Introduction
Necrosis of the femoral head in children, also known as Perthes disease (Legg-Calvé-Perthes, LCP), is a self-limited and non-systemic disease occurring in the femoral heads of children, which is mainly manifested as an ischemic necrosis of the femoral osteoepiphysis leading to subchondral ossification injury of the femoral head [
1]. The clinical manifestations are mainly claudication and limitation of the affected hip joint movement.
Currently, it is generally believed that Perthes disease is a multifactorial disease caused by a combination of genetic and environmental factors. Genetic factors that mainly affect the sensitivity of the femoral heads to blood supply disruption and the tendency to thrombosis, and environmental factors that lead to trauma, such as excessive activities brought by childhood hyperkinetic syndrome, as well as maternal smoking and passive smoking, contribute to the disease. The tendency to thrombosis is one of the possible causes of Perthes disease that disputes mainly focus on, and some studies have demonstrated that the disease is associated with abnormalities in blood coagulation factors [
2‐
10], whereas others do not [
11‐
16]. The deficiency of protein C has been considered a possible etiological factor of Perthes disease [
17,
18]. However, the meta-analysis of Matos M.A. et al. shows that there is insufficient evidence to prove that protein C is related to the pathogenesis of Perthes disease [
19].
In addition, a growing body of research has revealed some other causes of Perthes disease, including repeated minor trauma [
20,
21], vascular occlusion [
22], bone growth stagnation [
23,
24], abnormal insulin-like growth factor-1 pathway [
25,
26], maternal smoking [
27], secondhand smoke exposure [
28‐
31], type II collagen mutation [
32,
33], and low blood manganese level [
34], but there’s not enough evidence to support them, and some studies have even questioned these views [
35‐
38]. In recent years, the association between endothelial cells and Perthes disease has also been proposed [
39,
40], but further studies are needed to prove it. In terms of its relationship with other diseases, Perthes disease has been reported to be associated with congenital malformation [
41], fibrinolytic system disease [
42], transient synovitis [
43] and osteochondritis [
44], which has been preliminarily recognized. Long-term use of glucocorticoids in large doses is associated with necrosis of the femoral head in adults [
45‐
47], which is the most common and important risk factor that results in 10-30 % of necrosis of the femoral head in adults [
48]. However, the relationship between glucocorticoids and necrosis of the femoral head in children is rarely documented in literature. At present, there is no research on the association between Perthes disease and the use of glucocorticoids throughout the world. This paper presents a case of the association between necrosis of the femoral head in children and the use of glucocorticoids, which would provide a new possibility for the causes of Perthes disease, so as to supplement the etiology and pathophysiology of this disease.
Discussion and conclusions
Although increasing studies on the etiology or pathogenesis of Perthes disease have been performed for the past several decades, the causes of Perthes disease still remain unclear. In this case, with MRI examination finding the epiphyseal necrosis of right humeral head, femur and tibia, and X-ray examination finding bilateral femoral head necrosis, the child was diagnosed as Perthes disease based on his clinical and imaging data. And we suppose that long-term and high-dose glucocorticoids may be one of the causes of Perthes disease. It is generally recognized that excessive glucocorticoids can cause femoral head necrosis in adults, but regarding the use of glucocorticoids causing Perthes Disease, this case report may be the first to put forward this view. The child in this case can be diagnosed as Perthes Disease, but further discussion is needed about/on whether it is caused by drugs, especially glucocorticoids. Through the analysis of the following aspects, it could be concluded that the main cause of Perthes disease for the child in this case is the long-term and high-dose use of glucocorticoids.
The use of glucocorticoids in this case is characterized by long term and high dose. With respect to the medical history, the first time the child took glucocorticoids was at the age of 9 after transplantation in June 2016. At the beginning, methylprednisolone tablets (12 mg, bid) were used. It maintained for about half a year, began to be reduced to 8 mg from January 2017, halved in February and stopped in March 2017. The dose of glucocorticoids used during this period is moderate for adults but is already too high for children to be ignored. After his hospitalization in March 2018, methylprednisolone tablets began to be reduced to half a tablet, twice a day, but it was discontinued after short-term use because of the poor efficacy. From the transplantation in 2016 to 2018, the child underwent the treatment of high-dose glucocorticoids intermittently, and then aseptic necrosis was found in his right femoral epiphysis in March 2018. During the treatment, given that glucocorticoids may cause drug-induced femoral head necrosis not only in adults but in children, the clinicians were cautious to maintain the minimum effective dose, and adjusted the dosage in time to avoid poor efficacy or adverse reactions.
During the past three years of treatment, the child could not identify glucocorticoid specifically amongst the classes of drugs he was on at different times. However, every time he underwent the treatment of glucocorticoids, he suffered from pain in the hips but got relief after the drug withdrawal, which could exclude the interference from psychological factors of the patient. Besides, his two bone mineral density CT examinations showed the possibility of osteoporosis. It follows that the use of glucocorticoids is certainly associated with femoral head lesions.
In this case, immunosuppressants (cyclosporine, sirolimus, etc.) are also used and therefore it is also necessary to consider whether necrosis of femoral heads is the adverse reaction of immunosuppressant instead of glucocorticoids. Aside from methylprednisolone tablets, cyclosporine is the longest-used drug for this patient, which can help prevent allograft rejection. However, the use of cyclosporine in this case is in conventional dose, and there have been no reports of cyclosporine causing femoral head lesions in adults or children. On the contrast, studies show that patients with immunosuppressants such as cyclosporine or tacrolimus, for example, had lower rates of hip osteonecrosis after renal transplantation [
49]. Therefore, the use of cyclosporine may not cause Perthes disease in this case. The treatment with rituximab, sirolimus and ganciclovir in 2018 was just for a short period, and the right femoral head lesions have been found before using these drugs, so they are also not related to the cause of Perthes disease in this case.
Regardless of whether it is for adults or children, aplastic anemia itself does not cause femoral head necrosis. Aseptic necrosis of the femoral head complicated by adult aplastic anemia is reported to be actually caused by the use of glucocorticoids during treatment [
50]. Additionally, no research has ever shown that aplastic anemia can cause Perthes disease.
In this case, the 11-year-old child got sick about 2 years ago and his body weight was stable at about 30 kg, namely at a normal level, indicating that he was not overweight or malnourished, and thus his Perthes disease might not have much to do with his own growth and development process.
As a result, the femoral head necrosis of the patient in this case is most likely to be resulted from the long-term and high-dose use of glucocorticoids. Through this case report and literature review, glucocorticoids may be considered as a risk factor for Perthes disease. Although there’re some limitations during the whole therapeutic procedure, such as inadequate amounts of calcium and vitamin D supplements given for osteoporosis, doctors had prescribed herbal medicine or other alternative medicine for management of it. It is hoped that more cases could be reported in the future and related experimental studies could be performed to further validate and renew this view.
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