Abstract

Growth hormone (GH) replacement seems to represent an additional risk factor for epiphysiolysis. The femoral diaphyseal–epiphyseal angle (Southwick's angle), which is observed to become decreased in the presence of slipped capital femoral epiphysis, is increased in risk groups, such as obese patients, suggesting a potential marker for epiphysiolysis. To evaluate the pattern of Southwick's angle in GH deficiency (GHD) patients, we measured it in 44 GHD patients. We found that Southwick's angle increased significantly after 2 years on GH replacement compared with the pretreatment period. Our data suggest that increasing in Southwick's angle during GH treatment might represent an increased risk for epiphysiolysis in GHD patients.

Introduction

Patients with growth hormone deficiency (GHD) have a higher risk of epiphysiolysis than the general population [1–3]. In children with GHD, slipped capital femoral epiphysis (SCFE) can reach an incidence of 272 cases per 100 000, which is at least 25-fold increased compared with the incidence of 8.3–10.8 per 100 000 in the general population in the pubertal age range [2,4,5]. In addition, the use of recombinant human growth hormone (rhGH) has also been associated with an increase risk of epiphysiolysis [1,6,7].

The most common cause of hip pain in adolescents, SCFE leads to limitation of movements, anatomical deformities, and potential progression to osteoarthrosis and chondrolysis of the hip articulation [8,9]. Epiphysiolysis occurs at the level of the hypertrophic zone of the growth plate, a thin cartilage between epiphysis and metaphysis of long bones, where the process of longitudinal growth takes place. The etiology of SCFE remains unknown, but the condition is associated with endocrine disorders and bone maturation delay. Epiphysiolysis occurs primarily during the pubertal spurt, when growth is under strict hormonal regulation [10,11].

Measurement of the Southwick's angle is useful for planning the surgical fixation of the slipped epiphysis [12]. Santili and coworkers [13] have shown that high-risk groups, such as obese adolescents and the normal hip of patients with unilateral epiphysiolysis, have an increased Southwick's angle, which seems to represent an additional risk marker for SCFE. Recently, the same group characterized and showed that anteroposterior (AP) Southwick's angle tends to decrease in normal adolescents with both, chronological and bone age, contrasting the previous finding in obese adolescents [14]. Other methods may also be used to investigate preslipping stage, such as MRI and computed tomography, which are recommended in specific circumstances, such as the follow-up of the contralateral hip in unilateral affected individuals. Unfortunately, they are more expensive and require anesthesia in young patients [15].

This study aimed to determine Southwick's angle in GHD patients before and during rhGH therapy, to identify the inherent risk of epiphysiolysis in GHD patients and the additional risk imposed by rhGH therapy.
Patients and methods

The study was approved by the local ethical committee of human research, and informed consent was obtained from parents or legal guardian of each patient.
Study population

The study group included 44 GHD patients (14 females and 30 males), 39 with isolated GHD and five with others pituitary hormonal deficiencies, with age varying from 7.9 to 16.1 years, and followed at the pediatric endocrinology unit of Santa Casa de São Paulo, Brazil. The diagnosis of GHD was defined by short stature (<-2 SDS), stature more than 1 SDS below the mid-parental height, growth velocity less than the 25th percentile and two stimulatory tests with GH response under 5 ng/ml (chemoluminescent assay) or 7 ng/ml (immunoradiometric assay). All patients received treatment with rhGH (0.033 mg/kg per day, subcutaneously). Patients with multiple pituitary deficiencies were under standard replacement therapy for all deficiencies. This study did not include other patients with higher doses of GH or other conditions at risk such as Turner syndrome. Every year after the start of GH replacement, pelvic radiography was obtained for measurement of Southwick's angle. The study was dynamic and continuing, and included all new patients starting GH therapy in the endocrinology pediatric unit. At the end of 2 years, of 44 GHD patients with pelvic radiography taken pretreatment, 28 patients had completed one-year treatment, and 10 patients had finished the second year of GH replacement. Every 6 months, weight, height, and pubertal stage were assessed by the method of Tanner [15]. The control group included 97 normal children and adolescents (42 females and 55 males) with chronological age varying from 8 to 17 years without endocrine or orthopedic diseases [14]. The z-scores for height and body mass index (BMI) were calculated by using the National Center Health for Statistics (2000) data, using the Growth Analyser 3 software (Department of Growth and Reproduction, University Hospital, Copenhagen, Denmark; version 3, 2004). Obesity was defined by BMI z-score higher than 2 SDS and overweight by BMI z-score between 1 and 2 SDS. Bone age was calculated by the Greulich–Pyle method. The clinical characteristics of the GHD and control group are summarized in Table 1.

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[Email Jumpstart To Image]     Table 1 Southwick's angle and clinical features of GHD patients and controlsThe results are expressed as mean (SD).BA, bone age; GHD, growth hormone deficient patients.
Southwick's angle measurement

The measurement of Southwick's angle was performed using an AP radiograph of the pelvis. One line was drawn passing through the extremities of the proximal femoral epiphyseal plate, and then a second line was drawn perpendicular to the first line. A third line was drawn along the femoral diaphysis axis. The angle between the second and third lines was taken as Southwick's head-shaft angle (Fig. 1). The mean of the left and the right side values was used for data analysis. Both bone age and measurement of Southwick's angle were assessed by a single investigator (A.C.A.). It is worthy of note that our group have previously shown that the AP Southwick's angle can be determined with acceptable accuracy, with a maximal intraobserver and interobserver variation of 1.7 and 1.8% for the AP angle, respectively [13].

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[Email Jumpstart To Image]     Fig. 1 Measurement of the anteroposterior head-shaft angle from pelvic radiographs (Southwick's method).
Statistical analysis

Student's t-test was used to compare Southwick's angle between the GHD and the control group; and a repeated measured analysis of variance test was used to analyze GHD group in different time points. Repeated measures analysis of variance followed by Holm–Sidak all pairwise multiple comparisons. Mann–Whitney and Kruskal–Wallis were used for samples without normal distribution. Regression analysis was obtained to see whether Southwick's angle varies with age, sex, puberty, and bone age. Significant level was established at P<0.05.
Results

We analyzed the mean value of Southwick's AP angle (APm) from both right and left sides, as there was no difference between the two sides (P=0.9, paired t-test). No difference was observed between GHD patients' AP angle pretreatment and control individuals (P=0.2, Table 1). However, we observed a wide variability of the Southwick's angle in both control and GHD groups, with the highest values in the group of GHD patients (Table 1). Normal reference values for Southwick's AP angle in prepubertal and pubertal adolescents were recently published, and show a similar range for AP angle [14].

Of the 28 GHD patients for whom we obtained the Southwick's angle pretreatment and after 1 year of GH therapy, 17 patients showed an increase in Southwick's angle. In this group, the mean Southwick's angle showed an increase after 1 year on rhGH therapy which was not statistically significant (153.7±4.9° vs. 152.2±5.7°, P=0.3; Fig. 2).

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[Email Jumpstart To Image]     Fig. 2 Southwick's angle means (AP view) of GHD patients: (a) pretreatment and after 1 year of GH therapy (n=28), and (b) pretreatment, 1 and 2 years during GH therapy (n=10). AP, anteroposterior; GHD, growth hormone deficiency.

A subset of 10 patients was followed up after 2 years of GH replacement. In nine of these patients, a further increase in the Southwick's angle was observed. In this group, the mean angle increased significantly at 2 years compared with the pretreatment measurement (154.1±2.9° vs. 149.8±5.6°; P=0.02, Fig. 2). Southwick's angle of both the pretreatment GHD patients (r=-0.4, P=0.01; Fig. 3) and controls (r=-0.2, P=0.02) showed a negative correlation with chronological age, but did not vary with bone age (r=-0.3, P=0.08).

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[Email Jumpstart To Image]     Fig. 3 Linear correlation between Southwick's angle mean (AP view) and chronological age (CA) of growth hormone deficient patients. AP, anteroposterior.

To evaluate the effect of puberty in Southwick's angle, we divided the GHD group in pubertal and prepubertal according to Tanner standard [16] and bone age (threshold of 10 and 12 years for female and male, respectively). The Southwick's angle tends to decrease with Tanner stage (P=0.06), but no significant difference was observed with bone age (P=0.1). A multiple regression analysis did not reveal a primary relationship between Southwick's angle and puberty (P=0.7), or sex (P=0.8), or bone age (P=0.9). The Southwick's angle did not have any relationship to BMI z-score (r=0.2, P=0.2).

Regarding to the presence of other hormonal deficiencies, there was no relationship with Southwick's AP-angle values (r=0.1, P=0.4). Only three out of 28 patients in the after 1-year GH-treated group (3/28), and none among the 2-year GH-treated group (0/10) had additional hormonal deficiency.

Throughout the following period, no patients developed SCFE or referred pain or other symptoms that would be correlated with the angles values or development of SCFE. The absence of symptoms and development of SCFE in our group during the study period is compatible with the incidence of epiphysiolysis in both GHD and normal population.
Discussion

The presence of SCFE has been strongly associated with obesity and other hormonal abnormalities such as hypothyroidism and gonadal dysfunction. It occurs predominantly in overweight adolescents during the pubertal spurt. GHD patients are also under higher risk for developing epiphysiolysis during GH treatment, perhaps secondary to the action of either GH or IGF-I on the growth plate. Although SCFE most often occurs during the pubertal spurt and in association with obesity, in the setting of GHD patients epiphysiolysis also occurs in prepuberal children with normal or even low weight [11]. In addition, bilateral epiphysiolysis is more often in the presence of endocrine diseases, reaching 40–100% in some case series compared with 25% in cases with epiphysiolysis in the absence of endocrine disorders [10,17]. GHD, as well exogenous GH administration, might aggravate growth plate weakness and increase susceptibility to epiphyseal slipping. Further studies should address the pathogenetic mechanisms involved in the growth plate lesion.

The reduction in Southwick's angle is an essential sign to confirm the diagnosis and to recognize the severity of epiphysiolysis. Our group have recently established the normal reference values of Southwick's AP angle, and we found that the angle tend to decrease with age [14]. In an earlier study, we have shown that obesity is strongly correlated to an increase in Southwick's AP angle [13]. On the basis of the cited studies and in our findings, the increase in Southwick's angle should be considered as a preslipping risk marker, and may be used in the follow-up of risk groups such as obese, unilateral epiphysiolysis, and GHD patients as well.

This is the first study describing observed values of Southwick's angle in children with GHD, both before and during GH therapy. We found that Southwick's angle of GHD patients are comparable with normal adolescents at diagnosis, and increase during growth hormone therapy, in agreement with the fact that these patients are more predisposed to epiphysiolysis. The wide variability in the values of AP angle in both groups, GHD and control, seems to be intrinsic to each individual, as such variability was not observed within the same patients in different time points. Contrarily to normal population, in which the angle decreases with age and pubertal development [14], in GHD patients, Southwick's angle increased after 2 years of GH therapy (P=0.02, paired t-test). Additionally, there was no relationship between the AP-angle values and age, sex, or other factors that would justify such variability among different patients.

Age and pubertal stage progression are usually associated with a decrease in the Southwick's angle [11]. However, in GHD patients, pubertal stage was not associated with changes in Southwick's angle, suggesting that this protective phenomenon of decreasing in the Southwick's angle did not occur in GHD patients. Therefore, we observed a decrease in BMI z-score and no relationship of Southwick's angle to BMI z-score, which put away the obesity as an essential etiologic risk factor in GHD patients. Our study identified growth hormone replacement as an independent factor determining the increase in Southwick's angle, especially during the second year of treatment.

Most of the series published in the literature shows a higher risk of epiphysiolysis in patients with organic GHD associated with others pituitary deficiencies, suggesting a multiplicity of factors in the pathogenesis of SCFE [1,18]. In this study, there was no difference in the Southwick's angle between patients with multiple hormonal deficiencies or isolated GHD. All patients under complete 2 years treatment with GH analyzed in this study were only GHD, which rules out the influence of other hormonal deficiencies and suggests a role for exogenous GH treatment in the observed increase of Southwick's AP angle. Further longitudinal studies are, however, required to recognize the cutoff value of Southwick's angle that defines progression of epiphysiolysis in patients of risk.

In summary, our data demonstrated that the Southwick's angle increase with exogenous GH therapy, suggesting that GH causes a progressive abnormality that places the patient at increased risk for epiphysiolysis. Therefore, we suggest an annual measurement of Southwick's angle during the follow-up of patients with isolated or multiple pituitary deficiencies receiving exogenous GH replacement. A closer follow-up should be done when the angle shows an increasing value in the same patient during GH therapy, specially for AP-angle values above 2 SD from normal population [14], accompanied by an orthopedic evaluation and more specific exams, such as MRI of hip. Further studies are, however, necessary to determine the Southwick's angle cutoff value that represents a higher risk for imminent epiphysiolysis.
Acknowledgements

A.C. deA was partially supported by CAPES scholarship program.

Conflict of interest: none declared.
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Keywords: epiphysiolysis; growth hormone deficiency; slipped capital femoral epiphysis; Southwick's angle

 
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