The patient was the only child of a non-consanguineous Chinese couple and was born at full term by normal vaginal delivery with a birth weight of 2.85 kg. She had good past health except for admission for a reflex-anoxic attack at age 7 months. Physical examination at that time was unremarkable with normal growth parameters and normal blood pressure for her age. Investigations showed normal anion gap metabolic acidosis and hyperkalaemia with a potassium of 7.1 mmol/L but normal serum sodium and renal function. In view of the biochemical findings, the provisional diagnosis was type IV renal tubular acidosis. Fludrocortisone was started with sodium bicarbonate and furosemide and a low potassium diet commenced. However, recurrent episodes of hyperkalaemia continued despite good compliance, requiring potassium binder and medication adjustment.

In December 2019, because of the suboptimal control of hyperkalaemia, with a fluctuating potassium level of 4.5 to 6.4 mmol/L, the patient was referred to our unit at age 10 years. Her blood pressure remained normal throughout. Blood test results revealed hyperreninaemic hyperaldosteronism with elevated supine renin at 5.59 ng/mL/hr (reference: 0.15-2.33 ng/mL/hr) and elevated aldosterone at 785 pmol/L (reference: 28-444 pmol/L). Pseudohypoaldosteronism type I was suspected initially.

Trio whole exome sequencing revealed a paternally inherited novel missense change in WNK4:NM_032387.5:c.1685A>G:p.(Glu562Gly), confirming a diagnosis of pseudohypoaldosteronism type IIB. This patient was coincidentally part of a larger whole exome sequencing cohort where the study was focused on cost-effectiveness of rapid whole exome sequencing.1 The patient was treated with oral 25 mg hydrochlorothiazide once daily and remained stable with normal growth and development. The serum potassium and blood pressure were well controlled and there were no dental or renal complications on follow-up examination.

Family cascade screening revealed that her father, paternal grandmother, and paternal aunt had hyperkalaemia. All were subsequently confirmed to have the same mutation (Fig 1). Retrospectively, the father had provided a history of kidney stone, hyperkalaemia, hypercalciuria and hypertension since age 35 years. He was found to have a serum potassium level of 7 mmol/L during the cascade screening. Although asymptomatic, his electrocardiogram already showed hyperkalaemic changes with tented T waves and high blood pressure at 176/116 mmHg. He was started on hydrochlorothiazide with normalisation of both serum potassium and blood pressure a few days later. The paternal grandmother also had a history of hyperkalaemia and partially controlled hypertension. The paternal aunt was asymptomatic with good past health but was found to be hypertensive and hyperkalaemic on screening. They were also started on hydrochlorothiazide with good response.

We report a Chinese family with the rare cause of hyperkalaemia and type IV renal tubular acidosis due to an autosomal dominant condition called Pseudohypoaldosteronism type II (PHAII). Whole exome sequencing established the diagnosis in our index patient, and subsequently, other affected family members were identified through cascade family screening.

Pseudohypoaldosteronism type II, also referred to as familial hyperkalaemic hypertension, or Gordon’s syndrome, was first described in 1964.2 By 2013, around 100 to 200 individuals and families with PHAII had been reported.3 Hyperkalaemia with normal renal function is the main characteristic. Other common features include metabolic acidosis, diminished renal potassium excretion, hypercalciuria, low plasma renin/aldosterone levels and hypertension. Short stature and dental abnormalities have also been reported.4

Mutation in the gene encoding with-no-lysine kinase 4 (WNK4), one of the novel proteins involved in the pathogenesis of PHAII, was identified in our patient. Other identified genes include WNK1, kelch-like 3 and cullin 3.3 The WNK4 is one of the WNK isoforms that regulates sodium-chloride co-transporter (NCC) in the distal convoluted tubule. Without the inhibitory effect of normal WNK4, sodium and chloride reabsorption are increased via the NCC, leading to volume expansion and consequent hypertension. The NCC is more proximal to the epithelial sodium channel at the distal convoluted tubule. Excessive sodium reabsorption at NCC results in reduced sodium delivery to epithelial sodium channels for potassium secretion at Na⁺/K⁺ exchange.3 This theory explains why thiazide is effective in PHAII as it inhibits NCC. Increased intracellular sodium due to increased NCC activity will cause decreased basolateral Na⁺/Ca²⁺ exchange that may result in hypercalciuria as in the father of our index patient. It has been suggested that mutant WNK4 decreases the activity of renal outer medullary potassium channels more than wild-type WNK4. Another proposed mechanism of this Chloride Shunt Syndrome is increased chloride reabsorption through paracellular pathways due to the mutant WNK4, resulting in reduced negativity at the distal epithelial sodium channel.3 These can all lead to reduced urinary potassium excretion (Fig 2) with consequent increase in serum potassium. With increased potassium retention, the excretion of hydrogen is impaired leading to metabolic acidosis. Hypertension tends to appear later in life, in men aged 30-40 years and in women aged 40-50 years,5 but can also be absent in 20% of cases.3

In this patient, pseudohypoaldosteronism type I was initially suspected in view of the grossly elevated renin and aldosterone levels. However, the age of disease onset and normal sodium level were atypical. The elevated renin and aldosterone levels in our patient could be explained by the use of furosemide that could have resulted in hypovolaemia and thus activation of the renin-angiotensin-aldosterone-system. This made the interpretation of the biochemical picture challenging. In this regard, the use of genetic testing demonstrated superiority in guiding the diagnosis of these chronic conditions in which a classic clinical phenotype had already been modified by existing treatments.

Our case also highlights the importance of cascade family screening. The three family members were identified to have potentially life-threatening hyperkalaemia and were treated promptly based on their genetic mutation. Affected patients will continue regular follow-up with serum electrolyte and blood pressure monitoring. With specific treatment, the disease can be well-controlled. This case illustrates the importance of precision medicine, as well as its benefits of personalised and targeted interventions.

Concept or design: HY Lam, ALT Ma.
Acquisition of data: YH Chan, ALT Ma.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: HY Lam, EYH Chan.
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 genetic investigation was supported by the Health and Medical Research Fund (HMRF) by the Hong Kong Food and Health Bureau (Project Ref No: 06172806) and The Society for the Relief of Disabled Children.

The patient was treated in accordance with the tenets of the Declaration of Helsinki. The father of the patient consented verbally to publication of this case report.

1. Chung CC, Leung GK, Mak CC, et al. Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. Lancet Reg Health West Pac 2020;1:100001. Crossref

2. Paver WK, Pauline GJ. Hypertension and hyperpotassaemia without renal disease in a young male. Med J Aust 1964;2:305-6. Crossref

3. Healy JK. Pseudohypoaldosteronism type II: history, arguments, answers, and still some questions. Hypertension 2014;63:648-54. Crossref

4. Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 1986;8:93-102. Crossref

5. Farfel A, Mayan H, Melnikov S, Holtzman EJ, Pinhas-Hamiel O, Farfel Z. Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension. Nephrol Dial Transplant 2011;26:1547-53. Crossref

In October 2019, an 8-year-old girl with Diamond–Blackfan anaemia on long-term maintenance steroid therapy was admitted to a paediatric unit with meningitis. The meningitis was caused by extended spectrum beta-lactamase-producing Klebsiella pneumonia that was sensitive to meropenem but resistant to cephalosporin and penicillin group of antibiotics. She was treated with intravenous meropenem and her fever subsided.

On day 21 of meropenem treatment the patient’s fever recurred with temperature of 39.7°C and associated abdominal pain, diarrhoea, and rash (Fig 1). Physical examination revealed a generalised blanchable erythematous maculopapular rash over her face, torso, and limbs with no mucosal involvement or lymphadenopathy (Fig 2). She was tachycardic at 150 beats per minute but her blood pressure was normal. She was given fluid boluses and managed in the paediatric intensive care unit with a noradrenaline infusion (0.05 μg/kg/min), prednisolone (increased to 20 mg daily), and the addition of vancomycin.

Autoimmune disease and infection workup including serology for Epstein–Barr virus, cytomegalovirus, and human herpesvirus 6 and stool culture for ova, cysts, and parasites examination were all negative. The patient’s C-reactive protein level was 166.43 mg/L (normal range <10 mg/L) and procalcitonin was 3.63 ng/mL (normal range <0.5 ng/mL). There was evolving eosinophilia since fever recurrence. The absolute eosinophil count was elevated to 1.2×10⁹/L (18.9% of total white cell count) on the first day of fever recurrence with a peak of 1.4×10⁹/L (35.4% of total white cell count). Gamma-glutamyl transferase level was elevated (57 IU/L). Skin biopsy showed non-specific perivascular lymphocyte infiltration with no eosinophils. There was no erythema multiforme-like pattern, spongiosis, interface change or vasculitis and staining showed no fungus.

Meropenem-associated drug reaction with eosinophilia and systemic symptoms (DRESS) was suspected in view of her fever, rash, persistent eosinophilia, and deranged liver function alongside prolonged meropenem use and a negative infection workup. Meropenem was therefore stopped, and her fever subsided after 6 hours. She was also weaned off inotrope support. She remained hemodynamically stable and the rash did not worsen and gradually subsided in 48 hours. She was discharged from the paediatric intensive care unit 2 days later. There was no residual rash and eosinophil count had normalised 2 weeks after onset of DRESS symptoms.

Children with fever and rashes pose challenges in diagnosis and management. Differential diagnoses must consider “drug versus bug” scenarios.1 Drug reaction with eosinophilia and systemic symptoms is a rare reaction to certain medications and involves a widespread skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities including eosinophilia, thrombocytopenia and atypical lymphocytosis.2 Drug reaction with eosinophilia and systemic symptoms is classified as a form of severe cutaneous adverse reaction that usually develops within 6 weeks of initiation of the suspected drug.3 It may be associated with hepatitis, carditis, interstitial nephritis or interstitial pneumonitis and is potentially life-threatening with a reported mortality rate up to 10%.2 The estimated incidence of DRESS is 1 in 1000 to 1 in 10000 drug exposures and is more commonly observed in adults than children.4

The RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions) developed a scoring system in 2007 to classify patients as having no, possible, probable, or definite DRESS based on clinical features and laboratory findings.5 Our patient had a score of 3 and was classified as possible DRESS, with extreme eosinophilia, rash with >50% body surface area involvement and negative microbiological investigations. One point was deducted from the score for “rash resolution more than 15 days”. Her aminotransferase and bilirubin level remained normal throughout although gamma-glutamyl transferase was elevated. Skin biopsy revealed perivascular lymphocytosis, a commonly observed feature among patients with DRESS.5 Skin biopsy is indicated as one of the parameters in RegiSCAR if facilities are available.

Carbapenems, as members of the beta-lactam antibiotics, are reported to pose a low risk of allergic reaction or DRESS. The incidence of rash, pruritis and urticaria after use of carbapenem has been reported to be only 0.3 to 3.7%, with rash reported in only 1.4% of patients treated with meropenem.6 Early suspicion of DRESS is crucial as discontinuation of the culprit drug can prevent development of potentially life-threatening complications. This case illustrates that all sepsis symptomatology subsided in a febrile patient with rash and eosinophilia, not by adding more drugs but by considering the possibility of severe cutaneous adverse reactions and removing the culprit drug.

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 an editor of the journal, KL Hon was not involved in the peer review process. 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 and a parent provided informed consent for all treatments and procedures. Consent was obtained from the patient and her parents for publication.

1. Hon KL, Choi CL. Steven Johnson syndrome: drug or bug? Indian J Pediatr 2016;83:1508-9. Crossref

2. Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking. Clin Exp Dermatol 2011;36:6-11. Crossref

3. Adler NR, Aung AK, Ergen EN, Trubiano J, Goh MS, Phillips EJ. Recent advances in the understanding of severe cutaneous adverse reactions. Br J Dermatol 2017;177:1234-47. Crossref

4. Shiohara T, Kano Y. Drug reaction with eosinophilia and systemic symptoms (DRESS): incidence, pathogenesis and management Expert Opin Drug Saf 2017 2020;16:139-47.

5. Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013;169:1071-80. Crossref

6. Linden P. Safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem. Drug Saf 2007;30:657-68. Crossref

In March 2021, a 64-year-old man who was injured in a fall was brought to our emergency department. He had lost his balance and fallen while harvesting avocados from a tree. He reported severe right hip and right lateral chest pain and was unable to move his right hip. His vital signs were unremarkable. He held his right hip in flexion and abduction (Fig 1a). The limb was neurologically intact and good distal arterial pulses were present. Plain anteroposterior radiograph of the pelvis revealed an inferior dislocation of the femoral head (Fig 1b).

Computed tomography (CT) scan of the chest (not shown) revealed an ipsilateral nondisplaced rib (8-10) and scapular spine fractures. A CT scan of the pelvis (Fig 2) demonstrated an empty acetabulum with no associated fractures. Later, the patient was brought to the operating theatre and 0.5 mg/kg propofol and 0.5 μg/kg remifentanil administered intravenously for the first 90 s. Thereafter, further doses of both propofol 0.25 mg/kg and remifentanil 0.25 μg/kg were administered. After 3 to 4 minutes the patient was adequately sedated and pain-free.

The dislocation was reduced under sedation and fluoroscopy by manual traction in the line of deformity, initially followed by adduction of the femur, resulting in an uneventful reduction (Video 1). Fluoroscopy confirmed that the hip range of motion was safe after reduction; the hip was safe at 90° of flexion, 20° of adduction, 30° of abduction, and 30° of internal or external rotation.

After clinic follow-up the next day, the patient was discharged home and advised to remain on bed rest for 3 weeks, and to use a walker (with toe-touch weight-bearing) solely for going to the toilet.

To prevent heterotopic bone formation and thromboprophylaxis, 25-mg indomethacin orally 3 times daily and 0.4-mL enoxaparin sodium daily were prescribed for the first 2 weeks after surgery. The use of indomethacin for prophylaxis is well documented in the literature and its use to prevent heterotopic ossification following treatment for posterior hip dislocation with acetabular fractures has been reported by Mitsionis et al.1 Deep venous thrombosis has rarely been reported after an isolated hip dislocation.1 Nevertheless, indomethacin for prophylaxis was prescribed to our patient in view of the need for prolonged bed rest and his relatively advanced age.

At follow-up examination 3 weeks after reduction, the patient was able to bear weight with a mildly antalgic gait (Video 2). The observed antalgic gait prompted us to be more conservative so the patient was advised to avoid strenuous activity and to use crutches with partial weight-bearing. At the same visit, a post-reduction radiograph and CT scan was performed to rule out chip or flake fractures of the femoral head or acetabulum during reduction; if hip pain persists, a magnetic resonance imaging scan can be performed to look for evidence of a labral tear. No associated acetabular or femoral head fracture was observed (Fig 3). The patient will continue to be monitored for a year for possible aseptic necrosis and myositis ossificans.

There are two types of inferior hip dislocation: obturator and ischial. Parvaresh et al2 analysed acetabular development and concluded that between the ages of 12 and 16, the three ossification centres and triradiate cartilage are ossified in both sexes. It is realistic then to consider it an adult hip if the patient is >16 years.2 Few cases of inferior (ischial type) hip dislocation have been reported. We reviewed the English-language literature search and found only five reported cases of inferior hip dislocation in adult patients (age >16 years).3 4 5 6 7 Among them, our patient is the oldest case reported with uneventful reduction.

Traumatic hip dislocation can cause complications that include avascular necrosis (6%-27% for early closed reduction), post-traumatic osteoarthritis (17%-48%), heterotopic ossification (up to 32%),1 8 and sciatic nerve injury (approximately 10%).9 To avoid complications, early and uneventful reduction is critical. In our patient, reduction was achieved within 2 hours of initial presentation. Our patient may be the only case documented with radiographic imaging performed before and after the reduction (including CT) and video of the reduction manoeuvre and a clinical video of the patient (demonstrating the patient walking in the third week after the reduction).

Brogdon and Woolridge10 described the mechanism of ischial and obturator injury. In the ischial type, the person falls on the trunk with the hip flexed and lands on the flexed knee. The accumulated force from further flexion of the upper trunk and body weight may create the momentum to push the femoral head inferiorly through the shallow and relatively rimless inferior margin of the acetabulum. Treatment consists of closed reduction under sedation or general anaesthesia with axial traction, together with gradual extension of the femur with additional internal rotation manoeuvres.9

The common obturator type of dislocation occurs when the femur is physically abducted and twisted outwards when the patient slips or when another force is applied. If the forcible abduction and external rotation continue with flexion against the pelvis, the femur is levered anteriorly out of the acetabulum. Treatment comprises closed reduction under sedation/general anaesthesia with longitudinal traction in the direction of the femoral axis and gentle adduction and flexion of the hip with additional internal rotation manoeuvres.10

There is a strong consensus in the literature that CT examination be performed prior to reduction to assess a probable acetabular wall fracture or head split fracture of the femoral head.8 In the present case, we could not complete all markings on the CT scan because the abducted hip automatically blocked the CT platform. Fortunately, we evaluated the anterior and posterior acetabular walls and confirmed no remnants in the acetabular fossa nor any fractures on the acetabular walls. Based on the reduction and stability confirmed by physical examination after the reduction, radiographic examination after reduction and CT was postponed until 3 weeks after reduction, when the patient was allowed to fully weight bear for the first time.

Inferior hip dislocation is rare and can be successfully treated with closed reduction. Orthopaedic surgeons must be able to diagnose and optimally treat this type of dislocation. This report and videos serve as a teaching tool for this reduction manoeuvre.

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

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.

Both 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 according to the principles of the Declaration of Helsinki. The patient provided informed consent for all treatments, procedures, and consent for publication.

1. Mitsionis GI, Lykissas MG, Motsis E, et al. Surgical management of posterior hip dislocations associated with posterior wall acetabular fracture: a study with a minimum follow-up of 15 years. J Orthop Trauma 2012;26:460-5. Crossref

2. Parvaresh KC, Pennock AT, Bomar JD, Wenger DR, Upasani VV. Analysis of acetabular ossification from the triradiate cartilage and secondary centers. J Pediatr Orthop 2018;38:e145-50. Crossref

3. Kolar MK, Joseph S, McLaren A. Luxatio erecta of the hip. J Bone Joint Surg Br 2011;93:273. Crossref

4. Singh R, Sharma SC, Goel T. Traumatic inferior hip dislocation in an adult with ipsilateral trochanteric fracture. J Orthop Trauma 2006;20:220-2. Crossref

5. Walther MM, McCoin NS. Luxatio erecta of the hip. J Emerg Med 2013;44:985-6. Crossref

6. Tekin AÇ, Çabuk H, Büyükkurt CD, Dedeoğlu SS, İmren Y, Gürbüz H. Inferior hip dislocation after falling from height: a case report. Int J Surg Case Rep 2016;22:62-5. Crossref

7. Zeytin AT, Kaya S, Kaya FB, Ozcelik H. Traumatic inferior hip dislocation. J Med Cases 2015;6:238-9. Crossref

8. Yang RS, Tsuang YH, Hang YS, Liu TK. Traumatic dislocation of the hip. Clin Orthop Relat Res 1991;(265):218-27. Crossref

9. Cornwall R, Radomisli TE. Nerve injury in traumatic dislocation of the hip. Clin Orthop Relat Res 2000;(377):84-91.Crossref

10. Brogdon BG, Woolridge DA. Luxatio erecta of the hip: a critical retrospective. Skeletal Radiol 1997;26:548-52. Crossref

In October 2019, a 42-year-old pregnant woman was admitted to hospital at 35+2 weeks of gestation for an elective caesarean section because of anterior placenta praevia type I and suspected placenta accreta. She was gravida 6 and parity 3+2. Her first pregnancy in 1996 resulted in a normal vaginal delivery. The second and third pregnancies were surgically terminated in the first trimester. Fourth and fifth pregnancies resulted in a lower segment caesarean section in China due to oligohydramnios and previous caesarean section.

The patient had an uneventful antenatal course in the current pregnancy. Nonetheless ultrasound examination at 35+2 weeks of gestation revealed an anterior placenta praevia type I with the placenta’s leading-edge 2.7 cm from the os. A diagnosis of placenta accreta was made due to vascularities over the subserosal surface of the lower segment.

A classical caesarean section was performed after completing a course of antenatal corticosteroid at 36+4 weeks of gestation. Around four-fifths of the placenta separated spontaneously after 30 minutes. The placenta was trimmed away and 3 × 3 cm of anterior adherent placenta around the internal os was left in place. Active bleeding from the lower segment of the uterus and anterior placental bed was controlled with Sengstaken–Blakemore balloon tamponade (Rüsch Teleflex, Germany). Uterine artery embolisation was performed at the same operation by interventional radiologists. Total blood loss for the operation was 500 mL.

After surgery, the patient was transferred to the intensive care unit. Balloon tamponade was removed on day 1 (Fig 1). Prophylactic amoxicillin and clavulanate was administered intravenously after the operation. She complained of dysuria and developed a persistent swinging fever from day 2. Amoxicillin and clavulanate was switched to piperacillin/tazobactam on day 4 after blood and urine tests for sepsis. Culture of midstream urine showed Morganella morganii sensitive to piperacillin/tazobactam and a gram-negative bacillus. Microbiologists advised continuation of piperacillin/tazobactam for 7 to 10 days.

Examination under anaesthesia and ultrasound-guided suction evacuation were performed on day 14 due to increased per-vaginal bleeding. Intra-operatively, yellowish pus was seen leaking from the cervical os and retained product of gestation weighing 48 g was retrieved. Culture of the pus grew Escherichia coli sensitive to piperacillin/tazobactam. The patient again presented with fever postoperatively and blood culture revealed E coli septicaemia. Piperacillin/tazobactam was switched to meropenem on day 17. Blood culture sensitivity testing revealed E coli sensitive to meropenem and cefuroxime. Hence, meropenem was switched to cefuroxime. Ultrasound examination on day 24 revealed no evidence of retained product of gestation. Cefuroxime was continued for 14 days.

At 5-week follow-up examination, the patient reported a 1-week history of whitish debris in her urine, dysuria, and urinary frequency. Ultrasonography revealed incomplete emptying of the bladder with a lot of frothy shadows (Fig 2a). Urinary tract infection was suspected so amoxicillin and clavulanate and phenazopyridine were prescribed for 1 week. Culture of the midstream urine showed Candida glabrata (Fig 2b). A microbiologist was consulted and fluconazole 400 mg prescribed for 10 days.

Susceptibility testing of the C glabrata isolated from urine collected after admission was performed by using Sensititre YeastOne (TREK Diagnostic Systems, United Kingdom) and revealed a required fluconazole minimal inhibitory concentration of 16 μg/mL, confirming that it was in the susceptible-dose dependent category. However, the patient’s symptoms persisted after completing 24 days of fluconazole and ultrasound showed persistent “fungal debris” inside the bladder. She was readmitted 13 weeks after the operation for further management. Amphotericin B deoxycholate was administered intravenously for 7 days. A drug-related fever developed during the first dose but resolved after premedication with oral acetaminophen and intravenous diphenhydramine.

Flexible cystoscopy revealed necrotic tissue approximately 3 × 4 cm over the left posterior bladder wall, away from the left ureteric orifice, with an underlying ulcer (Fig 3a and b). It was removed with forceps and a basket. A fistula was suspected, and second flexible cystoscopy scheduled 2 months later. A computed tomography urogram with contrast was arranged to exclude fistula.

The second flexible cystoscopy revealed a normal bladder and a healed ulcer over the left posterior wall (Fig 3c). Computed tomography urogram showed no evidence of fistula. During postnatal follow-up, there were no urinary symptoms.

This is the first case of C glabrata cystitis as a complication in our case series of planned conservative management of placenta accreta.1 Candida species are a part of the normal flora of the gastrointestinal and vaginal tracts. The incidence of candiduria has been increasing in recent decades and the presence of C glabrata has become clinically significant due to its high resistance to routine antifungal agents. Risk factors for candiduria in our case included urinary catheterisation, intensive care unit stay, use of broad-spectrum antibiotics, female sex, and prior surgery.2

The placental remnants in our case induced infection and septicaemia. Subsequent prolonged use of broad-spectrum antibiotics predisposed our patient to fungal cystitis. There was no clinical or pathological evidence of placenta percreta. Chandraharan et al3 introduced the use of the Triple-P procedure to manage patients with morbidly adherent placenta. As the Triple-P procedure removes all intrauterine placental remnants, it may reduce the risk of intrauterine infection and sepsis. Nevertheless, there is limited surgical expertise in this procedure in our unit.

Compared with other Candida species, many C glabrata isolates are resistant to azoles due to efflux pump–mediated resistance, genetic alterations under stress and biofilm protection.4 A study in the United States revealed that 14% of C glabrata isolates were resistant to fluconazole.5

The presence of fungus ball/fungal bezoars in urinary tract infection is extremely rare in adults. According to treatment guidelines of the Infectious Diseases Society of America, removal of the obstructing mycelial mass by surgical or endoscopic means is strongly recommended.6 Although culture results revealed that the C glabrata was susceptible-dose-dependent to fluconazole, use of fluconazole alone was likely to be insufficient due to the fungal ball in the bladder. A multidisciplinary approach including microbiologists and urologists is essential.

In symptomatic Candida cystitis, first-line treatment is oral fluconazole 200 mg daily for 2 weeks. For fluconazole-resistant C glabrata, amphotericin B deoxycholate or oral flucytosine are the drugs of choice. Around 50% of patients prescribed an amphotericin B infusion experience infusion-related adverse events, such as fever, chills, rigors, hypotension, and rarely, hypokalaemia resulting in ventricular fibrillation. In addition, renal toxicity is a well-known adverse effect.5 Close monitoring of renal function and electrolytes is essential.

Placenta accreta spectrum treated conservatively by leaving the placenta in situ is a recognised and successful management option, but is associated with risks of infection or postpartum haemorrhage. Our case demonstrates that fungal infection can develop during the period of conservative management and requires multidisciplinary consultation.

Concept or design: CK Wong, WC Leung.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: CK Wong, WC Leung.
Critical revision of the manuscript for important intellectual content: All authors.

The authors have no conflicts of interest to disclose.

The authors thank interventional radiologists Dr KH Lee and Dr CW Tang for their contributions to this report.

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, provided informed consent for all treatments and procedures, and provided consent for publication.

1. Lo TK, Yung WK, Lau WL, Law B, Lau S, Leung WC. Planned conservative management of placenta accreta—experience of a regional general hospital. J Maternal Fetal Neonatal Med 2013;27:291-6. Crossref

2. Gajdács M, Dóczi I, Ábrók M, Lázár A, Burián K. Epidemiology of candiduria and Candida urinary tract infections in inpatients and outpatients: results from a 10-year retrospective survey. Cent European J Urol 2019;72:209-14.

3. Chandraharan E, Rao S, Belli A, Arulkumaran S. The Triple-P procedure as a conservative surgical alternative to peripartum hysterectomy for placenta percreta. Int J Gynecol Obstet 2012;117:191-4. Crossref

4. Rodrigues CF, Silva S, Henriques M. Candida glabrata: a review of its features and resistance. Eur J Clin Microbiol Infect Dis 2013;33:673-88. Crossref

5. Pfaller MA, Messer SA, Hollis RJ, et al. Variation in susceptibility of bloodstream isolates of Candida glabrata to fluconazole according to patient age and geographic location in the United States in 2001 to 2007. J Clin Microbiol 2009;47:3185-90. Crossref

6. Pappas PG, Kauffman CA, Andes DR, et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:409-17. Crossref

In January 2019, an 85-year-old woman with a history of osteoporosis and collapsed L1 had gastric antral vascular ectasia with multiple failed attempts of argon photo-coagulation, resulting in severe iron deficiency anaemia (haemoglobin 4 g/dL). The patient had been repeatedly admitted for congestive heart failure precipitated by anaemia that required blood transfusion. In view of her severe and ongoing blood loss, intravenous iron isomaltoside (Monofer) 800 mg monthly was started in February 2019. Before commencement of iron isomaltoside, iron saturation was 5% (normal 15%-50%). She was optimally nourished with normal serum calcium (2.27 mmol/L; normal 2.15-2.55 mmol/L), phosphate (1.4 mmol/L; normal 0.8-1.5 mmol/L), alkaline phosphatase (108 IU/L; normal 53-141 IU/L) and vitamin D level (79 nmol/L; normal 50-220 nmol/L). Hypophosphataemia (0.5 mmol/L) was first noted in June 2019 (Fig). Owing to the patient’s history of collapsed vertebra, she was given a first dose of denosumab in October 2019 by a private orthopaedic surgeon but serum phosphate further worsened to 0.1 mmol/L despite aggressive oral phosphate replacement. She refused hospital admission at this time. In December 2019, the patient was hospitalised for anaemia and hypophosphataemia (0.4 mmol/L) with concomitant serum calcium 2.07 mmol/L and alkaline phosphatase 199 IU/L. Her estimated glomerular filtration rate was >90 mL/min/1.73 m². Fractional excretion of phosphate confirmed renal phosphate wasting (FePO4 14%; normal <5%) and bicarbonate was 30 mmol/L (normal 22-26 mmol/L). Urinary protein and glucose were negative. Iron saturation was 24% and parathyroid hormone 22.6 nmol/L (normal 1.6-7.2 nmol/L). Fibroblast growth factor 23 (FGF23), measured 3 weeks after the last dose of iron isomaltoside, was 155 IU/mL (normal <188 IU/mL). Intravenous iron-induced hypophosphataemia was suspected. Iron isomaltoside was stopped and rocaltrol was commenced in January 2020 with prompt improvement in phosphate level. Another intravenous iron preparation, iron sucrose (Venofer), was started due to her severe anaemia. Attempted re-challenge with iron isomaltoside resulted in recurrent hypophosphataemia. Rocaltrol and phosphate sandoz were gradually tapered down over 6 months. Serum phosphate remained normal while on iron sucrose and denosumab.

Iron deficiency anaemia is a commonly encountered problem in daily practice. Although oral iron remains the recommended route of replacement due to its low cost and availability, intravenous iron is considered superior in several respects. First, the gastrointestinal side-effects of oral iron are avoided. Second, bioavailability is improved where that of oral iron is reduced in conditions such as achlorhydria (eg, proton pump inhibitors, gastric bypass), small bowel malabsorption (eg, inflammatory bowel disease, prior small bowel resection, celiac disease) and chronic inflammation (via upregulation of hepcidin). Third, intravenous iron allows rapid repletion of iron, making it a more suitable choice when there is severe and/or ongoing blood loss.

The new-generation intravenous iron preparations are all stable iron-carbohydrate complexes. The three commonly used intravenous iron preparations locally are iron carboxymaltose (Ferinject), iron isomaltoside (Monofer) and iron sucrose (Venofer). They differ in the attaching carbohydrate ligands that affect the capacity, stability and immunogenicity of the complex. Hypophosphataemia is a well-described complication of iron carboxymaltose but is far less common in the other two preparations: the incidence1 of hypophosphataemia is 58%, 4% and 1% for patients with preserved renal function given iron carboxymaltose, iron isomaltoside and iron sucrose, respectively. In addition, iron carboxymaltose–induced hypophosphataemia can be severe and protracted resulting in osteomalacia and multiple fractures. Although the pathogenesis2 is not fully understood, it is believed to be mediated through iron carboxymaltose–induced production of biologically active intact FGF23. The FGF23 is a phosphaturic hormone produced by osteocytes and osteoblasts. It reduces phosphate reabsorption by downregulation of sodium-phosphate co-transporter in the proximal renal tubule. The FGF23 also inhibits 1,25-dihydroxyvitamin D synthesis, leading to vitamin D deficiency and secondary hyperparathyroidism that contribute to reduced intestinal phosphate uptake and further increased renal phosphate wasting, respectively. Iron isomaltoside also increases intact FGF23 secretion, but to a much lesser extent than iron carboxymaltose.3 Again, such difference is speculated to be due to the carbohydrate ligand, since iron carboxymaltose and iron isomaltoside are equally effective in replenishing iron store. Although other indicators of proximal renal tubular dysfunction such as fractional excretion of urate and urine amino acid were not measured in this patient, the absence of glycosuria and non-suppressed FGF23 level were not typical of a diagnosis of renal Fanconi syndrome. In addition, improved serum phosphate level after stopping iron isomaltoside supported the diagnosis of iron-induced phosphaturia in this patient.

In the meta-analysis by Schaefer et al,4 low baseline iron saturation and normal renal function were identified as positive predictors of iron-induced hypophosphataemia; both were present in this patient. Severe iron deficiency may cause a higher increase in FGF23 transcription and renal impairment is protective due to intrinsic kidney resistance to FGF23. Furthermore, denosumab may have worsened the pre-existing hypophosphataemia induced by iron isomaltoside in this patient since serum phosphate level fell abruptly in October 2019, 1 week after denosumab injection. Denosumab is an anti-RANKL (receptor activator of nuclear factor-κB ligand) antibody that inhibits osteoclastic activity and hence bone resorption. Severe hypophosphataemia caused by denosumab has been described in a patient with tenofovir-induced osteomalacia5 and is possibly mediated through the following two mechanisms: first, decreased bone resorption directly reduces phosphate release; second, fall in bone-derived calcium worsens secondary hyperparathyroidism that in turn enhances phosphaturia. These may explain the profound hypophosphataemia in this patient after denosumab injection.

There are several reasons for the normal FGF23 level in this patient. First, the commercial FGF23 assay detects both intact and cleaved FGF23; an increased intact FGF23 together with a reduced cleaved FGF23 may result in a “normal” FGF23 level. Second, FGF23 may have dropped significantly 3 weeks after the last dose of iron isomaltoside. Third, FGF23 transcription was reduced with correction of iron deficiency as reflected by the normal iron saturation.

In addition to phosphate replacement and switching to a less phosphaturic intravenous iron preparation, activated vitamin D is needed to increase phosphate reabsorption during the initial phase, even in a patient with preserved renal function. This is because FGF23 inhibits renal activation of 25-dihydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D.

In conclusion, although hypophosphataemia is much less common in patients on iron isomaltoside than iron carboxymaltose, it is advisable to monitor phosphate level 1 to 2 weeks after iron isomaltoside injection in high-risk patients, such as those with severe anaemia who require repeat dosing, and patients with pre-existing vitamin D deficiency and/or hyperparathyroidism.

All authors contributed to the concept, acquisition of data, interpretation of data, drafting of the manuscript, and critical revision 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 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 provided informed consent for the treatment/procedures and publication.

1. Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens 2017;26:266-75. Crossref

2. Edmonston D, Wolf M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol 2020;16:7-19. Crossref

3. Wolf M, Rubin J, Achebe M, et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. JAMA 2020;323:432-43. Crossref

4. Schaefer B, Tobiasch M, Viveiros A, et al. Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside—a systematic review and meta-analysis. Br J Clin Pharmacol 2021;87:2256-73. Crossref

5. Chung TL, Chen NC, Chen CL. Severe hypophosphatemia induced by denosumab in a patient with osteomalacia and tenofovir disoproxil fumarate-related acquired Fanconi syndrome. Osteoporos Int 2019;30:519-23. Crossref