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

Table 4 The main findings of the included in vitro human studies are reported

Ref.	Subjects	Association/molecule studied	Results
O’Sullivan et al[40] (1985)	A family in which Legg-Calvé-Perthes disease (LCPD) occurred in four members	Genetic factors and LCPD	This unusually high incidence in one family raises questions about the genetic versus the environmental factors in the aetiology of LCPD.
Livesey et al[41] (1998)	Case report of three family with three female first-degree relatives affected by LCPD	Genetic factors and LCPD	First case of three first-degree relative affected
Miyamoto et al[42] (2007)	A Japanese family with an autosomal dominant hip disorder manifesting as LCPD	LCPD and COL2A1	This is the first report of a mutation in hereditary LCPD. COL2A1 mutations may be more common in LCPD patients than currently thought, particularly in familial and/or bilateral cases.
Al-Omran and Sadat-Ali[43] (2013)	2 generations of 4 male family members with LCPD-like features and mutation of the COL2A1 gene of the 12q13 chromosome	LCPD and COL2A1	If LCPD occurs in any family member, we recommend genetic analysis and counselling as well as early radiological screening of related children.
Kannu et al[44] (2011)	Two children who presented with abnormal development of both hips and in whom novel mutations in the COL2A1 gene were found	LCPD and COL2A1	The purpose of our report is to alert clinicians to the possibility that children who present with bilateral Perthes-like disease of the hip might have an underlying mutation in the gene encoding type II collagen.
Su et al[45] (2008)	Forty-two members of a 5-generation family	LCPD and COL2A1	The p.Gly1170Ser mutation of COL2A1 in the family described is responsible for pathology confined to the hip joint, which presents as isolated precocious hip OA, AVN of the femoral head, or Legg-Calvé-Perthes disease.
Li et al[46] (2014)	Forty-five members of a four-generation family	LCPD and COL2A1	In our research, we identify a heterozygous mutation (c.1888 G>A, p. Gly630Ser) in exon 29 of COL2A1 in the Gly-X-Y domain, in a Chinese family affected by LCPD and ANFH.
Woratanarat et al[47] (2014)	Twelve case–control studies met inclusion criteria and had sufficient data for extraction	Hypercoagulability and LCPD	The factor V Leiden mutation is significantly related to Perthes disease, and its screening in at‐risk children might be useful in the future.
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.
Liu et al[50] (2015)	Age- and sex-matched serum samples from 10 control subjects and 10 patients with LCPD were compared using the isobaric tags for relative and absolute quantification (iTRAQ) technique.	Serum proteomes in LCPD	The complement and coagulation cascades, and abnormal lipid metabolism may be involved in the pathogenesis of LCPD.
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 pg/mL ± 519 pg/mL, non-LCPD: 19 pg/mL ± 22 pg/mL; P = 0.0005) on the multi-cytokine assay.
Su et al[55] (2010)	a five-generation family with 42 members with a new type II collagenopathy	LCPD and COL2A1	Our study demonstrated that the p.Gly1170Ser mutation of COL2A1 caused significant structural alterations in articular cartilage, which are responsible for the new type II collagenopathy.
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	Our 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 show 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; COL2A1: Collagen type II gene; IGF: Insulin-like growth factor.