Aetiology of Legg-Calvé-Perthes disease: A systematic review

Table 1 Main findings of the included case-control studies

Ref.	Subjects	Association/molecule studied	Results
Perry et al[12] (2017)	A hospital case-control study (n = 149/146)	Tobacco smoke exposure during pregnancy	The odds of Perthes' disease significantly increased with reported in utero exposure after adjustment for socioeconomic deprivation (maternal smoking OR = 2.06, 95%CI: 1.17-3.63; paternal smoking OR = 2.09, 95%CI: 1.26-3.46).
Daniel et al[13] (2012)	128 children with LCPD and 384 children attending the hospital for other orthopaedic complaints	environmental tobacco smoke, firewood smoke and socioeconomic status and the risk of LCPD	The main risk factors for LCPD were indoor use of a wood stove (adjusted OR, 2.56) and having a family member who smoked indoors (adjusted OR, 2.07).
García Mata et al[15] (2000)	90 patients with LCPD and 183 normal children, as controls, selected at random to determine whether the condition of passive smoking is related to the disease	LCPD and passive smoking	The association between LCPD and passive smoking, after controlling for age and gender, became significant (p = 0.0000). Thus the risk of LCPD in passive smoking children is more than five times higher than in children who are not exposed to smoke.
Bahmanyar et al[17] (2008)	The Swedish Inpatient Register identified 852 individuals with a diagnosis of LCPD from 1983 to 2005, individually matched by year of birth, age, sex and region of residence with 4432 randomly selected control subjects.	Maternal smoking pregnancy and LCPD	Maternal smoking during pregnancy was associated with an increased LCPD risk, and heavy smoking was associated with a risk increase of almost 100%. Very low birth weight and caesarean section were independently associated with approximately 240% and 36% increases in the risk of LCPD, respectively.
Wiig et al[29] (2006)	402 patients with a matched control group of non-affected children (n = 1025952) from the Norwegian Medical Birth Registry	Epidemiology and possible aetiology of LCPD	Applying Sartwell's log-normal model of incubation periods to the distribution of age at onset of Perthes' disease showed a good fit to the log-normal curve. Our findings point toward a single cause, either genetic or environmental, acting prenatally in the aetiology of Perthes' disease.
Perry et al[32] (2013)	146 cases of LCPD and 142 hospital controls, frequency matched by age and sex	LCPD and hyperactivity	Significant associations (P < 0.05) existed with the majority of the psychological domains captured by the Strength and Difficulties Questionnaire [OR for "high" level of difficulties-Emotion OR 3.2, Conduct OR 2.1, Inattention-Hyperactivity OR 2.7, Prosocial behaviour OR 1.9]. Hyperactivity was especially marked among individuals within 2 years of diagnosis (OR = 8.6; P < 0.001), but not so among individuals over 4 years from diagnosis.
Berman et al[34] (2016)	16 children with LCPD (age 9.1 ± 3.3, 75% males) were compared with their closest-aged siblings (age 9.3 ± 2.6, 30% males).	LCPD and ADHD	Our findings in a small cohort of children with LCPD and their comparably aged siblings do not support an association between LCPD and ADHD
Hailer et al[35] (2012)	2579 patients with LCPD in Sweden during the period 1964-2005. 13748 individuals without LCPD were randomly selected from the Swedish general population	LCPD and risk of injury	Patients with LCPD are vulnerable to injuries that could be interpreted as a marker of hyperactive behaviour.
Hailer et al[36] (2014)	4057 individuals with LCPD in Sweden during the period 1964-2011. 40570 individuals without LCPD were randomly selected from the Swedish general population	LCPD and ADHD	Compared to the control group, individuals with LCPD had a raised HR of 1.5 (95%CI: 1.2-1.9) for ADHD.
Türkmen et al[37] (2014)	The study included 3 groups of patients: Perthes patients, trauma patients and orthopaedic patients without Perthes disease or history of trauma. Each group was comprised of 56 males and 4 females.	LCPD and ADHD	ADHD was diagnosed in 7 patients in the Perthes group. The findings are not significant
Lee et al[39] (2013)	38 male and 3 female patients with LCPD, and an equal number of age (range was 4-12) and sex-matched control patients with healthy fractures.	LCPD and leptin	Leptin, disease severity and treatment outcomes were associated. This correlation suggests that leptin might play an important role in LCPD pathogenesis.
Srzentić et al[51] (2014)	37 patients with Perthes disease and 50 healthy controls	LCPD and IL-6	Our study revealed that heterozygote subjects for the IL-6 G-174C/G-597A polymorphisms were significantly overrepresented in the control group than in the Perthes patient group.
Kamiya et al[52] (2015)	28 patients with matched controls	LCPD and IL-6	In the synovial fluid of the affected hips, IL-6 protein levels were significantly increased (LCPD: 509 ± 519 pg/mL, non-LCPD: 19 ± 22 pg/mL; P = 0.0005) on the multi-cytokine assay.
Perry et al[76] (2012)	149 cases and 146 controls	Vascular abnormalities in LCPD patients	Children with Perthes disease exhibit small artery calibre and reduced function, which is independent of body composition. These data imply that that Perthes disease may reflect a wider vascular phenomenon that could have long-term implications for the vascular health of affected individuals.
Kitoh et al[78] (2003)	125 children (105 boys, 20 girls) with unilateral LCPD	Delayed ossification in LCPD	Our findings support the hypothesis that a delay in endochondral ossification in the proximal capital femoral epiphysis may be associated with the onset of Perthes' disease.
Kocjančič et al[79] (2014)	135 adult hips of patients who had been treated for Perthes disease in childhood with matched controls	Hip stress distribution in LCPD	No differences were found in resultant hip force and in peak contact hip stress between the hips that were in childhood subject to Perthes disease and the control population, but a considerable (148%) and significant (P < 0.001) difference was found in the contact hip stress gradient index, expressing an unfavourable, steep decrease of contact stress at the lateral acetabular rim.
Neidel et al[83] (1992)	59 consecutive children with Perthes' disease and 59 matched controls	IGF-1 and LCPD	Our data may reflect an impaired synthesis or release of IGF I relative to age in Perthes' disease or changes in the affinity or metabolism of IGF binding proteins. The observed changes seem to be of a temporary nature.
Kim et al[82] (2009)	56 immature pigs	HIF-1α and LCPD	Acute ischemic injury to the immature femoral head induced severe hypoxia and cell death in the bony epiphysis and the deep layer of the epiphyseal cartilage. Viable chondrocytes in the superficial layer of the epiphyseal cartilage showed HIF-1α activation and VEGF upregulation with subsequent revascularization occurring in the cartilage.
Matsumoto et al[84] (1998)	27 children with Perthes' disease and 10 age-matched control subjects	IGF binding protein-3 and LCPD	The bone age was delayed 2 years or more compared with the chronological age in 7 of 18 patients, and all of them, except 1, showed decreased levels of IGFBP-3 on WLB.
Graseman et al[85] (1996)	23 children with unilateral LCPD and in 23 sex and age matched controls	IGF binding protein-3 and LCPD	Data confirm that most children with LCPD are skeletally immature. However, IGF-I measured with IGF-II-blocked IGFBP binding sites, and IGFBP-3 serum concentrations analysed with respect to bone age showed no evidence for a disturbance of the hypothalamo-pituitary-somatomedin axis in these children.
Neidel et al[86] (1993)	55 children with Perthes' disease and 55 age- and sex-matched controls	IGF and LCPD	Our findings indicate that low levels of circulating IGF I in Perthes' disease, as we have reported previously, are caused neither by altered concentrations of the principal IGF-binding protein, IGFBP-3, nor by an underlying growth hormone deficiency.

LCPD: Legg-Calvé-Perthes disease; OR: Odds ratio; CI: Confidence interval; ADHD: Attention deficit hyperactivity disorder; IL-6: Interleukin 6; IGF: Insulin-like growth factor; IGFBP: Insulin-like growth factor binding protein; HR: Hazard ratio: HIF: Hypoxia-inducible factor.