Original articlePrevalence of RIB anomalies in normal Caucasian children and childhood cancer patients
Introduction
Tumor predisposition syndromes might account for a larger percentage of childhood cancers than is currently estimated. In such syndromes, like Down syndrome and Beckwith-Wiedemann syndrome, the same constitutional genetic defects lead prenatally to an abnormal clinical phenotype of the individual patient, while postnatally they may lead to abnormal cellular proliferation, predisposing the individual for cancer development [1], [2].
Several studies have shown a relationship between childhood cancer and the presence of major [3] and minor anomalies [4] in children. Recently a large population of childhood cancer patients was submitted to a detailed clinical morphological examination, showing childhood cancer patients to have a strikingly high prevalence of phenotypic abnormalities, such as supernumerary nipples, café-au-lait spots, abnormal palmar flexion creases, and leg length asymmetry (Merks et al, submitted). We reasoned that not only phenotypic abnormalities detectable by clinical examination, but also skeletal anomalies can provide clues for underlying constitutional defects, as has been shown in several conditions [5]. Gorlin syndrome can serve as an example, constitutional mutations in the causative Patched-gene leading prenatally to formation of specific phenotypic abnormalities, including skeletal anomalies (calcification of the falx cerebri, jaw cysts, bifid ribs, and vertebral anomalies) [6]. Postnatally, the same Patched mutations result in abnormal cellular proliferation predisposing the affected individual for basal cell carcinoma [7], and several other childhood cancers, such as rhabdomyosarcoma [8] and medulloblastoma [9].
In children with cancer different radiological techniques are used to establish the diagnosis, the extent of the cancer, or to detect possible complications. These radiological studies can also be used to search for findings that are not directly related to the primary diagnosis, and may provide clues for the etiology of the tumor. Most children with cancer undergo a chest radiograph as part of their oncological work-up, which makes these available for reviewing. Schumacher and co-workers earlier reported a higher prevalence of rib anomalies in childhood cancer patients, compared to a small group of pediatric controls [10]. They were able to review a large number of childhood cancer patient radiographs. However, several critical remarks can be made. First of all, definitions of the different rib anomalies were unclear. Furthermore nothing is mentioned about blinding of the observers, ‘lower thoracic border anomalies’ were not scored, and the number of controls is low. Therefore, we decided to firstly generate prevalence figures for the presence of rib anomalies on chest radiographs in control children (normal values), and secondly to analyze chest radiographs of an equal large amount of childhood cancer patients, using a well defined terminology, and a strict scoring methodology.
Section snippets
Controls
For the control group we selected all chest radiographs made in children (age 0 – 18 years) at our hospital between January 1, 1992 and September 31, 2002 (flow-chart: Fig. 1). In order to prevent the inclusion of unusual and selected patients referred to our tertiary center, we selected from the total radiographs only those that were ordered by general practitioners, the general pediatricians at the outpatient ward of our hospital, and physicians at the emergency department. In order to
Results
Male-female ratios for 881 pediatric controls and the 906 pediatric cancer patients were comparable (1.26 and 1.13, respectively). The mean age was 4.8 years for controls (standard deviation 4.9), and 8.4 years for cases (standard deviation 6.6).
Three hundred ninety nine positively scored radiographs were centrally reviewed by all 4 observers reducing the number of positively scored radiographs from 399 (216 cases and 183 controls) to 260. In total 270 rib anomalies were found on these 260
Discussion
We have generated normal values for rib anomalies in a large group of Caucasian control children (Table 2). The overall prevalence of rib anomalies in the cohort of 881 pediatric controls was 14.2% (125/881), which is higher than reported in the major reference adult control population (5.72%) from 1956 by Pionnier and Depraz [15] (Table 4). Patients with asthma or an atopic constitution form a considerable part of the present controls (44/165, Table 1), and one may wonder about a possible
Conclusion
We generated normal values for the presence and type of rib anomalies on chest radiographs in a large group of pediatric controls, and found a significantly higher prevalence of cervical rib anomalies in children with specific types of childhood cancer. Alterations of Hox family gene(s) expression are good candidates for this higher prevalence. The results are in line with a recent, similar study on external phenotypic abnormalities (Merks et al., submitted). Constitutional genetic defects,
Acknowledgments
The authors would like to thank D. Geurts (medical student) for his help in data acquisition, Prof. A.H. Zwinderman (Department of Clinical Epidemiology and Biostatistics) for his help with statistical analyses, R.J. Oostra (Department of Anatomy and Embryology) for sharing his experience in malformations of the axial skeleton, and C. Bor (AMC Medical Photography and Illustrations) for drawing the reference chart with rib anomaly definitions.
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