Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.

Surgical Treatment of Acetabular Dysplasia With Labral Tears.

Acetabular dysplasia results in abnormal forces across the hip joint and can result in both labral tears and cartilage degeneration. A continuum exists from classic dysplasia to normal acetabular morphology. Diagnosis is aided by several radiographic measurements and parameters including a lateral center edge angle of less than 20°, an anterior center edge angle of less than 20°, a Sharp's angle of greater than 42°, and a Tonnis angle of greater than 10°, or version abnormalities. When patients with acetabular dysplasia present with intra-articular hip pain, skeletal maturity, and preserved radiographic joint space, a periacetabular osteotomy (PAO) is considered as a surgical treatment option when conservative measures have failed. The Bernese PAO was developed in 1984 as a way for reorienting the acetabulum to restore more normal femoral head coverage and orientation. The long-term results of this procedure have been promising with 10-year and 20-year survivorships of approximately 85% and 60%, respectively. When dysplasia is coupled with a labral tear or other intra-articular pathology including focal chondral damage, ligamentum teres tears, or capsular defects, hip arthroscopy and PAO are performed. Although there is a paucity in the literature of the long-term evidence for the combined procedure, early results indicate improved patient reported outcome measures. Appropriate treatment of borderline hip dysplasia remains controversial.

MRI Predictors of Residual Dysplasia in Developmental Dysplasia of the Hip Following Open and Closed Reduction.

BACKGROUND: Following open or closed reduction for children with developmental dysplasia of the hip, there remains a significant risk of residual acetabular dysplasia which can compromise the long-term health of the hip joint. The purpose of this study was to use postoperative in-spica magnetic resonance imaging (MRI) data to determine factors predictive of residual acetabular dysplasia at short-term follow-up. METHODS: We retrospectively reviewed 63 hips in 48 patients which underwent closed or open reduction and spica casting for developmental dysplasia of the hip. MRI performed in-spica at ∼3-week follow-up were used to assess 11 validated metrics and 2 subjective factors. Acetabular index (AI) was measured on anteroposterior pelvic radiographs at 2-year postoperative follow-up. Binary logistic regression was then used to identify variables predictive of residual dysplasia, defined as an AI greater than the 90th percentile for age based on historic normative data. RESULTS: Average age at surgical reduction was 9.3±3.2 months. 58.7% (37/63) of reductions were open. A total of 43 (68.3%) hips demonstrated residual acetabular dysplasia at 2 years postoperatively based on normative values. In those with persistent dysplasia, patients were on average older at the time of reduction (10.0 mo±3.2 vs. 8.0 mo±2.8, P=0.010) and more likely female (88.4% vs. 60.0%, P=0.010). Patients with residual dysplasia were more likely to have mild subluxation on postoperative MRI (40.0% vs. 10.5%, P=0.022). Hips with a cartilaginous acetabular index (CAI) of >23 degrees were 7.6 times more likely to develop residual dysplasia. Type of reduction (ie, closed vs. open) did not appear to influence the rate of residual dysplasia (P=0.682). CONCLUSION: In this series, the rate of residual dysplasia after surgical reduction was higher than most previous reports, with no appreciable difference between closed and open reductions. Older age, female sex, and a higher CAI were associated with a greater risk of persistent radiographic dysplasia. In particular, hips with a CAI >23 degrees were 7.6 times more likely to be dysplastic at 2-year follow-up. LEVEL OF EVIDENCE: Level III.

ARTHROPLASTY IN DYSPLSATIC COXARTHROSIS.

Objective - to justify the use of hip endoprosthesis techniques in dysplastic coxarthrosis depending on the type of dysplasia according to Crowe JF. The study is based on the analysis of hip replacement in 390 patients with dysplastic coxarthrosis, who underwent 436 endoprosthetics. There were 192 patients with type 1 dysplasia according to Crowe, type II - 142, type III - 38 and type IV - 18 patients. The age of patients ranged from 15 to 61 years and averaged 43 years. Pathology was prevalent in women, which accounted for 90 %. Preference was given to prostheses with a cementless type of fixation, which accounted for 89 %. An important task of the surgeon during hip replacement in patients with dysplastic coxarthrosis is to install the acetabulum component of the prosthesis in an anatomical position in compliance with the recommendations of spatial location, especially in types III and IV of dysplasia. Endoprosthetics in types 1 and II of hip dysplasia did not present any difficulties. The amount of bone tissue of the acetabulum of the pelvis is sufficient for the use of cups with primary press-fit fixation. Usually, acetabular components of small size were used. In type III dysplasia, there was a significant deficit of bone tissue of the anterior, posterior columns and acetabular roof. In such cases, bone grafting is used. Shortening of the limb in type III dysplasia, as a rule, does not exceed 4 cm, so the surgery may be performed in one stage and without a shortening osteotomy. In type IV dysplasia with shortening of the lower limb to 4 cm, a single stage endoprosthetics is performed it is possible to perform a shortening osteotomy of the proximal femur. Іn patients with a unilateral process and shortening of the limb more than 4 centimeters, we used the two-stage surgery method. At the first stage, we applied a rod device for external fixation with the introduction of rods into the pelvis and hip, then gradually performed hip traction in order to lower the femoral head to the level of the acetabulum, after which the device was dismantled and at the second stage hip replacement was performed. The acetabular component in hip replacement in Crowe type III or IV dysplasia should be placed in the anatomical position of the acetabulum. If the cranial displacement of the femoral head is less than 4 cm, hip replacement should be performed in one stage. In a unilateral cranial displacement of the femoral head of more than 4 cm, in order to avoid neurovascular bundle traction damage and facilitate the reduction of the prosthesis, preparation should be performed with the reduction of the femoral head to the level of the anatomical acetabulum using an external fixation rod device. It is possible to use a shortening osteotomy of the proximal femur, but then the length of the limb is not restored.

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.

Larger Acetabular Labrum Is Associated With Hip Dysplasia, Joint Incongruence, and Clinical Symptoms.

PURPOSE: To evaluate the association of labral length with acetabular morphology and clinical symptoms. METHODS: Patients treated at our hip joint clinic between January 2015 and December 2018 were retrospectively enrolled in the study. Our sample included patients who received a diagnosis of one or more of the following: hip labral tear, femoroacetabular impingement (FAI), and developmental dysplasia of the hip. Patients with osteoarthritis and/or osteonecrosis were excluded. Bilateral labral length was measured as the distance from the acetabular rim to the edge of the labrum at the level of the central coronal T1-weighted magnetic resonance imaging scan cross-referenced to the axial plane (3- to 9-o'clock position). The lateral center-edge angle (LCEA) and acetabular roof obliquity (ARO) were evaluated with plain radiographs. An LCEA of 25° or less was defined as developmental dysplasia of the hip, whereas a positive crossover sign in the presence of an LCEA of 30° or greater, an LCEA greater than 40°, or acetabular inclination lower 0° was defined as pincer FAI. An alpha angle greater than 50° or head-neck offset lower 8 mm was considered cam FAI. The severity of hip symptoms was evaluated bilaterally using the Japanese Orthopaedic Association pain scale, on which hips scoring full points (i.e., a perfect score) were defined as asymptomatic whereas hips with all other scores were considered symptomatic. We used simple linear regression to examine the correlations of labral length with the LCEA and ARO. Labral length was also compared according to patient hip symptom status using the Mann-Whitney U test. RESULTS: The study included 102 patients (14 with bilateral symptoms and 88 with unilateral symptoms). Labral length was strongly correlated with the LCEA (r = -0.612, P < .001) and ARO (r = 0.635, P < .001). Additionally, patients with symptomatic hips had significantly larger labra (9.5 ± 3.0 mm) than those with asymptomatic hips (7.9 ± 2.1 mm, P = .004). CONCLUSIONS: Acetabular labral length is significantly greater in dysplastic, irregularly congruent, symptomatic hips. LEVEL OF EVIDENCE: Level Ⅳ, retrospective cross-sectional study.

Whole genome sequencing of pairwise human subjects reveals DNA mutations specific to developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening.

Are there clinically relevant anatomical differences of the proximal femur in patients with mild dysplastic and primary hip osteoarthritis? A CT-based matched-pairs cohort study.

AIM: To investigate the three-dimensional anatomy and shape of the proximal femur, comparing patients with secondary osteoarthritis (OA) due to mild developmental dysplasia of the hip (DDH) and primary hip OA. MATERIALS AND METHODS: This retrospective radiographic computed tomography (CT)-based study investigated proximal femoral anatomy in a consecutive series of 84 patients with secondary hip OA due to mild DDH (Crowe type I&II/Hartofilakidis A) compared to 84 patients with primary hip OA, matched for gender, age at surgery, and body mass index. RESULTS: Men with DDH showed higher neck shaft angles (127±5° vs. 123±4°; p<0.001), whereas women with DDH had a larger femoral head diameter (46±4 vs. 44±3 mm; p=0.002), smaller femoral offset (36±5 vs. 40±4 mm; p<0.001), decreased leg torsion (25±13° vs. 31±16°; p=0.037), and a higher neck shaft angle (128±7° vs. 123±4°; p<0.001) compared to primary OA patients. Similar patterns of the three-dimensional endosteal canal shape of the proximal femur, but a high inter-individual variability for femoral canal torsion at the meta-diaphyseal level were found for DDH and primary OA patients. CONCLUSION: Standard cementless stem designs are suitable to treat patients with secondary hip OA due to mild DDH; however, high patient variability and subtle anatomical differences in the proximal femur should be respected.

Can Computed Tomography Accurately Measure Acetabular Anterversion in Developmental Dysplasia of the Hip? Verification and Characterization Using 3D Printing Technology.

BACKGROUND: One of the important pathologic changes in developmental dysplasia of the hip (DDH) is increased acetabular version angle (AA). Reasonable correction for excessive AA is an important step in the treatment of DDH, making accurate AA measurement very crucial. However, the results of different AA measurement methods vary. Thus, this study aimed to compare the difference in AA measurements between 2-dimensional computed tomography (2D-CT) and 3-dimensional computed tomography (3D-CT) in children with DDH and to identify the AA degree in children with DDH to guide treatment. METHODS: AA was measured by 2D-CT and 3D-CT in 186 children with DDH, and the measurement results were compared with the physical measurement result in the 3D-printed pelvis (3D-PP) model. The 3D-PP was a 1:1 model identical to the human pelvis. All patients were unilaterally affected. RESULTS: The results of AA measurement through 2D-CT, 3D-CT, and 3D-PP of normal hips were 14.0±6.6, 11.9±5.3, and 11.9±3.4 degrees, respectively, whereas those of the dislocated hips were 24.9±8.9, 19.8±5.2, and 19.5±4.3 degrees, respectively. In both the normal and dislocated hip groups, the results between 2D-CT and 3D-CT was significantly different (P<0.05), but there was no difference between the results of 3D-CT and 3D-PP (P>0.05). The AA of the normal and dislocated hips as measured by 3D-PP was 11.9±3.6 and 19.6±4.3 degrees, respectively, with statistically significant difference (P<0.05). In the dislocated hips, a significant positive correlation was found between age and AA (r=0.756, P<0.05) and between AA and degree of dislocation (r=0.837, P<0.05). CONCLUSIONS: 3D-CT is more accurate than 2D-CT for AA measurement, and compared with normal hips, AA in dislocated hips increased by ∼7.7 degrees on average. AA increases as age and degree of dislocation increase. LEVEL OF EVIDENCE: Level II.

Developmental dysplasia of the hip: A special pathology.

Developmental dysplasia of the hip (DDH) is one of the most common congenital disorders in childhood. Its diverse pathological changes require different treatments and result in different outcomes. Although many studies have been conducted on DDH, some special pathology is still unrecognized. We here presented a rare case of a one-year and eleven-month old girl with DDH; a half-free intra-articular osteocartilaginous tissue was found in her right hip joint. X-ray, computer assisted tomography (CT) and magnetic resonance imaging (MRI) were performed to evaluate the pathological changes. MRI revealed some positive findings. The patient experienced open reduction and histopathological examination of the small tissue. Through gross anatomy it is a half-free intra-articular osteocartilaginous tissue, which can fully match a fossa observed at the femoral head. Histopathological examination found that the tissue was composed of collagenous fiber and cartilage-like tissue. Interestingly, we found the expression of type I collagen according to immunohistochemical analysis, which indicated that the cartilage-like tissue was formed due to laceration of the articular cartilage. This kind of disorder should be included as one of the pathologies of DDH. The most possible origin of this tissue is the femoral head which we speculate may have been fractured before.

Longitudinal morphological change of acetabular subchondral bone cyst after total hip arthroplasty in developmental dysplasia of the hip.

PURPOSE: The purpose of this study is to clarify morphological changes of acetabular subchondral bone cyst after total hip arthroplasty for osteoarthritis secondary to developmental dysplasia of the hip. METHODS: Two hundred and sixty-one primary cementless total hip arthroplasties of 208 patients, 18 males, 190 females, were retrospectively reviewed. Morphological changes of subchondral bone cyst were evaluated by computed tomography (CT). The mean cross-sectional area of the cyst from CT scans at 3 months postoperatively and after 7-10 years (average 8.4 years) were compared. RESULTS: Acetabular subchondral bone cysts were found in 49.0% of all cases in preoperative CT scans. There was no cyst which was newly recognized in CT scan performed after postoperative 7-10 years. All the cross-sectional areas of the cysts evaluated in this study were reduced postoperatively. CONCLUSIONS: This study revealed that acetabular subchondral bone cysts do not increase or expand after total hip arthroplasty and indicated that the longitudinal morphological change of acetabular bone cysts in patients of developmental dysplasia of the hip do not influence long-term implant fixation in total hip arthroplasty.

Emerging role of Lon protease as a master regulator of mitochondrial functions.

Lon protease is a nuclear-encoded, mitochondrial ATP-dependent protease highly conserved throughout the evolution, crucial for the maintenance of mitochondrial homeostasis. Lon acts as a chaperone of misfolded proteins, and is necessary for maintaining mitochondrial DNA. The impairment of these functions has a deep impact on mitochondrial functionality and morphology. An altered expression of Lon leads to a profound reprogramming of cell metabolism, with a switch from respiration to glycolysis, which is often observed in cancer cells. Mutations of Lon, which likely impair its chaperone properties, are at the basis of a genetic inherited disease named of the cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Cyclic compressive stress-induced scinderin regulates progress of developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder characterized by a mismatch between acetabulum and femoral head. Mechanical force plays an important role during the occurrence and development of abnormities in acetabulum and femoral head. In this study, we established a mechanical force model named cyclic compressive stress (Ccs). To analyze the effect of Ccs on DDH, we detected special genes in chondrocytes and osteoblasts. Results showed that Ccs downregulated chondrogenesis of ADTC5 in a concentration-dependent manner. Moreover, the mRNA level of Scinderin (Scin) considerably increased. We established lentivirus-SCIN(GV144-SCIN) to transfect hBMSCs, which were treated with different Ccs levels (0.25 Hz*5 cm, 0.5 Hz*5 cm, and 1 Hz*10 cm); the result showed that overexpression of Scin upregulated osteogenesis and osteoclastogenesis. By contrast, expression of chondrocyte-specific genes, including ACAN, COL-2A, and Sox9, decreased. Further molecular investigation demonstrated that Scin promoted osteogenesis and osteoclastogenesis through activation of the p-Smad1/5/8, NF-κB, and MAPK P38 signaling pathways, as well as stimulated the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Moreover, Scin-induced osteogenesis outweighed osteoclastogenesis in defective femur in vivo. The results of the analysis of Micro-CT confirmed these findings. Overall, Ccs influenced the development of DDH by promoting osteogenesis and cartilage degradation. In addition, Scin played a vital role in the development of DDH.

A murine model for developmental dysplasia of the hip: ablation of CX3CR1 affects acetabular morphology and gait.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a debilitating condition whose distinguishing signs include incomplete formation of the acetabulum leading to dislocation of the femur, accelerated wear of the articular cartilage and joint laxity resulting in osteoarthritis. It is a complex disorder having environmental and genetic causes. Existing techniques fail to detect milder forms of DDH in newborns leading to hip osteoarthritis in young adults. A sensitive, specific and cost effective test would allow identification of newborns that could be non-invasively corrected by the use of a Pavlik harness. Previously, we identified a 2.5 MB candidate region on human chromosome 3 by using linkage analysis of a 4 generation, 72 member family. Whole exome sequencing of the DNA of 4 severely affected members revealed a single nucleotide polymorphism variant, rs3732378 co-inherited by all 11 affected family members. This variant causes a threonine to methionine amino acid change in the coding sequence of the CX3CR1 chemokine receptor and is predicted to be harmful to the function of the protein To gain further insight into the function of this mutation we examined the effect of CX3CR1 ablation on the architecture of the mouse acetabulum and on the murine gait. METHODS: The hips of 5 and 8 weeks old wild type and CX3CR1 KO mice were analyzed using micro-CT to measure acetabular diameter and ten additional dimensional parameters. Eight week old mice were gait tested using an inclined treadmill with and without load and then underwent micro-CT analysis. RESULTS: (1) KO mice showed larger a 5-17% larger diameter left acetabula than WT mice at both ages. (2) At 8 weeks the normalized area of space (i.e. size discrepancy) between the femur head and acetabulum is significantly larger [38% (p = 0.001)-21% (p = 0.037)] in the KO mice. (3) At 8 weeks gait analysis of these same mice shows several metrics that are consistent with impairment in the KO but not the WT mice. These deficits are often seen in mice and humans who develop hip OA. CONCLUSION: The effect of CX3CR1 deletion on murine acetabular development provides suggestive evidence of a susceptibility inducing role of the CX3CR1 gene on DDH.

Severe cartilage degeneration in patients with developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a developmental disorder that has long-term chronic pain and limited hip joint mobility as major pathological characteristics. This study aims to access the association between the development of DDH and cartilage metabolic disorders. Cartilage tissue samples were acquired from patients with DDH, osteoarthritis (OA) and femoral neck fracture. The proteoglycan level was evaluated by safranin O-fast green, toluidine blue and hematoxylin-eosin (HE) staining. The levels of collagen-II (Col-II), collagen-X (Col-X) and metal matrix proteinase-13 (MMP-13) were evaluated by immunohistochemistry (IHC) and Western blotting analysis. The morphologic evaluation of cartilage was conducted by transmission electron microscopy (TEM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA level of aggrecan, Col-II, Col-X and MMP-13. The aggrecan level in the cartilage matrix was significantly decreased in DDH patients by safranin O-fast green and toluidine blue staining in comparison with that in the OA and control groups. In contrast with the OA group, the Col-II expression was reduced while the MMP-13 expression increased in DDH patients, as shown by IHC and Western blotting analysis. The collagenous fibrils in cartilage of DDH patients appeared significantly sparse and disordered in the TEM analysis. In DDH patients, the mRNA expression levels of Col-II and aggrecan were markedly reduced, while the mRNA expression of Col-X was markedly increased, compared with the OA patients. There is severe articular cartilage degeneration in DDH patients. This observation provides us with new insight into cartilage metabolic regulation in DDH. © 2017 IUBMB Life, 69(3):179-187, 2017.

Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle radiographic signs through mild instability to frank dislocations with acetabular dysplasia. A Saudi family with three affected individuals with DDH was identified and genetic analysis was performed to detect the possible genetic defect(s) underlying DDH in the affected members of the family. METHODS: We performed whole genome genotyping using Illumina HumanOmni 2.5 M array and whole exome sequencing (WES) using Nextera Rapid capture kit and Illumina NextSeq500 instrument in four individuals of a family with DDH. RESULTS: SNP data analysis did not identify any runs of homozygosity and copy number variations. Identity-by-descent (IBD) analysis on whole genome genotyping data identified a shared haplotypes on chromosome 1 in affected individuals. An analysis of the WES data identified rare heterozygous variants in HSPG2 and ATP2B4 genes in the affected individuals. Multiple prediction software predicted that the variants identified are damaging. Moreover, in silico analysis showed that HSPG2 regulates ATP2B4 expression using a variety of transcription factors. CONCLUSION: Our results indicate that there might be a functional epistatic interaction between HSPG2 and ATP2B4, and DDH in the family studied is due to a combined effect of both variants. These variants are also present in the asymptomatic mother suggesting that the variants in HSPG2 and ATP2B4 are incompletely penetrant. This study provides the first evidence of digenic inheritance of DDH in a family and extends the spectrum of genetic heterogeneity in this human disorder.

The Fate of DDH Hips Showing Cartilaginous or Fibrous Tissue-filled Joint Spaces Following Primary Reduction.

BACKGROUND: Because the use of magnetic resonance imaging is still not universal for the patients with developmental dysplasia of the hip patients, orthopaedists do not generally distinguish widened joint spaces which are "empty" after primary treatment (and therefore still reducible), from those which are filled and much more difficult to treat. To date no studies have focused on the latter hips. We treated and observed the outcomes for 19 hips which showed filled joint spaces after primary treatment. METHODS: We retrospectively reviewed 19 cases of developmental dysplasia of the hip: (1) who showed a widened joint space on radiographs after primary treatment; and (2) whose magnetic resonance imaging showed that the widened joint space was accompanied by acetabular cartilage hypertrophy and/or was filled with fibrous tissues. All patients were over 1 year old at the time of primary reduction (reduction was closed in 4 patients, open in 6, and open with pelvic osteotomy in 9). Thirteen patients received at least 1 secondary treatment. Final results were classified using a modified Severin classification. RESULTS: Final outcomes were satisfactory in 10 (52.6%) and unsatisfactory in 9 (47.4%). The widened joint spaces gradually filled with bone, resulting in a shallow acetabulum in the patients with unsatisfactory results. Of 9 patients who underwent combined pelvic osteotomy at the time of primary reduction, results were satisfactory in 6 (66.7%), whereas all patients who had only closed or open primary reduction had unsatisfactory results. CONCLUSIONS: Combined pelvic osteotomy at the time of primary reduction is advisable in hips with widened joint spaces. However, hips with filled joint spaces after primary treatment often have unsatisfactory results even after additional pelvic and/or femoral osteotomy. LEVEL OF EVIDENCE: Level IV-prognostic study.

Developmental dysplasia of the hip: usefulness of next generation genomic tools for characterizing the underlying genes - a mini review.

Developmental dysplasia of the hip (DDH) is one of the most common skeletal anomalies. DDH encompasses a spectrum of the disorder ranging from minor acetabular dysplasia to irreducible dislocation, which may lead to premature arthritis in later life. Involvement of genetic factors underlying DDH became evident when several studies reported chromosomal loci linked to DDH in families with multiple affected individuals. Moreover, using association studies, variants in genes involved in chondrogenesis and joint formation have been shown to be associated with DDH. At least, one study identified a pathogenic variant in the chemokine receptor gene in DDH. No genetic analysis has been reported or carried out in DDH patients from the Middle East. Here, we review the literature related to genetics of DDH and emphasized the usefulness of new generation technologies in identifying genetic variants underlying DDH in consanguineous families.

Factors Associated With Severity of Intra-articular Lesions in Patients With Severe Hip Dysplasia.

PURPOSE: To identify demographic and morphologic factors associated with the severity of intra-articular lesions in patients with severe hip dysplasia. METHODS: One hundred twenty-one patients (134 hips) with symptomatic hip dysplasia were retrospectively reviewed. The cartilage and labral lesions were scored according to the Outerbridge and the original classification systems, respectively. The association of the cartilage and labrum scores with patient demographics (age, gender, body mass index, bilateral hip dysplasia, and treatment history for developmental hip dislocation) and morphologic factors (the lateral center-edge angle, Sharp angle, acetabular index, acetabular head index, acetabular depth ratio, Shenton line disruption, roundness index of the femoral head, and femoral neck shaft angle) were determined using a multiple linear regression analysis. RESULTS: The cartilage and labral scores were significantly associated with radiographic osteoarthritis; however, these scores showed wide distribution among hips with equivalent degrees of radiographic osteoarthritis. Age (38.4 ± 12.8 years) (P < .001), lateral center-edge angle (0.2 ± 9.0°) (P = .014), acetabular head index (54.4 ± 9.1%) (P = .001), and the roundness index of the femoral head (55.6 ± 4.6%) (P = .022) were identified as independent factors associated with the cartilage score. Age (P < .001), having a medical history of developmental hip dislocation (P = .002), acetabular index (27.8 ± 6.8°) (P = .011), and the roundness index of the femoral head (P = .022) were identified as independent factors associated with the labral score. CONCLUSIONS: Our findings suggest that the morphologic factors responsible for severe intra-articular lesions differ for cartilage degeneration and labral tears in patients with severe hip dysplasia. Decreased acetabular coverage of the femoral head was responsible for cartilage degeneration severity, whereas an increased acetabular index was responsible for labral tear severity. LEVEL OF EVIDENCE: Level III, diagnostic study.