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

Table 2 Main findings of included cohort studies

Ref.	Subjects	Association/molecule studied	Results
Gordon et al[14] (2004)	60 patients with LCPD	Smoking and socio-economic status and the severity of LCPD	A significant association was noted between living with a smoker and LCPD as well as between increasing smoke exposure and increased risk of developing LCPD. No significant association was noted between lower income and LCPD. There was no association between increased smoke exposure and increased severity of LCPD as measured by the lateral pillar classification.
Glueck et al[16] (1998)	39 children with Legg-Perthes disease	Second-hand smoke exposure	Second-hand smoke exposure had no significant effects on other measures of coagulation. Second-hand smoke exposure while in utero and during childhood appears to lower stimulated tissue plasminogen activator activity and additionally may depress heritable low stimulated tissue plasminogen activator activity, leading to hypofibrinolysis. Hypofibrinolysis may facilitate thrombotic venous occlusion in the head of the femur, leading to venous hypertension and hypoxic bone death, Legg-Perthes disease.
Sharma et al[18] (2005)	240 children (263 hips) who presented with Perthes' disease in Greater Glasgow	Socio economic deprivation and LCPD	There was no significant evidence of a preponderance of Perthes' disease in the most deprived groups.
Pillai et al[19] (2005)	40 LCPD patients and the Southwest Scotland registry	The incidence of LCPD in Southwest Scotland	The incidence of LCPD increases with deprivation and poor living standards.
Kealey et al[20] (2000)	313 children with LCPD and Northern Ireland registry	Socio economic deprivation and LCPD	While the incidence of Perthes' disease was found to be associated with indicators of the level of deprivation for areas, there was no evidence to suggest that there was an increased risk in urban areas; the highest rate was found in the most deprived rural category
Perry et al[21] (2012)	The General Practice Research database was analysed to identify incident cases between 1990 and 2008 in children aged 0-14 years	LCPD incidence in United Kingdom	The incidence was declining in the study period. The declining incidence, along with the geographic variation, suggests that a major etiologic determinant in LCPD is environmental and closely linked to childhood deprivation.
Perry et al[22] (2012)	Scottish Morbidity Record, based in Scotland, United Kingdom using data from 2000-2010. A total of 443 LCPD patients	Socio economic deprivation and LCPD	The occurrence of Perthes' disease within urban environments is high, yet this appears to be a reflection of higher socioeconomic deprivation exposure. Disease rates appear equivalent in similarly deprived urban and non-urban areas, suggesting that the determinant is not a consequence of the urban environment.
Perry et al[23] (2011)	1082 children with Perthes' disease (682 from a geographically defined area). Regional disease register in Merseyside, United Kingdom, 1976-2009	Social deprivation and the declining incidence of LCPD	There was a marked decline in disease incidence over the study period, particularly in more deprived areas. The magnitude of the association with deprivation, and the changing incidence, strongly suggest that environmental factor(s) are a major aetiological determinant in Perthes' disease.
Hall and Barker[24] (1989)	Yorkshire region registry	Perthes incidence over the region	There were large geographical differences in incidence that could not be explained by urban-rural or social class differences.
Hall et al[25] (1983)	Case registry in Liverpool and adjacent parts of Knowsley and Sefton during 1976-81	Incidence of LCPD in the region	The inner city of Liverpool, which has been shown to be underprivileged, had the highest yearly incidence of the disease ever reported: 21.1 cases/100000 children aged 14 years and under. The associations with poverty support the hypothesis that undernutrition is a causative factor in the disease.
Margetts et al[26] (2001)	Registry of Liverpool (1982-1995)	Incidence and distribution of LCPD in Liverpool	We suggest that environmental influences may come into play some years before a child presents with pain in the hip. There may be a genetic predisposition to the disease.
Metcalfe et al[27] (2016)	All twin pairs from the Danish Twin Registry (DTR) in which at least 1 individual had LCPD (81 twin pair)	Twin study of LCPD	This study found evidence of familial clustering in LCPD but did not show a genetic component. The absolute risk that a co-twin of an affected individual will develop LCPD is low, even in the case of monozygotic twin pairs.
Lappin et al[28] (2003)	320 patients on the Northern Ireland Perthes' database	Birthweight and LCPD	We observed that the low birthweight twin in each case was the affected child. It is proposed that environmental factors associated with low birthweight are involved in the aetiology of Perthes' disease.
Loder et al[30] (1993)	24 LCPD patients	LCPD and ADHD	One third (33%) of the children had abnormally high scores in profiles associated with ADHD (impulsive, hyperactive and psychosomatic categories), much higher than the 3%-5% incidence of ADHD in the general population.
Perry et al[31] (2012)	General Practise Research database in United Kingdom	LCPD comorbidities	The risk of Perthes' disease was significantly increased with the presence of congenital anomalies of the genitourinary and inguinal region, such as hypospadias (OR = 4.04, 95%CI: 1.41-11.58), undescended testis (OR = 1.83, 95%CI: 1.12-3.00) and inguinal herniae (OR = 1.79, 95%CI: 1.02-3.16). Attention deficit hyperactivity disorder was not associated with Perthes' disease (OR = 1.01, 95%CI: 0.48-2.12), although a generalised behavioural disorder was (OR = 1.55, 95%CI: 1.10-2.17). Asthma significantly increased the risk of Perthes' disease (OR = 1.44, 95%CI: 1.17-1.76), which remained after adjusting for oral/parenteral steroid use.
Podeszwa et al[33] (2015)	11 LCPD patients	Psychological finding in patients undergoing surgery	A significant presence of depression and anxiety symptoms was reported.
Neal et al[38] (2016)	150 patients (172 hips) with LCPD	LCPD and obesity	Obesity is common in patients with LCPD and is associated with a later stage of disease presentation.
Srzentić et al[48] (2015)	37 LCPD patients	Markers of coagulation, inflammation and apoptosis in LCPD	The results presented indicate that apoptosis could be one of the factors contributing to the lack of balanced bone remodelling process in Perthes patients.
Calver et al[56] (1981)	50 children with “irritable hip”	Radionuclide scanning in LCPD	Five of the 50 children seen during the one year had areas of ischemia in the capital femoral epiphysis demonstrated on the scan. All five developed radiological signs of Perthes' disease within 6 mo. The remaining 45 had radiographically normal hips at one year.
Royle and Galasko[60] (1992)	192 patients with a typical transient synovitis syndrome	Scintigraphy in LCPD patients	Fifteen patients had evidence of ischemia of the femoral head, but only four patients went on to develop the typical radiographic features of Perthes' disease. The other 11 patients are thought to represent a minor, radiographically silent form of Perthes' disease.
Lamer et al[61] (2002)	26 DGS MRI and bone scintigraphies of 25 hips in 23 children	Blood supply in LCPD	DGS MRI allows early detection of epiphyseal ischemia and accurate analysis of the different revascularisation patterns. These changes are directly related to the prognosis of LCPD
Atsumi et al[62] (2000)	28 hips in 25 patients with LCPD	Blood supply in LCPD	We suggest that in Perthes' disease the blood supply of the LEAs is impaired at their origin and that revascularisation occurs from this site by ingrowth of small vessels into the femoral epiphysis. This process may be the result of recurrent ischemic episodes.
de Camargo et al[63] (1984)	30 patients, including 26 aortographies and 6 selective angiographies	Blood supply in LCPD	The major angiographic alterations were: general decrease of blood flow in the affected hip, lack of a patent medial circumflex artery, an atrophic medial circumflex artery or obstruction of its branches, distended vessels in subluxations of the hip joint and almost complete absence of the obturator artery
Theron et al[64] (1980)	11 cases of LCPD	Blood supply in LCPD	The balance between the respective vascular territories of the dilated superior and inferior capsular arteries is variable and seems to affect the position of the sequestrum and the centering of the femoral head.
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.

LCPD: Legg-Calvé-Perthes disease; ADHD: Attention deficit hyperactivity disorder; OR: Odds ratio: CI: Confidence interval; MRI: Magnetic resonance imaging.