Pathological progress and prognosis of traumatic femur head necrosis after femoral neck fracture in children and adolescent: a retrospective case series of 64 patients

Background: The pathological progression and prognosis of traumatic femur head necrosis (TFHN) after femoral neck fracture (FNF) in children and adolescent is relatively unknown and has never been specically characterized. As we speculated, the prognosis in such population would be poor and characterized as the high risk of femoral head collapse, hip deformity and degeneration in a short term. Methods: This retrospective case series enrolled 64 children and adolescent with TFHN who treated with observational treatment from 2000.1 to 2018.1. The primary outcomes, such as the progression of femoral head collapse, hip deformity (Stulberg classication) and hip degeneration (Tönnis grade), and their prognostic factors were analysed. Results: 42 males and 22 females with a mean age of 13 years (6-16 years), were included. A total of 28 hips (44%) showed unsatisfactory outcome and Twenty-ve (39%) hips collapsed progressively during a mean follow-up of 48 months (24-203 months). Finally, 38 hips (59%) experienced hip deformity, 20 of them were class IV/V. 34 hips (53%) generally progressed to osteoarthritis, 14 of them were classied as grades II/III. The location of the lesion and the presence of lateral subluxation were found to be independently related to progression of femoral head collapse; however, the presence of lateral subluxation was the only independent risk factor of severe hip deformity and degeneration. Conclusion: TFHN in children and adolescent is a rapidly progressing disease with a poor prognosis characterized by a high risk of femoral head collapse progression. If the lateral subluxation emerged, collapsed cases showed increasingly tendency towards severe hip deformity and degeneration.


Background
Traumatic femur head necrosis (TFHN) is a debilitating, potentially disabling complication that occurs after femoral neck fracture (FNF) in children and adolescent [1,2]. As TFHN is the most common complication, a meta-analysis that included 30 studies and 935 immature cases revealed an average incidence of 23.5% [3]. Moreover, to the best of our knowledge, a retrospective study that included 239 hips, as the largest known sample size for paediatric FNF, indicated an incidence of 24.5% for TFHN [4].
However, this condition remains unfamiliar to most orthopaedic surgeons because of the rare incidence of primary injury [5,6].
Numerous studies have attempted to elucidate the incidence of TFHN and the relevant risk factors, but few have provided additional information such as the characteristics of the natural history, the pathologic progression, prognosis or the targeted treatment. Mirrored to the experience of adult FHN, or other childhood osteonecrosis caused by other common aetiologies, hip-preserving operations, such as core decompression [7], free vascularized-bular grafting [8] and hip osteotomy [9], have been used without con rmed evidence. In the absence of clear guidance, surgeons failed to make timely treatment plan, and observational treatment, such as non-weight bearing exercises [5,10] or pharmacotherapy [11], were used reluctantly.
As we have observed in clinical practice, TFHN rarely has a promising prognosis in children and adolescent. These patients seemingly present with a strong tendency for femoral head collapse, a crucial pathologic change leading to poor outcomes, and hip deformity that occurs with skeletal maturity, which indicates a high risk of hip degeneration in immature patients [12]. We believe that these indicators, including femoral head collapse, hip deformity and degeneration, are the basis of the disease progression of TFHN in children and adolescent if they haven't receive proper treatment, but that have not yet been described in detail.
To the best of our knowledge, the largest sample size to date of 64 patients who underwent observational treatment was used for inclusion in the current study, which aimed to analyse the disease progression of TFHN in children and adolescent with a hypothesis that the prognosis in this paediatric population would be poor because of the high risk of femoral head collapse, hip deformity and osteoarthritic change.

Materials And Methods
This study was a retrospective study of a clinical case series and was reported according to the STROBE statement [13]. The evidence level was level 4 according to the Oxford Centre for Evidence-based Medicine (Oxforf CEBM). After the approval of the Institute Ethics Committee, a retrospective case study was conducted based on hospitalized patients with TFHN in children and adolescent in our institute from 2000-1 to 2018-1, according to the following inclusion criteria: (1) participants diagnosed with TFHN [1,14] as a complication of a previous fracture of the femoral neck; (2) patients with no history of corticosteroid administration or alcohol abuse; (3) Epiphyseal plate of femoral head were not closed completely when the fracture occurred; (4) patients with no other complications from FNF, such as nonunion or infection, or from other diseases, such as dysplasia of the hip joint or rheumatoid arthritis; (5) patients with complete medical records or radiographic data; (6) patients who completed a follow-up period of more than 2 years; and (7) patients who had not received hip-preserving surgery except for reduction or xation of a FNF.
The extracted data consisted of medical record data and radiographic data. We found the medical records and extracted the following items: (1) age, sex and other personal information; (2) contact information used to for follow-up and completion date; (3) symptoms such as pain, limp and restricted hip function; (4) interval between the fracture of the femoral neck and necrosis; (5) information on the presence of reduction or xation for the FNF; and (6) the follow-up time.
According to our practical experience, only the cases at severe collapsed stage, and combined with hip subluxation were suggested hip preserved operations; Those with signi cant hip degeneration already were suggested to hip arthroplasty. Patients at early stage or refusing our suggestion of operations would receive observational treatments, consisted of pain relief, restricted weight bearing, and physical treatment, within the rst 2 years after diagnosis of TFHN. We did not use any type of anti-osteoporosis medication because of the unknown complications in children and adolescents. Symptomatic treatments consisted of nonsteroidal anti-in ammatory drugs (NSAIDs) or analgesics, as needed. The clinical and radiographic data were assessed at time of diagnosis and serially every 3 to 4 months within the rst 2 years after treatment and every 6 months in the third year and subsequently. Unsatisfactory outcomes were characterized by the conversion to THA or the presence of a "fair or poor result" according to Ratliff's clinical criteria [1]. Good was de ned as "clinical, no or negligible pain; full or minimal restrictive hip movement; and normal activity or the avoidance of games". Fair was de ned as "clinical or occasional pain; hip movement restriction less than 50%; and normal activity or the avoidance of games". Poor was de ned as "clinical or disabling pain; hip movement restriction more than 50%; and restricted activity." Radiographic data were collected, including X-ray, CT and MRI data. According to the classi cation system of the Japanese Investigation Committee (JIC) [15], all hips were classi ed into four types. Types A, B and C1 were assigned to groups where the necrotic area did not extend to the acetabular edge (inside coverage). Type C2 was assigned to groups where there was inside coverage of the necrotic area. Then, we analysed whether the location of the necrotic area affected the prognosis. The degree of collapse was also measured according to evaluated by concentric circles on both anteroposterior and lateral radiographs using ImageJ (1.52a, National Institutes of Health, USA), referring to previous literatures [16,17]. With the increasing progression of femoral head collapse, lateral subluxation was de ned when Shenton's line was not continuous.
As the three primary outcomes, the progression of femoral head collapse more than 2mm, hip deformity and hip degeneration were assessed by concentric circles, the Stulberg classi cation and the Tönnis grade, respectively. The Stulberg classi cation [12] was used to describe the shape of the femoral head at skeletal maturity and to predict the long-term outcome at the last follow-up. All the hips in all the patients at the last follow-up demonstrated skeletal maturity. Class I/II hips still maintain a spherical femoral head. Class III hips have an ovoid femoral head, and class IV/V hips demonstrate a attened femoral head. The degree of osteoarthritis was de ned according to the Tönnis grade (grade 0 to 3). Grade 0 indicates the absence of degenerative changes; grade 1 indicates mild joint-space narrowing, mild sclerosis evidenced by widening of the sclerotic zone, and small marginal osteophytes; grade 2 indicates moderate joint-space narrowing, moderate sclerosis of the femoral head or acetabulum, and the presence of small subchondral cysts within the femoral head or acetabulum; and grade 3 indicates severe jointspace narrowing (<1 mm) or obliteration of the joint space and evidence of large subchondral cysts on the femoral head or acetabulum.
All the radiographic characteristics and outcomes were evaluated independently by two experienced orthopaedic surgeons. If inconsistent results existed, a third surgeon would participate and decide the ultimate result.
Statistical analyses were carried out to analyse which factors, such as age, sex, internal xation, the interval between FNF and TFHN, symptomatic or asymptomatic disease, the presence of collapse at diagnosis, the location of the lesion and the presence of lateral subluxation, would affect the primary outcomes. Then, adjusted-ORs of the factors would affect severe hip deformity (type IV/V) and degeneration most signi cantly (grade 2/3) were analysed by binary logistic regression. Cox proportional hazard model was used to identify the adjusted-HRs of predictive factors related to femoral head collapse progression. With an endpoint of the "progression of femoral head collapse" according to X-ray images, a Kaplan-Meier analysis was performed, and survival curves were created with the log-rank test. A value of p < 0.05 was considered to indicate signi cance. These statistical analyses were performed using SPSS Statistics (version 25; IBM, USA).

Results
A total of 155 children and adolescents (155 hips) were diagnosed with TFHN from 2000-1 to 2018-1. A total of 115 patients had complete medical records or radiographic data. Thirty-ve patients were excluded for receiving hip-preserving surgery after diagnosis. In addition, 80 patients were treated conservatively, 64 of whom had been followed for more than 2 years and were nally analysed in our studies ( Figure 1).
These patients included 42 males and 22 females with a mean age of 13.3 years (6-16 years) when they had FNF. In terms of the internal xation methods used for the fracture, 8 patients were treated without any surgeries. Six patients were treated via xation with Kirschner wires. A total of 19 and 31 patients underwent xation surgery with the use of 2 and 3 cannulated screws, respectively. TFHN was diagnosed on average 13.1 months after the fracture. At the time of diagnosis, only 24 patients were symptomatic, while 40 patients were asymptomatic. Of these, 19 patients suffered from varying degrees of hip pain, 17 patients had a limp, and 9 had restricted hip function. The mean follow-up time was 48.38 months (24-203 months).
Regarding the localization of the necrotic area, 13 patients were classi ed with type A or B hips (less than two-thirds of the weight-bearing portion). Twenty-four patients were classi ed with type C1 hips (more than two-thirds of the weight-bearing portion but not extending to the acetabular rim), and 27 patients were classi ed with type C2 hips (extending to the acetabular rim). In light of the anteroposterior X-ray upon diagnosis of TFHN, 33 and 31 hips remained at the non-collapsed and collapsed stages, respectively. Nineteen hips collapsed by less than 2 mm, 6 hips collapsed in a range from 2 to 4 mm, and 6 hips collapsed by more than 4 mm. When patients were diagnosed, 14.1% (9/64) of hips exhibited lateral subluxation on imaging (Shenton's line was discontinuous). Then, 29.7% (19/64) of hips had lateral subluxation after an average of 33.6 months (24 to 69 months).
At the last follow-up, according to Ratliff's clinical criteria, 36, 17 and 11 patients showed good, fair and poor outcomes, respectively, at the recent follow-up. Five patients with poor clinical outcomes underwent conversion to total hip arthroplasty.
Upon TFHN diagnosis, 48.4% (31/64) of hips had collapsed. Throughout the follow-up time, 39.1% (25/64) of hips progressively collapsed by more than 2 mm. A total of 24.2% (8/33) of hips collapsed at the early stage, and 54.8% (17/31) of the hips that collapsed at the collapsed stage demonstrated collapse progression during follow-up. In addition, 70.3% (45/64) of hips ultimately progressed to the collapsed stage. If we de ned collapse progression with an endpoint of more than 2 mm at follow-up, the type of symptoms, JIC classi cation, initial femoral head collapse and lateral subluxation were four factors that affected the results in univariate analysis (Table 1). Furthermore, multivariate analysis indicated that the JIC classi cation (adjusted-HR=6.127 95%CI=1.8~20.9) and the presence of lateral subluxation (adjusted-HR=5.338, 95%CI=1.6~17.8) were prognostic factors for the progression of femoral head collapse ( Table 2) (Table 1). However, multivariate analysis indicated that lateral subluxation (adjusted-OR=25.82 95%CI=2.1~323.1) was the only indicator of severe hip deformity ( Table   2).
In terms of the Tönnis grade, 53.1% (34/64) of hips generally progressed to osteoarthritis. Twenty (27.8%) hips were classi ed as grade I, and 10 (13.9%) and 4 (5.6%) hips were classi ed as grades II and III, respectively. In univariate analysis, the type of symptom, JIC classi cation, initial degree of femoral head collapse and lateral subluxation were four factors that affected the results (P 0.05). (Table 1). However, multivariate analysis indicated that lateral subluxation of the hip (adjusted-OR=13.46, 95%CI=1.2~146.6) was the only indicator of severe hip degeneration.

Discussion
A series of studies, rst reported by Ratliff and his colleagues in the 1960s, have portrayed TFHN as a severe complication secondary to paediatric FNF [1,2]. Since then, the unsatisfactory outcomes of this condition have been repeatedly reported by numerous studies; however, the speci c pathologic progression, prognosis and relevant risk factors for TFHN in children and adolescent remain unknown. This study is the first, to our knowledge, to address these deficiencies through a retrospective study that included 64 conservatively treated cases, which is thought to be the largest currently utilized sample size. The pathologic progression and prognosis of TFHN in children and adolescent was characterized in detail by femoral head collapse, hip deformity and hip degeneration, which can aid in the treatment planning process. The most important nding in our study is that TFHN in children and adolescent is a rapidly progressing disease with a prognosis characterized by a high risk of femoral head collapse and deformity; some cases showed hip degeneration in the short term when lateral subluxation of the hip appeared.
Several limitations still exist. First and foremost, although more than thirty patients treated surgically in our institute, they were inappropriately enrolled as the control group for a variety of indications. Only the cases at severe collapsed stage, and combined with hip subluxation were suggested hip preserved operations; Those with severe hip degeneration already were suggested to hip arthroplasty. Such outcome will be reported in other study. Numeral included cases in current study who had met our surgical indication were suggested surgical treatment, but they refused for personal reasons, which gave us a chance to observe their rapid progression of disease and poor outcome in a short term. Second, the hospitalized patients included in current study have potential risk of selective bias. But due to the rareness of this kind of disease, the data collection and follow-up of outpatients have much di culty. Third, we set up a minimum follow-up of 2 years, and nally presented a middle-term result of 4 years on average. To be sure, it was not a long enough period to describe the complete course for most hip problems in paediatric population. However, under the limited follow-up, our results provided a cautionary and useful note of TFHN in children and adolescent, "rapid deterioration and relevant factors", that would be bene cial for clinical decision. Further prospective multi-centre control trials with more cases or control groups are suggested to con rm the results. At last, we did not analyse the correlations between the fracture type and prognosis of the following TFHN, because of the limited data of images when the fracture occurred. And it would be further studied in future.
Femur head necrosis in the paediatric population can be induced by both non-traumatic and traumatic aetiologies. The non-traumatic aetiologies include corticosteroid-associated osteonecrosis, Legg-Calve-Perthes disease and the like [18]. Unlike non-traumatic cases, TFHN are far less common due to the rare incidence of FNF in children and adolescents. Thus, therapists might remain unfamiliar to TFHN because of the lack of guidelines and consensus documents. According to our study, a distinct difference exists in the pathologic progression and prognosis of cases of TFHN and other non-traumatic cases of osteonecrosis.
The most intuitive characteristic during our observation of TFHN in children and adolescent was the high incidence of femoral head collapse progression, which is generally considered a turning point indicating poor prognosis in the short term [15]. Eight of 33 hips collapsed at the early stage, and 17 of 31 hips that collapsed at the collapsed stage demonstrated collapse progression during the follow-up. The presence of collapse primarily depended on the lesion size and the location of the necrotic area, as the large involvement of necrotic lesions results in a high risk of femoral head collapse [14,15]. We believe that patients with TFHN were susceptible to extensive necrosis due to and large damage of blood supply induced by high-energy primary trauma. Ratliff et al demonstrated the highest incidence of TFHN occupying the total head (type I), followed by partial necrosis of the epiphysis (type II) and necrosis between the epiphyseal plate and the fracture line (type III) [1]. A high risk of total head necrosis, ranging from 35.7% to 80.7% [1,5,[19][20][21][22], has been con rmed repeatedly by studies on the same subject.
The high risk of large lesions and disease progression does not seem to be common in corticosteroidassociated children and adolescents. Kaste et al used MRI to detect 462 cases of corticosteroidassociated osteonecrosis in children and adolescents, and the overall rate of osteonecrosis and the rate of extensive cases involving >30% were 21.7% and 6.5%, respectively, with a four-year follow-up. Similarly, Karimova et al reported that the proportion of extensive cases involving >30% and the rate of lateral involvement (Type C) of osteonecrosis in paediatric and young adult patients with leukaemia or lymphoma were 26.3% (30/114 hips) and 31.6% (36/114 hips), respectively. In contrast, 79.7% (51/64) of hips in this study were de ned to have lateral involvement (type C). The actual ratio must be higher in our institute because the remaining patients treated surgically all had hips with largely lateral involvement.
Legg-Calve-Perthes disease is also a common aetiology of childhood osteonecrosis, usually with extensive and severe involvement of the epiphysis. Canavese et al described the prognosis of Legg-Calve-Perthes disease in patients under six years old [23]. According to the Catterall classi cation, 50 hips had mild involvement (grade I/II), and 116 hips had severe involvement (grade III/IV). Similarly, 358 patients with Legg-Calve-Perthes disease (mean age, 5.8 years) were followed for more than ve years with radiographic data by Wiig et al, 87.7% (314/358) of whom exhibited severe involvement (grade III/IV) [24]. However, these severely involved patients with Legg-Calve-Perthes disease had a better prognosis than children and adolescent with TFHN. First, TFHN tended to be associated with severe deformity. The percentages of Stulberg class III and IV/V hips in our study were 28.1% hip degeneration progressed rapidly, with an incidence of 30% in the rst years and 50% in total, which was obvious different from patients with Legg-Calve-Perthes disease, who experienced hardly any osteoarthritic changes in the short term until their 40s and 50s [12].
In general, TFHN seemed to be more susceptible to hip deformity and degeneration compared with Legg-Calve-Perthes disease in paediatric population, nally resulting worse prognosis. As we speculated, the weakened abilities of bone repair and remodelling with older age were other potential causes of poor prognosis in patients with TFHN. The average age of the included patients in our study was nearly 13 years old. In this age group, patients with bone necrosis lack satisfactory repair and remodelling abilities and show completely different prognosis and pathological processes than younger patients [25,26]. Spontaneous femoral head repair and remodelling into a spherical shape were never observed in our patients at the collapsed stage. Even with the largest sample size of such condition, the sample still did not report the results for all ages of children and adolescents. For instance, we only included small proportion of children younger than 11 years of age (six cases), who would presumably have a better prognosis.
Hip incongruency and instability secondary to irreversible deformity were the major causes of rapid cartilage damage. According to our multivariate analysis, as lateral subluxation of the hip occurred during the follow-up, the risk increased sharply by 26-fold for severe hip deformity and 13-fold for severe hip degeneration ( Table 2). In addition, it was di cult to rule out the adverse effect on cartilage of the femoral head, even chondrolysis, due to the presence of primary dramatic injury. Osteoarthritic changes represented the primary cause of arthroplasty in our patients. Our work determined that the pathologic progression and prognosis of TFHN in children and adolescent was speci c and different from corticosteroid-associated osteonecrosis or Perthes disease. However, such a comparison was theoretical and indirect.
As a sign of a "head at risk", lateral subluxation of the hip was de ned as the strongest independent risk factor for primary outcomes in our results. For immature patients, lateral subluxation signi es poor containment and instability of the hip joint. The former is a widely recognized adverse effect of femoral head remodelling, and the latter increasingly exacerbates hip degeneration. Other recognized prognostic factors of progression of femoral head collapse for most types of osteonecrosis of femoral head, such as the initial degree of femoral head collapse [27], JIC classi cation [15] and symptoms [28], show no apparent relation to severe hip deformity and degeneration. Therefore, these factors did have value for predicting femoral head collapse, but after collapse, not all hip showed further progression to severe hip deformity and degeneration. If the lateral subluxation emerged, cases at collapsed stage showed increasingly tendency towards severe hip deformity and degeneration in the short term (Figure 3), otherwise they might keep satisfactory hip condition ( Figure 4).

Conclusions
In summary, our recent study rst identi ed the characterization of the prognosis of TFHN in child and adolescent. Over half of our patients had hip involvement with osteoarthritic changes or femoral head deformities. Therefore, we believe that TFHN in children and adolescent is a rapidly progressing disease with a prognosis characterized by a high risk of femoral head collapse. For patients who also have hip subluxation, a sign of "head at risk", severe hip deformity and degeneration will occur and result in poor outcomes in the short term. For such conditions, the ideal treatment should be targeted at decreasing the risk of femoral head collapse and rectifying the poor containment and hip instability induced by lateral subluxation at the same time.

List Of Abbreviations
TFHN: traumatic femur head necrosis FNF: femoral neck fracture Declarations Ethics approval and consent to participate: All data of patients, including the minors, were got from the Medical records and radiographs with the consent of patients or their guardians. Tables   Table 1 The characteristics of TFHN and unadjusted analysis of factors related to primary outcomes   Figure 1 Adolescent of TFHN at collapsed stage showed an increasingly progression towards severe hip deformity and degeneration in the short term, if the lateral subluxation emerged. A male patient of 16 years old, with left FNF, treated with 3 cannulated screws (a). TFHN (JIC classi cation C2) was diagnosed one year after FNF, which already progressed to collapsed stage with lateral subluxation(b). During observational treatment, radiographs showed progressively femoral head collapse and lateral subluxation 11 months after diagnosis of avascular necrosis (c). At latest follow-up, 2 years after FNF, left hip showed poor outcome according to Ratliff's clinical criteria, with severe hip deformity (Stulberg classi cation IV) and hip degeneration (Tönnis grade III).  The Kaplan-Meier curve showed the cumulative percentage of the progression of femoral head collapse (a) and demonstrated a signi cant relationship between survival time and prognostic factors (b, c). With the endpoint of "femoral head collapse progressing more than 2mm", the overall survival rates were 100.0%, 83.3% and 22.2%in the JIC classi cation A/B C1 and C2 respectively(b); the overall survival rates were 15.6% and 94.7% in those without and with lateral subluxation of hip during follow-up.