally important. The first successful thoracoscopic repair of oesophageal atresia was reported in 1999.1 A subsequent international multicentre study published 15 years ago further confirmed that thoracoscopic repair of oesophageal atresia was at least as good as traditional thoracotomy.2 However, this operative approach is still not widely practised.

In our unit, we started to perform thoracoscopic surgery in 2007. In our early experience reported in 2012,3 we selected patients with a reasonably large body size for minimally invasive surgery. With the accumulation of neonatal operative experience, we became confident performing these operations on smaller-sized babies. Prior to our case, Son et al4 published their experience in thoracoscopic repair of oesophageal atresia in babies <2 kg, and Rothenberg1 reported a successful experience in a 1.2-kg baby. We believe that thoracoscopic repair of oesophageal atresia in neonates can be performed safely in experienced centres with proper case selection.

Traditionally, the Spitz classification has been considered the prognostic indicator. Neonates with oesophageal atresia with birth weight <1.5 kg and major cardiac anomalies (as in our patient) are predicted to have only a 50% survival rate with a traditional open surgical approach. However, advances in surgical skills, neonatal care, and anaesthesia combined with the ability to optimise the surgical approach have resulted in improved surgical outcomes and consequent survival rates.1 4

The challenges faced in this operation included the patient’s small size and presence of cardiopulmonary complications before and during surgery. The pneumothorax created during thoracoscopy may compress the lung causing difficulty in ventilation and compromise cardiac function, further increasing the complexity of anaesthesia. We overcame this by limiting the pressure to 3 to 4 mm Hg, resulting in less operative space but better patient tolerance. In our opinion, the reduced working space is not a major hurdle for a surgeon competent in minimally invasive surgery. In a baby with congenital heart disease, an anaesthetist who has experience in neonatal thoracic surgery is essential for optimum intra-operative management.

Holcomb et al2 demonstrated in a multi-institutional study that there were no significant differences in reported postoperative complication rates between minimally invasive surgery and open repair. A minimally invasive approach has the additional benefits of smaller wounds and less pain. More specifically, thoracoscopic repair allows for clearer magnification. Although CO₂ pneumothorax will compress the right lung during surgery, its effect is significantly less than that of manual compression during open surgery. Long-term studies of musculoskeletal problems also reveal a superior outcome for thoracoscopic surgery.1

In conclusion, we report a successful thoracoscopic repair of oesophageal atresia in a high-risk neonate with very low birth weight. To the best of our knowledge, this is the smallest baby with oesophageal atresia in Hong Kong to have this operation. While proper case selection to ensure patient safety remains the top priority, small body size should not preclude a thoracoscopic surgical approach. The combined efforts and advances in surgery, anaesthesia and neonatal care are key to success.

All authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, 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.

As the editor of the journal, KKY Wong was not involved in the peer review process for this article. Other authors have no conflicts of interest to disclose.

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’s parents provided informed consent for all treatments and procedures and provided consent for publication.

1. Rothenberg SS. Thoracoscopic repair of esophageal atresia and tracheo-esophageal fistula in neonates: evolution of a technique. J Laparoendosc Adv Surg Tech A 2012;22:195-9. Crossref

2. Holcomb GW 3rd, Rothenberg SS, Bax KM, et al. Thoracoscopic repair of esophageal atresia and tracheoesophageal fistula: a multi-institutional analysis. Ann Surg 2005;242:422-8. Crossref

3. Huang J, Tao J, Chen K, et al. Thoracoscopic repair of oesophageal atresia: experience of 33 patients from two tertiary referral centres. J Pediatr Surg 2012;47:2224-7. Crossref

4. Son J, Jang Y, Kim W, et al. Thoracoscopic repair of esophageal atresia with distal tracheoesophageal fistula: is it a safe procedure in infants weighing less than 2000 g? Surg Endosc 2021;35:1597-601. Crossref

In June 2020, a previously healthy 7-year-old boy presented with a 1-week history of persistent fever. He had an unremarkable medical history, and had gone hiking a week before the onset of his fever. He was initially treated for a presumed viral illness but his condition worsened over the subsequent 2 days. His fever became high and fluctuating, with a peak of 39°C, and he developed dyspnoea without cough. He had no headache or body aches. Physical examination revealed crepitations with diminished breath sounds over both lung fields and tachypnoea with a respiratory rate of 30 per minute. Cervical lymphadenopathy and hepatomegaly were present. There was no eschar. He had distributive shock with hypotension (80/40 mm Hg) and tachycardia (150 beats per minute) and a norepinephrine infusion was commenced. Within one day, type I respiratory failure became evident with increasing oxygen requirement from room air to FiO₂ 0.4 and continuous positive airway pressure of 6 cmH₂O to maintain oxygen saturation above 90%. The PaO₂:FiO₂ ratio was 232.5 mm Hg. Plain radiograph of the chest revealed bilateral opacities and peribronchial thickening (Fig). Echocardiography and lung ultrasound confirmed normal heart function and the absence of pleural effusion. By definition, the boy was diagnosed with paediatric acute respiratory distress syndrome (PARDS: an acute lung injury occurring within 7 days of a known clinical insult, with acute hypoxaemia of PaO₂:FiO₂ ratio ≤300 when the child is on non-invasive ventilation, and new infiltrates consistent with acute pulmonary parenchymal disease on chest radiograph, which cannot be explained by acute left ventricular heart failure or fluid overload), where he had progressive respiratory failure and bilateral diffuse infiltration on chest radiography.1 Further blood tests and bone marrow findings met the diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH: a life-threatening clinical syndrome of systemic hyperinflammation and progressive immune-mediated organ damage due to excessive immune activation): anaemia (haemoglobin 8.3 g/dL), thrombocytopenia (45 × 10⁹/L), hypertriglyceridaemia (4.5 mmol/L), high ferritin (4467 pmol/L), hypofibrinogenaemia (0.9 g/L), and elevated soluble CD25 (8569 pg/mL).2 Bone marrow aspiration and trephine biopsy showed haemophagocytosis. There was no evidence of Epstein–Barr virus association on immunohistochemical analysis. Orientia tsutsugamushi antibody titre of 512 increased to 4096 (ie, more than a fourfold increase) after 2 weeks. The child was diagnosed with PARDS and secondary HLH associated with scrub typhus infection and prescribed oral doxycycline 50 mg twice daily (~3.7 mg/kg/day) for the scrub typhus. Intravenous dexamethasone 5 g every 12 hours (10 mg/m²/day) was commenced as treatment of HLH with a starting dose as per the HLH-2004 study protocol. He became afebrile within 1 day of commencing treatment and respiratory distress gradually resolved. He was weaned off continuous positive airway pressure ventilation after 3 days. Platelet count rose to >100 × 10⁹/L after 4 days. Ferritin lowered the day after treatment and was within normal range after 2 weeks. The boy completed a 1-week course of doxycycline and dexamethasone was also tapered off in 1 week.

Our patient presented with non-specific symptoms of scrub typhus and developed severe complications including PARDS and HLH without the pathognomonic eschar. Scrub typhus is caused by the bacterium O tsutsugamushi and is spread to humans through the bites of infected chiggers, Leptotrombidium mites, that can be both a vector and a reservoir for O tsutsugamushi.3 It is a notifiable disease in Hong Kong with between 7 and 28 cases reported each year over the past 10 years.4 Symptoms of scrub typhus usually begin within 10 days of being bitten and can range from non-specific signs including fever, headache, body aches and rash, to multiorgan failure and death with a median mortality rate of 6% if left untreated.3 Although eschar is pathognomonic for scrub typhus, it is rare among Southeast Asian patients. Laboratory confirmation of the diagnosis usually requires indirect fluorescent antibody test and is the mainstay of serologic diagnosis. Polymerase chain reaction assay of whole blood sample if available can speed the diagnosis.

Acute respiratory distress syndrome is a serious complication of scrub typhus; it has been reported in 4% to 22% of cases,5 6 and can involve over 50% of children who developed secondary HLH associated with scrub typhus infection.7 The pulmonary manifestations vary from bronchitis and interstitial pneumonitis to acute respiratory distress.5 6 Acute respiratory distress has also manifested in many patients with HLH due to other causes and has been reported as the initial manifestation of HLH. Nahum et al8 reported that 7 of 11 children with HLH and multiple organ failure exhibited PARDS after HLH was diagnosed, highlighting the importance of close monitoring and early intervention for children with PARDS and HLH. The presentation of acute respiratory distress syndrome in children differs from that in adults and a consensus on a formal PARDS definition was reached in 2015 by the Paediatric Acute Lung Injury Consensus Conference.1

In some cases, HLH can cause cytokine release syndrome, a life-threatening disorder of severe excessive inflammation (hyperinflammation) caused by uncontrolled proliferation of activated lymphocytes, macrophages and secretion of inflammatory cytokines.9 Although rare, O tsutsugamushi is a significant cause of HLH, especially in Asia.7 The HLH-2004 protocol, which includes etoposide, dexamethasone and cyclosporine as the initial therapy, is designed for treatment of patients with primary HLH.2 For patients with secondary HLH, treatment of the underlying infection or malignancy may help control the HLH and avoid the need for cyclosporine and etoposide. Single antibiotic therapy with doxycycline, minocycline, chloramphenicol, azithromycin or clarithromycin has been reported to result in rapid defervescence in patients with HLH associated with scrub typhus.10 Thus, an accurate diagnosis of scrub typhus in patients with HLH can help timely targeted antibiotic therapy with subsequent rapid clinical improvement.

This case illustrates an atypical severe manifestation of scrub typhus presenting with non-specific signs and symptoms resulting in complications including PARDS and HLH. Early diagnosis and treatment with doxycycline are crucial to prevent complications. Physicians should be vigilant for scrub typhus as a potential diagnosis in a child who presents with pyrexia of unknown origin and a history of participation in rural outdoor activities.

Concept or design: RCM Fung, KKY Leung, CC Au, KL Hon.
Acquisition of data: RCM Fung, KL Hon.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: RCM Fung, KKY Leung, KL Hon.
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.

As an editor of the journal, KL Hon was not involved in the peer review process. Other 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 tenets of the Declaration of Helsinki. The patient’s parents provided written informed consent for all treatments and procedures and consent for publication.

1. Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16:428-39. Crossref

2. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. Crossref

3. Peesapati N, Rohit T, Sunitha S, Pv S. Clinical manifestations and complications of scrub typhus: a hospital-based study from North Andhra. J Assoc Physicians India 2019;67:22-4.

4. Center for Health Protection, Department of Health, Hong Kong SAR Government. Number of notifiable infectious diseases by month. 2020. Available from: https://www.chp.gov.hk/en/statistics/data/10/26/43/6896.html. Accessed 25 Jun 2020.

5. Sankuratri S, Kalagara P, Samala KB, Veledandi PK, Crossref

6. Kumar Bhat N, Dhar M, Mittal G, et al. Scrub typhus in children at a tertiary hospital in north India: clinical profile and complications. Iran J Pediatr 2014;24:387-92.

7. Naoi T, Morita M, Kawakami T, Fujimoto S. Hemophagocytic lymphohistiocytosis associated with scrub typhus: Systematic review and comparison between pediatric and adult cases. Trop Med Infect Dis 2018;3:19. Crossref

8. Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: Unrecognized cause of multiple organ failure. Pediatr Crit Care Med 2000;1:51-4. Crossref

9. Hon KL, Leung KK, Oberender F, Leung AK. Paediatrics: how to manage septic shock. Drugs Context 2021;10:2021-1-5. Crossref

10. Hon KL, Leung AS, Cheung KL, et al. Typical or atypical pneumonia and severe acute respiratory symptoms in PICU. Clin Respir J 2015;9:366-71. Crossref

A 76-year-old frail man was admitted to hospital with fever and delirium. His medical history was significant for diabetes mellitus, hypertension, and dyslipidaemia. White blood cell count was 9.3 × 10⁹/L and C-reactive protein 18.20 mg/dL. Blood cultures yielded serogroup D Salmonella enteritidis. Computed tomography (CT) angiogram showed an aortic arch aneurysm of 4.7 cm (Fig 1a). Gallium scintiscan confirmed focal uptake at the proximal aortic arch. He developed progressively worsening chest discomfort for the subsequent 3 weeks, and a new CT angiogram showed rapid increase in the aneurysm size to 5.3 cm (Fig 1b).

A diagnosis of mycotic aortic arch aneurysm was made, and multidisciplinary consultation concluded that he was too frail to undergo conventional open repair. A custom-made double inner-branched aortic arch endograft (Cook Medical, Bloomington [IN], US) was arranged. During the interim, he received intravenous ceftriaxone. The left subclavian artery was revascularised with a left common carotid artery (CCA) to left subclavian artery bypass as a first-stage procedure. The custom-made endograft was available 3 weeks later (Figure 2a,b) and the endovascular procedure was performed accordingly.

Briefly, all procedures were performed under general anaesthesia in a well-equipped hybrid operating room by experienced endovascular surgeons. The endografts were flushed with heparinised saline multiple times to completely evacuate trapped gas in the sheath. Access was gained through an open groin cutdown exposing the common femoral artery and vein, and bilateral neck cutdowns to expose the right and left CCA. After full systemic heparinisation and under fluoroscopic guidance, a Terumo wire and pigtail catheter were positioned in the left ventricle and exchanged for a double-curved extended Lunderquist Extra-Stiff Wire (Cook Medical). The main stent graft body was then delivered to the aortic arch. The branched endograft was deployed under fluoroscopy, with controlled systolic hypotension by an inferior vena cava occlusion balloon (Coda 46 mm balloon; Cook Medical) introduced via the right femoral vein. Accurate alignment of the orientation markers with the coronary and supra-aortic vessels was essential. After deployment of the main stent graft, the proximal inner branch was sequentially cannulated in a retrograde fashion through the exposed carotid arteries. A custom-made thoracic stent graft extension was used (Cook Medical) to bridge the proximal inner branch and the innominate artery. A similar procedure was repeated for the distal inner branch via the left carotid artery, where a Fluency self-expanding covered stent (CR Bard, Murray Hill [NJ], US) was used to bridge the distal inner branch and the left CCA, taking care not to cover the left CCA to left subclavian artery bypass. The left subclavian artery origin was finally occluded with an Amplatzer vascular plug (St Jude Medical, Saint Paul [MN], US) to prevent endoleak into the sac. Completion angiogram showed successful exclusion of the aneurysm with patent supra-aortic branches (Fig 2c,d).

The patient recovered well without neurological sequelae. He was discharged on postoperative day 13 with lifelong oral ciprofloxacin prescribed. Computed tomography angiogram at 3 months (Fig 3a,b) and 1 year (Fig 3c,d) after surgery showed successful and durable results.

To the best of our knowledge, this is the first reported use of a custom-made double inner-branched thoracic aortic endograft for treatment of Salmonella-related mycotic aortic arch aneurysm. In septic and frail patients, a custom-made endovascular device should not generally be first-line treatment as the manufacturing time may take up to a few months. However, in our patient, urgency was emphasised and availability of the stent-graft expedited.

Conventional open repair has always been the gold standard therapy for mycotic aortic aneurysms, but endovascular stent grafts may be a temporising or permanent option in critically ill patients who will not tolerate open surgery.1 2 Custom-made branched thoracic endovascular aortic repair now adds to the armamentarium of options. The use of custom-made inner-branched thoracic endografts is technically challenging and requires endovascular expertise and experience. Meticulous preoperative planning with analysis using the iNtuition workstation (TeraRecon, San Mateo [CA], US) is paramount, with reference to the characteristics of the proximal and distal landing zones in relation to the diameter, angulation, and length of the supra-aortic arteries. The cervical left CCA to left subclavian artery bypass debranching procedure can be a staged or simultaneous procedure. The operative technique is well described in published literature.3 4

As with most endovascular aortic arch repairs, the most feared complication is of stroke that can occur when atherosclerotic or gaseous emboli are released from the arch or proximal supra-aortic branches during wire and graft manipulation, from clamping of carotid arteries, or due to peri-operative fluctuation of blood pressure. Another major concern after stenting the ascending aorta is the risk of retrograde type A dissection, which can be mitigated by controlled hypotension during the deployment of the stent graft. Care must also be taken to not cover the orifices of the coronary arteries with the stent graft.

Off-the-shelf solutions for single and double inner-branched aortic arch endografts are currently under development and were not available at the time of preparation of this case report. The use of a custom-made thoracic endograft is a major development for these patients who would otherwise require traditional open repair, frozen elephant trunk procedure, or hybrid procedures. Frail elderly patients with co-morbidities or prior sternotomies would be denied surgery as they would not tolerate extracorporeal cardiopulmonary bypass with deep hypothermic circulatory arrest. Endovascular experience and technical support are important as the access vessel is remote to the arch. There is often a fine balance between the procedure and maintenance of cerebral perfusion. Comparing non-custom chimney and custom graft for arch pathology, O’Callaghan et al5 showed that mortality was higher in the non-custom group (7% vs 18%), and a trend favouring better durability of fenestrated grafts for sealing and re-intervention rates was noted. All patients should have regular CT surveillance to monitor durability and exclude aneurysm-related complications. Long-term postoperative antibiotic therapy is also important since endovascular options preclude debridement of infected tissue.

This new technique involving a custom-made double inner-branched aortic arch endograft can be considered in patients with mycotic aneurysms of the thoracic arch, with favourable and durable results.

All authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, 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.

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 written informed consent for all procedures.

1. Chan YC, Morales JP, Taylor PR. The management of mycotic aortic aneurysms: is there a role for endoluminal treatment? Acta Chir Belg 2005;105:580-7. Crossref

2. Taylor PR, Chan YC. Endovascular treatment in the management of mycotic aortic aneurysms. In: Thompson MM, Morgan RA, Matsumura JS, Sapoval M, Loftus IM, editors. Endovascular Intervention for Vascular Disease. Principles and Practice. Boca Raton: Taylor & Francis Group; 2008: 235-42.

3. Fiorucci B, Tsilimparis N, Rohlffs F, Heidemann F, Debus ES, Kölbel T. How to confirm catheterization of inner branches in aortic endografting: The Universal Flush Test. J Endovasc Ther 2017;24:539-41. Crossref

4. Tsilimparis N, Detter C, Law Y, et al. Single-center experience with an inner branched arch endograft. J Vasc Surg 2019;69:977-85.e1. Crossref

5. O’Callaghan A, Mastracci TM, Greenberg RK, Eagleton MJ, Bena J, Kuramochi Y. Outcomes for supra-aortic branch vessel stenting in the treatment of thoracic aortic disease. J Vasc Surg 2014;60:914-20. Crossref

We present the clinical data of eight patients with genetically confirmed facioscapulohumeral muscular dystrophy type 1 (FSHD1) in Hong Kong (Table).

In June 2015, Patient 1 presented with right ptosis and bilateral sensorineural hearing loss at age 1 year. He had early-onset FSHD1 of the most severe phenotype, with early development of asymmetrical facial and upper limb weakness, significant hearing impairment requiring hearing aids, and an early need for ventilation and feeding support (Fig 1).

In May 2019, Patient 2 presented with progressive asymmetrical facial weakness with predominant upper limb girdle weakness from age 11 years (Fig 2). Magnetic resonance imaging scan was taken at age 13 years (Fig 3).

In September 2014, Patient 3 presented with upper and lower limb proximal muscle weakness from age 18 years. Magnetic resonance imaging scan was taken at age 23 years (Fig 4).

Patients 2 to 8 had insidious onset of muscle weakness during adolescence or adulthood and a slow deterioration of motor function. Asymmetrical muscle involvement was common. Three patients had their lung function assessed of whom two had a restrictive pattern suggestive of expiratory muscle weakness.

Patients 1 and 2 were referred to the neuromuscular disorder clinic of the Department of Paediatrics and Adolescent Medicine, The University of Hong Kong for diagnostic examination and testing. Patients 3 to 8 were referred to the Clinical Genetic Service of the Department of Health for genetic testing. All DNA diagnostic tests were performed overseas, either self-financed (Patients 3 to 8 with the genetic testing performed in United Kingdom) or through research collaboration with financial support from the ‘Diagnosis and therapy development of rare neurological diseases and neuromuscular diseases’ fund (Patients 1 and 2, with the genetic testing performed in The Netherlands). For these patients, the diagnosis of FSHD was confirmed by standard genetic testing using Southern blotting and hybridisation with the P13E-11 probe. Restriction enzyme digestion with EcoRI, which recognises the D4Z4 locus on chromosome 4 and 10, was applied. The EcoRI/BlnI digestion further fragments the chromosome 10 array to identify the D4Z4 arrays located on chromosome 4, and the length and number of D4Z4 units were determined.

The median age of disease onset was 14 years (range, 1-32). The male: female ratio was 3:1. The median time between onset of symptoms and genetic diagnosis in this cohort was 16 years (range, 2-44). Of the patients who required a walking stick (Patients 5 to 8), the median age at which the need arose was 47.5 years (range, 43-53). Two patients also required a wheelchair for outdoor mobility, from age 49 and 57 years. None of the patients had hearing problems.

All eight patients with FSHD1 had a significant contraction—from one to four units—of the D4Z4 repeats. There was no correlation between the number of D4Z4 units and the age of onset or clinical severity; Patients 1 and 7 both had two D4Z4 units, but age of onset differed by 30 years.

A positive family history was observed in 38% of our patients. Patients 1 and 4 inherited the autosomal dominant FSHD1 from their mildly symptomatic mother, as confirmed by genetic testing. Patient 6 inherited the condition from his father. Patient 8 passed on FSHD1 to her daughter. Clinical variability and reduced penetrance were evident.

This is the first case series of genetically confirmed FSHD1 in Hong Kong. Worldwide, FSHD (OMIM No. 158900) is the third most common form of dystrophy, with a prevalence of 1:15000 to 1:20000. It can be classified as type 1 (FSHD1) or type 2 (FSHD2). Most patients with FSHD have FSHD1 (95%) that has autosomal dominant inheritance. Up to one third of cases are caused by de novo mutations.1

Typically, FSHD presents during the second or third decade of life as asymmetrical facial weakness followed by muscle weakness around the scapula and upper arms, then truncal and lower extremity weakness. Asymmetrical muscle involvement is typical. In all, 10% to 30% of individuals eventually become non-ambulatory. Around 38% of patients develop a restrictive lung disease pattern, and 1% to 3% eventually require ventilatory support.

Early-onset FSHD accounts for 10% of total FSHD. Affected individuals typically present with facial weakness before age 5 years and shoulder girdle weakness before age 10 years. Early-onset FSHD is generally associated with fewer D4Z4 repeats and higher disease severity. Patients often present with global developmental delays, dysarthria, dysphagia, intellectual disabilities, epilepsy, cochlear dysfunction, and retinal vasculopathy.2

The genetic mechanisms of FSHD1 are complex (Fig 5). Genetic diagnosis of FSHD1 typically involves the Southern blot technique or the molecular combing technique using fluorescence in situ hybridisation.3 Presently, specific genetic testing for FSHD1 is currently unavailable in the laboratories of the public healthcare system in Hong Kong.

There are several possible reasons for the delay in diagnosis in our cases. First, the lack of patient awareness of an underlying neuromuscular disease at their initial presentation often led to delayed consultation. Second, many doctors are unfamiliar with neuromuscular diseases with consequent delayed referrals. Most importantly, publicly funded genetic diagnostic testing for FSHD1 is currently unavailable. Most patients with a clinical suspicion of FSHD cannot afford expensive overseas genetic testing to confirm their diagnosis. Some patients with FSHD simply do not have the option of diagnosis.

Early molecular diagnosis of FSHD is crucial to enable timely assessment and management, including ophthalmic and hearing assessment in early-onset FSHD; regular motor, pulmonary and neuromuscular pain evaluations, referral for an aerobic exercise programme, and surgical scapular fixation if needed. Routine cardiac screening is unnecessary in the absence of cardiac symptoms.4 Early genetic diagnosis can also help to identify other affected or asymptomatic family members. Prenatal diagnosis in pregnancies of affected individuals provides couples with informed choices. Registries for patients with FSHD have been established in different countries to facilitate recruitment for clinical studies and trials.

The landscape of clinical trials is promising. A phase 2 study of losmapimod, an oral agent that inhibits and reduces the expression of myotoxic DUX4, is currently underway.5

This study increases professional awareness of FSHD and highlights the importance of early recognition and diagnosis for this condition, as well as a current service gap in the genetic diagnosis of FSHD. Establishing a local registry will help recruit patients into clinical trials.

Concept or design: SHS Chan, WY Leung, HM Luk, V Vardhanabhuti.
Acquisition of data: All authors.
Analysis or interpretation of data: SHS Chan, WY Leung, HM Luk, V Vardhanabhuti, Yuan Gao.
Drafting of the manuscript: SHS Chan, WY Leung.
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.

The authors thank Professor Silvère M van der Maarel and Dr R Lemmers of the Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands, for their expert advice on the diagnosis of facioscapulohumeral dystrophy in the two paediatric patients. The authors also thank Ms Rachel BY Lee for editing the English in a draft of this manuscript.

This study was supported by donations from Mrs Yang to the ‘Diagnosis and therapy development of rare neurological diseases and neuromuscular diseases’ fund that provides financial support for overseas genetic testing for patients with facioscapulohumeral muscular dystrophy.

This study was approved by the Hong Kong University Institutional Review Board (Ref: UW_20-405). All patients provided verbal consent to be included in this publication. Two patients (Patients 1 and 2) and their families provided written consent for the publication of clinical photographs.

1. Sacconi S, Salviati L, Desnuelle C. Facioscapulohumeral muscular dystrophy. Biochim Biophys Acta 2015;1852:607-14.Crossref

2. Mah JK, Chen YW. A pediatric review of facioscapulohumeral muscular dystrophy. J Pediatr Neurol 2018;16:222-31. Crossref

3. Lemmers RJ, O’Shea S, Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord 2012;22:463-70. Crossref

4. Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 2015;85:357-64. Crossref

5. Michelle Mellion M. Efficacy and safety of losmapimod in subjects with facioscapulohumeral muscular dystrophy (FSHD). Available from: https://clinicaltrials.gov/ct2/show/NCT04003974. Accessed 2 Nov 2020.

In June 2008, a 9-month-old boy with unremarkable medical and developmental history presented to the emergency department with acute cyanosis. The child had been fed about 200 g of congee containing rice, vegetables, fish, and egg. He was then noted to have pallor of face and perioral cyanosis. He was conscious and irritable and reported to have vomiting. His respiratory rate was 40 breaths per minute and heart rate was 190 beats per minute. Pulse oximetry showed 90% oxygen saturation on 100% oxygen via a face mask. Physical examination was otherwise unremarkable. He was admitted to the paediatric intensive care unit. During blood sampling, his blood was noted to be chocolate brown. While on 100% oxygen, his arterial blood gas showed a pH value of 7.33, PaO₂ 51.8 kPa, PaCO₂ 4.2 kPa, and bicarbonate 17 mmol/L. Blood methaemoglobin (MetHb) level was 51%. He was treated with intravenous methylene blue 15 mg (about 1.5 mg/kg) and urine was observed to be light blue (Fig). His cyanosis resolved within 1 hour after treatment and blood oxygen saturation returned to normal without oxygen supplementation. The MetHb level dropped to 1% within 30 minutes after treatment. Mutation screen of cytochrome B5 reductase gene (CYB5R3) was negative for the patient and both parents.

A high urinary nitrate level of 315 mg/L (reference range, 41.0-55.6 mg/L) was detected. Toxicology showed high nitrate and nitrite content in the congee consumed by the infant, 150 mg/L and 47.7 mg/L, respectively. The uncooked vegetable Amaranthus remnant contained nitrate but at a safe level. Water used for cooking had come from a regular tap, not from a well that could otherwise have been a source of contamination.

The advised daily intake of nitrates and nitrites is 0 to 3.7 mg/kg and 0 to 0.07 mg/kg body weight, respectively. Our patient weighted 9.2 kg and his single-day consumption of nitrates and nitrites was 34 mg and 0.644 mg, respectively. When he consumed 200 g of congee, he consumed 31.8 mg of nitrates and 9.74 mg of nitrites in one meal. The prescribed advised daily intake is for adults; a lower limit should apply for children. The patient has been followed up for 5 years with no recurrence of methaemoglobinaemia.

In November 2018, a 50-year-old man with a history of schizophrenia was admitted following massive zopiclone overdose. He had taken more than 100 tabs of the hypnotic of 7.5 mg each. There was no evidence of carbon monoxide inhalation. His presenting symptoms were dizziness, nausea, and reduced urine output. He was noted to be cyanotic and with oxygen saturation of 85% on 100% oxygen. During blood sampling, his blood was noted to be chocolate brown. Serum MetHb level was 40.3% initially. Methylene blue 70 mg (around 1 mg/kg) as a slow intravenous bolus was administered in the emergency department and 1 hour later serum MetHb level had fallen to 19.3%. Carboxyhaemoglobin was 3.8%. He was admitted to the adult intensive care unit and received a further dose of intravenous methylene blue 70 mg. His saturation improved to 96% on pulse oximetry on oxygen supplementation at 1 litre per minute. Repeat measurement of MetHb showed it to be <0.1%. Carboxyhaemoglobin level peaked at 10% and gradually decreased. Urine was deep green in colour after methylene blue treatment. He also developed acute kidney injury (creatinine level peaked at 1239 μmol/L) that required haemodialysis and a normochromic normocytic anaemia (trough haemoglobin level 6.2 g/dL). Haptoglobin level was low, indicative of haemolytic anaemia. Although evidence of oxidative haemolysis, such as Heinz bodies, was not documented on blood film examination, zopiclone-induced oxidative stress was probably the cause of haemolysis. Renal ultrasonography showed only mild renal parenchymal disease. His condition stabilised after an 11-day stay in the intensive care unit.

To supplement the above cases, we searched through the computerised medical record system of our institution and identified all in-patients with International Classification of Diseases-9 code of 289.7, ‘Methemoglobinemia’, from January 2000 to December 2018. We identified 21 patients with acquired methaemoglobinaemia, aged 14 days to 67 years (Table). The most common cause was deliberate self-harm by overdosing with zopiclone. The most common clinical presentation was unexplained desaturation on pulse oximetry despite oxygen supplementation. Nine patients received methylene blue. One patient with coexisting glucose-6-phosphate dehydrogenase (G6PD) deficiency was given ascorbic acid. Response to methylene blue was prompt in all cases, with MetHb falling to a non-toxic level soon after treatment.

Infants or young children may be more susceptible to methaemoglobinaemia as the haemoglobin enzymes, such as cytochrome-b5 MetHB reductase, are immature. As in Case 1, nitrates in vegetables can cause methaemoglobinaemia, and this underlying cause is preventable. Nitrates are commonly found in agricultural products and well water, and can be formed by bacteria from nitrates. Home-prepared vegetables should be avoided in infants younger than 3 months of age.1 Farmers should avoid excessive use of nitrate-containing products during vegetable production, as suggested by agricultural guidelines.2 Well water should be monitored for nitrate contamination. Nitrate content can be converted to nitrite due to improper storage in a flask. Nitrate can also be reduced to nitrite by nitrate reductase intrinsic to plants or bacteria. Thus, proper washing, cooking and storage of food rich in nitrates is essential.

Medication is a main cause of acquired methaemoglobinaemia. Zopiclone overdose accounted for a significant portion in our series. As a non-benzodiazepine hypnotic, zopiclone is widely prescribed. Massive zopiclone overdose is relatively more common in Hong Kong because it can be obtained without a prescription. Intentional overdose has been reported in those attempting suicide.3 Zopiclone is known to be associated with methaemoglobinaemia especially following massive overdose, and with haemolytic anaemia and kidney injury. The elevated carboxyhaemoglobin in Case 2 was possibly endogenous due to haemolysis, as metabolism of haem via haem oxidase produces one molecule of CO per molecule of haem degraded.4

Other substances that can lead to methaemoglobinaemia include dapsone, nitrogen, and alanine. They induce oxidative stress in erythrocytes. In susceptible subjects who lack antioxidative enzymatic activity, the ferrous ion in the haem group is oxidised to a ferric state, forming MetHb that is incapable of binding oxygen. The oxygen dissociation curve is shifted to the left; oxygen desaturation, around 85%, is common in methaemoglobinaemia. The underlying mechanism is related to the absorption of light wavelengths employed by emitter and detector of the pulse oximeter.

Clinical presentations of methaemoglobinaemia include both central and peripheral cyanosis, dizziness, headache, dyspnoea, and malaise. In extreme cases, coma or death may occur if MetHb exceeds 30% to 40%. G6PD deficiency can exacerbate the methaemoglobinaemia and concomitant haemolysis. Vigilance is needed for clinical diagnosis. Unexplained cyanosis or poor oxygen saturation should prompt clinicians to consider methaemoglobinaemia. Medication and dietary histories, chemical contacts, recent medical or dental procedures and occupational exposure are conducive to diagnosis. Treatment mainly depends on the level of MetHb. For low levels, no specific treatment is needed. Methylene blue is usually indicated if MetHb exceeds 20%. It acts as a cofactor to increase erythrocyte reduction of MetHb to haemoglobin in the presence of NADPH. Therapeutic response is usually prompt. In our series, MetHb level dropped in all cases to below 20% after a single dose of methylene blue. Methylene blue should be used with caution in patients with G6PD deficiency as haemolysis can result from repeated use. An excessive cumulative dose of methylene blue can also potentially induce haemolysis. Ascorbic acid, an antioxidant, may be used as an alternative, either orally or intravenously.5 It works by scavenging free radicals and protects cells against oxidative stress, acting as a co-factor for NADP reductase and directly reducing MetHb.

In conclusion, methaemoglobinaemia can affect a wide age range of patients and be due to a variety of agents. Effective treatment exists and the response is usually satisfactory.

Concept or design: All authors.
Acquisition of data: TT Chan, RSK Chang.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: TT Chan, RSK Chang.
Critical revision 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.

The authors have no conflicts of interest to disclose.

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, and provided informed consent for all treatments and procedures. The retrospective analysis of patient data was approved by the University of Hong Kong/Hospital Authority Hong Kong West Cluster institutional review board (Ref UW 19-205) and the requirement for patient consent for publication was waived.

1. Greer FR, Shannon M, American Academy of Pediatrics Committee on Nutrition, American Academy of Pediatrics Committee on Environmental Health. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics 2005;116:784-6. Crossref

2. European Commission. Encouraging low-input farming in the EU. Available from: https://ec.europa.eu/info/food-farming-fisheries/sustainability/environmental-sustainability/low-input-farming. Accessed 8 Aug 2019.

3. Chan TY. Zopiclone induced methemoglobinemia and hemolytic anemia. Int J Clin Pharmacol Ther 2014;52:402-6. Crossref

4. Hampson NB. Carboxyhemoglobin elevation due to hemolytic anemia. J Emerg Med 2007;33:17-9. Crossref

5. Lee KW, Park SY. High-dose vitamin C as treatment of methemoglobinemia. Am J Emerg Med 2014;32:936. Crossref