Does the Capital Femoral Physis Bony MorphologyDiffer in Children with Symptomatic Cam-type Femoroacetabular Impingement.

BACKGROUND: The epiphyseal tubercle, the corresponding metaphyseal fossa, and peripheral cupping are key stabilizers of the femoral head-neck junction. Abnormal development of these features in the setting of supraphysiologic physeal stress under high forces (for example, forces that occur during sports activity) may result in a cam morphology. Although most previous studies on cam-type femoroacetabular impingement (FAI) have mainly focused on overgrowth of the peripheral cupping, little is known about detailed morphologic changes of the epiphyseal and metaphyseal bony surfaces in patients with cam morphology. QUESTIONS/PURPOSES: (1) Does the CT-based bony morphology of the peripheral epiphyseal cupping differ between patients with a cam-type morphology and asymptomatic controls (individuals who did not have hip pain)? (2) Does the CT-based bony morphology of the epiphyseal tubercle differ between patients with a cam-type morphology and asymptomatic controls? (3) Does the CT-based bony morphology of the metaphyseal fossa differ between patients with a cam-type morphology and asymptomatic controls? METHODS: After obtaining institutional review board approval for this study, we retrospectively searched our institutional database for patients aged 8 to 15 years with a diagnosis of an idiopathic cam morphology who underwent a preoperative CT evaluation of the affected hip between 2005 and 2018 (n = 152). We excluded 96 patients with unavailable CT scans and 40 patients with prior joint diseases other than cam-type FAI. Our search resulted in 16 patients, including nine males. Six of 16 patients had a diagnosis of bilateral FAI, for whom we randomly selected one side for the analysis. Three-dimensional (3-D) models of the proximal femur were generated to quantify the size of the peripheral cupping (peripheral growth of the epiphysis around the metaphysis), epiphyseal tubercle (a beak-like prominence in the posterosuperior aspect of the epiphysis), and metaphyseal fossa (a groove on the metaphyseal surface corresponding to the epiphyseal tubercle). A general linear model was used to compare the quantified anatomic features between the FAI cohort and 80 asymptomatic hips (aged 8 to 15 years; 50% male) after adjusting for age and sex. A secondary analysis using the Wilcoxon matched-pairs signed rank test was performed to assess side-to-side differences in quantified morphological features in 10 patients with unilateral FAI. RESULTS: After adjusting for age and sex, we found that patients with FAI had larger peripheral cupping in the anterior, posterior, superior, and inferior regions than control patients who did not have hip symptoms or radiographic signs of FAI (by 1.3- to 1.7-fold; p < 0.01 for all comparisons). The epiphyseal tubercle height and length were smaller in patients with FAI than in controls (by 0.3- to 0.6-fold; p < 0.02 for all comparisons). There was no difference in tubercle width between the groups. Metaphyseal fossa depth, width, and length were larger in patients with FAI than in controls (by 1.8- to 2.3-fold; p < 0.001 for all comparisons). For patients with unilateral FAI, we saw similar peripheral cupping but smaller epiphyseal tubercle (height and length) along with larger metaphyseal fossa (depth) in the FAI side compared with the uninvolved contralateral side. CONCLUSION: Consistent with prior studies, we observed more peripheral cupping in patients with cam-type FAI than control patients without hip symptoms or radiographic signs of FAI. Interestingly, the epiphyseal tubercle height and length were smaller and the metaphyseal fossa was larger in hips with cam-type FAI, suggesting varying inner bone surface morphology of the growth plate. The docking mechanism between the epiphyseal tubercle and the metaphyseal fossa is important for epiphyseal stability, particularly at early ages when the peripheral cupping is not fully developed. An underdeveloped tubercle and a large fossa could be associated with a reduction in stability, while excessive peripheral cupping growth would be a factor related to improved physeal stability. This is further supported by observed side-to-side differences in tubercle and fossa morphology in patients with unilateral FAI. Further longitudinal studies would be worthwhile to study the causality and compensatory mechanisms related to epiphyseal and metaphyseal bony morphology in pathogenesis cam-type FAI. Such information will lay the foundation for developing imaging biomarkers to predict the risk of FAI or to monitor its progress, which are critical in clinical care planning. LEVEL OF EVIDENCE: Level III, prognostic study.

Joint disease-specificity at the regulatory base-pair level.

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran.

BACKGROUND: Primary immunodeficiency (PID) is a heterogeneous group of inheritable genetic disorders with increased susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy. Timely precise diagnosis of these patients is very essential since they may not be able to live with their congenital immunity defects; otherwise, they could survive with appropriate treatment. DNA biobanks of such patients could be used for molecular and genetic testing, facilitating the detection of underlying mutations in known genes as well as the discovery of novel genes and pathways. METHODS: According to the last update of the International Union of Immunological Societies (IUIS) classification, patients are registered in our biobank during a period of 15 years. All patients' data were collected via questionnaire and their blood samples were taken in order to extract and protect their DNA content. RESULTS: Our study comprised 197 patients diagnosed with PID. Antibody deficiency in 50 patients (25.4%), phagocytic defect in 47 patients (23.8%) and combined immunodeficiency with associated/syndromic feature in 19 patients (9.6%) were the most common PID diagnoses, respectively. The most common variant of PID in our study is common variable immunodeficiency, which accounted for 20 cases (10.1%), followed by chronic mucocutaneous candidiasis in 15 patients (7.9%) and congenital neutropenia in 13 patients (7%). Mean age at onset of disease was 4 years and mean age of diagnosis was 9.6 years. The average diagnostic delay was 5.5 years, with a range of 6 months to 46 years. Parental consanguinity and history of PID in family were observed in 70.2 and 48.9% of the patients, respectively. The majority of PID patients (93.3%) were from families with low socioeconomic status. CONCLUSION: This prospective study was designed to establish a PID Biobank in order to have a high quality DNA reservoir of these patients, shareable for international diagnostic and therapeutic collaborations. This article emphasizes the need to raise the awareness of society and general practitioners to achieve timely diagnosis of these patients and prevent current mismanagements.