Studies have consistently demonstrated anthropometric abnormalities among affected children. The most detailed of such study was a large cross-sectional study of 232 children from three centers in the UK [23]. This demonstrated a subtle global growth disturbance in affected individuals with a normal head size, yet increasing growth restriction more distally along limbs – a pattern of dysmorphism described as “rostral sparing” (Fig.58.3). A later study sought to determine if the growth restriction was a true disease phenomena or a function of deprivation [24]. This was achieved by comparing anthropometric markers with siblings of affected children, therefore matching for urban deprivation and family tendencies. This study of 38 cases and 49 sibling controls demonstrated a clear growth restriction most notable in the feet of affected children.

The dysmorphic growth seen was similar to that of intrauterine growth restriction, with head size preserved at the expense of other body parameters. This suggested that there may be an abnormality evident with shape and size from birth and potentially arising in the prenatal period.

Birth weight is difficult to study as it is complicated by the number of confounding factors such as gestational age, deprivation, and parental smoking. Numerous studies have sought to quantify this association, but no consistent association has been identified [2, 26, 27]. The most comprehensive study to investigate this used the Swedish Inpatient Register which concluded that, after adjusting for confounding, birth weights less than 1,500 g had an association with Perthes’ disease (OR 3.5 95 % CI 1.1–10.8) [28]. The width of the confidence intervals reflects the paucity of cases within this group (9 of 731 cases). It is possible that unmeasured confounders may be apparent, such as steroids used for neonatal chronic lung disease, which may explain this association. It does therefore seem apparent that no major association with birth weight exists.

A possible indication of prenatal exposures may be the presence of congenital malformations. A 1971 study identified an association between with both inguinal hernias and genitourinary malformations, with the frequency of inguinal hernia being eight times the expected number among individuals with Perthes’ disease [29]. However, the patient group was selected from a specialized clinic in a tertiary center, and therefore selection bias may have influenced the validity of this finding. Subsequent studies failed to replicate these associations [5, 30] until recently, when large population-based case-control studies confirmed these associations. These studies used the Medical Birth Registry of Norway and the UK General Practice Research Database (GPRD) and confirmed a triad of genitourinary associations including undescended testis, inguinal hernias, and hypospadias, though the magnitude of these was less than previously suggested [2, 31].

These findings are important because they suggest a prenatal component to the disease etiology. The triad of associations identified is also interesting because they are often seen in combination, thought to be caused by altered fetal androgen metabolism [32, 33], which may be important in Perthes’ disease, and could explain the strong male disease preponderance of the disease.

The association with socioeconomic deprivation, epidemiological similarities with cardiovascular disease, and possible prenatal insult has led to the suggestion that maternal tobacco smoke exposure may be implicated in the disease. Measuring the effects of tobacco smoke exposure is fraught with difficulties, owing to recall bias, parental guilt, and the influence of confounding factors (particularly socioeconomic status). Several studies have investigated this relationship, the most comprehensive of these being a case-control study from the Swedish Inpatient Register [28] and a large case-control study from India [18]. The Swedish study was able to reduce recall bias by using tobacco smoke exposure data collected prior to disease onset, demonstrating a dose-response relationship with a greater risk of Perthes’ disease corresponding to a greater degree of tobacco smoke exposure (1–9 cigarettes, OR 1.4 (95 % CI 1.1–1.7); >10 cigarettes, OR 2.0 (95 % CI 1.6–2.6)). The authors considered socioeconomic status as a confounder, although it is unclear how this was measured. The study from India similarly showed an association with tobacco smoke exposure (OR 2.1 (95 % CI 1.3–3.3)), recording current exposure to indoor tobacco smoke as a proxy measure of “lifetime exposure” and adjusting for social class. A tobacco association therefore appears evident, though the effects of bias cannot be completely eliminated, and the effect size is less than that of socioeconomic deprivation suggesting that a different factor confounded by the smoking relationship may be the responsible determinant.

Manganese deficiency has a known association with a disproportionate growth abnormality found in chickens and epiphyseal dysplasia in rats. A case–control study within Liverpool demonstrated the existence of this association among children with Perthes’ disease [34], but a later second smaller study failed to replicate this finding [35]. This association therefore remains uncertain.

Thrombotic tendencies , such as sickle cell disease, are known to precipitate avascular necrosis of the hip. This has led to widespread belief that Perthes’ disease is the result of a primary coagulopathic process. This appears plausible as the pathology of Perthes’ disease is avascular necrosis; however, it is difficult to resolve how such a process would solely affect the hip and typically be unilateral.