Primary penile tuberculosis masquerading as penile cancer: a case report

Hong Kong Med J 2023 Dec;29(6):554–5 | Epub 2 Nov 2023
https://doi.org/10.12809/hkmj2210280
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Primary penile tuberculosis masquerading as penile cancer: a case report
Ankitkumar Sharma, MS, DrNB (Urology); Deepak Velmurugan, MB, BS; Kuppurajan Narayanasamy, MS, FRCS (Urology)
Department of Urology, Kovai Medical Center and Hospital, Coimbatore, India
 
Corresponding author: Dr Ankitkumar Sharma (dr.ankitkumarsharma@gmail.com)
 
 Full paper in PDF
 
 
Case presentation
A 53-year-old man from northwest Tamil Nadu, India presented to our institution in January 2021 with a 3-month history of new-onset phimosis with swelling of the glans and an ulcer and penile discharge. The lesion presented initially with seropurulent discharge from the preputial sac. The patient later noticed some induration over the dorsal aspect that progressed further to an ulcer with frank purulent discharge. He had no family history of tuberculosis (TB) and no venereal disease or significant past surgical intervention. He had type 2 diabetes mellitus controlled by regular medication. His spouse had no significant history of pelvic inflammatory disease or secondary infertility and no present complaint of vaginal discharge, lower abdominal pain or productive cough.
 
On examination, the patient was of average built and nourishment. Vital signs were stable and examination of the respiratory, cardiovascular and gastrointestinal systems was unremarkable. Local examination of the external genitalia revealed staining of garments, phimosis, and an ulcer of 1×1 cm in size over the dorsal aspect of the penis with foul smelling purulent discharge near the corona. The glans palpable through the prepuce was hard in consistency and non-tender. The penile shaft was indurated up to the base and non-tender. There was no significant inguinal lymphadenopathy. Testes, spermatic cord and scrotum were clinically normal.
 
Blood investigations revealed haemoglobin level of 13.1 g/dL, white blood cell count of 6900/mm3, neutrophil level of 60%, platelet count of 234 000/μL, and glycated haemoglobin level of 7.8%; serology showed that human immunodeficiency virus, hepatitis B surface antigen and syphilis were non-reactive. Ultrasound of bilateral groin revealed a few inguinal nodes bilaterally, with the largest on the right measuring 8.7 mm. All nodes showed preserved fatty hilum and normal vascularity.
 
With the clinical diagnosis of localised carcinoma penis in mind, the patient was counselled about the need for intervention in the form of penile biopsy followed by total amputation of the penis with perineal urethrostomy. Under spinal anaesthesia, a dorsal slit was made in the penis that revealed penile oedema with purulent discharge from the preputial edge, multiple small granulomas and a hard and purulent cover over the glans. The glans penis was partially necrosed but the meatus was preserved. On extension of the dorsal slit to the base, the shaft was found to be covered in pus and slough with a hard consistency of the corpora cavernosa. Penile biopsy was taken from the glans and shaft. The slit cut surface was approximated at the base and haemostatic sutures placed over the glans to let the wound drain. A 16-Fr catheter was passed. Postoperatively, the patient was started on 4.5-g piperacillin sodium and tazobactam sodium via intravenous route three times a day. His postoperative course was uneventful with the wound showing purulent discharge, managed with twice daily saline dressings. The possibility of infectious origin of the disease was discussed with the patient.
 
After discussion with the pathologist, a provisional report was obtained of granulomatous inflammation with a few areas of necrosis. The need for culture and sensitivity was discussed with the patient, but due to financial constraints the patient was unwilling to proceed. He was initiated on anti-tubercular therapy as per regional antimicrobial policy. The final histopathology confirmed necrotising and granulomatous inflammation, with no acid-fast bacilli noted.
 
The patient and his partner were screened for pulmonary and genitourinary TB after the final histopathology report. The patient was discharged on postoperative day 9 with instructions to continue ATT for 6 months. He was advised to attend a local clinic for dressing changes every week until the wound had healed. The wound showed signs of healing on follow-up (Fig 1). After 6 weeks there were signs of build-up of slough. At 8 weeks, after completion of the intensive phase, the patient was referred for local surgical debridement and wound closure due to build-up of slough over the wound surface. He completed the course of ATT and the wound healed well (Fig 2). He has since developed erectile dysfunction, probably owing to secondary fibrosis of the corpora cavernosa. He does not desire treatment at this time.
 

Figure 1. Postoperative image of the patient at 2 weeks following dorsal slit and biopsy showing sloughed tissue extending to the base of penis
 

Figure 2. Intraoperative image of the patient at 8 weeks showing healthy granulation tissue following mobilisation of skin flaps of the penis
 
Discussion
Genitourinary TB is the most common form of extrapulmonary TB, but penile presentation is one of the least common forms of genitourinary TB (<1%).1 The epididymis (42%) followed by seminal vesicle (23%), prostate (21%), testis (15%) and vas deferens (12%) are common sites of presentation.2 In its primary form, local spread of bacilli from clothing, ejaculation, endometrial secretions, circumcision, and intravesical Bacillus Calmette–Guérin has been reported.2 The secondary form arises due to the subsequent complication of lung TB or TB in other parts of the urogenital tract, extending through the urethra or via a haematogenous route.
 
Tuberculosis of penis may affect the skin, glans penis or cavernous bodies. It can mimic penile carcinoma in presentation, much like our patient. Tuberculosis affecting the glans penis can present as tuberculous chancre, papulo-necrotic tuberculoid, TB cutis orificialis or tuberculous gumma. In most cases, the lesion takes the form of an ulcer that is difficult to differentiate from a malignant tumour. The lesion can be extensive, with involvement of the urethra and corpus cavernosum. Since young adults are affected, their partner should always be evaluated for genital TB.3 Although there are several tests for diagnosis of TB, biopsy remains confirmatory. Surgical management may be required in doubtful cases in spite of successful treatment with ATT. Organ sparing surgery coupled with ATT should be the goal of treatment.4
 
Our experience highlights the similarities in presentation of penile carcinoma and primary penile TB, further cementing the need for a dorsal slit prior to definitive procedure. A high index of suspicion should be maintained considering the endemic status of TB in South-East Asian countries. Biopsy should always be performed in doubtful cases.
 
Author contributions
Concept or design: A Sharma.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: A Sharma.
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient for publishing of data relevant to the case report.
 
References
1. Nimisha E, Gupta G. Penile lupus vulgaris: a rare presentation of primary cutaneous tuberculosis. Int J STD AIDS 2014;25:969-70. Crossref
2. Amir-Zargar MA, Yavangi M, Ja’fari M, Mohseni MJ. Primary tuberculosis of glans penis: a case report. Urol J 2004;1:278-9.
3. Gangalakshmi C, Sankarmahalingam. Tuberculosis of glans penis—a rare presentation. J Clin Diagn Res 2016;10:PD05-6. Crossref
4. Rajeev TP, Pranab KR, Phukan PK, Baruna SK, Das Roop R. Tuberculosis of penis mimicking an advanced penile cancer—a case report. Int J Sci Res 2018;7:16-7.

The underestimated power of cooked meat in affecting plasma creatinine level: three case reports

Hong Kong Med J 2023 Dec;29(6):551–3 | Epub 8 Dec 2023
https://doi.org/10.12809/hkmj2210271
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
The underestimated power of cooked meat in affecting plasma creatinine level: three case reports
CY So1; Toby CH Chan, MB, BS1; KY Yuet, BSc, FAACB1; Eugene YH Chan, FHKAM (Paediatrics)2; Terry TW Chow, FHKAM (Paediatrics)3; Matthew CW Yeung, MB, BS, FHKAM (Pathology)1; Alison LT Ma, FHKAM (Paediatrics), FRCPCH2; Frankie WT Cheng, FRCPCH, MD3; Chloe M Mak, PhD, MD1
1 Chemical Pathology Laboratory, Department of Pathology, Hong Kong Children’s Hospital, Hong Kong SAR, China
2 Division of Nephrology, Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong SAR, China
3 Division of Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, Hong Kong Children’s Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Chloe M Mak (makm@ha.org.hk)
 
 Full paper in PDF
 
 
Introduction
The use of plasma creatinine as biomarker for renal function is not foolproof. Pre-analytical factors such as dietary intake of cooked meat can significantly influence plasma creatinine level, giving rise to pseudo-renal failure. We report three cases of paediatric oncology patients who presented with spuriously high plasma creatinine level secondary to ingestion of a large amount of cooked meat, domestically prepared in the form of essence. The frequent occurrence of such practice is likely rooted in the traditional Chinese food culture of ingesting meat essence as a tonic.
 
Case presentations
Case 1
A drastic increase in plasma creatinine level to 206 μmol/L (reference interval [RI]: 33-59) from normal baseline was noted in a 6-year-old boy with a history of acute lymphocytic leukaemia in remission during a routine pre-clinic blood test taken at 4 pm. Urgent admission was arranged for suspected acute kidney injury (AKI). On admission, his creatinine level measured about 26 hours after the clinic visit had spontaneously normalised in the absence of any treatment. Urgent urinary system ultrasonography and other blood tests were unremarkable. Clinically, the patient was well and asymptomatic. He was discharged uneventfully.
 
Case 2
Renal function test requested as part of pre-consolidation chemotherapy assessment for a 14-year-old boy with B-cell acute lymphoblastic leukaemia showed a rise of plasma creatinine level to 125 μmol/L (RI: 45-77) from the normal baseline. Intravenous fluid was started for suspected AKI and the plasma creatinine level normalised the following morning. However, a reassessment after 3 days showed an elevated creatinine level once again. A third reassessment after 5 more days revealed a creatinine level of 110 μmol/L. The patient was admitted for intravenous rehydration with retesting the following morning showing a normal plasma creatinine level. Consolidation was eventually started 9 days later than the initial planned date. The patient remained well and asymptomatic throughout the course.
 
Case 3
A sudden increase in creatinine level (154 μmol/L, RI: 33-59) from the normal baseline was noted during a pre-clinic blood test at 1 pm in a 5-year-old girl with B-cell acute lymphoblastic leukaemia on maintenance chemotherapy. Clinically, the patient exhibited no symptoms. Subsequent blood tests at 4 pm and 3 days later showed gradual reduction of creatinine levels to 83 μmol/L and 65 μmol/L, respectively.
 
In light of this ‘outbreak’ of spuriously high creatinine level in multiple paediatric oncology patients, extensive investigations were performed on the residual samples for suspected interference. Analytical interference was excluded by dilution study, and re-analysis performed on alternative analyser platforms with the same enzymatic method and by other methods, including Jaffe and liquid chromatography–tandem mass spectrometry (Table). A normal and stable plasma cystatin C level was detected in Case 1, indicating that the actual renal function remained stable despite the rise in plasma creatinine level. Unfortunately, the residual samples D and E for Cases 2 and 3, respectively, were insufficient for cystatin C testing. The clinical status and other renal function markers of both cases had remained stable during the episode, despite the spurious transient and abrupt increase in creatinine levels. The levels also returned quickly to normal without active management. Furthermore, the creatinine increase was found to be paired with creatine increase in all three cases, up to 2 to 4 times the upper limit of normal, indicating recent creatine and creatinine loads.
 

Table. Temporal change to plasma creatinine, creatine, cystatin C, and intake of meat essence
 
Dietary history was pursued. Initially, all parents denied excessive meat, fish, or egg intake, but later disclosed habitual preparation of cooked meat in the form of essence (燉肉汁) for their child. Intriguingly, the caretakers had been frequently preparing tonic by double-boiling a large amount of pork meat in a slow cooker, a cooking method resembling that of ‘chicken essence’, a popular traditional health remedy in Asia, especially in Chinese.
 
Discussion
Renal function can be conveniently estimated by plasma creatinine level but it has its limitations that should not be overlooked. The level can be influenced by multiple patient factors such as age, sex, muscle mass, tubular secretion, and dietary intake of cooked meat.1
 
Foods rich in creatine include meat, fish, and poultry. Red meat and fish contain 4 to 10 g creatine per kilogram.2 The average daily creatine intake is estimated to be 0.54 to 0.60 g in children and 0.81 to 0.87 g in adults.2 Cooking enhances the in vitro conversion of creatine in meat to creatinine that is readily absorbed in the gastrointestinal tract. Experiments showed that a single cooked meat meal (225 g boiled beef) can lead to a sharp and transient increase in plasma creatinine, with a peak postprandial increase in adults of 52%, followed by a gradual decrease to baseline after 12 to 24 hours.3 4 This phenomenon, also known as ‘goulash effect’, may affect clinical interpretation of plasma creatinine level and the estimated glomerular filtration rate.5 6 7
 
The three paediatric cases described above demonstrated a transient exaggerated increase in creatinine following consumption of homemade meat essence. The rise in plasma creatinine level was 7.5-fold in Case 1 and mimicked a stage 3 AKI. Clinical features including normal urine output and stable haemodynamics hinted at an inaccurate estimate of renal function by plasma creatinine level. An alternative blood test that is less susceptible to interference such as cystatin C would provide comforting reassurance as illustrated in Case 1. Locally, Lee et al8 reported a case of pseudo-renal failure (creatinine level of 222 μmol/L) in a healthy 14-month-old boy secondary to consumption of domestically prepared concentrated meat broth. Aggarwal et al9 reported a case of fluctuating plasma creatinine level in a transplant recipient who consumed homemade meat soup before blood taking, hindering optimal clinical management. In this series, the caretakers had been preparing meat essence as tonics for their sick child, a healthy remedy favoured among Chinese parents. It is worth noting that this important piece of history might be missed if medical professionals do not question parents about their child’s diet. Pseudo-renal failure secondary to consumption of homemade meat essence resulted in unnecessary hospital admissions, blood taking and imaging studies, as well as a delay in scheduled chemotherapy treatment.
 
This series highlights domestic preparation of meat essence as a recurring cause of pseudo-renal failure in the local population. Medical professionals should be alert to the influence of cooked meats on plasma creatinine level. Early recognition can prevent excessive or unnecessary treatment and investigations. An alternative blood test for renal function, eg, cystatin C, should be considered in the presence of a spurious rise in plasma creatinine level. Serum cystatin C test is recently available in our laboratory in the Hong Kong Children’s Hospital. Parental advice to avoid excessive cooked meat intake prior to blood taking will also reduce future occurrence.
 
Author contributions
All 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. 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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The study was approved by the Hong Kong Children’s Hospital Research Ethics Committee (Ref No.: HKCH-REC-2021-059). The requirement for patient consent was waived by the Committee due to the retrospective nature of the study and the use of anonymised data.
 
References
1. Samra M, Abcar AC. False estimates of elevated creatinine. Perm J 2012;16:51-2. Crossref
2. Korovljev D, Todorovic N, Stajer V, Ostojic SM. Temporal trends in dietary creatine intake from 1999 to 2018: an ecological study with 89,161 participants. J Int Soc Sports Nutr 2021;18:53. Crossref
3. Mayersohn M, Conrad KA, Achari R. The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance. Br J Clin Pharmacol 1983;15:227-30. Crossref
4. Jacobsen FK, Christensen CK, Mogensen CE, Andreasen F, Heilskov NS. Pronounced increase in serum creatinine concentration after eating cooked meat. Br Med J 1979;1:1049-50. Crossref
5. Nair S, O’Brien SV, Hayden K, et al. Effect of a cooked meat meal on serum creatinine and estimated glomerular filtration rate in diabetes-related kidney disease. Diabetes Care 2014;37:483-7. Crossref
6. Pimenta E, Jensen M, Jung D, Schaumann F, Boxnick S, Truebel H. Effect of diet on serum creatinine in healthy subjects during a phase I study. J Clin Med Res 2016;8:836-9. Crossref
7. Cottrell A. Renal function. In: Probert JL, editor. Urology: an atlas of investigation and diagnosis. Oxford: Clinical Publishing; 2009.
8. Lee HC, Mak MC, Tong RC, et al. Congee: a cause of gross but transient elevation in plasma creatinine concentration. Br J Biomed Sci 2011;68:47-8. Crossref
9. Aggarwal S, Sukkar L, Wynter L, Richards K, Cheung J, Chadban SJ. Dangers of broth after transplantation. Nephrology (Carlton) 2015;20:297-9. Crossref

Tuberculosis of the knee as a great mimicker of inflammatory arthritis: a case report

Hong Kong Med J 2023 Dec;29(6):548–50 | Epub 2 Nov 2023
https://doi.org/10.12809/hkmj2210277
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Tuberculosis of the knee as a great mimicker of inflammatory arthritis: a case report
Holy MH Chan, MB, BS1; Henry Fu, MB, BS, FRCSEd (Orth)2; KY Chiu, MB, BS, FRCSEd (Orth)2
1 Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
2 Department of Orthopaedics and Traumatology, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
 
Corresponding author: Dr Henry Fu (drhfu@ortho.hku.hk)
 
 Full paper in PDF
 
 
Case presentation
In January 2015, a 36-year-old man with good past health presented to a hospital in Hong Kong with intermittent low-grade fever and left knee effusion. Physical examination revealed mild effusion, erythema, warmth and tenderness over the left knee, with 10˚ flexion contracture and flexion range up to only 70˚. The levels of inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], and antinuclear antibodies [ANA]) were elevated. Single-attempt arthrocentesis on the affected knee yielded 1 mL of yellow fluid, subsequently negative for Gram stain and culture only. No obvious abnormalities were observed on plain radiograph (Fig 1a), but magnetic resonance imaging (MRI) in June 2015 demonstrated synovial thickening, bone marrow oedema and subtle cortical erosion at the lateral femoral condyle (Fig 1b). Infection could not be excluded. Non-steroidal anti-inflammatory drugs were prescribed for symptomatic control. The recurrent left knee effusion persisted despite treatment, but no further attempts at arthrocentesis were made until 2018.
 

Figure 1. Left knee of the patient. (a) Anteroposterior plain radiograph showing no obvious arthritic changes in 2015. (b) Coronal T2-weighted magnetic resonance imaging (MRI) showing bone marrow oedema in distal femur, proximal tibia and proximal fibula (arrows), mild bony erosion in lateral femoral condyle (dashed arrow) and synovial thickening (circles) in June 2015. (c) Anteroposterior plain radiograph showing severe joint space narrowing (arrow), bone erosion (dashed arrow), and a caseating lesion (circle) in the proximal tibia in 2018. (d) Coronal and (e) sagittal T2-weighted MRI showing diffuse synovial thickening, multifocal bone erosions (dashed arrows in [d]), cartilage thinning (arrow in [e]), and joint space narrowing in 2018. (f) Anteroposterior plain radiograph 1 year post–total knee arthroplasty in September 2021
 
In view of the joint stiffness, recurrent knee effusion and persistently elevated levels of inflammatory markers, the patient was referred to a rheumatologist. A working diagnosis of atypical rheumatoid arthritis (RA) was made despite negative testing of anticyclic citrullinated peptide antibody and rheumatoid factor. Sulphasalazine was started in September 2015. Due to persistent knee inflammation, intraarticular steroid injection was given in November 2015 with limited effect. Methotrexate and leflunomide were prescribed in escalating doses. The patient was simultaneously followed up by the orthopaedic department where analgesics and physiotherapy were prescribed. Interval MRI in December 2017 showed diffuse synovial thickening, multifocal erosive changes and bone marrow oedema in the proximal tibia, reported to be in keeping with RA. Due to progressive worsening of his knee, the patient attended the private sector and was prescribed golimumab biologics in February 2018.
 
In April 2018, a cystic swelling developed over the posterolateral aspect of his left knee. Results of aspiration yielded a positive acid-fast bacilli smear and rapid cultures via Mycobacteria Growth Indicator Tube grew Mycobacterium tuberculosis. Knee X-ray revealed complete erosion of the medial and lateral tibiofemoral joints (Fig 1c) while MRI showed synovial thickening and intraosseous collection over the medial and lateral tibia (Fig 1d and e). Disease-modifying antirheumatic drugs were discontinued and the patient commenced a 9-month course of antituberculous drugs, namely isoniazid, rifampicin, ethambutol, pyrazinamide, and pyridoxine.
 
Despite eventually controlling the tuberculosis (TB), the patient’s knee function deteriorated and he was referred to a tertiary hospital for consideration of total knee arthroplasty (TKA). Preoperative assessment revealed 60˚ ankylosis of the left knee (Fig 2a) and healed sinus tracts without signs of residual infection. Preoperative investigations revealed normal ESR and CRP levels. Robotic arm–assisted TKA with varus-valgus constrained insert (Fig 1f) was performed in March 2020 and the patient was prescribed a 12-month course of antituberculous chemotherapy postoperatively. Postoperative range of motion (ROM) was 0˚ to 70˚ with 10˚ extension lag at 6 weeks due to quadriceps atrophy. Manipulation under anaesthesia was performed 3 months postoperatively to enhance flexion range. A final ROM was of 0˚ to 95˚ was achieved with no residual extension lag (Fig 2b and c). The latest follow-up 1.5 years postoperatively showed stable ROM with no signs of reinfection. The patient could walk unaided.
 

Figure 2. Clinical photos of the left knee of the patient showing (a) ankylosis at 60˚ before operation; (b) 1-year full extension after operation; and (c) 1-year flexion range of 95˚ after operation
 
Discussion
Tuberculosis of the knee is a rare form of osteoarticular TB that is prone to misdiagnosis due to its nonspecific presentation. It has an indolent course compared with bacterial septic arthritis. The clinical, radiological and laboratory features mimic inflammatory arthritis such as RA. Both diseases can present with monoarticular joint pain, erythema, swelling, and stiffness. In knee TB, the Phemister triad of juxta-articular osteopenia, joint space narrowing and peripheral bone erosions can be observed on plain radiographs, but these can also be evident in RA. Magnetic resonance imaging features of TB include multifocal bone erosions, articular surface destruction, cartilage erosions, and marrow oedema.1 Similar laboratory results include elevated white cell count (WCC) and percentage of polymorphonuclear neutrophils (PMNs) in blood and synovial fluid, and sustained elevation of ESR, CRP and anti-nuclear antibody levels due to active inflammation.
 
As in all circumstances of suspected infection, a patient’s symptoms and risk factors such as diabetes mellitus, RA and prior surgery should be assessed.2 Local skin condition, effusion and ROM should be noted on physical examination. Synovial fluid from arthrocentesis should be sent for total and differential cell counts, biochemistry, microbiology, crystals, and cytology. Total and differential counts are helpful in differentiating infective and inflammatory causes. Synovial fluid with WCC of >50 000/mm3 and PMN level of >75% point towards acute septic arthritis, while WCC of 2000 to 100 000/mm3 and PMN level of >50% suggest inflammatory arthritis.3 Nonetheless in TB, the WCC is typically in the inflammatory range of 10 000 to 20 000/mm.3 4 Joint aspirate should be sent for fungal and acid-fast bacilli smear, culture and TB–polymerase chain reaction (TB-PCR) to identify atypical organisms in refractory patients. Although the high specificity and shorter turnaround time of TB-PCR can complement cultures and help achieve an early diagnosis of TB, culture remains the gold standard to exclude TB infection due to its higher sensitivity. When synovial fluid aspirate is inadequate, repeated aspiration or even arthroscopic synovial biopsy should be considered. Autoimmune markers should be determined to exclude an autoimmune cause. Serial knee X-rays and MRIs should be taken regularly to monitor disease progression. In equivocal cases, arthroscopic synovial biopsy can be performed. A typical histological finding of caseating granuloma with lymphocytic infiltration is diagnostic of TB. Although arthrocentesis is less invasive, it has a lower diagnostic sensitivity (80%) for knee TB than synovial biopsy (90%).4
 
Tuberculosis of the knee can be managed conservatively by 12 to 18 months of antituberculous chemotherapy if identified early. With increasing joint damage, surgical intervention including debridement, synovectomy and arthroplasty might be necessary. The long disease course of joint destruction leads to fibrosis and ankylosis of the knee joint. Total knee arthroplasty is regarded as a primary treatment for advanced TB of the knee. Sultan et al5 suggest TKA be performed 1 to 5 years following eradication of TB to minimise reinfection risk. Postoperatively, 12 to 18 months of antituberculous drug therapy is believed to be highly effective in preventing recurrent infection, possibly due to the biofilm-lacking nature and poor metal adherence of TB.5
 
Robotic arm–assisted TKA with varus-valgus constrained insert was performed for our patient. The use of a constrained implant facilitated greater coronal plane stability in view of the extensive bone loss, ankylosis and ligamentous laxity secondary to prolonged TB infection. Robotic arm–assisted TKA was adopted since it enables higher accuracy in bone cutting and implant positioning than manual TKA.6 This is important for a patient receiving TKA at a young age.
 
Tuberculosis of knee is rarely documented in Hong Kong. This case highlights the importance of recognising TB as an important differential diagnosis of inflammatory arthritis. Maintaining a high index of suspicion will facilitate early diagnosis, potentially sparing the patient from joint destruction and TKA at a young age. In the event of recurrent knee effusion, synovial fluid samples should be sent for TB-PCR in addition to cell count, cytology, bacterial, acid-fast bacilli smear and cultures. Total knee arthroplasty plays a significant role in restoration of acceptable ROM in a knee with extensive bone erosion and ankylosis.
 
Author contributions
Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: HMH Chan, H Fu.
Critical revision of the manuscript for important intellectual content: H Fu, KY Chiu.
 
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and provided consent for publication of this case report.
 
References
1. Choi JA, Koh SH, Hong SH, Koh YH, Choi JY, Kang HS. Rheumatoid arthritis and tuberculous arthritis: differentiating MRI features. AJR Am J Roentgenol 2009;193:1347-53. Crossref
2. Margaretten ME, Kohlwes J, Moore D, Bent S. Does this adult patient have septic arthritis? JAMA 2007;297:1478-88. Crossref
3. Horowitz DL, Katzap E, Horowitz S, Barilla-LaBarca ML. Approach to septic arthritis. Am Fam Physician 2011;84:653-60.
4. Wallace R, Cohen AS. Tuberculous arthritis: a report of two cases with review of biopsy and synovial fluid findings. Am J Med 1976;61:277-82. Crossref
5. Sultan AA, Cantrell WA, Rose E, et al. Total knee arthroplasty in the face of a previous tuberculosis infection of the knee: what do we know in 2018? Expert Rev Med Devices 2018;15:717-24. Crossref
6. Hampp EL, Chughtai M, Scholl LY, et al. Robotic-arm assisted total knee arthroplasty demonstrated greater accuracy and precision to plan compared with manual techniques. J Knee Surg 2019;32:239-50. Crossref

Novel contrast echocardiographic features of cardiac myxoma with cystic degeneration: a case report

Hong Kong Med J 2023 Dec;29(6):545–7 | Epub 18 Dec 2023
https://doi.org/10.12809/hkmj2210246
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Novel contrast echocardiographic features of cardiac myxoma with cystic degeneration: a case report
Derek PH Lee, MB, ChB, FHKCP1; TW Ho, MB, BS2; Ivan MH Wong, MB, BS, FHKCP1; Eric CY Wong, MB, BS, FRCP1; Michael KY Lee, MB, BS, FRCP1
1 Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China
2 Department of Pathology, Queen Elizabeth Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Derek PH Lee (lph748@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
A 63-year-old lady presented to our emergency department with a 6-month history of chronic cough and progressive shortness of breath on exertion with New York Heart Association class III heart failure. She also reported episodic non-exertional chest pain and bilateral ankle swelling. On examination, she was afebrile, with blood pressure 121/77 mm Hg, heart rate 97 beats/min and respiratory rate 16 breaths/min. Cardiac examination revealed an elevated jugular venous pressure at 4 cm above the sternal notch with a right parasternal heave. A loud pulmonary second heart sound and a diastolic murmur were detected. The murmur was variable with posture and was best heard at the apex in the right lateral position on end expiration. Respiratory examination showed clear lung fields, and mild pitting ankle oedema was noted. Chest X-ray revealed enlarged bilateral pulmonary trunks. Electrocardiogram showed sinus rhythm of 94 beats/min, right axis deviation and tall right precordial R waves. Inflammatory markers were within normal range. However, levels of highly sensitive troponin I and N-terminal prohormone of brain natriuretic peptide were elevated (85 ng/L and 1786 ng/L, respectively). Bedside transthoracic echocardiography screening in the emergency department revealed a large left atrial mass. The clinical impression was pulmonary hypertension secondary to a left-sided cardiac tumour.
 
The patient had a history of left parotid pleomorphic adenoma for which she had undergone partial excision 15 years ago. She had no history of cardiopulmonary disease and no family history of cardiac tumours.
 
Differential diagnosis
The top differential diagnosis of primary cardiac tumour was cardiac myxoma but other primary malignant tumours such as sarcoma and secondary cardiac tumours were possible. Given the clinical history, absence of fever and normal inflammatory markers, an infective process was deemed unlikely.
 
Investigations
A detailed transthoracic echocardiography examination demonstrated a double-barrel–shaped left atrial mass with central echolucent space of 5.8 cm × 2.7 cm in size (Fig 1a). The mass was seen attached to a thick echogenic base at the interatrial septum and was prolapsing through the mitral valve into the left ventricle during each diastolic phase, causing a mild degree of mitral regurgitation and significant mitral inflow obstruction. The average mean gradient across the mitral valve was 15 mm Hg (Fig 1b). Bi-atrial enlargement was seen. The right ventricle was dilated with preserved systolic function. There was a significant degree of pulmonary hypertension and right ventricular systolic pressure was 87 mm Hg. Left ventricular size and systolic function were normal. A contrast echocardiographic study was performed by intravenous administration of SonoVue (Bracco Diagnostics Inc, Milan, Italy) and revealed an initial contrast enhancement at the base of the stalk (Fig 1c), followed by delayed contrast enhancement of the central echolucent space (Fig 1d and 1e) and subsequent early contrast washout prior to the cardiac chambers (Fig 1f).
 

Figure 1. Two-dimensional transthoracic echocardiographic examination of the cardiac mass of the patient. (a) Double-barrel–shaped left atrial myxoma with central echolucent space (arrow). (b) Doppler mitral inflow showing significant gradient across mitral valve. (c) Early contrast phase showing enhancement of the stalk of cardiac myxoma. (d) Delayed contrast enhancement of echolucent space. (e) Homogeneous opacification of previous echolucent space of the cardiac myxoma (arrow). (f) Early contrast washout prior to the cardiac chambers
 
Urgent in-house cardiothoracic surgical consultation was obtained and immediate open-heart excision of the cardiac tumour was performed. Intraoperative findings showed a large left atrial cystic mass with an internal solid component and wide-based stalk attaching to the interatrial septum. The mitral valve appeared normal. The left atrial mass, along with the stalk and part of the involved interatrial septum, was resected en bloc. No significant mitral regurgitation was detected with saline testing and there was no interatrial flow detected on intraoperative transoesophageal echocardiography following resection. The patient was successfully decannulated and the sternum was closed uneventfully.
 
Gross examination of the specimen showed a solid cystic tumour measuring 5.5 cm × 4.5 cm × 2.5 cm with a base measuring 2.5 cm × 1.5 cm (Fig 2a). The tumour was carefully cut open to reveal multilocular surfaces with small gelatinous semitranslucent areas. Serially sectioned specimens showed prominent cystic change with solid myxoid areas adjacent to the base (Fig 2b). Microscopic examination showed thick-walled blood vessels at the stalk of the mass (Fig 2c). The tumour cells exhibited a classic concentric arrangement around capillary and a halo of matrix around cellular clusters (Fig 2d). Sampling from the cystic area revealed morphology similar to the rest of the tumour. Immunostaining for calretinin showed positive nuclear staining in tumour cells (Fig 2e). Overall histopathological features were compatible with cardiac myxoma.
 

Figure 2. Gross (a and b) and microscopic (c to e) examination of excised cardiac mass of the patient. (a) Gross examination of intact specimen with cauterised base (arrow). (b) Serially sectioned specimen showing prominent cystic change with solid myxoid areas near the base. (c) Thick-walled blood vessels (arrow) at the base/stalk of the lesion (haematoxylin and eosin staining, ×4). (d) Tumour cells showing classic concentric arrangement around capillary (arrow) and classic ‘halo of matrix’ around cellular clusters (haematoxylin and eosin staining, ×20). (e) Immunostaining for calretinin showing positive nuclear staining in tumour cells (immunohistochemical stain with calretinin, ×4)
 
Management
The patient made an uneventful postoperative recovery and pre-discharge echocardiogram showed no residual mass, significant mitral regurgitation or pericardial effusion. She did not report any chest pain or shortness of breath. She was discharged uneventfully on postoperative day 7.
 
Follow-up
The patient was followed up in the outpatient clinic 2 months after discharge. Her exercise tolerance had improved and ankle swelling resolved. She did not complain of any chest pain or shortness of breath. Her chronic cough had subsided.
 
Discussion
Cystic degeneration of cardiac myxoma is rare. It is caused by foci of myxoma stromal liquefaction resulting in a cyst-like structure with clear fluid content. The stalk of cardiac myxoma is typically dominated by the presence of large, thick-walled and occasionally dysplastic arteries giving rise to the described ‘tumour blush’ occasionally observed at coronary angiography.1 Previous histopathological studies of cardiac myxomas have shown that these tumours produce vascular endothelial growth factor that likely induces angiogenesis for tumour growth.2 3 On microscopic tissue examination of our patient, we also found these thick-walled blood vessels at the stalk of cardiac myxoma (Fig 2c). Vascular communication between the stalk and the fluid content of cardiac myxoma with cystic degeneration has not been described before.
 
The use of contrast agent in echocardiography is particularly helpful in assessing vascular communications, vascularity of cardiac masses and to differentiate masses from intracardiac thrombi.4 Compared with contrast computed tomography, contrast echocardiography offers the advantage of capturing the extended real-time contrast enhancement sequence. To the best of our knowledge, only one case report has discussed the feature of cystic degeneration of cardiac myxoma on contrast echocardiography.5 We have described a novel feature on contrast echocardiography of cystic degeneration of myxoma: initial enhancement of the base of stalk (Fig 1c), followed by delayed contrast enhancement of the central echolucent space (Fig 1d and 1e) and early contrast washout prior to the cardiac chambers (Fig 1f). This suggested the presence of some degree of vascularity at the contrast-enhanced base of stalk with vascular communication between the stalk and the echolucent cystic space of the mass.
 
Conclusion
Left atrial tumour is a rare cause of pulmonary hypertension. Variable diastolic murmur may be detected on physical examination. Cystic degeneration of cardiac myxoma is rare with specific features on contrast echocardiography. Histopathological examination of the cardiac mass provided a histological basis for the unique contrast enhancement pattern on echocardiography.
 
Author contributions
Concept or design: DPH Lee.
Acquisition of data: All authors.
Analysis or interpretation of data: DPH Lee.
Drafting of the manuscript: 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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and has provided consent for all procedures and publication.
 
References
1. Tazelaar HD, Maleszewski JJ. Tumors of the heart and pericardium. In: Fletcher CD, author. Diagnostic histopathology of tumors. 5th ed. Philadelphia (PA): Elsevier; 2021: 13.
2. Kono T, Koide N, Hama Y, et al. Expression of vascular endothelial growth factor and angiogenesis in cardiac myxoma: a study of fifteen patients. J Thorac Cardiovasc Surg 2000;119:101-7. Crossref
3. Sakamoto H, Sakamaki T, Kanda T, et al. Vascular endothelial growth factor is an autocrine growth factor for cardiac myxoma cells. Circ J 2004;68:488-93. Crossref
4. Lanzoni L, Bonapace S, Dugo C, et al. Cardiac masses and contrast echocardiography. Eur Heart J Cardiovasc Imaging 2022;23 (Suppl 1):jeab289.296. Crossref
5. Yousaf H, Patel M, Khandheria BK, et al. Myxoma blush with contrast echocardiography. Int J Cardiol 2013;166:e1-2. Crossref

Occult intravascular large B-cell lymphoma presenting as postoperative thrombotic microangiopathy: a case report

Hong Kong Med J 2023 Oct;29(5):462–5 | Epub 26 Jul 2023
https://doi.org/10.12809/hkmj2210171
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Occult intravascular large B-cell lymphoma presenting as postoperative thrombotic microangiopathy: a case report
WK Lam, MB, BS1; Edmond SK Ma, FHKCPath, MD2; SY Kong, FHKCP, FHKAM (Medicine)3; SF Yip, FHKCPath, FHKCP1
1 Department of Clinical Pathology, Tuen Mun Hospital, Hong Kong SAR, China
2 Clinical Laboratory, Hong Kong Sanatorium & Hospital, Hong Kong SAR, China
3 Department of Medicine and Geriatrics, Pok Oi Hospital, Hong Kong SAR, China
 
Corresponding author: Dr WK Lam (lwk936@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentation
In August 2017, a 59-year-old male with good past health was admitted via the emergency department with a 4-day history of abdominal distension and epigastric pain. He had passed no stool for 2 days. Physical examination revealed epigastric tenderness and an empty rectum. Abdominal X-ray showed intestinal obstruction and erect chest X-ray showed no free gas under the diaphragm. Blood tests on admission revealed a normal complete blood count and acute renal failure (Table). The patient was started on intravenous (IV) fluid and IV amoxicillin and clavulanate. Urgent computed tomography (CT) abdomen and pelvis with contrast showed acute appendicitis with perforation and dilated small bowel without an obvious transition point. Emergency laparotomy revealed appendiceal diverticulitis with walled-off localised abscess formation around the appendix. The base of the appendix was healthy. Microscopic examination of the appendix showed dense mixed inflammatory cell infiltration in periappendiceal fat and serositis, with no evidence of malignancy, thrombosis or ischaemia.
 

Table. Laboratory findings of the patient during the episode
 
Three days postoperatively, the patient developed fever and hypotension and was given IV piperacillin and tazobactam. There was no organomegaly, lymphadenopathy or skin lesions on physical examination. He became dull looking but there was no focal neurological deficit. Septic workups with blood and urine were negative. Sputum culture showed Enterobacter cloacae, resistant to amoxicillin and clavulanate. Widal test, Weil–Felix test, human immunodeficiency virus serology and tests for viral hepatitis were all negative. A second abdomen CT showed no gross infective foci and only a few subcentimetre lymph nodes. Plain brain CT showed no focal intracranial lesions. Blood tests showed a leukoerythroblastic blood picture and no circulating abnormal cells, and acute hepatic and renal failure with markedly elevated lactate dehydrogenase level (Table). Fever did not abate despite IV piperacillin and tazobactam, IV meropenem and IV anidulafungin were prescribed for support. In the second week postoperatively, blood tests showed progressive anaemia and thrombocytopenia with microangiopathic haemolytic anaemia (MAHA) and a leukoerythroblastic blood picture (Table and Fig a). Ferritin and triglyceride levels were markedly elevated.
 

Figure. Peripheral blood and bone marrow aspirate, trephine biopsy and immunohistochemistry findings in the patient. Peripheral blood ([a], May-Grünwald stain ×200) shows microangiopathic haemolytic anaemia with many schistocytes (black arrows), prominent polychromasia, and nucleated red blood cells (arrowhead). Bone marrow aspirate ([b] & [c], May-Grünwald stain ×400) shows many large pleomorphic lymphoid cells with irregular to grossly bizarre nuclear configuration, coarse chromatin, prominent nucleoli, and moderate to large amount of basophilic cytoplasm (red arrows in [b]). Some haemophagocytic figures mostly engulfing erythroid precursors are evident (blue arrow in [c]). Trephine biopsy ([d], haematoxylin and eosin stain ×400) shows clusters of pleomorphic large cells with irregular and bizarre nuclear configuration, mildly condensed chromatin and prominent nucleoli are enclosed by the sinusoidal endothelial cells (arrowheads). Immunohistochemical staining ([e], ×200) for the marker cluster of differentiation 20 highlights the focal linear filing and intrasinusoidal clusters of large B-cells
 
Bone marrow biopsy was subsequently performed and revealed many abnormal pleomorphic large cells and haemophagocytosis (Fig). In view of the fever of unknown origin, cytopenia, hypertriglyceridaemia, markedly elevated ferritin and haemophagocytosis in the bone marrow, a diagnosis was reached of haemophagocytic lymphohistiocytosis (HLH) and dexamethasone 15 mg daily orally and IV immunoglobulin started. Trephine biopsy showed prominent infiltration of pleomorphic large cells in focal linear profiling and intrasinusoidal clusters. With immunohistochemistry, the large cells were shown to be positive for the markers cluster of differentiation (CD20) [Fig e], CD30, CD5, and negative for activin receptor-like kinase 1 and cyclin D1. Epstein-Barr virus–encoded small RNA in situ hybridisation was negative. A diagnosis was made of intravascular large B-cell lymphoma (IVLBCL).
 
The ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, antigen and autoantibody assays were performed. There was severe reduction in ADAMTS13 activity to 5% with ADAMTS13 antigen level moderately reduced to 215 ng/mL (reference range: 430-970) and autoantibody level at 2.5 units/mL (negative: <15). This confirmed ADAMTS13 deficiency and functional defect compatible with the picture of malignancy-associated thrombotic thrombocytopenic purpura (TTP). The patient was prescribed immunochemotherapy with rituximab (recombinant anti-CD20), cyclophosphamide, vincristine and prednisolone, and rasburicase for prophylaxis of tumour lysis syndrome. Hydroxydaunorubicin was added in the second cycle of immunochemotherapy (R-CHOP, ie, a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) after which blood counts and liver and renal function test results markedly improved (Table). The patient was in complete remission after six cycles of R-CHOP. Nonetheless he died of inoperable squamous cell carcinoma of oesophagus 3 years after the diagnosis of lymphoma.
 
Discussion
Intravascular large B-cell lymphoma is a rare subtype of extranodal large B-cell lymphoma characterised by selective growth of neoplastic cells inside the lumina of small- and medium-sized vessels, often with an aggressive clinical course. There are two major patterns of clinical presentation: the classic form with neurocutaneous involvement and the haemophagocytic syndrome–associated form with multiorgan failure, hepatosplenomegaly, and pancytopenia. Diagnosis of IVLBCL is challenging due to its variable presentation. Imaging may be negative due to the lack of detectable tumour masses.
 
The initial presentation of this patient was atypical, with appendiceal diverticulitis and perforation. Review of the appendix specimen confirmed the absence of lymphoma involvement. There was no hepatosplenomegaly. The abrupt onset of anaemia and thrombocytopenia with MAHA raised the possibility of postoperative TTP. Patients with postoperative TTP characteristically have a normal complete blood count prior to surgery, but subsequently show MAHA with thrombocytopenia about 5 to 9 days after surgery.1 Fever, renal impairment, and neurological symptoms are variably present. Nonetheless the abundance of schistocytes and nucleated red cells in the blood film and acute liver failure did not support a diagnosis of postoperative TTP, warranting further investigations.
 
Neoplastic cells may cause endothelial damage and result in release of ultra-large von Willebrand factor multimers. Autoantibodies against ADAMTS13 may also play a role in pathogenesis, leading to platelet activation and thrombotic microangiopathy.2 In our case, ADAMTS13 activity was markedly reduced at 5%, unusually low for malignancy-associated TTP (median ADAMTS13 activity: 50%).3 Some secondary TTP cases have been reported with markedly reduced ADAMTS13 activity4 but the significance is uncertain. The ADAMTS13 activity was also disproportionately lower than the antigen level, indicating a functional defect that may be seen in acquired TTP. Negative autoantibody against ADAMTS13 suggests against a diagnosis of idiopathic TTP. Distinguishing malignancy-associated TTP from idiopathic or postoperative TTP is important since therapeutic plasma exchange is effective in idiopathic or postoperative TTP but not in malignancy-associated TTP.
 
Although the anaemia and thrombocytopenia could be explained by the MAHA, hyperferritinaemia, hypertriglyceridaemia and haemophagocytosis in bone marrow were compatible with HLH. Of note, the current diagnostic criteria for HLH were originally proposed for diagnosis in paediatric patients.5 Criteria cut-offs such as a ferritin level >500 ng/mL may not be applicable in adults where there are many other reasons for such a high level. Bone marrow biopsy is the preferred investigation in the diagnosis of HLH and IVLBCL. A high index of suspicion should be maintained since the peripheral blood may not show abnormalities specific to these diagnoses.
 
Author contributions
Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: WK Lam.
Critical revision of the manuscript for important intellectual content: WK Lam, ESK Ma, SF Yip.
 
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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and has provided informed consent for all treatments and procedures, and consent for publication.
 
References
1. Eskazan AE, Buyuktas D, Soysal T. Postoperative thrombotic thrombocytopenic purpura. Surg Today 2015;45:8-16. Crossref
2. Sill H, Höfler G, Kaufmann P, et al. Angiotropic large cell lymphoma presenting as thrombotic microangiopathy (thrombotic thrombocytopenic purpura). Cancer 1995;75:1167-70. Crossref
3. George JN. Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia. Oncology (Williston Park) 2011;25:908-14.
4. Hassan S, Westwood JP, Ellis D, et al. The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry. Br J Haematol 2015;171:830-5. Crossref
5. 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

Ultrasound-guided spinal anaesthesia in a patient with achondroplastic dwarfism and scoliosis: a case report

Hong Kong Med J 2023 Oct;29(5):459–61 | Epub 19 Sep 2023
https://doi.org/10.12809/hkmj2210169
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Ultrasound-guided spinal anaesthesia in a patient with achondroplastic dwarfism and scoliosis: a case report
Banu Kilicaslan, MD
Department of Anesthesiology and Reanimation, Faculty of Medicine, Hacettepe University, Ankara, Turkey
 
Corresponding author: Dr Banu Kilicaslan (banuk9oct@gmail.com)
 
 Full paper in PDF
 
 
Case presentation
In February 2019, a 27-year-old woman who was classified as American Society of Anesthesiologists class III and 8 weeks pregnant presented for elective therapeutic curettage and tubal ligation. She was 110 cm tall and weighed 30 kg. Her medical history was notable for thoracolumbar kyphoscoliosis, congenital dwarfism, and restrictive lung disease. The patient’s medical history revealed that her previous two pregnancies were terminated due to shortness of breathing, reduced exercise tolerance, and the possibility that progressing pregnancy might create a life-threatening condition, first one in the 17th week and the other one in the 22nd week of pregnancy. Her airway assessment was normal but pulmonary function testing revealed a restrictive lung disease. Ultrasound-guided spinal anaesthesia was planned.
 
In the operating room, after standard monitorisation, she was placed in a sitting position. The midline of the spines and intervertebral disc space were impossible to palpate because of the severely rotated lumbar spines by marked scoliosis. Preprocedural ultrasound scan using curved array probe 2-5 MHz with LOGIQ e R7 ultrasound system (GE HealthCare, Washington DC, United States) for marking of insertion site were conducted in both paramedian longitudinal and transverse planes at different intervertebral levels.
 
In the scanning of the paramedian longitudinal plane, the transducer was placed over the lumbosacral spine approximately 2 cm lateral to the midline in a cephalad-caudad direction to find the appropriate lumbar interlaminar spaces (the ligamentum flavum–dura mater complex and posterior face of the vertebral body). The L2-L3 to L4-L5 interlaminar spaces were identified. In the transverse plane scanning, deeper structures were visible between the spinous process. In this view, the presence of bilateral transverse processes in the same plane was the clue for the correct intervertebral space. In this space, the vertebral column did not rotate due to scoliosis and was the most suitable intervertebral space for the needle puncture. The depth of the dorsal dura from the skin was measured as 3.73 cm in transverse view (Fig 1). The appropriate intervertebral space (L2-L3) was determined to be 2 cm laterally away to the right of the expected spinal midline as the intersection point of the line obtained from the paramedian longitudinal image and the line obtained from the transverse image (Fig 2).
 

Figure 1. Ultrasound image in the transverse plane showing the L2-L3 intervertebral space and depth of the dorsal dura from the skin
 

Figure 2. Puncture point of lumbar puncture (red four-point star) from the posterior view of the patient, which is determined as 2 cm laterally away to the right of the expected spinal midline as the intersection point of the line obtained from the paramedian longitudinal image and the line obtained from the transverse image
 
After aseptic precautions, spinal anaesthesia was performed by using 5-mg 0.5% hyperbaric bupivacaine, with 10-μg fentanyl (1.2 mL in volume) at the L2-L3 interspace without any complications. The sensorial block was achieved up to the T4 dermatome level bilaterally and the patient was sedated with dexmedetomidine (200 mcg/2 mL). Motor functions regressed to her basal level 4 hours after the initial intrathecal injection and the sensory component of the block returned by 5 hours.
 
The patient was discharged on postoperative day 2 uneventfully without postdural puncture headache and back pain. A follow-up 1 month after the surgery showed no further deterioration in her neurological condition.
 
Discussion
This case illustrates two important points. First, the transverse plane image shows the rotation point of the vertebral column better than the longitudinal plane; thus, this makes it easier to decide on the most appropriate intervertebral puncture point in the placement of a spinal block in a patient with abnormal spinal anatomy. Second, this case highlights the value of a systematic approach and an individual risk-benefit ratio on a case-by-case basis when performing neuraxial anaesthesia in patients with severe scoliosis and dwarfism.
 
Shiang et al1 demonstrated that nearly all cases of achondroplasia are autosomal dominant and most of those with achondroplasia will have a normal or near-normal life expectancy. Therefore, they may live long enough to experience anaesthesia for various reasons. Clinical features that may be important for anaesthesia management are midfacial abnormality, craniocervical constriction, thoracolumbar kyphosis, lumbosacral spinal stenosis, and cardiac and pulmonary abnormalities.
 
The patient whom we have described with achondroplastic dwarfism resulting severe in scoliosis and moderate restrictive lung disease had a potential risk for general anaesthesia due to instability of the cervical spine, limited respiratory reserve, and predisposition to the risk of malignant hyperthermia. On the other hand, scoliosis and spinal stenosis might further complicate patient management with neuraxial anaesthesia technique.2 In our case, the patient’s previous two pregnancies were terminated without using any anaesthetic methods. The terminations were performed by medical abortus (200 mcg oral and vaginal misoprostol) with intramuscular meperidine analgesia. For the intervention in our case, spinal anaesthesia was planned after mutual consent had been achieved with the patient and the medical team. Because of spinal deformity of the patient, spinal anaesthesia was predicted to be challenging even with ultrasound assistance.2 3
 
The drug and the dosage choice for spinal anaesthesia in achondroplastic patients with severe scoliosis may be of concern, as an unpredictable spread of drug may contribute to a high blockade that could be catastrophic in patients with a difficult airway and limited pulmonary reserve. It has been reported that a satisfactory block level was obtained with an administration of 0.06 mg/cm height of intrathecal bupivacaine.4 In the present case, as the height of the patient was 110 cm and the body mass index was 24.8 kg/m2, 5-mg bupivacaine and 10-μg fentanyl (1.2 mL in volume) were administered intrathecally, and a T4-level block was obtained. For local anaesthetic for spinal anaesthesia in these patients, we do not recommend dosages >0.06 mg/cm height to avoid complications caused by abnormal block levels.
 
In our patient in whom we had predicted difficult spinal anaesthesia, we preferred to use ultrasound before the procedure for landmark identification. Numerous reports indicate that this application facilitates technical performance in obstetric and paediatric patients and in patients with difficult spinal anatomy.5 However, real-time ultrasound guidance may provide additional advantages by taking into account the positional changes of the patient during the procedure. Ravi et al6 compared the efficacy of real‑time ultrasound‑guided paramedian approach and preprocedural ultrasound landmark‑guided paramedian approach in obese patients. They determined that the time taken for the identification of the space and for successful lumbar puncture, and the number of attempts and passes was more in the latter group as compared to the former group.6 Although it is not technically difficult to recognise spinal spaces with real-time ultrasonography, the success rates for spinal anaesthesia were similar for both techniques.6 Real-time ultrasonography may be a better alternative as it can show all structures that cannot be observed during the procedure with ‘pre-procedural ultrasonography’.
 
An experienced practitioner can achieve >90% success rate in identifying the epidural space in difficult situations using ultrasonography, as in the current patient with difficult spinal anatomy.5 In our experience, a single screening method of ultrasound imaging in the transverse plane gives working knowledge about the anatomical structures. Thus, the asymmetry of structures on the two sides of the spinal canal, mainly the articular and the transverse processes in the interspace, can be used as a guide to determine the level of the rotation on the spinal column. In our patient, no anatomical landmarks were identifiable, and it was impossible to detect the level of rotation of scoliosis. By using ultrasound, we precisely determined the L2-L3 intervertebral space available for the placement of spinal block and also the depth of the dorsal dura from the skin that was measured as 3.73 cm in the transverse view.
 
In conclusion, ultrasound-guided spinal anaesthesia is feasible and can greatly facilitate a spinal technique, especially in the transverse plane, in the presence of severe scoliosis with achondroplastic dwarfism.
 
Author contributions
The author 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. The author had full access to the data, contributed to the study, approved the final version for publication, and takes responsibility for its accuracy and integrity.
 
Conflicts of interest
The author declares no conflicts of interest.
 
Acknowledgement
The author thanks Dr Coskun Salman and his team at the Department of Obstetrics and Gynecology, Hacettepe University for their sincere support of taking care of the patient during and after the operation.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and has provided informed consent for the publication of the report along with the data, radiological images, and photographs.
 
References
1. Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78:335-42. Crossref
2. Mikhael H, Vadivelu N, Braveman F. Safety of spinal anesthesia in a patient with achondroplasia for cesarean section. Curr Drug Saf 2011;6:130-1. Crossref
3. Lange EM, Toledo P, Stariha J, Nixon HC. Anesthetic management for cesarean delivery in parturients with a diagnosis of dwarfism. Can J Anaesth 2016;63:945-51. Crossref
4. Samra T, Sharma S. Estimation of the dose of hyperbaric bupivacaine for spinal anaesthesia for emergency caesarean section in an achondroplastic dwarf. Indian J Anaesth 2010;54:481-2. Crossref
5. Perlas A, Chaparro LE, Chin KJ. Lumbar neuraxial ultrasound for spinal and epidural anesthesia: a systematic review and meta-analysis. Reg Anesth Pain Med 2016;41:251-60. Crossref
6. Ravi PR, Naik S, Joshi MC, Singh S. Real-time ultrasound-guided spinal anaesthesia vs pre-procedural ultrasound-guided spinal anaesthesia in obese patients. Indian J Anaesth 2021;65:356-61. Crossref

Surgical correction of persistent eyelid lymphoedema after radiotherapy: four case reports

Hong Kong Med J 2023 Oct;29(5):456–8 | Epub 2 Aug 2023
https://doi.org/10.12809/hkmj2110011
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Surgical correction of persistent eyelid lymphoedema after radiotherapy: four case reports
HY Chan, MB, BS, MRCSEd1; Leo KY Chan, MB, ChB, MSc2; Tracy YT Kwok, FCOphthHK, FHKAM2; Hunter KL Yuen, FRCSEd, FRCOphth (UK)2
1 Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong SAR, China
2 Department of Ophthalmology, Hong Kong Eye Hospital, Hong Kong SAR, China
 
Corresponding author: Dr HY Chan (chy896@ha.org.hk)
 
 Full paper in PDF
 
 
Case presentations
Case 1
A 40-year-old man presented with right upper lid swelling for several months. There was no pain or redness. He had received radiotherapy for nasopharyngeal carcinoma 12 years ago. The swelling did not respond to antibiotics nor non-steroidal anti-inflammatory medication. On examination, there was mechanical ptosis and loss of skin crease. The marginal reflex distance, palpebral fissure height (PFH), and levator function on the right eye were 2 mm, 8 mm, and 8 mm, respectively. Extraocular movement was normal and there was no proptosis (Fig 1a).
 

Figure 1. Case 1. (a) Right upper lid lymphoedema with mechanical partial ptosis and loss of skin crease. (b) Postoperative picture following right upper lid blepharoplasty, levator resection, biopsy, and lid crease formation. There was reduced swelling, improved partial ptosis, and restoration of lid crease
 
The diagnosis was periocular lymphoedema affecting mainly the right upper lid. He underwent right upper lid blepharoplasty, levator resection with biopsy, debulking of orbital septum, preseptal tissues and preaponeurotic fat pad, and lid crease formation under local anaesthesia. Histological examination revealed skin, adipose tissue and fibrovascular tissue with no evidence of malignancy. Postoperatively, there was significant improvement in symptoms and cosmesis (Fig 1b) and no recurrence after 9 months.
 
Case 2
A 57-year-old woman underwent left hemiglossectomy and adjuvant radiotherapy for carcinoma of tongue. She presented with gradual swelling of the left upper lid causing visual obstruction. Examination revealed left upper lid swelling with secondary mechanical ptosis (Fig 2a). Her marginal reflex distance PFH, and levator function on the left eye were 0 mm, 4 mm, and 9 mm, respectively. There was also left hemifacial swelling. Visual acuity, intraocular pressure, fundal and pupil examination, and extraocular movement were all normal. There were no signs of recurrent carcinoma of tongue and no palpable cervical lymph nodes.
 

Figure 2. Case 2. (a) Left upper lid and left hemifacial swelling. There was mechanical partial ptosis, loss of lid crease, and no signs of inflammation. (b) Postoperative picture showing resolved lid swelling, improved ptosis, and reformation of lid crease
 
Similar to Case 1, surgical correction of eyelid lymphoedema was performed. Postoperatively, lid swelling resolved with reformation of lid crease (Fig 2b). The patient remained well 4 years after the surgery with no recurrence.
 
Case 3
A 71-year-old man received radiotherapy for nasopharyngeal carcinoma in 1982. He presented with persistent non-pitting left upper lid swelling for 20 years. Incisional biopsy performed in 2004 revealed non-specific changes with no malignant cells. Additional eyelid surgery was offered but the patient opted for conservative management. Interval computed tomography imaging showed left eyelid swelling with no retrobulbar mass, and rectus muscles were not thickened. Examination revealed left upper lid swelling with secondary mechanical ptosis and loss of lid crease. Marginal reflex distance, PFH, and levator function on the left eye were 0 mm, 1 mm, and 5 mm, respectively. Extraocular movement and other physical examinations were normal.
 
Due to persistent symptoms, the patient elected surgical correction of eyelid lymphoedema. Biopsy showed no signs of malignancy. Postoperatively, left upper lid swelling resolved. The patient remained well 3 years postoperatively with no recurrence.
 
Case 4
A 65-year-old woman presented with persistent right upper lid swelling in 2008. She had a history of nasopharyngeal carcinoma (T2N2M0) treated with radiotherapy in 1995. There was non-pitting oedema of the right upper lid. Liver and renal function tests were normal. She had no oedema in her extremities or elsewhere.
 
Computed tomography of the orbits showed smooth soft tissue oedema of the right upper lid with no abnormal mass. Cavernous sinuses were normal. Patchy sclerosis in the skull base was present and thought to represent post-radiotherapy changes.
 
Right upper lid blepharoplasty had been performed elsewhere in March 2009, where excessive and thickened skin was excised together with hypertrophic orbicularis muscles. The orbital septum was kept intact with preservation of the preaponeurotic fat pad. A similar repeat procedure was performed 4 months later by the same surgeon for persistent symptoms.
 
In 2019, the patient presented to us with residual bilateral upper lid oedema. Palpebral fissure height was 5 mm on the right eye and 6 mm on the left. Marginal reflex distance was 0 mm on the right eye and 1 mm on the left. Levator function was 9 mm on both eyes. There was secondary mechanical partial ptosis, loss of lid crease, and facial lymphoedema.
 
Surgical correction of eyelid lymphoedema was performed. Histological examination was compatible with lymphoedema. The patient recovered well postoperatively and there was no recurrence 6 months after surgery.
 
Discussion
There are only a few reports of eyelid lymphoedema following neck dissection, surgery or radiation.1 2 3 As none of our cases underwent neck dissection, we hypothesise that radiotherapy alone can impede lymphatic drainage with consequent periocular lymphoedema. In this series, eyelid lymphoedema was frequently related to nasopharyngeal carcinoma, unlike other series.
 
Eyelid lymphoedema presents as a non-pitting oedema with thickening of the eyelid. In cases with severe swelling, visual field defect and disfigurement may occur.
 
Rosacea is the most reported eyelid lymphoedema association, albeit rare. More common presentations are blepharitis, conjunctivitis, and meibomianitis.3 4 5 6 7
 
Lymphoedema can usually be managed conservatively with manual drainage, compression garments, and skin care.8 Medical therapy with tetracycline and steroids have limited efficacy.4 5 7 Surgical treatment by debulking and split thickness skin grafting has been reported with favourable results.3 4 9 Lymphovenous anastomosis or bypass is also performed to divert lymphatic drainage to venous circulation.10 Nonetheless this is difficult in the periocular region where a lack of large superficial veins may result in an unsightly facial scar. Therefore, surgical debulking may remain the treatment of choice.
 
For surgical debulking, excessive skin and orbicularis should be addressed. Orbital septum debulking is essential since fluid tends to accumulate in this loose connective tissue. Debulking of the preaponeurotic fat pad can reduce upper lid swelling and enhance formation of skin crease. In our fourth case without such debulking, there was residual swelling. We addressed this in her last surgery resulting in marked improvement. In all four cases, there was no recurrence as the loose connective tissue was removed with orbital septum and preaponeurotic fat pad debulking. Levator resection should be performed in cases with long-standing oedema and levator muscle dysfunction. Skin crease forming sutures are placed for symmetry with the opposite eye, noting that Asian patients have thicker skin and orbicularis muscle, affecting skin crease formation and margin reflex distance. We prefer an incision 1 to 2 mm lower than the opposite normal side for better symmetry. Although surgery can improve eyelid oedema, patients should be informed that abnormal-appearing skin will persist. The longevity of improvement may be enhanced with presence of scar tissue making oedematous fluid less likely to accumulate.
 
Author contributions
Concept or design: All authors.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: HY Chan, HKL Yuen.
 
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.
 
Conflicts of interest
As an editor of the journal, HKL Yuen was not involved in the peer review process. Other authors have disclosed no conflicts of interest.
 
Declaration
Case 2 in this study has been previously published in part in: Yuen KLH, Kwok YT. Surgical management of unusual eyelid swelling. iPlastics: official newsletter of the Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery: 2016; 2(4): 4-6. Permission from the newsletter editor for publication of the case has been obtained. The authors confirm that there is no intentional or unintentional plagiarism in the present manuscript.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
This study was conducted in accordance with the Declaration of Helsinki. All patients were informed of the purpose of the study and their consent was obtained for all treatments, procedures, photography, and publication.
 
References
1. Sagili S, Selva D, Malhotra R. Eyelid lymphedema following neck dissection and radiotherapy. Ophthalmic Plast Reconstr Surg 2013;29:e146-9. Crossref
2. Possin ME, Burkat CN. Severe symmetric and chronic lower eyelid lymphedema in the setting of neck surgery and psoriasis. Open J Ophthalmol 2012;2:103-9. Crossref
3. Chalasani R, McNab A. Chronic lymphedema of the eyelid: case series. Orbit 2010;29:222-6. Crossref
4. Bernardini FP, Kersten RC, Khouri LM, Moin M, Kulwin DR, Mutasim DF. Chronic eyelid lymphedema and acne rosacea. Report of two cases. Ophthalmology 2000;107:2220-3. Crossref
5. Carruth BP, Meyer DR, Wladis EJ, et al. Extreme eyelid lymphedema associated with rosacea (Morbihan disease): case series, literature review, and therapeutic considerations. Ophthalmic Plast Reconstr Surg 2017;33(3S Suppl 1):S34-8. Crossref
6. Marzano A, Vezzoli P, Alessi E. Elephantoid oedema of the eyelids. J Eur Acad Dermatol Venereol 2004;18:459-62. Crossref
7. Lai TF, Leibovitch I, James C, Huilgol SC, Selva D. Rosacea lymphoedema of the eyelid. Acta Ophthalmol Scand 2004;82:765-7. Crossref
8. Mayrovitz HN. The standard of care for lymphedema: current concepts and physiological considerations. Lymphat Res Biol 2009;7:101-8. Crossref
9. Kabir SM, Raurell A, Ramakrishnan V. Lymphoedema of the eyelids. Br J Plast Surg 2002;55:153-4. Crossref
10. Chang EI, Skoracki RJ, Chang DW. Lymphovenous anastomosis bypass surgery. Semin Plast Surg 2018;32:22-7. Crossref

Calcific myonecrosis misdiagnosed as right leg abscess: a case report

Hong Kong Med J 2023 Oct;29(5):453–5 | Epub 27 Sep 2023
https://doi.org/10.12809/hkmj219898
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Calcific myonecrosis misdiagnosed as right leg abscess: a case report
CY Lee, MB, BS1; CH Lin, MB, BS2
1 Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2 Department of Medical Imaging, Chi Mei Medical Center, Tainan, Taiwan
 
Corresponding author: Mr CH Lin (chienhung0822@gmail.com)
 
 Full paper in PDF
 
 
Case presentation
A 63-year-old man attended hospital with a 2-year history of a slow-growing painful mass in his right leg. He had undergone successful surgical drainage of an abscess. Plain X-ray of the right leg at that time (Fig 1a) revealed a longitudinally distributed fusiform mass (29.4 cm×5.1 cm) with plaque-like amorphous calcifications at the right anterolateral aspect. No obvious periosteal reaction or cortical destruction of the tibia or fibula was noted. There was varus deformity of the tibia with medial cortex thickening and angulation that suggested old fracture. He had sustained a crush injury to the right leg 10 years previously and developed peroneal nerve injury with foot drop.
 

Figure 1. (a) Anteroposterior view of the right leg of the patient at presentation disclosed one longitudinal fusiform-shaped mass (29.4 cm×5.1 cm) at the anterolateral aspect with plaque-like amorphous calcifications and no obvious osteoid or chondroid bone matrix. No associated periosteal reaction and bone density change over the fibula and tibia was noted. There was varus deformity of the tibia with medial cortex thickening and angulation that suggested an old fracture. Two years later, plain film of the right leg (b) showed a similar calcified mass with smaller size at the anterior aspect, while sonography of the same leg (c) showed a 23.4 cm×3.1 cm×4.1 cm hypoechoic mass with internal and peripheral calcification in the muscle layer of the lateral aspect (arrows). Under colour doppler, calcification-related twinkling artifact is depicted without obvious internal or peripheral vascularity (not shown)
 
Physical examination of the patient revealed a mass at the anterolateral aspect of the right leg. There were no skin changes, redness or tenderness. The patient was afebrile. Biochemical and haematological investigations were normal. The range of motion of the right lower limb was not impaired but obvious muscle atrophy at the posterolateral compartment of the right leg was noted. Further imaging was requested due to concerns about malignancy.
 
The plain film of the right leg 2 years later (Fig 1b) showed a similar but smaller calcified mass at the anterior aspect. A 23.4 cm×3.1 cm×4.1 cm corresponding hypoechoic mass with internal and peripheral calcification foci in the muscle layer of the lateral aspect of the same leg and paucity of vascularity was observed under lower extremity sonography examination using Toshiba Aplio 500 (Canon Medical Systems, Tustin [CA], US) [Fig 1c]. Further magnetic resonance imaging study using Discovery MR750 (GE Healthcare, Chicago [IL], US) revealed an elongated and lobulated intramuscular cystic mass with variable internal T1- or T2-weighted signal intensity and low-signal peripheral rim (Fig 2a and 2b). Mild peripheral enhancement after intravenous gadolinium administration was noted (Fig 2c). Additional findings included varus deformity of the right tibia and severe muscle atrophy with muscle fibrosis involving the deep posterior and lateral compartments of the right leg.
 

Figure 2. (a) T1- and (b) T2-weighted magnetic resonance imaging of bilateral leg of the patient shows varus deformity with more severe condition on the right side. There is one intramuscular longitudinally elongated and lobulated mass (arrows) at the lateral aspect of the right leg. Internal content with variable T1- and T2-weighted signal intensity implies variable stage haematoma. Thin peripheral low-signal rim under T1- or T2-weighted image is consistent with peripheral calcification under plain radiography. (c) T1-weighted fat-saturated post-gadolinium image shows no obvious internal enhancement, but mild peripheral enhancement is seen (arrows). (d) Axial T1-weighted magnetic resonance image shows severe muscle atrophy with intramuscular fibrosis involving posterior compartments of the right leg (arrows), particularly deep posterior compartment. It is most likely related to ancient post-traumatic compartment syndrome
 
The tibial and fibular bones were intact and without involvement. No regional inflammatory change around the calcified cystic mass, prominent vascularity and significant peripheral enhancement was observed. The findings were consistent with calcific myonecrosis and muscle fibrosis, which is most likely related to a remote post-traumatic compartment syndrome (Fig 2d). In the absence of any symptoms that impacted daily living, the patient declined invasive treatment and opted for regular follow-up.
 
Discussion
Calcific myonecrosis is a rare, delayed manifestation of post-traumatic muscle injury or sequelae of neurovascular injury that occurs almost exclusively in the lower limbs.1 It is likely due to previous muscle injury complicated by compartment syndrome.1 Muscle injury may be a result of trauma, nerve injury with denervation, snake bite complicated by compartment syndrome,2 chronic inflammation (eg, dermatomyositis),3 or repeated contraction due to static epilepsy.4
 
The most common site of compartment syndrome in the leg is the anterior compartment followed by the lateral and deep posterior compartment. Compartment syndrome results in chronic vascular insufficiency and ischaemic change to muscular tissue. Following long-term hypoperfusion, muscles become necrotic and fibrosed with a consequent reduction in mass and development of contracture. If extensive necrosis with cystic change, haematoma formation, and calcification are present, calcific myonecrosis may develop, evident as a slow-growing mass.
 
In most cases, calcific myonecrosis presents as a painful or painless mass. Pain is likely due to pressure on surrounding tissue. Signs of inflammation (skin erythema, tenderness, and warmth) are often absent. Cosmetic problems and concerns of malignancy (eg, soft tissue sarcoma) are common reasons for seeking medical advice after decades of the disease course.
 
Plain radiography and computed tomography usually reveal lesions confined to muscle compartments in a longitudinally oriented pattern with peripheral fusiform and amorphous calcifications parallel to muscle orientation. Magnetic resonance imaging usually shows a circumscribed fusiform intramuscular cystic mass with the peripheral calcification rim in the longitudinally oriented pattern as muscle bulk. The internal content usually shows variable signal intensities in T1- and T2-weighted images that depend on the internal content (proteinaceous necrotic fluid, serous fluid, and different blood stages). Mild peripheral rim enhancement may be observed following intravenous gadolinium administration. The central cystic part lacks enhancement secondary to extensive necrosis. Post-compartment syndrome–related muscle atrophy, fibrosis, and contracture usually coexist in these disease entities.1 Other common differential diagnoses should be excluded including myositis ossificans, soft tissue sarcoma, and musculoskeletal tuberculosis.5 6
 
Calcific myonecrosis is essentially benign although previous reports have revealed postoperative complications such as sinus tract formation,7 poor wound healing, and secondary infection. This implies that wound healing is difficult, probably due to previous compartment syndrome and chronic microvascular insufficiency. In cases of uninfected calcific myonecrosis, observation is the recommended management given the high risk of postoperative complications. Nonetheless cosmetic problems and symptoms may persist.1 For calcific myonecrosis with infection, conservative management with wound dressing and antibiotics is usually not sufficient. Extensive debridement, removal of diseased tissue, and flap coverage are recommended.8 Secondary surgery may be needed if postoperative complications (poor wound healing, secondary infection, and sinus tract formation) are observed. Advanced wound management (eg, negative pressure wound therapy) facilitates healing with a moist environment and topical negative pressure.8 9
 
In our patient, the calcified mass in his right leg 2 years previously had been drained since abscess was suspected. Plain X-ray at that time suggested calcific myonecrosis or other differential diagnoses (myositis ossificans, soft tissue sarcoma, etc.). Thus, further magnetic resonance imaging surveys and more details about a previous crush injury would have been helpful to reach a diagnosis and avoid unnecessary surgery. Knowledge of calcific myonecrosis is important for clinicians and radiologists to optimise patient care.
 
Conclusion
Calcific myonecrosis is a benign disease process. Generally, ‘do not touch’ is a treatment strategy. Prompt recognition, proper diagnosis based on imaging, and detailed history taking are important.
 
Author contributions
Concept or design: CH Lin.
Acquisition of data: CY Lee.
Analysis or interpretation of data: CY Lee.
Drafting of the manuscript: CY Lee.
Critical revision of the manuscript for important intellectual content: Both 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.
 
Conflicts of interest
Both authors declared no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki and has provided informed consent for the treatment/procedures, and consent for publication.
 
References
1. O’Dwyer HM, Al-Nakshabandi NA, Al-Muzahmi K, Ryan A, O’Connell JX, Munk PL. Calcific myonecrosis: keys to recognition and management. AJR Am J Roentgenol 2006;187:W67-76. Crossref
2. Yuenyongviwat V, Laohawiriyakamo T, Suwanno P, Kanjanapradit K, Tanutit P. Calcific myonecrosis following snake bite: a case report and review of the literature. J Med Case Rep 2014;8:193. Crossref
3. Batz R, Sofka CM, Adler RS, Mintz DN, DiCarlo E. Dermatomyositis and calcific myonecrosis in the leg: ultrasound as an aid in management. Skeletal Radiol 2006;35:113-6. Crossref
4. Karkhanis S, Botchu R, James S, Evans N. Bilateral calcific myonecrosis associated with epilepsy. Clin Radiol 2013;68:e349-52. Crossref
5. De Vuyst D, Vanhoenacker F, Gielen J, Bernaerts A, De Schepper AM. Imaging features of musculoskeletal tuberculosis. Eur Radiol 2003;13:1809-19. Crossref
6. Burrill J, Williams CJ, Bain G, Conder G, Hine AL, Misra RR. Tuberculosis: a radiologic review. Radiographics 2007;27:1255-73. Crossref
7. Jeong BO, Chung DW, Baek JH. Management of calcific myonecrosis with a sinus tract: a case report. Medicine (Baltimore) 2018;97:e12517. Crossref
8. Sreenivas T, Nandish Kumar KC, Menon J, Nataraj AR. Calcific myonecrosis of the leg treated by debridement and limited access dressing. Int J Low Extrem Wounds 2013;12:44-9. Crossref
9. Tan AM, Loh CY, Nizamoglu M, Tare M. A challenging case of calcific myonecrosis of tibialis anterior and hallucis longus muscles with a chronic discharging wound. Int Wound J 2018;15:170-3. Crossref

Metastatic adenocarcinoma of the stomach presenting as malignant acanthosis nigricans and tripe palms: a case report

Hong Kong Med J 2023 Aug;29(4):355–7 | Epub 25 Jul 2023
https://doi.org/10.12809/hkmj2110002
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Metastatic adenocarcinoma of the stomach presenting as malignant acanthosis nigricans and tripe palms: a case report
Carla PM Lam, MB, BS, FHKAM (Medicine)1; Mandy WM Chan, MB, BS (UCL), MRCP (London)2
1 Division of Gastroenterology and Hepatology and Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
2 Division of Dermatology, Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Carla PM Lam (lpm496@ha.org.hk)
 
 Full paper in PDF
 
 
Case report
A 46-year-old lady with good past health presented to a tertiary hospital in August 2020 with a 6-month history of chronic cough, epigastric discomfort, and weight loss of 20 kg. She also reported progressive darkening and thickening of skin over both hands, neck, axilla, and groins since March 2020. She had consulted general practitioners and Chinese medicine practitioners and been given topicals and herbal treatment with no improvement. Physical examination revealed velvety hyperkeratosis and hyperpigmentation over both palms (Fig a), nape (Fig b), bilateral axilla (Fig c), and inguinal regions. The mucosal surfaces were not involved. Physical examination revealed stony dullness to percussion over the right mid-to-lower zone of the lungs and absent breath sounds on auscultation. A non-tender enlarged supraclavicular lymph node of 1 cm was palpable over the left supraclavicular region. Chest radiograph showed moderate right pleural effusion. Therapeutic thoracocentesis drained 2 L of clear straw-coloured fluid. Pleural fluid analysis revealed an exudative pleural effusion with 47.3 g/L fluid protein (70 g/L serum protein) and 224 U/L fluid lactate dehydrogenase (226 U/L serum lactate dehydrogenase). Pleural fluid cytology revealed suspicious cells with high nuclear-to-cytoplasmic ratio, coarse chromatin and enlarged, irregular hyperchromatic nuclei. Other laboratory findings were unremarkable: haemoglobin level 14 g/dL, white blood cell count 3.62 × 109/L, platelet count 156 × 109/L, creatinine level 71 μmol/L, bilirubin level 8 μmol/L, albumin level 28 g/L, alanine aminotransferase level 13 U/mL, and aspartate aminotransferase level 20 U/mL. Tumour markers including carcinoembryonic antigen, cancer antigen (CA) 15-3, CA 19-9, CA-125, and alpha-fetoprotein were all within the normal limits.
 

Figure. (a) Tripe palms; (b) velvety hyperkeratosis and hyperpigmentation of the nape; and (c) velvety hyperkeratosis and hyperpigmentation over the left axilla of the patient
 
A clinical diagnosis of malignant acanthosis nigricans (AN) with tripe palms was made after dermatology review. Upper endoscopy revealed two Forrest class III gastric ulcers in the proximal greater curvature surrounded by abnormal 3-cm mucosal thickening with irregular mucosal surface and microvascular pattern under narrow-band imaging. Biopsy of the gastric ulcers was negative for Helicobacter pylori but confirmed poorly differentiated adenocarcinoma on histopathology. Positron emission tomography–computed tomography scan revealed a hypermetabolic focus in the stomach, multiple intra-abdominal lymph nodes, and a large hypermetabolic pelvic tumour. A clinical diagnosis was made of Krukenberg tumour. The patient was referred to medical oncology for palliative chemotherapy. She subsequently developed massive pulmonary embolism and succumbed 3 months after the initial diagnosis.
 
Discussion
Acanthosis nigricans is a velvety hyperkeratotic, hyperpigmentation of the skin that occurs most commonly in intertriginous areas such as the back of the neck, axilla, and groins. Eight types of AN have been described and all share a common mechanism. They stimulate receptor tyrosine kinase signalling pathways; epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF-1), and fibroblast growth factor receptors. Increased circulating insulin stimulates keratinocyte IGF receptors, especially IGF-1 and at high concentrations, displaces IGF-1 from IGF-1–binding protein. Increased serum-free IGF-1 in turn stimulates the proliferation of keratinocytes and dermal fibroblasts.1 2
 
Malignant AN is a paraneoplastic phenomenon most commonly associated with gastric adenocarcinoma with an incidence of 55% to 61%, followed by pancreatic cancer, gynaecological malignancies, and lung carcinoma.2 Increased transforming growth factor alpha (TGF-α) is postulated to be the underlying mechanism. The TGF-α acts on EGFR, stimulating soft tissue growth.1 Amelioration of malignant AN following tumour resection, associated with a reduction in elevated circulating TGF-α, supports the participation of EGFR signalling in malignant AN. Malignant AN can manifest preceding, together, or after diagnosis of an underlying malignancy. Rapid evolution of the velvety hyperpigmentation, tripe palms and signs of Leser-Trélat, a rare finding of sudden eruption of seborrhoeic keratoses, are strongly indicative of malignant AN.3 Affected patients are typically not obese and may be cachectic because of the underlying malignancies. Histological features are non-specific and commonly include hyperkeratosis, papillomatosis, basal layer hyperpigmentation, and some dermal papillae that project upwards in the form of finger-like projections.4 Malignant AN may resolve following tumour resection but can recur if there is tumour recurrence.
 
Krukenberg tumours are defined by the World Health Organization as ovarian carcinomas characterised by the presence of stromal involvement, mucin-producing neoplastic signet ring cells, and ovarian stromal sarcomatoid proliferation. The most common sites of primary malignancies are from the gastrointestinal tract and the breasts. The mean age at diagnosis of Krukenberg tumours is 49.3 ± 13.3 years. The prognosis is generally very poor, probably because of the late stage of diagnosis. The median survival time is 35.0 ± 3.5 months while the 5-year overall survival is around 25%.5
 
This case illustrates the classic presentation of malignant AN and tripe palms that are associated with metastatic gastric adenocarcinoma. Physicians need to be aware of these features since they may be the only presenting symptoms of the underlying malignancies. Full systemic evaluation for underlying malignancies is warranted to enable early diagnosis and timely management.
 
Author contributions
Concept or design: CPM Lam.
Acquisition of data: CPM Lam.
Analysis or interpretation of data: CPM Lam.
Drafting of the manuscript: CPM Lam.
Critical revision of the manuscript for important intellectual content: Both 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.
 
Conflicts of interest
Both authors have disclosed no conflicts of interest.
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki. Written informed consent for publication was obtained from the patient’s next-of-kin.
 
References
1. Phiske MM. An approach to acanthosis nigricans. Indian Dermatol Online J 2014;5:239-49. Crossref
2. DermNetNZ. Acanthosis nigricans. December 2021. Available from: https://dermnetnz.org/topics/acanthosis-nigricans. Accessed 18 Jul 2023.
3. Kilickap S, Yalcin B. Images in clinical medicine. The sign of Leser-Trélat. N Engl J Med 2007;356:2184. Crossref
4. Yu Q, Li XL, Ji G, et al. Malignant acanthosis nigricans: an early diagnostic clue for gastric adenocarcinoma. World J Surg Oncol 2017;15:208. Crossref
5. Xu KY, Gao H, Lian ZJ, Ding L, Li M, Gu J. Clinical analysis of Krukenberg tumours in patients with colorectal cancer—a review of 57 cases. World J Surg Oncol 2017;15:25. Crossref

Novel compound heterozygous mutation of the diacylglycerol kinase epsilon gene and membranoproliferative glomerulonephritis: a case report

Hong Kong Med J 2023 Aug;29(4):351–4 | Epub 12 Jul 2023
https://doi.org/10.12809/hkmj219939
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Novel compound heterozygous mutation of the diacylglycerol kinase epsilon gene and membranoproliferative glomerulonephritis: a case report
Sharon HY Lau, MB, ChB, MRCPCH1; Eugene YH Chan, FHKAM (Paediatrics)2; Liz YP Yuen, FHKCPath, FHKAM (Pathology)3; WF Ng, FHKAM (Pathology)3; Alison LT Ma, FHKAM (Paediatrics)2
1 Department of Paediatrics, Prince of Wales Hospital, Hong Kong SAR, China
2 Paediatric Nephrology Centre, Department of Paediatrics, Hong Kong Children’s Hospital, Hong Kong SAR, China
3 Department of Pathology, Hong Kong Children’s Hospital, Hong Kong SAR, China
 
Corresponding author: Dr Eugene YH Chan (eugene.chan@ha.org.hk)
 
 Full paper in PDF
 
 
Case report
A 10-year-old Chinese boy first presented in June 2015 at the age of 4 years with steroid-resistant nephrotic syndrome. He had been taking full-dose prednisolone at 60 mg/m2/day for 4 weeks. Renal biopsy confirmed immune complex–mediated membranoproliferative glomerulonephritis (MPGN) with predominant immunoglobulin M (IgM) and scanty IgG or C3 deposits. Cyclosporin A, a calcineurin inhibitor (CNI), was introduced and successfully brought the disease into partial remission. His urine protein–to-creatinine ratio (UPCR) reduced from 13.9 mg/mg to 0.95 mg/mg after 2 months. He remained in partial remission for 4 years with cyclosporin A and low-dose prednisolone. He showed a urinary relapse following discontinuation of cyclosporin A in 2020 with a rebound in UPCR from 0.64 mg/mg to 1.57 mg/mg (Table).
 

Table. Blood and urine test results of the patient
 
Renal biopsy was repeated and revealed mild-to-moderate global mesangial cell proliferation and a few clusters of arterioles showing hyaline arteriolosclerosis with a peripheral and segmental distribution (Fig). Of note, there was evidence of mesangiolysis with loss of argyrophilic basement membrane material in a segmental pattern. The direct immunofluorescence portion showed finely granular deposits of IgA (2+), IgG (3+), IgM (2+), C1q (3+), and C3 (+) in a diffuse global and capillary distribution. Electron microscopy showed focal fusion of podocyte foot processes, splitting of glomerular basement membrane in association with mesangial cell interposition and scattered subendothelial and intramembranous dense electron deposits in keeping with immune complex. The features were indicative of immune complex–mediated MPGN with evidence of CNI toxicity. The presence of segmental mesangiolysis was suggestive of previous endothelium injury, possibly an episode of glomerular thrombotic microangiopathy (TMA).
 

Figure. (a) Representative glomerulus showing mesangial proliferative glomerulonephritis pattern of changes with lobular accentuation of glomerular tuft and mild global mesangial cellular proliferation and thickened capillary wall (periodic acid–Schiff stain, original magnification ×400). (b) Representative glomerulus showing mesangial proliferative glomerulonephritis pattern of changes with lobular accentuation of glomerular tuft and mild global mesangial cellular proliferation and tram-track split capillary wall (arrow) [methenamine silver stain, original magnification ×400]. (c) Occasional glomerulus showing evidence of mesangiolysis evident by loss of argyrophilic mesangial material on the right part of the glomerulus. Such mesangiolysis may indicate previous injury of thrombotic microangiopathy (TMA) as there is no active TMA (methenamine silver stain, original magnification ×400). (d) Direct immunofluorescence study showing global mesangial and capillary deposit of immunoglobulin G in a fine granular pattern (original magnification ×400). (e) Electron microscopy. An inverted u-shaped glomerular capillary is present in the centre of the field surrounded by a nucleated podocyte (P) on the left upper corner and other podocytes in the middle and right side. Focal foot process fusion, denoted as FPF in the upper centre, is noted. The lumen of the capillary tuft is denoted by the oval circle on the left side of the field and this part is occupied by the cytoplasm of the endothelial cells. The glomerular basement membrane (GBM, small white arrow on the left lower side) is normal at this region. In the upper part of the capillary loop, there are two areas of mesangial interposition (MIP) with splitted and thickened GBM (two small white arrows). Large white arrows indicate the small intramembranous and subendothelial immune-complex dense deposits. The electron microscopy features are typical of immune complex–mediated membranoproliferative glomerulonephritis
 
Next-generation sequencing was performed and detected two mutations in the diacylglycerol kinase epsilon (DGKE) gene, including a c.1068_1071del p.(Asn356Lysfs*6) frameshift mutation and a c.1282_1284+18del deletion. Sanger sequencing of the mother detected heterozygous DGKE gene c.1068_1071del p.(Asn356Lysfs*6). The father was unavailable for genetic analysis. In view of these results, the two DGKE variants were likely to act in trans in the patient. According to the American College of Medical Genetics/Association for Molecular Pathology classification, these two variants are considered pathogenic. Additional whole-exome sequencing revealed no significant variants in genes related to monogenic lupus.
 
Throughout the course of the disease, his blood tests showed no features of haemolytic uraemic syndrome (HUS). Apart from a mildly elevated lactate dehydrogenase, his complete blood count, blood smear and haptoglobin were normal. Complement function testing showed no evidence of complement activation. He was commenced on an angiotensin-converting enzyme inhibitor, prednisolone, and mycophenolate mofetil. He responded promptly with marked improvement in proteinuria: UPCR decreased to 0.36 mg/mg within 1 month. At last follow-up, his UPCR was 0.24 mg/mg with normal kidney function (estimated glomerular filtration rate = 116 mL/min/1.73 m2).
 
Discussion
We report the first Chinese patient with DGKE nephropathy who presented as nephrotic syndrome and immune complex–mediated MPGN. Importantly, the patient responded well to immunosuppressive agents including CNI and mycophenolate mofetil. To the best of our knowledge, the pathogenic variants in this case are the first reported in DGKE-related nephrotic syndrome.
 
Diacylglycerol kinase epsilon gene is important in the regulation of thrombotic status and is present in podocytes, platelets, and endothelium. A loss-of-function in the DGKE gene is associated with a prothrombotic state, leading to episodes of HUS that are complement-independent.1 Interestingly, a subset of patients develop MPGN with nephrotic syndrome.2 Along with the new classification, it is believed that chronic microangiopathy often results in a form of MPGN that is neither immune complex–mediated nor complement-mediated.3 The exact mechanism of DGKE mutations leading to MPGN remains unknown.
 
Azukaitis et al4 reported 44 cases of DGKE nephropathies, including 33 cases with HUS, nine cases with MPGN/nephrotic syndrome, and two rare cases with a mixed HUS/MPGN presentation. Among the nine reported cases of DGKE-MPGN, three other pathogenic variants were identified. Mutations of p.Gln43*, p.IVS5-2a and p.Thr204Glnfs*6 were found in four, three and two of the patients, respectively. Interestingly, the first case of DGKE nephropathy confirmed in our territory-wide next-generation sequencing cohort had nephrotic syndrome and MPGN.
 
The pathology of renal biopsy in this child is particularly interesting in terms of the presence of TMA features and an immune complex–mediated MPGN picture. The presence of mesangiolysis signifies endothelial injury such as TMA. These lesions might be caused by the underlying disease process related to DGKE mutations. Of note, about half of the patients with DGKE-HUS recovered spontaneously from the initial TMA episode without any HUS-specific treatment.4 A potential explanation of this observation in our patient is that an episode of subclinical TMA had resolved on its own. Another interesting finding was the positive immunofluorescence on renal biopsy, not commonly seen in TMA-related MPGN. The immune-complex deposition in our patient could not be explained by either autoimmune disease or hepatitis. Although he had an isolated elevation of anti–double stranded DNA that occurred only on disease relapse, a confirmed diagnosis of systemic lupus could not be excluded. Whole-exome sequencing revealed no clinically significant variants in the monogenic lupus genes. Whether or not the finding of immune complex deposition at a histological level was an event secondary to the genetic mutation remains unknown. Clinicians need to be mindful of such a discrepant genetic finding and the clinical phenotype with close follow-up. There have been reported cases of patients with TMA who developed immune complex–mediated MPGN, one of whom also carried a DGKE mutation.4 5 The pathogenic and prognostic differences of this immune complex–mediated subgroup require further elucidation.
 
Regarding prognosis and treatment, most patients with DGKE-MPGN show some response to immunosuppressants. Nonetheless Azukaitis et al4 reported a high prevalence of chronic proteinuria in DGKE-MPGN patients. Although statistically insignificant, a trend towards a lower 10-year renal survival was also observed (50% in DGKE-MPGN vs 89% in DGKE-HUS).4 After initiation of CNI or mycophenolate mofetil, our patient showed a promising response and attained remission. At 5-year follow-up, he remained in remission with normal kidney function.
 
This is the first Chinese patient with DGKE nephropathy presenting as nephrotic syndrome with an MPGN picture. Of interest, our patient responded promptly to immunosuppressants, suggesting its potential role in this disease entity. This case highlights the importance of genetic testing in children with an atypical course of nephrotic syndrome. Further international collaborative studies are warranted to understand the pathogenesis and optimal management in this patient population.
 
Author contributions
Concept or design: SHY Lau, EYH Chan.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: SHY Lau, 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.
 
Conflicts of interest
All authors have disclosed no conflicts of interest.
 
Acknowledgement
We thank the Department of Pathology, Pamela Youde Nethersole Eastern Hospital for their permission to review the patient’s first renal biopsy.
 
Declaration
This case was accepted as poster presentation in the Joint Annual Scientific Meeting 2021 of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association and Hong Kong College of Paediatric Nursing (hybrid, 30 October 2021).
 
Funding/support
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
 
Ethics approval
The patient was treated in accordance with the Declaration of Helsinki, with informed consent provided by the patient’s mother for treatment, procedures, and publication.
 
References
1. Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45:531-6. Crossref
2. Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013;24:377-84. Crossref
3. Masani N, Jhaveri KD, Fishbane S. Update on membranoproliferative GN. Clin J Am Soc Nephrol 2014;9:600-8. Crossref
4. Azukaitis K, Simkova E, Majid MA, et al. The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase ε. J Am Soc Nephrol 2017;28:3066-75. Crossref
5. Ankawi GA, Clark WF. Atypical haemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), different diseases or a spectrum of complement-mediated glomerular diseases? BMJ Case Rep 2017;2017:bcr2017220974. Crossref

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