The number of geriatric patients admitted to our hospital with hip fracture has been increasing steadily over the last decade. Such osteoporotic fractures are difficult to treat because of poor bone quality. The often extreme age of the patients and other comorbidities make the management of such patients even more challenging. The clinical outcome of geriatric patients with hip fracture depends on surgical management as well as many other medical factors.

Hip fracture is a significant cause of mortality.1 Haentjens et al2 reported a 5- to 8-fold increased risk for all-cause mortality in the first 3 months following hip fracture. Some clinical scores and assessments—for example, the American Society of Anesthesiologists (ASA) classification, the Barthel index, the Goldman index, the POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity) scoring system, the Charlson index and the visual analogue scale for risk scale, or the cumulated ambulation score—are reported to correlate with postoperative complications and mortality of hip fracture.3 4 5 Some of these scores can predict complication rates and others better predict short-term mortality.4 6 Individual clinical parameters also correlate with mortality rates.6 7 8 9 10 11

Among all these scores, the Nottingham Hip Fracture Score (NHFS) is one of the most well-known for the prediction of short- and long-term mortality in geriatric hip fracture patients, and has been validated in both western and Asian populations.12 13 14 This excellent score includes patient age, sex, admission haemoglobin level, Mini-Mental State Examination (MMSE) score, previous institution, number of comorbidities, and also presence of malignancy.

In our hospital, a multidisciplinary hip fracture clinical pathway programme was started in 2007. The implementation of this pathway has not only shortened hospital stay, but also improved clinical outcomes, including pressure sore rate, infection rate, and mortality rate.15 To enable early patient assessment and quantification of the risks of hip fracture surgery, a score that is easy to calculate and readily obtainable should be identified. This can greatly improve the rapport between the surgeon and patient, as well as their family, with regard to the operative risks and mortality risks. The NHFS is an excellent score that has been widely validated. Nonetheless it involves assessment of the MMSE score by a therapist and is not always possible before surgery. In this retrospective study, we used the Charlson Comorbidity Index (CCI) to evaluate patient comorbidities (Table 1).

The objective of this study was to determine the association of the CCI in operated hip fracture in patients older than 65 years with the in-patient, 30-day, and 1-year mortality.

Our hospital is a tertiary trauma referral centre in Hong Kong. When geriatric patients with hip fracture present to the accident and emergency department, they are transferred to the orthopaedic ward for preoperative workup and assessment once they are stabilised. Surgery is performed within 2 days. Postoperatively, they are observed in an acute ward for a mean of 5 days before being transferred to another convalescence hospital for rehabilitation. Patients are discharged after a mean of 3 weeks.

From 1 January 2009 to 31 December 2010, we recruited all patients aged over 65 years who underwent surgery for geriatric hip fracture. Patients with pathological fractures, multiple fractures, or old fractures were excluded from this study. Patient records were retrieved from the electronic medical record system. Since all these patients were managed according to our hip fracture clinical pathway protocol, all demographic data, premorbid walking status, comorbidities, past surgery, complications, and also length of stay in both acute and convalescence hospitals were available. Most importantly, the in-patient, 30-day, and 1-year mortality rates could be traced. In-patient mortality was defined as death that occurred in the acute or convalescence hospital, and the 30-day and 1-year mortality was defined as death occurring within 30 days and 1 year of admission, respectively. Mortality records are available when death occurs in any public hospital in Hong Kong with an electronic medical record system.

The CCI was calculated from the medical records of patients admitted with hip fracture obtained from the hospital electronic medical system. The clinical history of patients was reviewed by medical officers with comorbidities recorded. The final patient outcome was not known to the medical officers unless it was recorded in the same medical records. Using the CCI, three scores can be calculated—the total Charlson comorbidity score (TCCS) is the sum of all comorbidities combined with the score derived from the patient’s age; the highest Charlson comorbidity score (HCCS) is the highest single comorbidity score of a patient; and the Charlson comorbidity score (CCS) is the sum of all comorbidity scores without consideration of age. All these scores were used to analyse and correlate with different mortality rates.

The independent sample Mann-Whitney U test was used to test the statistical association of different comorbidity scores and mortality rates. Receiver operating characteristic (ROC) curve was used to measure the best cut-off for the score with respect to different mortality rates. Multiple variant analysis using Cox regression model was employed to measure the survival rate of hip fracture patients with respect to the cut-off scores derived from the ROC curves. Age, sex, fracture sites, and the Charlson scores were the independent variables. This regression model can be used as a means to predict patient mortality rate before surgery is performed.

During the 2-year period, we performed surgery on 759 geriatric patients with acute hip fracture. Among them, 28% were male and 72% were female. The mean age was 84 years: 25% aged from 70 to 79 years, 50% aged from 80 to 89 years, and 21% aged from 90 to 99 years. The oldest patient operated on was 102 years old. Overall, 72% of patients lived at home before the admission, and the remainder in a home for the elderly. With regard to premorbid mobility, 36% of them could walk unaided and 56% could walk with some form of aid such as a stick or walking frame.

With regard to the comorbidities, the three most common diseases were hypertension, diabetes mellitus, and dementia. Mini-Mental State Examination was used to evaluate the patients’ mental function and revealed that 65% were considered severely or moderately demented. Premorbid functional status was assessed by the modified Barthel index: 40% of patients were independent, 42% were mildly and moderately dependent, and 18% were severely or totally dependent in their daily function. The ASA score was also documented: 2.5% were ASA 1 (with normal health), 38% were ASA 2 (with mild systemic disease), and 58% were ASA 3 (with severe systemic disease). When the type of fracture was analysed, 49% were at the femoral neck and 49% the trochanter. The remaining 2% were subtrochanteric fractures. Internal fixation was performed in 75%. Among this group of internally fixed hip fractures, 24% of them were impacted fractured neck of femur that was fixed by screws only. The remaining 76% were fixed by either an extramedullary or intramedullary device for the pertrochanteric fractures. The remaining 25% of fractures were displaced fractured neck of femur, managed by hemiarthroplasty. Postoperatively, 72% of patients did not require a blood transfusion. The mean preoperative waiting time was 1.44 days. The longest waiting time was 14 days due to unstable medical conditions. The mean total length of stay in both acute and convalescence hospitals was 26.6 days.

The statistical analysis of the difference in mortality rates compared with the difference scores is summarised in Table 2. Among these 759 operated patients, six died in the hospital. The in-patient mortality rate was 0.8%. Within 30 days of admission, 19 patients died. The 30-day mortality rate was 2.5%. In 1-year time, 124 patients died. The 1-year mortality rate was 16.3%. Mann-Whitney analysis showed that the in-patient mortality was significantly related to the TCCS (P=0.031). Regarding the 30-day mortality rate, statistical analysis showed that it was significantly related to TCCS (P<0.001) and CCS (P=0.010). Using Spearman’s rank correlation coefficient, the TCCS was statistically correlated with HCCS and CCS. All three different scores derived from the CCI were significantly related to this 1-year mortality rate (P<0.001; Table 2).

An ROC curve analysis was used to identify the relationship between TCCS and mortality rates. Both 30-day mortality and 1-year mortality rates were analysed using MedCalc software (MedCalc Software, Ostend, Belgium). Both ROC findings were significant for 30-day and 1-year mortality (area under the curve=0.72 and 0.75 respectively, P<0.001). In both situations, the best cut-off value was a TCCS of ≥6 according to the Youden index method, with 30-day mortality (sensitivity 79%, specificity 59%, positive predictive value [PPV] 4.7%, and negative predictive value [NPV] 99%) and 1-year mortality (sensitivity 71%, specificity 64%, PPV 28%, and NPV 92%). Nonetheless when referring to the actual curve (Fig 1), this optimal cut-off point was not well-defined versus using the adjacent higher cut-off value of TCCS of ≥7.

If a TCCS cut-off value of ≥7 was used, the respective value of sensitivity, specificity, PPV, and NPV was 58%, 79%, 6.5%, and 99% for 30-day mortality, and 50%, 83%, 37%, and 90% for 1-year mortality. In a clinical situation, better specificity is preferred for predicting mortality. Thus we elected to use a 3-tier stratification of patients based on their TCCS in the regression analysis—low-risk group: TCCS 0-5, borderline group: TCCS 6-7, high-risk group: TCCS ≥8. These values are shown in Table 3.

Cox regression model was used to demonstrate the relationship between mortality rates by using the TCCS as the predictor (Fig 2). Using a score of ≤5 (low-risk group) as baseline, when score was equal to 6 or 7 (borderline group), the 30-day and 1-year mortality hazard ratio (HR) was 3.41 (95% confidence interval [CI], 0.88-13.19; P=0.075) and 2.66 (95% CI, 1.71-4.10; P<0.001), respectively. If the score was ≥8 (high-risk group), the 30-day mortality and 1-year mortality HR was 7.93 (95% CI, 1.93-32.54; P=0.004) and 5.08 (95% CI, 3.06-8.42; P<0.001), respectively.

The logistic regression model revealed that the 30-day mortality rate correlated with the TCCS in a good exponential relationship (Fig 3a). If the graph was analysed in more detail, it would show that operating on the hip fractures was generally safe. Even when the TCCS reached 9 points, the 30-day mortality rate remained <5%.

The 1-year mortality rate showed a different correlation with TCCS. The curve became more linear in shape (Fig 3b). When TCCS was <3, 1-year morality rate remained <5%. When the TCCS was >5, mortality rate rose almost linearly with the TCCS. When the TCCS was ≤10, 1-year mortality rate was approximately 50%. The increase in mortality rate appeared to plateau at TCCS of >15, where it reached 88%. An overview of our hip fracture patients reveals that there was a reasonable 1-year survival with only 10% 1-year mortality rate after hip fracture surgery if the TCCS was <5.

In the last two decades, there has been an increasing attention on geriatric fragility fractures with a special focus on hip fractures.6 Many parameters are significant predictors of associated clinical outcome and mortality. These include type of injury and surgery,7 postoperative delirium,8 timing of rehabilitation,9 and surgical technique.10 11 In addition, many other preoperative indicators have been found to affect postoperative mortality. The most commonly identified factors include advanced age,16 17 18 male gender,16 18 19 poor premorbid functional capability,18 20 and presence of multiple comorbidities.21 22

The CCI is a system that allows classification of severity and uses recorded secondary diagnoses to assign a weight to morbidity, thereby generating the patient’s risk of death.23 This score can be combined with age to form a single index. This is particularly useful in our geriatric hip fracture patient group because our patients’ age ranged from 65 to 102 years, which is a major factor in their mortality rates.

We have shown that the TCCS correlates well with both short-term and long-term mortality. The TCCS includes all the comorbidities and the age of the patient and reflects the general health of the patient on admission to hospital. Thus the poorer the general health is, the higher the short-term mortality rate will be. As most of these patients require surgery to either fix or replace the fractured hip, there is additional stress on their physiologically compromised body. Although many of the common comorbidities of geriatric hip fracture patients are minor problems, such as diabetes, hypertension, or previous cerebrovascular accident, these problems are nonetheless chronic diseases that lead to gradual multi-organ dysfunction and deterioration. The most commonly affected organs are the lungs, heart, general vascular system, kidneys, and brain. Surgery poses a major stress challenge to these diseased organs and can result in a rapid decline in general health. Therefore the severity of a patient’s comorbidities has a significant prognostic implication for short-term mortality post-surgery. This explains why the TCCS correlates significantly with the in-patient and 30-day mortality rates.

Using the logistic regression graph correlating the TCCS and 30-day mortality rate, different TCCSs correspond to an estimated 30-day mortality rate. This is valuable information when frontline staff are required to explain the risks to the newly admitted patient and their family. Many patients and their family are concerned about the impending need for surgery, believing that surgery will lead to death of their loved one who already has multiple existing comorbidities. With the information available, we can reassure the patient about their low mortality risk, despite these multiple comorbidities. Informed discussion between the patient, their family, and the surgeon can allay fears about surgery and allow extra effort and care during the postoperative period. A more experienced surgeon and staff should be involved in care to minimise surgical trauma and the possibility of surgical complications. Geriatricians and anaesthetists should be informed about the higher incidence of major life-threatening conditions during the pre-, peri-, and post-operative period. This allows better utilisation and coordination of limited medical and human resources such as intensive care unit beds, sophisticated preoperative and postoperative monitoring machines, and specialist nursing care.

Analysis of the 1-year mortality rate revealed a statistically significant correlation with all scores, similar to another study.24 This is to be expected as the 1-year mortality relates more to general physical health and age, and not the hip fracture. The CCI independently predicts both short- and long-term mortality in acutely ill hospitalised elderly adults.25 In our series, the 1-year mortality rate was 16.3%, slightly lower than some studies17 but not uncommon.24 This may be partly due to the general health status of our population and may be partly due to differences in the medical system.

Information about short- and long-term mortality can help reassure the patient and their family and allay their fears about surgery in the presence of other comorbidities. It can alleviate some of the stress associated with uncertainty.

This study is not without limitations. There is a possible discrepancy between the actual number of deaths because a small number may have occurred outside of the public hospital system. As a retrospective study, we were not able to control the confounding factors that could influence the results. Although age, sex, and fracture sites were accounted in the regression model, other factors such as smoking, medications, fracture sites, surgeon experience, and surgical procedure were not included in the analysis. Possible errors in coding and rating of CCI also exist. There might also have bias in data collection for the comorbidity index if patient mortality was known during the data collection process. Nonetheless based on our results in this retrospective cohort, a prospective study should be conducted to further analyse the relationship between comorbidity and mortality of the geriatric patients with hip fracture.

Furthermore, non-operated hip fracture patients were not included in this study. During the study period, 15 hip fracture patients were treated conservatively. The most common reasons for non-operative treatment were being unfit for surgery or refusal of surgery by family. The 30-day mortality rate was 13.3%. The 1-year mortality rate was 20%. Both the short-term and long-term mortality rates of these non-operated patients were generally higher than that of operated patients. However, since the number of deaths was small, a statistical comparison was not performed. Interpretation of the data should also be cautious because non-operated patients are usually very fragile with pre-existing life-threatening medical conditions. These patients may have had a very high short-term mortality rate if surgery were performed that would have influenced the final statistical analysis. Nevertheless the small proportion of non-operated hip fracture patients would not have been expected to have a large effect on overall results.

In this retrospective study of the short- and long-term mortality rates of geriatric patients undergoing surgery for hip fracture, scores derived from the CCI correlated well with mortality rates. Use of CCI before surgery to assess the patients’ general health and operative risks can aid communication between the patient and doctors, and assist in deciding the best treatment option.

1. Frost SA, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Excess mortality attributable to hip-fracture: a relative survival analysis. Bone 2013;56:23-9. Crossref

2. Haentjens P, Magaziner J, Colón-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 2010;152:380-90. Crossref

3. Burgos E, Gómez-Arnau JI, Díez R, Muñoz L, Fernández-Guisasola J, Garcia del Valle S. Predictive value of six risk scores for outcome after surgical repair of hip fracture in elderly patients. Acta Anaesthesiol Scand 2008;52:125-31. Crossref

4. Foss NB, Kristensen MT, Kehlet H. Prediction of postoperative morbidity, mortality and rehabilitation in hip fracture patients: the cumulated ambulation score. Clin Rehabil 2006;20:701-8. Crossref

5. Kirkland LL, Kashiwagi DT, Burton MC, Cha S, Varkey P. The Charlson Comorbidity Index Score as a predictor of 30-day mortality after hip fracture surgery. Am J Med Qual 2011;26:461-7. Crossref

6. Smith T, Pelpola K, Ball M, Ong A, Myint PK. Preoperative indicators for mortality following hip fracture surgery: a systematic review and meta-analysis. Age Ageing 2014;43:464-71. Crossref

7. Smith EB, Parvizi J, Purtill JJ. Delayed surgery for patients with femur and hip fractures—risk of deep venous thrombosis. J Trauma 2011;70:E113-6. Crossref

8. Lee HB, Mears SC, Rosenberg PB, Leoutsakos JM, Gottschalk A, Sieber FE. Predisposing factors for postoperative delirium after hip fracture repair in individuals with and without dementia. J Am Geriatr Soc 2011;59:2306-13. Crossref

9. Siu AL, Penrod JD, Boockvar KS, Koval K, Strauss E, Morrison RS. Early ambulation after hip fracture: effects on function and mortality. Arch Intern Med 2006;166:766-71. Crossref

10. Cheng T, Zhang GY, Liu T, Zhang XL. A meta-analysis of percutaneous compression plate versus sliding hip screw for the management of intertrochanteric fractures of the hip. J Trauma Acute Care Surg 2012;72:1435-43. Crossref

11. Cho SH, Lee SH, Cho HL, Ku JH, Choi JH, Lee AJ. Additional fixations for sliding hip screws in treating unstable pertrochanteric femoral fractures (AO Type 31-A2): short-term clinical results. Clin Orthop Surg 2011;3:107-13. Crossref

12. Maxwell MJ, Moran CG, Moppett IK. Development and validation of a preoperative scoring system to predict 30 day mortality in patients undergoing hip fracture surgery. Br J Anaesth 2008;101:511-7. Crossref

13. Wiles MD, Moran CG, Sahota O, Moppett IK. Nottingham Hip Fracture Score as a predictor of one year mortality in patients undergoing surgical repair of fractured neck of femur. Br J Anaesth 2011;106:501-4. Crossref

14. Kau CY, Kwek EB. Can preoperative scoring systems be applied to Asian hip fracture populations? Validation of the Nottingham Hip Fracture Score (NHFS) and identification of preoperative risk factors in hip fractures. Ann Acad Med Singapore 2014;43:448-53.

15. Lau TW, Fang C, Leung F. The effectiveness of a geriatric hip fracture clinical pathway in reducing hospital and rehabilitation length of stay and improving short-term mortality rates. Geriatr Orthop Surg Rehabil 2013;4:3-9. Crossref

16. Holt G, Smith R, Duncan K, Hutchison JD, Gregori A. Gender differences in epidemiology and outcome after hip fracture: evidence from the Scottish Hip Fracture Audit. J Bone Joint Surg Br 2008;90:480-3. Crossref

17. Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing 2010;39:203-9. Crossref

18. Jamal Sepah Y, Umer M, Khan A, Ullah Khan Niazi A. Functional outcome, mortality and in-hospital complications of operative treatment in elderly patients with hip fractures in the developing world. Int Orthop 2010;34:431-5. Crossref

19. Endo Y, Aharonoff GB, Zuckerman JD, Egol KA, Koval KJ. Gender differences in patients with hip fracture: a greater risk of morbidity and mortality in men. J Orthop Trauma 2005;19:29-35. Crossref

20. Williams A, Jester R. Delayed surgical fixation of fractured hips in older people: impact on mortality. J Adv Nurs 2005;52:63-9. Crossref

21. Franzo A, Francescutti C, Simon G. Risk factors correlated with post-operative mortality for hip fracture surgery in the elderly: a population-based approach. Eur J Epidemiol 2005;20:985-91. Crossref

22. Hannan EL, Magaziner J, Wang JJ, et al. Mortality and locomotion 6 months after hospitalization for hip fracture: risk factors and risk-adjusted hospital outcomes. JAMA 2001;285:2736-42. Crossref

23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373-83. Crossref

24. Svensson O, Strömberg L, Ohlén G, Lindgren U. Prediction of the outcome after hip fracture in elderly patients. J Bone Joint Surg Br 1996;78:115-8.

25. Frenkel WJ, Jongerius EJ, Mandjes-van Uitert MJ, van Munster BC, de Rooij SE. Validation of the Charlson Comorbidity Index in acutely hospitalized elderly adults: a prospective cohort study. J Am Geriatr Soc 2014;62:342-6. Crossref

Geriatric hip fracture places an increasing burden on health care service providers around the world. Previous studies have shown that it is associated with significant morbidity and mortality.1 2 3 With the ageing population in many parts of Asia, it has been estimated that over half of all hip fractures will occur in Asia in 2050.4 Studies in France5 and the US6 have reported a drop in the incidence rate of geriatric hip fracture in the elderly population. This trend, however, has not been echoed by similar studies in Korea7 and Japan.8 Epidemiological studies performed in Hong Kong in 2007 and 2012 showed that, similar to western countries, there was a drop in the incidence rate of hip fracture in the territory.9 10

Hong Kong has one of the longest life expectancies in the world.11 The total number of geriatric hip fractures is expected to increase. It will therefore be important for policy-makers and society as a whole to adequately forecast future trends in the disease to prepare for the challenges ahead. This study aimed to analyse the latest trend in the epidemiology of geriatric hip fracture in Hong Kong, as well as to investigate the mortality rate and excess mortality rate in patients who underwent surgery for geriatric hip fracture.

Approximately 98% of geriatric hip fractures are managed in public hospitals run by the Hospital Authority of Hong Kong.10 All patients admitted to a public hospital in Hong Kong are assigned a code in the Clinical Management System by the attending doctor(s). The system also includes information on age, sex, principal diagnosis, and period of hospitalisation. Relevant data, including date of death, were collected using the Clinical Data Analysis and Reporting System (CDARS) from the Hospital Authority. All cases between January 2000 and December 2011 with a disease coding of acute hip fracture (ICD-9-CM diagnosis codes 820.8, 820.09, 820.02, 820.03, 820.20, and 820.22) were retrieved. Operations for geriatric hip fracture were defined as a patient-episode with ICD-9-CM procedure code of 81.52, 51.51, 81.40, 79.15, 79.35, or 78.55.

Only patients with a disease code for acute hip fracture and procedure code for geriatric hip fracture were included in the current study. Patients who were non-Chinese, who had an old fracture, were managed non-operatively, had a second hip fracture or complications of primary hip fracture were excluded. Based on the date of death, we analysed the 30-day and 1-year mortality regardless of cause of death. Postoperative 5-year mortality rate was calculated based on data from patients who underwent surgery from year 2000 to 2006.

Excess mortality is defined by the World Health Organization as “Mortality above what would be expected based on the non-crisis mortality rate in the population of interest.”12 In this study, the excess mortality rate was calculated by subtracting the age- and sex-specific mortality from the age- and sex-specified 1-year mortality of operated geriatric hip fracture. The age- and sex-specific mortality rates for the year 2006 were used for analysis. The actual and projected population size, and the age- and sex-specific mortality rates13 were obtained from the Census and Statistics Department of the HKSAR Government.

From January 2000 to December 2011, the annual number of patients admitted to public hospitals and who underwent surgery for hip fracture increased from 3678 to 4579. The annual incidence of geriatric hip fracture during the study period is shown in Figure 1. A slightly decreasing annual risk of hip fracture was observed for both male and female patients (Figs 2 and 3).

A total of 48 992 cases were retrieved after excluding non-Chinese patients, old fractures, cases managed non-operatively, second hip fractures, repeated admission for the same fracture, and complications of primary hip fracture.

Patient age ranged from 65 to 112 years with a mean and median age of 82.1 and 82.0 years, respectively. The overall 30-day and 1-year mortality was 3.01% and 18.56%, respectively.

The age- and sex-specific mortality after 30 days, 1 year, and 5 years for operated hip fracture are shown in Table 1. Female patients aged 65 to 69 years had the lowest 1-year and 5-year mortality of 6.91% and 23.80%, respectively. An increase in mortality was observed with advancing age and male sex.

The excess mortality rate in different age and sex groups is shown in Table 2 and Figure 4. Male gender and increasing age were associated with a higher excess mortality rate after operation for geriatric hip fracture. The excess mortality for a male patient aged ≥85 years was 23.45%.

A slight decrease in the annual risk of geriatric hip fracture was noted in this study. This trend echoes that of similar studies in the territory and in some western countries.5 6 10 Such a decrease has been postulated to be related to improved availability of medical intervention to prevent osteoporosis, increased attention to menopause and hormonal replacement therapy, changes in lifestyle, and community fall prevention programmes. Nonetheless few studies have been able to prove any causal relationship.

Surgery is generally offered to patients with geriatric hip fracture in order to decrease the morbidity and mortality associated with prolonged immobilisation. In this study, patients who were managed non-operatively were excluded as they represented a very small proportion of patients (estimated to be <1%) with poor pre-morbid medical conditions and very high anaesthetic risk.

Despite the decreasing annual risk of geriatric hip fracture, it is important to relate this to the ageing population in the territory. Using the projected percentage of elderly aged ≥65 years in Hong Kong,11 and assuming that the annual risk of hip fracture remains the same, we estimate that there will be more than 6300 cases of hip fracture in the year 2020. In the year 2040, the annual incidence of geriatric hip fracture will be more than 14 500, more than a 3-fold increase from 2011. Unless effective primary prevention measures are put in place, the burden of geriatric hip fracture on the public health system will continue to increase. Policy-makers should invest in the relevant specialties and departments in order to tackle the inevitable challenges ahead.

To our knowledge this is the first study to review the excess mortality of operated geriatric hip fracture in the territory. A systematic epidemiological review by Abrahamsen et al14 showed that the 1-year excess mortality rate following hip fracture ranged from 8.4% to 36%. In this study, the 1-year excess mortality following surgery for geriatric hip fracture ranged from 6.22% to 23.45%. Echoing the result of Abrahamsen et al,14 we also identified that men had a higher excess mortality rate after operation for geriatric hip fracture. The reasons for this higher excess mortality rate in males remain unclear. Endo et al15 reported that male gender was a risk factor for sustaining postoperative complications such as pneumonia, arrhythmia, delirium, and pulmonary embolism, even after controlling for age and the American Society of Anesthesiologists rating, as well as a higher mortality 1 year after hip fracture. Another study by Wehren et al16 reported an increased rate of death from infection in males for at least 2 years after hip fracture, suggesting that infection may contribute to the differential risk of death.

There are limitations to the present study. Patients with geriatric hip fracture who were treated in the private sector were not included, although they constituted only a small proportion of the total number of cases. Chau et al10 reported that approximately 98% of hip fractures were managed in the Hospital Authority.

In the CDARS of the Hospital Authority, the date of death was provided by the death registry of the Immigration Department of Hong Kong. We were unable to capture data for deaths that occurred outside the territory. Under the laws of Hong Kong, only deaths that occur in Hong Kong are registered with the Deaths Registries. According to the Census and Statistics Department, approximately 9% of the elderly population resides in the mainland.17 As Hong Kong residents are currently not eligible for free or subsidised health services in the mainland, we believe many elderly people will return to Hong Kong for medical treatment.

Other risk factors that may contribute to the excess mortality such as smoking and pre-morbid health status were not included in the present study. Further studies should also investigate the incidence and mortality of other fragility fractures. The effect of primary and secondary prevention by anti-osteoporotic medications on the incidence of geriatric hip fracture is also a potential area for further study.

Geriatric hip fracture will continue to be a major challenge for the health care system in the foreseeable future. Despite the emphasis on early surgery for geriatric hip fractures in recent years, the risk of premature death remained high for patients who underwent surgery for hip fracture. Future studies should be directed to identify the causes of this excess mortality and patients who are at increased risk of premature death, so that early interventions can be initiated to reduce their risk.

The authors would like to thank Mr Tony Kwok and the CDARS team of Hospital Authority for their help in data retrieval.

1. Mullen JO, Mullen NL. Hip fracture mortality. A prospective, multifactorial study to predict and minimize death risk. Clin Orthop Relat Res 1992;(280):214-22.

2. Omsland TK, Emaus N, Tell GS, et al. Mortality following the first hip fracture in Norwegian women and men (1999-2008). A NOREPOS study. Bone 2014;63:81-6. Crossref

3. Randell AG, Nguyen TV, Bhalerao N, Silverman SL, Sambrook PN, Eisman JA. Deterioration in quality of life following hip fracture: a prospective study. Osteoporos Int 2000;11:460-6. Crossref

4. Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992;2:285-9. Crossref

5. Maravic M, Taupin P, Landais P, Roux C. Change in hip fracture incidence over the last 6 years in France. Osteoporos Int 2011;22:797-801. Crossref

6. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA 2009;302:1573-9. Crossref

7. Yoon HK, Park C, Jang S, Jang S, Lee YK, Ha YC. Incidence and mortality following hip fracture in Korea. J Korean Med Sci 2011;26:1087-92. Crossref

8. Hagino H, Yamamoto K, Ohshiro H, Nakamura T, Kishimoto H, Nose T. Changing incidence of hip, distal radius, and proximal humerus fractures in Tottori Prefecture, Japan. Bone 1999;24:265-70. Crossref

9. Kung AW, Yates S, Wong V. Changing epidemiology of osteoporotic hip fracture rates in Hong Kong. Arch Osteoporos 2007;2:53-8. Crossref

10. Chau PH, Wong M, Lee A, Ling M, Woo J. Trends in hip fracture incidence and mortality in Chinese population from Hong Kong 2001-09. Age Ageing 2013;42:229-33. Crossref

11. Hong Kong Population Projections 2012-2041, Census and Statistics Department. Available from: http://www.censtatd.gov.hk/. Accessed Jun 2015.

12. Definitions: emergencies. Available from: http://www.who.int/hac/about/definitions/en/. Accessed Jun 2015.

13. The mortality trend in Hong Kong, 1981 to 2013. Hong Kong Monthly Digest of Statistics. November 2014, HKSAR: Census and Statistics Department. Available from: http://www.statistics.gov.hk/pub/B71411FB2014XXXXB0100.pdf. Accessed Jun 2015.

14. Abrahamsen B, va Staa T, Ariely R, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int 2009;20:1633-50. Crossref

15. Endo Y, Aharonoff GB, Zuckerman JD, Egol KA, Koval KJ. Gender differences in patients with hip fracture: a greater risk of morbidity and mortality in men. J Orthop Trauma 2005;19:29-35. Crossref

16. Wehren LE, Hawkes WG, Orwig DL, Hebel JR, Zimmerman SI, Magaziner J. Gender differences in mortality after hip fracture: the role of infection. J Bone Miner Res 2003;18:2231-7. Crossref

17. Characteristics of Hong Kong older persons residing in the Mainland of China. Hong Kong Monthly Digest of Statistics. September 2011. HKSAR: Census and Statistics Department. Available from: http://www.statistics.gov.hk/pub/B71109FC2011XXXXB0100.pdf. Accessed Jul 2015.

Click here to watch a video clip showing transurethral enucleation and resection of the prostate technique

Despite the availability of numerous minimally invasive techniques, transurethral resection of the prostate (TURP) remains the most common surgical treatment for lower urinary tract symptoms (LUTS) caused by benign prostatic enlargement (BPE) in small to medium-sized prostates.1 Nonetheless, TURP has been associated with significant complication rates.2

Bipolar TURP uses saline irrigation, which decreases the risk of TURP syndrome compared with monopolar TURP, and both bipolar and monopolar TURP result in comparable functional outcomes.3 The bipolar system can also be broadened to enucleate the prostate gland along the surgical capsule, using a resectoscope combined with a loop. This transurethral enucleation and resection of the prostate (TUERP) technique can potentially remove more prostatic tissue than TURP and requires no additional devices.

In the present study, we describe the technique and early postoperative outcomes of bipolar TUERP and compare our results with major international series.

Between January 2014 and June 2014, 28 consecutive patients underwent bipolar TUERP at Kwong Wah Hospital, Hong Kong. All patients were evaluated preoperatively by physical examination, digital rectal examination, transrectal ultrasonography (TRUS) of the prostate, and laboratory studies that included measurement of haemoglobin, sodium, and prostate-specific antigen (PSA). Patients were offered the option of ultrasound-guided transrectal prostate biopsy if the PSA level was >4 ng/mL or if the digital rectal examination showed suspicion of prostate cancer. Abnormal digital rectal examination findings included prostate nodule, asymmetry of the lateral lobes, or irregularity of the prostate. The TRUS was performed to measure the maximum length, width, and anteroposterior height of the prostate to calculate the prostate volume using the ellipse formula, where prostate volume (mL) = 0.52 x length x width x height. Patient baseline characteristics, indications for surgery, and operative data and complications were recorded by doctors. Patients with neurogenic bladder, previous genitourinary tract surgery, urethral stricture, or known bladder or prostate carcinoma were excluded from the technique of bipolar TUERP.

All bipolar TUERP procedures were performed by a single surgeon. This surgeon had performed 37 TUERPs using various techniques and devices previously, before the procedure was standardised as described below and shown in Figure 1. The technique used in this report was first described by and adopted from Prof CX Liu at Zhujiang Hospital of Southern Medical University in Guangzhou.4

Antiplatelet medications were stopped 3 days prior to surgery. Patients received general or spinal anaesthesia and were placed in the lithotomy position. Bladder stones where present were fragmented with a holmium laser via a 21-Fr rigid cystoscope and were evacuated with an Ellik evacuator before bipolar TUERP. A 26-Fr Olympus SurgMaster TURis resectoscope (Olympus Europe, Hamburg, Germany) with a standard loop was used. The incision was begun immediately proximal to the verumontanum using a cutting current. The surgical capsule plane was identified, and the whole gland dissected in a retrograde fashion from the cleavage plane using the resectoscope sheath, until the circular fibres of the bladder neck were identified. The loop electrode was used to coagulate all of the denuded vessels immediately during the detachment process. The adenoma was subtotally enucleated with a narrow pedicle attached to the bladder neck at the 6 o’clock position. The devascularised adenoma was rapidly resected in pieces by the loop electrode. The bladder neck at 5 to 7 o’clock was removed if it appeared relatively high. The anterior commissure at 12 o’clock was preserved except when it appeared obstructive endoscopically. The chips were evacuated with an Ellik evacuator. Finally, the prostatic fossa was inspected and haemostasis secured. A 24-Fr three-way urethral catheter was inserted at the end of the procedure for bladder irrigation. One of the patients in the series had open inguinal hernia repair performed after bipolar TUERP. Haemoglobin level and serum sodium concentration were measured on the same day after surgery. The protocol for postoperative care following bipolar TUERP was the same as that for monopolar and bipolar TURP in our unit. Bladder irrigation was stopped the following morning, and the catheter was removed on the second day postoperatively.

All patients were evaluated following bipolar TUERP during clinic visits at 4 weeks and 3 months. At each visit, history, physical examination, International Prostate Symptom Score (IPSS), and TRUS of the prostate were evaluated. The presence or absence of transient urinary incontinence was documented with direct questioning of the patient. Uroflowmetry was performed at 8 weeks, and serum PSA levels were measured at 3 months.

Table 1 lists the patients’ baseline characteristics, operative data, and early postoperative outcomes. Enucleation time was defined as the time from incision to completion of subtotal enucleation of the adenomatous tissue. Resection time was defined as the time needed for fragmentation of the en-bloc adenoma into chips. The mean enucleation and resection times were 13.6 (median, 15; range, 10-30) minutes and 47.7 (median, 35; range, 15-120) minutes, respectively, with a mean of 48.2 g of adenoma resected.

The mean PSA level decreased from 6.4 ng/mL to 0.9 ng/mL at 3 months postoperatively, representing an 85.9% decrease. Pathological examination of enucleated tissue revealed prostatic adenocarcinoma in one patient who had T1a disease with a Gleason score of 6; the serum PSA level decreased from 4.6 ng/mL to 1.7 ng/mL in this patient. There was a significant decrease in mean TRUS volume from 71.9 cm³ to 22.9 cm³ at 4 weeks and to 15.1 cm³ at 3 months postoperatively, corresponding to decreases of 68.2% and 79.0% at 4 weeks and 3 months, respectively.

More than half of the patients in our series (16 of 28 patients) presented with refractory acute urinary retention or obstructive uropathy and had required catheterisation prior to surgery. Preoperative uroflowmetry within the last year was available in only 15 patients, thus comparison between preoperative and postoperative urodynamic parameters was less representative. The mean peak urinary flow rate was 20.9 mL/s, and the mean post-void residual was 31.6 mL at 8 weeks postoperatively. The mean IPSS was 9.4, and the mean quality-of-life score was 1.9 at 4 weeks.

There was no requirement for blood transfusion nor incidence of clot retention in any patient. The mean decrease in haemoglobin was 11.5 g/L. Urinary tract infection presenting as acute epididymitis was noted in two (7.1%) patients. One (3.6%) patient required re-catheterisation on day 2 postoperatively and was successfully weaned off the catheter on day 5. Transient urinary incontinence was noted in three patients and one patient at 1 and 3 months postoperatively, respectively (10.7% at 1 month and 3.6% at 3 months). An average of two incontinence pads were required daily, and all cases of transient urinary incontinence subsided within 4 months. No urethral stricture, meatal stenosis, or bladder neck contracture was noted at 3 months.

The TURP has been considered the standard surgical therapy for LUTS caused by BPE. Despite improvements in equipment and techniques over the years, TURP remains associated with significant morbidity and re-treatment rates, particularly in patients with a large prostate.5 Open prostatectomy (OP) is therefore still considered a valid option for patients with a prostate of >80 g.6

Surgical enucleation for the treatment of LUTS caused by BPE remains the most complete method to remove adenomas of any size; the history of surgical enucleation dates back more than 100 years.7 In spite of the low re-operation rate and high success rate, OP is an invasive procedure associated with higher transfusion rates, longer catheterisation time, and longer hospital stay. As a result, the popularity of OP has declined.

The concept of surgical enucleation was revisited with the advent of endoscopic alternatives to open enucleation. Endoscopic enucleation allows for maximal removal of the adenoma and results in potentially equivalent efficacy compared with its open counterpart, with significantly lower morbidity. Holmium laser enucleation of the prostate (HoLEP) was the first endoscopic enucleative technique described.8 This technique has been compared with OP and TURP in various randomised controlled trials, yielding at least comparable outcomes and a favourable safety profile.9 The use of expensive high-energy holmium laser equipment and a steep learning curve, however, have limited the extensive application of HoLEP worldwide. There has also been a significant risk of bladder injury associated with the use of the mechanical tissue morcellator that is required for HoLEP.

The use of normal saline as an irrigant was made possible by the introduction of bipolar devices. As a result, the risk of TURP syndrome has been virtually eliminated, and bipolar TURP has been widely adopted for resection of larger prostates with longer operating times. The use of a bipolar device in endoscopic enucleation was first reported by Neill et al,10 and bipolar TUERP requires no additional devices in comparison with bipolar TURP. Moreover, the sheath of the resectoscope is used for mechanical enucleation of the adenoma along the plane of the surgical capsule, instead of the holmium laser used in HoLEP. The subtotally enucleated adenoma is then resected into chips by the loop electrode, and the use of a mechanical tissue morcellator is eliminated.

The nomenclature for this procedure has not been standardised, with terms such as TUERP, plasmakinetic enucleation of the prostate, and bipolar plasma enucleation of the prostate reported in the literature. All of these names generally refer to the same procedure with minor differences. The term ‘bipolar TUERP’ is used in this article.

Several modifications in technique and equipment since the introduction of bipolar TUERP have been suggested. For example, a spatula-like enucleation loop, combined with a loop electrode for haemostasis, was introduced by Olympus and is especially designed for this procedure. Alternatively, the use of thick loop electrodes and button electrodes has been described in some series to facilitate the enucleation process. Based on personal experience with these different loops, the alternative loops with different designs are generally stronger than the conventional loop electrode, and they can be used for mechanical enucleation without breakage. The use of the loop in performing enucleation, instead of the resectoscope sheath, also provides better, more direct visualisation during the enucleation process and potentially shortens the learning curve and improves the safety of the procedure, particularly in the early phase of learning. The resectoscope sheath, however, facilitates a shorter enucleation time without compromising safety with the surgeon’s experience. The initial technique adopted for bipolar TUERP was the ‘three-lobe’ technique. This procedure starts with deep incisions down to the surgical capsule at the 5 and 7 o’clock positions from the bladder neck to the verumontanum, with an additional incision at the 12 o’clock position also reported. The median and lateral lobes of the prostate are then subtotally enucleated and resected in sequence. Some authors have reported ‘hybrid’ techniques, with the median lobe resected as in conventional TURP and only the lateral lobes enucleated. It has also been noted that deep incisions might not be necessary, as the surgical capsule plane can generally be identified with a small incision immediately proximal to the verumontanum, and the whole gland can be enucleated without separation of the lobes. This procedure avoids the bleeding associated with deep incisions of the bladder neck and adenoma although a small lobe can sometimes be difficult to enucleate after separation of the lobes. The 12 o’clock incision has been mostly abandoned, as has also been advocated for HoLEP. The anterior commissure, particularly the distal part, has been preserved to decrease the rate of transient urinary incontinence postoperatively. The technique used in our centre is currently the most widely practised among different centres.

Several series have reported the perioperative outcomes of bipolar TUERP using similar surgical techniques. Only the largest series from each centre was included for comparison; most of the published series are from China. The results of our series were compared with the TUERP arms of the various published series; this list of series and a comparison of the preoperative parameters are listed in Table 2. After the first published article by Neill et al10 comparing HoLEP and bipolar TUERP in 2006, Liu et al11 published the largest series with 1600 patients in 2010. Zhao et al12 and Liao and Yu13 followed by comparing bipolar TUERP and TURP in medium-sized prostates. Kan et al14 compared bipolar TUERP and TURP in large prostates, and Rao et al,15 Ou et al,16 Geavlete et al,17 and Chen et al18 compared bipolar TUERP with OP. The operative and early postoperative outcomes of bipolar TUERP from various studies are listed in Table 3.

The operating time was generally longer when the preoperative TRUS volume and resected prostate weight increased. Although Liu et al11 reported enucleation and resection times without reporting the total operating time, the preoperative TRUS volume and resected prostate weight were comparable between Liu et al’s report11 and our series. In addition, the resection time was prostate-size–dependent, and a resection efficacy of approximately 1 g/min was reported in both Liu et al’s report11 and our series. The enucleation time was less size-dependent, varying from 10 to 30 minutes, despite the large range of prostate sizes in our series.

The decrease in haemoglobin of approximately 10 g/L was reported for both medium-sized and large prostates. Early control of denuded vessels during the enucleation process made the removal of large glands possible, with minimal blood loss during the resection process.

The catheterisation and hospitalisation times varied greatly among the series evaluated. Longer times for both have typically been reported in series from China.11 12 13 15 16 18 In addition, no standard protocols were stated in most of the series, and the decision for catheter removal and hospital discharge were at the discretion of the surgeons. We report short catheterisation and hospitalisation times with the adoption of the same protocol as TURP in our institution. Specifically, bladder irrigation was stopped on postoperative day 1, the catheter was removed, and the patient was discharged from the hospital on postoperative day 2. A total of 92.9% of the patients (26 of 28 patients) complied with the postoperative protocol.

Postoperative TRUS volume was rarely reported by the series despite the consistent reporting of preoperative volume. This lack of reporting reflects the difficulty in accurately estimating residual tissue volume by TRUS, as illustrated by the postoperative TRUS photo shown in Figure 2. In addition, the central cavity remaining after TUERP can lead to overestimation of the prostate volume with the application of the traditional ellipse formula. Instead, preoperative estimation of the peripheral zone volume, obtained by subtracting the volume of the central zone from the total prostate volume, may represent a better method for estimating the residual tissue volume after TUERP. A decrease in TRUS volume of approximately 70% after TUERP was consistently reported, despite the pitfalls of postoperative TRUS measurements.

It has also been shown from the experience of HoLEP that a reduction in PSA level correlated with the amount of prostate tissue removed.19 Thus, serum PSA may serve as a better surrogate marker in the estimation of postoperative residual tissue volume. A postoperative PSA level of approximately 1 ng/mL and a decrease in PSA by >70% were commonly reported in most of the series.

Adverse events were poorly and inconsistently reported, as shown in Table 4. The standard Clavien classification was not adopted. There was no Clavien grade 3 or 4 complication in our series. The transfusion rate was low, with the exception of the series by Ou et al,16 and clot retention was rare. The rate of urinary tract infection ranged from 2% to 7.3%, and the re-catheterisation rate was <5%. Major complications were not common but did occur, as reported by Kan et al14; four admissions to intensive care units and nine conversions to other procedures were reported in this series of 74 patients. The rate of urethral stricture or bladder neck stenosis was low and comparable with conventional TURP as reported by the series by Liu et al.11 Long-term outcome was not reported in our series due to the short duration of follow-up. Temporary urinary incontinence was the major concern with enucleative procedures, and OP resulted in temporary urinary incontinence in approximately 10% of cases. The reporting of transient urinary incontinence after TUERP was poor and did not feature in three of the nine series analysed. Furthermore, the definition, timing, and severity of urinary incontinence were not stated in the other studies. Dramatic changes in the symptomatology of the patients over time following benign prostatic hyperplasia–related surgery, however, likely explain the difficulty in defining transient urinary incontinence. In our experience, transient urinary incontinence is not uncommon after TURP, although it is difficult to differentiate the type of urinary incontinence, stress, urge or mixed, by history or urodynamic studies. The natural history of this phenomenon has rarely been reported in the literature. It was interesting to note that the rate of transient urinary incontinence was much higher for the TURP group (16.1%) compared with the TUERP group (7.5%) in the series by Liao and Yu.13 In our experience, 17.9% of patients reported episode(s) of urinary incontinence at any time point after TUERP; the rate of transient urinary incontinence was 10.7% and 3.6% at 1 and 3 months postoperatively, respectively. Patients who had transient urinary incontinence used two pads daily on average, and all cases of transient urinary incontinence subsided by 4 months. Further investigations with, for example, measurement of pad weight and urodynamic studies will better delineate the cause and natural history of postoperative transient urinary incontinence. There is currently no predictive factor identified for the phenomenon.

Comparison of outcome and complications between patients with and without urinary retention was limited by the small patient number in our study. No significant difference between outcome and complications was identified even though patients with retention were significantly older.

A learning curve of 50 cases was reported for HoLEP,20 and this learning curve was expected to be shorter for bipolar TUERP. The instrumentation for TUERP should be familiar to an endourologist experienced in TURP because no additional devices are required. Xiong et al21 analysed the learning curve of bipolar TUERP. The ratio of conversion to conventional TURP decreased after 30 cases, and the efficiency of enucleation and resection increased with accumulative experience after 50 cases. Our series showed that the early postoperative outcomes were comparable to those of large series after approximately 35 cases, without an increase in adverse events. The findings were based on analysis of the learning curve of a single surgeon and may not be applicable to all surgeons. Nevertheless, an estimation of a learning curve in a magnitude of 30 to 50 cases seems reasonable and serves as a valuable reference.

Our study suggests that bipolar TUERP is a safe technique for prostates of any size. This procedure should become the endourological equivalent to open adenomectomy, with fewer complications and shorter convalescence. This technique can also be acquired safely with a relatively short learning curve.

1. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: Diagnosis and treatment recommendations. J Urol 2003;170:530-47. Crossref

2. Madersbacher S, Lackner J, Brössner C, et al. Reoperation, myocardial infarction and mortality after transurethral and open prostatectomy: a nation-wide, long-term analysis of 23,123 cases. Eur Urol 2005;47:499-504. Crossref

3. Mamoulakis C, Ubbink DT, de la Rosette JJ. Bipolar versus monopolar transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. Eur Urol 2009;56:798-809. Crossref

4. Liu C, Zheng S, Li H, Xu K. Transurethral enucleative resection of prostate for treatment of BPH. Eur Urol 2006;5 Suppl:234. Crossref

5. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral resection of the prostate (TURP)—incidence, management, and prevention. Eur Urol 2006;50:969-79; discussion 980. Crossref

6. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 2013;64:118-40. Crossref

7. Freyer PJ. Total enucleation of the prostate. A further series of 550 cases of the operation. Br Med J 1919;1:121-120.2.

8. Gilling PJ, Kennett KM, Fraundorfer MR. Holmium laser enucleation of the prostate for glands larger than 100 g: an endourologic alternative to open prostatectomy. J Endourol 2000;14:529-31. Crossref

9. Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol 2010;58:384-97. Crossref

10. Neill MG, Gilling PJ, Kennett KM, et al. Randomized trial comparing holmium laser enucleation of prostate with plasmakinetic enucleation of prostate for treatment of benign prostatic hyperplasia. Urology 2006;68:1020-4. Crossref

11. Liu C, Zheng S, Li H, Xu K. Transurethral enucleation and resection of prostate in patients with benign prostatic hyperplasia by plasma kinetics. J Urol 2010;184:2440-5. Crossref

12. Zhao Z, Zeng G, Zhong W, Mai Z, Zeng S, Tao X. A prospective, randomised trial comparing plasmakinetic enucleation to standard transurethral resection of the prostate for symptomatic benign prostatic hyperplasia: three-year follow-up results. Eur Urol 2010;58:752-8. Crossref

13. Liao N, Yu J. A study comparing plasmakinetic enucleation with bipolar plasmakinetic resection of the prostate for benign prostatic hyperplasia. J Endourol 2012;26:884-8. Crossref

14. Kan CF, Tsu HL, Chiu Y, To HC, Sze B, Chan SW. A prospective study comparing bipolar endoscopic enucleation of prostate with bipolar transurethral resection in saline for management of symptomatic benign prostate enlargement larger than 70 g in a matched cohort. Int Urol Nephrol 2014;46:511-7. Crossref

15. Rao JM, Yang JR, Ren YX, He J, Ding P, Yang JH. Plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia >80 mL: 12-month follow-up results of a randomized clinical trial. Urology 2013;82:176-81. Crossref

16. Ou R, Deng X, Yang W, Wei X, Chen H, Xie K. Transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes >80 mL: a prospective randomized study. BJU Int 2013;112:239-45. Crossref

17. Geavlete B, Stanescu F, Iacoboaie C, Geavlete P. Bipolar plasma enucleation of the prostate vs open prostatectomy in large benign prostatic hyperplasia cases—a medium term, prospective, randomized comparison. BJU Int 2013;111:793-803. Crossref

18. Chen S, Zhu L, Cai J, et al. Plasmakinetic enucleation of the prostate compared with open prostatectomy for prostates larger than 100 grams: a randomized noninferiority controlled trial with long-term results at 6 years. Eur Urol 2014;66:284-91. Crossref

19. Tinmouth WW, Habib E, Kim SC, et al. Change in serum prostate specific antigen concentration after holmium laser enucleation of the prostate: a marker for completeness of adenoma resection? J Endourol 2005;19:550-4. Crossref

20. Shah HN, Mahajan AP, Sodha HS, Hegde S, Mohile PD, Bansal MB. Prospective evaluation of the learning curve for holmium laser enucleation of the prostate. J Urol 2007;177:1468-74. Crossref

21. Xiong W, Sun M, Ran Q, Chen F, Du Y, Dou K. Learning curve for bipolar transurethral enucleation and resection of the prostate in saline for symptomatic benign prostatic hyperplasia: experience in the first 100 consecutive patients. Urol Int 2013;90:68-74. Crossref

Intussusception is the most common cause of intestinal obstruction in infants and young children between the age of 3 months and 3 years, and the peak age of presentation is 4 to 8 months.1 The invagination of proximal bowel into more distal bowel results in venous congestion and bowel wall oedema. If this condition is not promptly diagnosed and treated, arterial obstruction and bowel necrosis and perforation may occur.2 Approximately 90% of intussusceptions in the paediatric age-group are ileocolic and idiopathic,3 presumably caused by lymphoid hyperplasia that has been suggested as the ‘lead point’ in its pathogenesis.4 Viral infection may also play a role.5 6 7 8

The reported incidence of a pathological lead point in paediatric intussusception is approximately 6%,9 the most common of which is Meckel’s diverticulum.10 Systemic conditions such as Henoch-Schönlein purpura, Peutz-Jeghers syndrome, and familial polyposis can also increase the risk of intussusception. Abdominal trauma and postoperative abdomen have also been reported to pose a higher risk for intussusception.11 12 13 14

The presenting symptoms of intussusception are often non-specific and may mimic viral gastro-enteritis, presenting as vomiting and diarrhoea. The classic triad of red currant jelly stool, abdominal pain, and abdominal mass is not often encountered, and the diagnosis may easily be delayed or missed.15 Plain abdominal films are neither sensitive nor specific for intussusception and may be completely normal.16 The most consistent finding is a paucity of gas in the right iliac fossa. Other possible features include soft tissue mass, target sign, or meniscus sign.17 The first-line investigation for diagnosis of intussusception in children is abdominal ultrasound, given its high sensitivity (98%-100%) and specificity (88%-100%).18

Non-operative reduction methods for intussusception include barium enema, and hydrostatic or pneumatic reduction.19 Pneumatic reduction is currently the preferred standard treatment, given the greater ease of performing the examination, the lesser morbidity with complications, and the slightly higher success rate of 84% to 100%.20 21 22

Operative reduction is required when non-operative reduction is either contra-indicated (eg peritonitis, perforation, profound shock) or unsuccessful. Open surgery has been the conventional approach although laparoscopic reduction is also feasible and successful in uncomplicated cases.23 24

In this study, we aimed to review our hospital’s experience in the management of paediatric intussusception over the last 17 years, with a focus on assessing the efficacy of non-operative reduction and identifying the risk factors that may lower its success rate.

We conducted a retrospective study of children who presented with intussusception from January 1997 to December 2014 in our hospital. We started with the year 1997 as some of earlier records were incomplete. Patient demographics, clinical presentation, duration of symptoms, treatment modalities, complication rate, and length of hospital stay were studied. The method of non-operative reduction in our institution was ultrasound-guided hydrostatic reduction before 2005 and pneumatic reduction with fluoroscopy after 2005, as the latter was easier and faster to perform. The procedure was performed by paediatric radiologists, with a paediatric surgeon available if necessary. In pneumatic reduction, air is insufflated via a Foley catheter (with size of 18-Fr to 22-Fr, depending on patient’s size, with balloon inflated with 10 mL water) placed inside the patient’s rectum under pressure monitoring at 120 mm Hg. Our radiologists would perform a maximum of three attempts. The patient might be given intravenous midazolam at a dose of 0.1 to 0.2 mg/kg if necessary. Successful reduction was demonstrated by free flow of air into the terminal ileum and disappearance of the caecal soft tissue mass.

For laparoscopic reduction, a 5-mm subumbilical port was used for camera access. Another two working ports (one in the upper and one in the lower abdomen) were inserted. Reduction of intussusception was performed with laparoscopic graspers. In open reduction, manual reduction was achieved by milking the intussusceptum out of the intussuscipient. Bowel resection was performed when bowel necrosis was found intra-operatively.

Data analysis was carried out using the Statistical Package for the Social Sciences (Windows version 21.0; SPSS Inc, Chicago [IL], US). Mean values were expressed with standard deviation. Continuous variables were compared with Mann-Whitney U test and categorical values with Chi squared test. Results were considered statistically significant when P≤0.05. Comparison of success, recurrence, and complication rates between hydrostatic and pneumatic reduction groups was performed. The length of hospital stay was also compared.

A total of 173 children (108 male, 65 female) presented to our hospital with intussusception during the study period. Of them, 83 (48%) were admitted directly to our paediatric surgical ward, 50 (29%) were referred from the paediatric medical ward in our hospital, and the remaining 40 (23%) were referred from other public and private hospitals. The median age at presentation was 12.5 months (range, 2 months to 16 years) and the mean (± standard deviation) duration of presenting symptoms was 2.3 ± 1.8 days. The common presenting symptoms and their percentage of occurrence are shown in Table 1. The most common symptom reported was vomiting and occurred in 132 (76.3%) patients.

All patients except one were diagnosed by ultrasonography. One patient underwent computed tomographic scan for diagnosis due to an atypical presentation of intussusception. All patients underwent either non-operative or operative treatment within 24 hours of admission. Pneumatic or hydrostatic reduction (Fig a) was performed in 160 patients, among which 127 (79.4%) were successful and three (1.9%) were complicated by bowel perforation. A total of 46 patients in our study required operative reduction, but two of the intussusceptions were found to be reduced upon laparotomy. These radiological misdiagnoses could be due to mistaken identity of the oedematous ileocaecal valve for intussusceptum. The indications for operative treatment are summarised in Table 1. Early recurrence of intussusception (<72 hours post-reduction) occurred in four (3.1%) of the 127 patients who had initial successful non-operative reduction. No recurrence was reported in patients treated surgically. Laparoscopic reduction was attempted in 13 patients, among whom five (38.5%) were successful. Conversion to open reduction was required in five patients because of the need for bowel resection and in a further three due to difficult reduction. Among the 46 patients who required operative reduction, 23 (50%) required bowel resection. A pathological lead point was noted intra-operatively in seven (15.2%) patients and four had a perforated bowel (three of which were complications of non-operative reduction). The remaining 12 had non-viable gangrenous bowel that was subsequently confirmed by histology. The operations were complicated with one burst abdomen and one anastomotic leak. The age distribution in our cohort of patients and the number of patients with pathological lead point are shown in Table 2.

We next analysed the possible risk factors for unsuccessful non-operative reduction in the 160 patients (Table 3). The only statistically significant factor was the presence of an abdominal mass (relative risk=2.0; 95% confidence interval, 1.8-2.2). The distribution of the duration of symptoms is presented in Table 4. Nonetheless, the duration of symptoms and the extent of the intussusception did not appear to affect the chance of a successful non-operative reduction (Table 5). There were 129 patients with intussusception at the hepatic flexure or a more proximal site, 93 (72.1%) of whom had successful non-operative reduction; 44 presented with intussusception at the transverse colon or a more distal site, of whom 34 (77.3%) underwent successful non-operative reduction. There was no significant difference in the success rate of non-operative reduction between the two groups (P=0.56). Approximately 50% of patients were admitted directly to our ward from the beginning. There was no difference in the success rate of non-operative reduction between this group of patients and those who were referred from other wards or hospitals (77.1% vs 77.3%, P=1.00).

The overall success rate of non-operative reduction was 79.4%. We also compared the success rate for the two non-operative treatment modalities. There was no statistically significant difference between the success rate of hydrostatic reduction (81.5%) versus pneumatic reduction (77.2%) in our study (P=0.56).

There was a statistically significant difference in the median length of post-reduction hospital stay for patients who were successfully treated non-operatively (3 days; range, 1-12 days) versus operatively (7.5 days; range, 3-73 days; P=0.01).

Intussusception is a true paediatric surgical emergency and is second only to appendicitis as the most common cause of an acute abdominal emergency in children.25 The complete classic triad of intermittent abdominal pain, red currant jelly stool, and a palpable abdominal mass is not a common presentation.26 Only five (2.9%) of our patients were documented to have all three symptoms present at the time of hospital admission. In accordance with previous studies, vomiting was the most common presenting symptom.4 27 Per rectal bleeding or red currant jelly stool signify bowel ischaemia and mucosal sloughing but is a rather late sign and was present in only 40.5% of our patients. Nonetheless, all except one patient had at least one of the symptoms of abdominal pain, abdominal mass, red currant jelly stool, vomiting, or irritability. These symptoms should be actively sought in any patient in whom intussusception is suspected.

The most reliable abdominal sign, if present, is a palpable mass in the right upper quadrant of the abdomen. It was present in 39.3% of our patients, and was a risk factor for the need of operative treatment. We postulate that a palpable mass may signify relatively longer duration of intussusception that causes complete intestinal obstruction, thus rendering non-operative reduction less successful as it becomes more difficult for the reduction medium to pass through. Many children with intussusception present with non-specific signs and symptoms, thus the diagnosis may easily be delayed or missed.15 Therefore, as clinicians we must maintain a high index of suspicion in order to identify this emergency in a timely manner. Early referral of suspected cases to a tertiary treatment centre can significantly reduce morbidity in the child.

With positive sonographic findings of intussusception, an enema is reserved for therapeutic purposes, although it may be necessary for diagnosis when ultrasonography findings are questionable. Computed tomography is seldom needed for diagnosis of paediatric intussusception, except in cases where an associated underlying pathological lead point is suspected. Our recommended diagnostic and treatment algorithm is summarised in Figure b. Pneumatic reduction is currently our preferred standard treatment of intussusception, given the greater ease of performing the examination, lesser morbidity with complication, and the high success rate.20 21 22 Major advantages of air enema reduction include a relatively low radiation dose and improved safety with constant pressure monitoring.28 29 The perforation rate is reported to be less than 3%.30 In a randomised trial performed by Hadidi and El Shal,22 pneumatic reduction was concluded to be the modality with fewest complications and highest success rate, when compared with barium enema and hydrostatic reduction. In our study, there was no statistically significant difference in the success rate between hydrostatic reduction and pneumatic reduction (81.5% vs 77.2%, P=0.56). We believe that this is attributable to the fact that both hydrostatic and pneumatic reductions are based on similar principles.

Laparoscopic reduction has been demonstrated to be feasible and successful in uncomplicated intussusception.23 24 In our series, five (62.5%) of the eight conversions from laparoscopic to open reduction were due to the need for bowel resection.

Non-operative reduction has a high overall success rate and low complication and recurrence rates. A high success rate was observed even in the group of patients with delayed presentation of over 72 hours. It also leads to a shorter hospital stay and is therefore recommended as the first-line treatment of this condition.

The presence of a palpable abdominal mass is a risk factor for failure of non-operative reduction. Operative intervention should not be delayed in these patients who encounter difficult or doubtful non-operative reduction. For patients in whom non-operative reduction fails, laparoscopic reduction appears to be a feasible option. From our experience, a significant proportion of this group of patients require bowel resection. If the viability of the bowel is doubtful during laparoscopy, early conversion to open surgery should be performed in order to avoid delay in treatment.

Non-operative reduction has a high success rate and low complication rate, but the presence of a palpable abdominal mass is a risk factor for failure. Operative intervention should not be delayed in these patients who encounter difficult or doubtful non-operative reduction.

1. Bines J, Ivanoff B. Acute intussusception in infants and children: incidence, clinical presentation and management: a global perspective. Report 02.19. Geneva: World Health Organization; 2002.

2. Stringer MD, Pablot SM, Brereton RJ. Paediatric intussusception. Br J Surg 1992;79:867-76. Crossref

3. Bajaj L, Roback MG. Postreduction management of intussusception in a children’s hospital emergency department. Pediatrics 2003;112:1302-7. Crossref

4. DiFiore JW. Intussusception. Semin Pediatr Surg 1999;8:214-20. Crossref

5. Mayell MJ. Intussusception in infancy and childhood in Southern Africa. A review of 223 cases. Arch Dis Child 1972;47:20-5. Crossref

6. Mangete ED, Allison AB. Intussusception in infancy and childhood: an analysis of 69 cases. West Afr J Med 1994;13:87-90.

7. Asano Y, Yoshikawa T, Suga S, Hata T, Yamazaki T, Yazaki T. Simultaneous occurrence of human herpesvirus 6 infection and intussusception in three infants. Pediatr Infect Dis J 1991;10:335-7. Crossref

8. O’Ryan M, Lucero Y, Peña A, Valenzuela MT. Two year review of intestinal intussusception in six large public hospitals of Santiago, Chile. Pediatr Infect Dis J 2003;22:717-21. Crossref

9. Blakelock RT, Beasley SW. The clinical implications of non-idiopathic intussusception. Pediatr Surg Int 1998;14:163-7. Crossref

10. Navarro O, Dugougeat F, Kornecki A, Shuckett B, Alton DJ, Daneman A. The impact of imaging in the management of intussusception owing to pathologic lead points in children. A review of 43 cases. Pediatr Radiol 2000;30:594-603. Crossref

11. Komadina R, Smrkolj V. Intussusception after blunt abdominal trauma. J Trauma 1998;45:615-6. Crossref

12. Stockinger ZT, McSwain N Jr. Intussusception caused by abdominal trauma: case report and review of 91 cases reported in the literature. J Trauma 2005;58:187-8. Crossref

13. Türkyilmaz Z, Sönmez K, Demiroğullari B, et al. Postoperative intussusception in children. Acta Chir Belg 2005;105:187-9.

14. Emil S, Shaw X, Laberge JM. Post-operative colocolic intussusception. Pediatr Surg Int 2003;19:220-2.

15. Reijnen JA, Festen C, Joosten HJ, van Wieringen PM. Atypical characteristics of a group of children with intussusception. Acta Paediatr Scand 1990;79:675-9. Crossref

16. Hernandez JA, Swischuk LE, Angel CA. Validity of plain films in intussusception. Emerg Radiol 2004;10:323-6.

17. Ratcliffe JF, Fong S, Cheong I, O’Connell P. The plain abdominal film in intussusception: the accuracy and incidence of radiographic signs. Pediatr Radiol 1992;22:110-1. Crossref

18. Bhisitkul DM, Listernick R, Shkolnik A, et al. Clinical application of ultrasonography in the diagnosis of intussusception. J Pediatr 1992;121:182-6. Crossref

19. Peh WC, Khong PL, Lam C, et al. Reduction of intussusception in children using sonographic guidance. AJR Am J Roentgenol 1999;173:985-8. Crossref

20. Lui KW, Wong HF, Cheung YC, et al. Air enema for diagnosis and reduction of intussusception in children: clinical experience and fluoroscopy time correlation. J Pediatr Surg 2001;36:479-81. Crossref

21. Rubí I, Vera R, Rubí SC, et al. Air reduction of intussusception. Eur J Pediatr Surg 2002;12:387-90. Crossref

22. Hadidi AT, El Shal N. Childhood intussusception: a comparative study of nonsurgical management. J Pediatr Surg 1999;34:304-7. Crossref

23. Schier F. Experience with laparoscopy in the treatment of intussusception. J Pediatr Surg 1997;32:1713-4. Crossref

24. Poddoubnyi IV, Dronov AF, Blinnikov OI, Smirnov AN, Darenkov IA, Dedov KA. Laparoscopy in the treatment of intussusception in children. J Pediatr Surg 1998;33:1194-7. Crossref

25. Waseem M, Rosenberg HK. Intussusception. Pediatr Emerg Care 2008;24:793-800. Crossref

26. Bruce J, Huh YS, Cooney DR, Karp MP, Allen JE, Jewett TC Jr. Intussusception: evolution of current management. J Pediatr Gastroenterol Nutr 1987;6:663-74. Crossref

27. Losek JD. Intussusception: don’t miss the diagnosis! Pediatr Emerg Care 1993;9:46-51. Crossref

28. Stringer DA, Ein SH. Pneumatic reduction: advantages, risks and indications. Pediatr Radiol 1990;20:475-7. Crossref

29. Meyer JS, Dangman BC, Buonomo C, Berlin JA. Air and liquid contrast agents in the management of intussusception: a controlled, randomized trial. Radiology 1993;188:507-11. Crossref

30. Daneman A, Alton DJ, Ein S, Wesson D, Superina R, Thorner P. Perforation during attempted intussusception reduction in children—a comparison of perforation with barium and air. Pediatr Radiol 1995;25:81-8. Crossref

Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical.1 Traditionally, diagnosis in these patients relies on extensive endocrine investigation. With advances in the understanding of the genes involved in sexual determination and differentiation,2 molecular diagnosis is playing an increasingly important role and may even overtake the role of hormonal assessment as the first-line test, with the latter being reserved for assessment of disease severity rather than diagnosis.3

One of the most common causes of 46,XY DSD in the western population is androgen insensitivity syndrome (AIS).4 Whether the same is true in our local population remains unknown. We performed a prospective multicentre study to explore the possible aetiological basis of 46,XY DSD in the Hong Kong Chinese population.

Patients who were referred to a paediatric endocrinologist for the first time or were followed up in their clinic at five public hospitals in Hong Kong between July 2009 and June 2011 were recruited for the study. Inclusion criteria were 46,XY ethnic Chinese patients who presented with incompletely virilised, ambiguous, or completely female external genitalia. Criteria that suggested DSD at birth were overt genital ambiguity, apparent female genitalia with an enlarged clitoris, posterior labial fusion, or an inguinal/labial mass, apparent male genitalia with bilateral undescended testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testes, and discordance between genital appearance and prenatal karyotype.1 Micropenis is defined as stretched penile length of <2.5 cm based on the published norm for Chinese.1 Written informed consent was obtained from the patients and/or parents and the study was approved by the local ethics committee. None of the patients/parents refused to participate in the study although seven refused genetic testing (Table 1).

Blood was taken from patients for electrolyte and baseline endocrine assessment and included measurement of cortisol, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate, testosterone (T), androstenedione (A4), dihydrotestosterone (DHT), anti-Müllerian hormone (AMH), and gonadotropins. Human chorionic gonadotropin (hCG) stimulation test was performed to test for testicular Leydig cell function. The short synacthen test was also performed when indicated.

Cortisol, dehydroepiandrosterone sulfate, and gonadotropins were measured by electro-chemiluminescence immunoassay (Modular Analytics E170; Roche, Mannheim, Germany); T was measured by a competitive immunoenzymatic assay (ACCESS 2; Beckman Coulter, Brea [CA], US); 17-OHP was measured by liquid chromatography–tandem mass spectrometry using an in-house method; AMH was measured by an enzyme-linked immunosorbent assay (AMH Gen II ELISA, A73818; Beckman Coulter, Brea [CA], US); DHT was measured by radioimmunoassay (DSL9600i; Beckman Coulter, Prague, Czech Republic); A4 was measured by solid-phase competitive chemiluminescent enzyme-labelled immunoassay (L2KAO2, Immulite 2000; Siemens, Tarrytown [NY], US). Male reference intervals were considered the most appropriate for data interpretation in this study.

Spot urine from patients under 3 months of age and 24-hour urine from those at or older than 3 months of age were processed for steroid profiling as described previously.5

DNA was extracted from peripheral whole blood using a QIAamp DNA blood kit (Qiagen, Hilden, Germany). Polymerase chain reaction and direct DNA sequencing were performed on targeted genes when suggested by the clinical and hormonal findings. Otherwise all patients had their AR (androgen receptor) and NR5A1 (steroidogenic factor 1) genes sequenced. Those patients with negative genetic findings were subjected to multiplex ligation-dependent probe amplification (MLPA) analysis (P185 Intersex probemix; P074 Androgen Receptor probemix and P334 Gonadal probemix; MRC-Holland) to test for gross deletion or gene duplication. The results were analysed by Coffalyser.Net. Family genetic studies were performed when mutation(s) were identified in the index patients.

The functional effect of novel missense mutations detected was tested by online in-silico analysis software SIFT, PolyPhen2, and Align GVGD.

Overall, 64 patients (53 male, 11 phenotypic female), including 14 new patients, with 46,XY DSD were recruited into the study. The clinical and hormonal findings of individual patients are listed in Table 1. A genetic diagnosis was made in 10 patients prior to the study. Other major structural abnormalities were evident in eight (Table 2). Their age at presentation ranged from birth to 17 years. Five (8%) were born prematurely (24-35 weeks) and nine (14%) with low birth weight (0.59-2.32 kg). All had non-consanguineous parents. A family history of sexual ambiguity was present in six. Overall, 61 (95%) presented with ambiguous external genitalia including 15 with isolated micropenis, eight with isolated severe hypospadias, and one with discordance between the prenatal karyotype and the postnatal phenotype. Three presented after birth, one each with inguinal hernia, delayed puberty, and primary amenorrhoea.

Regarding the hormonal findings, Figure 1 shows the baseline and post-hCG–stimulated T and DHT levels in patients with mutations detected in the AR gene and those without, where the results overlapped between the two groups. Eight patients (patients 13, 19, 21, 30, 31, 40, 49, and 56) underwent short synacthen test and with the exception of patient 19, all had an adequate cortisol response (>550 nmol/L). Patient 27 had a relatively low T/A4 ratio before and after hCG stimulation but sequencing revealed no mutation in his HSD17B3 (17β-hydroxysteroid dehydrogenase III) gene. All other patients had unremarkable T and A4 levels, as well as T/A4 ratio.

Eleven patients had characteristically low 5α- to 5β-reduced steroid metabolite ratios in their urine, compatible with the diagnosis of 5α-reductase 2 deficiency (5ARD). This was also confirmed by mutational analysis of the SRD5A2 (steroid 5α-reductase 2) gene. All other patients had unremarkable urinary steroid metabolite pattern.

Overall, 22 (39%) patients had a confirmed genetic diagnosis (Table 3). The most common diagnoses in our cohort were 5ARD (n=11) and AIS (n=7). Other genetic diagnoses included cholesterol side-chain cleavage enzyme deficiency (n=1), Frasier syndrome (n=1), NR5A1-related sex reversal (n=1), and persistent Müllerian duct syndrome (PMDS; n=1). The clinical and laboratory findings of patients 19 and 20 have been reported previously.6 7 Patients 12 and 15 had de-novo mutations in the AR gene and were in mosaic pattern. Patient 21 had a novel missense variant p.Ala260Val detected in his NR5A1 gene. His AMH level was not low, contrary to some of the previously reported cases.8 There was also a clinically significant rise in T level after hCG stimulation. Short synacthen test demonstrated an adequate cortisol response (baseline: 720 nmol/L; post–adrenocorticotropin hormone: 822 nmol/L). His father also carried the same heterozygous mutation although he denied any symptoms of DSD. This novel genetic variant was not detected in 100 normal Chinese subjects (control). Patient 22 had bilateral undescended testes. He underwent orchidopexy at the age of 1 year during which the presence of Müllerian duct structures was suspected. Further workup including pelvic ultrasound revealed Müllerian duct structures and extremely low AMH level. The diagnosis of PMDS was confirmed by the presence of three heterozygous novel missense variants in the AMH gene (Tables 3 and 4).

Six novel genetic variants were identified in the AMH, AR, and NR5A1 genes (Fig 2). At least two of the three in-silico analysis programmes predicted the variants to be pathogenic (Table 4). Multiple sequence alignment showed that the amino acids of concern were highly conserved across different animal species. All these findings support the pathogenic nature of these variants accounting for the patients’ phenotypes.

Eleven patients were reared as girls because of severe under-virilisation at birth, including three with 5ARD, three with AIS, and one with Frasier syndrome. The underlying genetic causes in the remaining four patients were undetermined. The longest follow-up period was 27 years. None of them has requested change of gender to date. Five patients (patients 2, 4, 7, 12, and 15) exhibited ‘tom-boy-like’ behaviour during childhood and required counselling by a clinical psychologist while two males (patients 17 and 47) requested exogenous T to augment penile growth after puberty. Patient 20 developed germinoma in her dysgenetic gonad with no recurrence after surgery.

46,XY DSD is a heterogeneous condition caused by a wide spectrum of disorders. Making an accurate diagnosis is difficult but important for emergency medical treatment as some DSDs are associated with life-threatening Addisonian crisis. In addition, the diagnosis is essential so that relevant information and counselling can be provided to parents and clinical management can be formulated, bearing in mind the best interests of the child. Initial workup includes a detailed antenatal and postnatal history, physical examination, karyotyping, and hormonal assays. This will guide further workup such as imaging and genetic analysis. Nonetheless, there are often limitations to hormonal studies as illustrated in the present series. The non-distinct pattern of T and DHT at baseline and following hCG stimulation in AR mutation–positive and –negative patients suggest the need to reconsider our laboratory diagnostic algorithm for AIS.

Androgen insensitivity syndrome is reported to be the most common cause of 46,XY DSD in a few ethnic groups,9 10 11 while 5ARD, which is believed to be rare, was also a major aetiology in our cohort. It is important to differentiate between 5ARD and AIS as soon as possible so that patients with 5ARD can be raised as boys whenever practical.12 The penile growth of patients with 5ARD can be promoted by topical DHT treatment and spontaneous virilisation may occur during puberty. Most of these patients who are reared as girls during childhood identify themselves as male and change their gender as an adult, although we have not received any such request from our cohort. Exposure to androgen during the antenatal, postnatal, and pubertal period may masculinise the brain and influence gender identity.13 It was found that 5ARD is easy to diagnose by its characteristic urinary steroid excretion pattern and its high mutational detection rate in the SRD5A2 gene.14 Of the 11 patients with 5ARD, eight harboured the missense mutation p.Arg227Gln in their SRD5A2 gene, a useful fact to enable screening for this mutation before proceeding to sequencing of the whole gene. Unfortunately, patients have previously been too easily labelled with AIS when laboratory diagnostic services were less advanced. This is illustrated by patient 7 who was labelled as AIS until her urine steroids were analysed and revealed classic features of 5ARD.15 We recommend that 5ARD is excluded in all 46,XY DSD patients before other differential diagnoses are considered. Moreover, since the baseline and post-hCG–stimulated T and DHT results are unreliable when diagnosing AIS, genetic study of the AR gene should also be performed as a first-line investigation.

HSD17B3 deficiency has been reported to be the most common cause of T biosynthetic defect leading to 46,XY DSD in some populations, with an estimated incidence of 1:147 000 in the Netherlands and as high as 1:200 to 1:300 in Arabians due to their high consanguinity rate.16 17 Nonetheless, no patient in our cohort was diagnosed with this condition based on the hormonal pattern. Ethnic differences in disease spectrum may be one of the reasons for this observation. Another possible explanation is the lack of reliable diagnostic cutoff for the pre- and post-stimulated T/A4 ratios. George et al18 have summarised the cutoffs used by various researchers, with the pre-stimulated cutoff range set at 0.006 to 1.64, and the post-stimulated level set at 0.09 to 3.4 for newborn to teenage groups. The difficulties in setting up reliable diagnostic cutoffs for the T/A4 ratio are similar to the T/DHT ratios and have been discussed in our previous study.14 Furthermore, HSD17B3 deficiency gives no characteristic findings on urinary steroid profiling.5 19 Molecular analysis of the HSD17B3 gene may have offered a means to diagnose this condition but unfortunately, due to budget constraints, we were unable to perform mutational analysis of this gene in all our patients, although a normal MLPA result in our patients made gross deletion in this gene unlikely.

The two novel mutations p.Asp266Asn and p.Thr576Pro in the AR gene lie within the N-terminal domain of the androgen receptor that is involved in transcription regulation and DNA binding, respectively. Missense mutations around these two codons have been reported in patients with AIS according to the Androgen Receptor Gene Mutations Database, April 2013.20 Multiple sequence alignment shows that both amino acids are highly conserved among different species, suggesting that aspartic acid at codon 266 and threonine at codon 576 are critical for proper receptor function. Similarly, the alanine at codon 260 of the NR5A1 gene is located in helix 3 of the ligand-binding domain of the nuclear receptor,21 and is also a highly conserved region. Mutation in this region has been reported to result in 46,XY DSD.8 Replacing alanine at this position by valine is therefore expected to be deleterious to the protein function. Phenotypic variability in NR5A1 gene mutation within a kindred has been reported and this may explain why patient 21 had ambiguous external genitalia to such an extent that he required the attention of a paediatric specialist, even though his father was fertile, and denied any symptoms of DSD or need for medical attention.22 For the AMH gene, the 3’ end of exon 5 is one of the mutational hotspots in patients with PMDS.23 Exon 5 encodes the bioactive C-terminal domain. The three mutations detected in patient 22 are all located at highly conserved regions. Although in-vitro functional characterisation for the mutant proteins was not performed, the undetectable serum AMH level in this patient was compatible with the mutations being pathogenic, possibly due to abnormal protein folding and increased instability, as reported previously in mutations located in this region.24

Gonadal malignancy was rare in our series, probably because gonadectomy was performed early in life when the decision of female sex assignment was made. Although this helps to avoid further virilisation and to establish gender identity, the timing of corrective surgery and gonadectomy remain controversial. Patient advocacy groups have suggested delaying any surgery for cosmetic reasons until the patient is mature enough to give informed consent25 but such practice has not been validated in our Chinese patients. Whether cultural factors have any impact on gender assignment remains uncertain in our community.

Prematurity or low birth weight was not uncommon in our series. This made diagnosis of DSD in our patients even more difficult because ethnic-specific and gestational age– or weight-adjusted anthropometric measurement of the external genitalia was not available. Assessment of the genital anatomy relies solely on the experience of the paediatric specialist and is obviously far from ideal. A conjoint effort by local paediatricians is needed to set up these normative data.

Less than half of our patients had a confirmed diagnosis in the present study. With the increasing availability of next-generation sequencing technology, and with its established role in molecular diagnostic services, including DSD,3 26 it is hoped that sooner rather than later, most patients will have a confirmed genetic diagnosis. Nonetheless, we speculate that some patients have a non-genetic aetiology since environmental factors may alter the phenotypic expression. Several animal and human studies have shown that antenatal exposure to pesticides and plasticisers may lead to fetal genital malformation.27

Altogether there was an average of 11 250 male live births every year in the five public hospitals that participated in this study. Since 11 newborns with 46,XY DSD were born in these five hospitals and were recruited during our study period, this gives an estimated incidence of 46,XY DSD of 1:2045 male births requiring the input of paediatric endocrinologists. This figure may underestimate the true incidence of this group of diseases as some patients present late and others may have subtle defects that go unnoticed by our specialists. If the actual number of patients with chromosomal and 46,XX DSD in our population is considered, the actual incidence of DSD can be expected to be much higher.

There are a few limitations in this study. First, the number of patients was relatively small. This may have resulted in bias in our observation and the data do not represent the prevalence of disease in our population. Second, in-vitro study was not performed on the novel genetic variants for functional characterisation, although we believe that all the available evidence indicates the pathogenic nature of these variants. Third, due to budget constraints, we were unable to sequence all genes related to 46,XY DSD.

Our findings indicate that 5ARD and AIS are possibly the major causes of 46,XY DSD in the Hong Kong Chinese population. Molecular analyses of the SRD5A2 and AR genes were demonstrated to be more reliable than hormonal testing. Since the missense mutation p.Arg227Gln was a recurrent hotspot mutation in 5ARD in our local patients, all patients should be screened for this mutation.

We thank Mr YC Ho, Ms YF Wong, and Ms YP Iu for their technical assistance. The study was supported by the Queen Elizabeth Hospital Research Grant 2009 QEH/RC/G/0910-A04/R0901 and Kowloon Central Cluster Research Grant 2012 KCC/RC/G/1213-B01.

1. Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006;118.e488-500. Crossref

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7. Chan WK, To KF, But WM, Lee KW. Frasier syndrome: a rare cause of delayed puberty. Hong Kong Med J 2006;12:225-7.

8. Allali S, Muller JB, Brauner R, et al. Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46,XY disorders of sex development (DSD) including hypospadias. PLoS One 2011;6:e24117. Crossref

9. Bangsbøll S, Qvist I, Lebech PE, Lewinsky M. Testicular feminization syndrome and associated gonadal tumors in Denmark. Acta Obstet Gynecol Scand 1992;71:63-6. Crossref

10. Boehmer AL, Brinkmann O, Brüggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001;86:4151-60. Crossref

11. Abdullah MA, Saeed U, Abass A, et al. Disorders of sex development among Sudanese children: 5-year experience of a pediatric endocrinology clinic. J Pediatr Endocrinol Metab 2012;25:1065-72. Crossref

12. Mieszczak J, Houk CP, Lee PA. Assignment of the sex of rearing in the neonate with a disorder of sex development. Curr Opin Pediatr 2009;21:541-7. Crossref

13. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 1979;300:1233-7. Crossref

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16. Boehmer AL, Brinkmann AO, Sandkuijl LA, et al. 17β-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab 1999;84:4713-21. Crossref

17. Rosler A. 17 Beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev 2006;3 Suppl 3:455-61.

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20. Androgen Receptor Gene Mutations Database. Available from: http://androgendb.mcgill.ca/. Accessed Aug 2013.

21. El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, Lin L, Achermann JC. Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 2011;20:38-46.

22. Ciaccio M, Costanzo M, Guercio G, et al. Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred. Horm Res Paediatr 2012;78:119-26. Crossref

23. Josso N, Belville C, di Clemente N, Picard JY. AMH and AMH receptor defects in persistent Müllerian duct syndrome. Hum Reprod Update 2005;11:351-6. Crossref

24. Belville C, Van Vlijmen H, Ehrenfels C, et al. Mutations of the anti-Müllerian hormone gene in patients with persistent Müllerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model. Mol Endocrinol 2004;18:708-21. Crossref

25. Consortium on the Management of Disorders of Sex Development: Clinical Guidelines for the Management of Disorders of Sex Development in Childhood. California, US: Intersex Society of North America; 2006. Available from: http://www.dsdguidelines.org/files/clinical.pdf. Accessed Aug 2015.

26. Hersmus R, Stoop H, Turbitt E, et al. SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype. BMC Med Genet 2012;13:108. Crossref

27. Kalfa N, Philibert PH, Baskin LS, Sultan C. Hypospadias: interactions between environment and genetics. Mol Cell Endocrinol 2011;335:89-95. Crossref