Etiology

The cause of Legg-Calvé-Perthes (Perthes) disease is hypothesized to be single or multiple vascular events, followed by revascularization. Although several theories have been proposed over the years, it appears that Perthes is most likely multifactorial. One study suggests the age of onset conforms to a pattern typical of infectious disease.[9] No inheritance pattern has been identified in affected patients and the frequency among relatives is low.[10][11]

The femoral head relies on lateral epiphyseal vessels for its blood supply between 4 and 7 years of age. The cause of the femoral head infarct is controversial and may be arterial in origin or due to venous thrombosis.[12][13][14] Arterial blood supply on the affected side may be attenuated, with an associated obstruction to the superior capsular arteries or medial circumflex artery.[15][16] In contrast, the veins in the femoral head are of a medium caliber, similar to cutaneous or cerebral veins. Venous hypertension has been documented in affected patients. It is, however, as yet unclear whether thrombosis is the primary event or contributes to the disease in combination with other etiologies.[17][18][19][20][21][22] The unique vascular anatomy of boys between 4 and 8 years makes them particularly vulnerable in the presence of hypercoagulable states and other factors.[23][24][25] A prothrombotic event in the setting of a hypercoagulable state could lead to thrombosis and infarction of the femoral head.

Vascular thrombosis is uncommon at a young age but may occur due to a genetic defect, such as resistance to activated protein C.[18]Protein C is a vitamin-K-dependent prothrombotic protein that leads to curtailment of procoagulant enzymes, factors Xa and thrombin, via factors V and VIII.[26] Factor V Leiden is implicated in the prothrombotic process by virtue of a substitution that blocks the binding of activated protein C to factor V.[27][28] It is not clear whether the deficiency is due to conversion or resistance to the activated form. However, protein C deficiency causes thrombosis in medium-caliber veins resulting in bone and cartilage ischemia.[17][18][19][20][21][29][30]

Children with Perthes disease exhibit small artery caliber and reduced function, which is independent of body composition.[31] The lateral epiphyseal vessels run in the retinacula and are susceptible to stretching and pressure in the event of an effusion.[23][24][25] The causative link between transient synovitis and Perthes disease has not been conclusively established. Transient synovitis is essentially a benign disease and occasionally children with protracted symptoms are at risk of developing Perthes disease.[32][33] Perthes disease has been shown to create a chronic hip synovitis with a significant elevation of interleukin (IL)-6 in the synovial fluid.[34] There may be an associated increase in intra-articular pressure, with a concomitant vascular event.[20]

A particular phenotype that is predisposed comprises small stature, delayed bone age and prepubertal skeletal arrest. This has led to a hypothesis that an underlying endocrinopathy may be present. These children, however, have a normal stature by 12 to 15 years of age.[10][35][36] Elevated somatomedin A or insulin-like growth factor (IGF) 2 levels suggest that Perthes may be a disease of growth transition.[37][38][39] However, somatomedin C (IGF1) levels are normal in these patients.[40] A large, cross-sectional, longitudinal study of clinically euthyroid children with Perthes disease found significantly elevated levels of free thyroxine (T4) and triiodothyronine (T3) compared with normal controls, particularly in patients with greater femoral head involvement.[12][41] A reduced bone turnover is also noted, although it is not clear whether this is cause or effect.[42]

Perthes disease is more common in patients with skeletal dysplasias. There is also an association between Perthes disease and ADHD.[36][43] Passive smoking in the household and/or maternal smoking during pregnancy may be contributory factors.[17][21][44][45][46] Perthes disease is a nontraumatic condition, although a history of minor trauma may be noted.

Pathophysiology

Understanding the pathophysiology of Perthes disease has come a long way since its first description. The disease goes through 4 stages in 2 to 4 years following first presentation:

  • Stage 1, ischemia: a variable sector of the femoral head is involved depending on the severity. The femoral epiphysis stops growing during this period which lasts 6 to 12 months. Radiographs may appear normal but the articular cartilage continues to grow and is thickened causing subtle changes. This is evident as "Waldenstrom sign" (increased joint space and apparent mild pseudosubluxation) on x-ray.[30]

  • Stage 2, resorption, fragmentation, revascularization, and repair: a subchondral fracture may be seen in the early stages in the infarcted area (crescent, Salter or Caffrey sign). Dead trabecular fragments are resorbed and replaced with fibrous tissue which may become calcified. Loss of structural support results due to resorption of the underlying cancellous bone in the proximal femoral epiphysis. This leads to the deformation of this epiphysis when subjected to the normal weight-bearing forces through the hip joint.[47] Bone is revascularized with new lamellae laid on dead trabeculae resulting in the necrotic bony nucleus appearing fragmented.[47] Resorption is usually complete after 12 to 18 months. Cysts appear in the proximal femoral metaphysis; increased severity could lead to osteolysis of the superolateral portion of the femoral head (Gage sign on x-ray).

  • Stage 3, reossification and resolution: reossification typically starts at the epiphyseal margin (paraphyseal ossification). Occasionally, reossification through the physis results in a bony bridge leading to growth arrest in the femoral neck. Resolution is usually complete within 6 to 24 months and results in healing, or a residual deformity in more severe cases.[48]

  • Stage 4, remodeling: femoral head collapse during remodeling can lead to flattening and distortion of the head. Five classes of structural hip joint changes, based on the sphericity of the femoral head and associated acetabular congruence, have been described.[49] These classes are closely linked to the final prognosis of degenerative changes in the hip joint and demonstrate that sphericity is not as important a prognostic variable as the hip joint congruence. An aspherical femoral head with a good congruence of the joint will at worst lead to a moderate hip osteoarthritis. However, an aspherical incongruous joint will more often lead to severe osteoarthritis at a younger age. [Figure caption and citation for the preceding image starts]: Stulberg classification and prognosis of future hip arthritisFrom the personal collection of Jwalant S. Mehta, MS (Orth), MCh (Orth), FRCS, FRCS (Orth) [Citation ends].com.bmj.content.model.Caption@34111fb9

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