The authors declared that they have no conflicts of interest.
Orthopedic manifestations and implications for individuals with Costello syndrome†
Article first published online: 27 JUN 2013
Copyright © 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 8, pages 1940–1949, August 2013
How to Cite
2013. Orthopedic manifestations and implications for individuals with Costello syndrome. Am J Med Genet Part A. 161A:1940–1949., , , , .
- Issue published online: 24 JUL 2013
- Article first published online: 27 JUN 2013
- Manuscript Accepted: 19 APR 2013
- Manuscript Received: 1 DEC 2012
- orthopedic manifestations;
- Costello syndrome;
- hip dysplasia
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- Supporting Information
Costello syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello syndrome. © 2013 Wiley Periodicals, Inc.
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- Supporting Information
Costello syndrome is a rare rasopathy caused by heterozygous, typically de novo, HRAS alterations. Patients with Costello syndrome present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurologic complications, intellectual disability and orthopedic complications including: ulnar deviation, hip dysplasia, tight Achilles tendons, and unusual kyphoscoliosis [Yassir et al., 2003; Aoki et al., 2005; Gripp and Lin, 2012a, ]. These orthopedic complications have previously been described in one study of 16 participants, with all individuals having short stature and ligamentous laxity [Yassir et al., 2003]. The majority also had characteristic hand appearance (short, broad, hyperextensible digits), decreased shoulder and elbow range of motion, tight Achilles tendons, and foot abnormalities [Yassir et al., 2003]. Rare findings included scoliosis, kyphosis, hip subluxation, pectus excavatum and radial head subluxation [Yassir et al., 2003]. Osteopenia/osteoporosis was not assessed in the orthopedic study, but White et al.  assessed bone mineral density for eight adults with Costello syndrome. All eight had low bone mineral density with the majority meeting a clinical diagnosis of osteoporosis [White et al., 2005]. Individual case studies noted hip contractures, hip dysplasia, ulnar deviation, hypotonia, lordosis and dysfunctional gait [Stevenson and Yang, 2011]. Although orthopedic issues have not been extensively studied in Costello syndrome, it is not because they are of little concern. When compared to control values, the POSNA Functional Health Outcome Questionnaire values of Costello syndrome individuals were lower on basic mobility and overall functionality [Yassir et al., 2003]. Some manifestations, such as tight Achilles tendons, required surgical intervention [Yassir et al., 2003]. This intervention can be problematic because these individuals are at higher risk for complications during and after surgery, and have anesthetic difficulties [Shukry et al., 2008]. They are also at risk for developing recurrent deformities needing further surgical intervention. Individuals with Costello syndrome and their caretakers indicate that major medical issues, including orthopedic concerns, have negative impact on their overall quality of life [Hopkins et al., 2009].
We reviewed the orthopedic manifestations in individuals with Costello syndrome in order to further delineate musculoskeletal abnormalities associated with this rare syndrome and to aid in screening and treatment.
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Institutional Review Board approval was obtained through the A.I. duPont Hospital for Children. All individuals had a clinical diagnosis of Costello syndrome that was molecularly confirmed. The majority of participants were evaluated by an orthopedic surgeon (M. M. T.) during an international Costello syndrome conference. Medical records and previously performed imaging studies were requested for review. We studied 43 participants total, reviewing the medical records of 41 of these subjects, examining 36 individuals, collecting orthopedic inquiry forms from 22 families, and analyzing hip and/or spinal imaging for 23 individuals. Serial radiographs were analyzed when available.
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The gender, age, and genotype of the 43 participants are outlined in Table I. There were more females (60%) than males (40%). Of note, ages ranged from less than 1 year to 35 years, with at least 19% of the participants considered skeletally mature.
|Manifestation||Number of patients (%, rounded)|
|Assessed by M.M.T.||36 (84%)|
|Conference attendance||34 (79%)|
|Medical records only||7 (16%)|
|Age range (years)|
Details of the 25 orthopedic concerns identified are documented in Table II. Ten concerns were seen in a majority of individuals. Many participants experienced or had experienced hypotonia (87%) and joint laxity (85%). Upper extremity involvement included characteristic hand (broad, short, and hyperextensible digits) along with ulnar deviation (63%) (Fig. 1A). The majority reported elbow and shoulder contractures. Hamstring contractures (33%) were seen less commonly than Achilles tendon contractures (73%) (Fig. 1B). Foot deformities as a whole were quite common, and included vertical talus, bilateral talipes equinovarus, pes planus and cavus, hallux valgus, and overriding toes. The distribution was quite variable without any individual deformity predominating. Hip dysplasia, including subluxation and dislocation was seen in 45% of participants, but only 31% experienced hip contractures The most common spinal concern was scoliosis (63%) followed by kyphosis (58%) and lordosis (19%). Lumbar kyphosis was noted in 28% and thoracic lordosis in 16% of the study participants.
|Orthopedic manifestation||Individuals with manifestation||Total individuals assessed for manifestation||Percent affected with manifestation (%, rounded)|
|Tight Achilles tendon||30||41||73|
|Tight tibialis anterior||3||39||8|
|Bilateral talipes equinovarus||1||41||2|
Surgical Implications of Orthopedic Manifestations
Forty-one participants were assessed for their surgical history (Table III). A total of 15 different surgical procedures were identified, and 8 of these were performed on only one individual. Achilles tendon lengthening was the most common procedure needed in 17 individuals, 3 of whom had to undergo a second lengthening procedure. Hip reconstruction surgeries were the next most common, with six individuals undergoing an initial surgery and half requiring a second hip procedure. Only two surgical procedures were associated with upper extremity orthopedic manifestations. Eight of the 15 different surgical procedures were associated with various foot deformities.
|Surgery||Number of individuals affected (%, rounded)||Number of individuals undergoing two procedures||Age range of surgery (mean age)|
|Achilles lengthening||17 (41)||3||2–19 (7.8)b|
|Hip reconstructiona||6 (15)||3||1.5–12 (6.7)c|
|Spinal fusion||4 (10)||1||9–19 (14.3)c|
|Tension band plate construct||1 (2)||0||9 (9)|
|Hamstring lengthening||1 (2)||1||4–11.5 (7.8)|
|Vertical talus correction||3 (7)||0||2–11 (5.7)|
|Clubfoot correction||1 (2)||0||ND|
|Tibial tendon transfer||4 (10)||1||6–12 (8.8)c|
|Plantar tendon release||1 (2)||0||3 (3)|
|Foot osteotomy||3 (7)||0||3–10 (6.5)c|
|Hallux osteotomy||1 (2)||0||9 (9)|
|Foot lengthening||1 (2)||0||ND|
|Toe adduction correction||2 (5)||0||12 (12)c|
|Wrist tendon transfer||1 (2)||0||ND|
|Wrist carpal removal||1 (2)||0||ND|
Age range and average age at time of surgery were collected for 11 surgical procedures (Table III). The earliest surgery reported was at age 18 months for hip reconstruction and the latest was a spinal fusion at age 19 years. The majority of surgical procedures were performed between ages 6 and 10 years.
Pelvic Imaging Studies
Pelvic imaging studies were collected for 19 individuals (Table IV). Of these 19 individuals, 11 had normal hip evaluations. The remaining eight had abnormalities ranging from coxa valga and subluxation to complete dislocation (Fig. 2). Special note was taken of the individuals' acetabular indices (defined in Fig. 3) and femoral head coverage (defined in Fig. 3) to assess the overall hip condition (Table IV). A normal acetabular index curve is at around 30° at birth and rapidly decreases in the first three years of life to around 15° [Harris, 1976]. Acetabular growth then slows and only changes by about 5° until reaching acetabular maturity at age 8 years [Harris, 1976]. The acetabular index values demonstrated in Table IV (and Supporting Information Online, Fig. 5) indicate that both normal and abnormal hips were present in this patient population.
|Patient||Age for image study (years)||HRAS mutation||Sex||Acetabular indicesa R/L||Femoral head coverage R/L (%)||Overall impression|
|29||8||p.G12S||M||21/19||65/65||Left hip dislocation, right hip subluxation|
|9b||20/31||65/55||Bilateral hip subluxation|
|11||20/30||64/33||Left hip dislocation, right hip subluxation|
|47||3||p.G12S||M||24/19||75/80||Bilateral coxa valga|
|53||22||p.G12S||M||56/40||0/90||Right hip dislocation|
|71||15||p.G12S||F||41/42||80/87.5||Right hip subluxation|
|213||1.5||p.A146V||F||30/27||66/70||Bilateral coxa valga|
|242||1||p.G12A||F||37/33||ND||Right hip dislocation, left hip subluxation|
|1.3c||31/31||ND||Right hip normal, left hip subluxation|
|283||4.75||p.G12A||M||25/24||65/50||Bilateral hip subluxation|
|358||11||p.G12S||M||7/24||90/90||Bilateral coxa valga|
A femoral head coverage values of >66% is considered normal (Reimers' migration index <33%). Values below 67% may indicate an abnormal hip, with smaller values indicating greater concern for hip dysplasia [Reimers, 1980]. Table IV (and Supporting Information Online, Fig. 6) reveals that, while many individuals had adequate femoral head coverage, there were multiple measurements indicating hip abnormalities.
Spinal Imaging Studies
Spinal imaging studies were collected for 16 individuals (Table V). Six of these had normal spinal evaluations. The remaining ten showed spinal abnormalities ranging from mild scoliosis (Fig. 4A,B) and curvature reversal (Fig. 4C) to significant scoliosis and severe, debilitating kyphosis. Spinal evaluations are subject to measurement error and are impacted by a patient's ability to stand straight. Therefore, there can be an innate variability between spinal evaluations.
|Costello syndrome ID#||Age for image study||HRAS mutation||Sex||Scoliosis (curvature °)||Scoliosis apex||Kyphosis (curvature °)||Lordosis||CNS concerns||Treatment for spinal concern||Overall impression|
|4||18||p.G12S||F||Dextrothoracic (40)||T9||None||None||Chiari/syrinx/tethered cord||None||Scoliosis|
|47||7.5||p.G12S||M||Dextrothoracic (25)||T9||None||None||None||Bracing||Slight scoliosis and curve reversal|
|8||Dextrothoracic (24)||T9||None||None||Borderline Chiari||Bracing|
|9||Dextrothoracic (30)||T9||None||None||Borderline Chiari||Bracing|
|10||Dextrothoracic (20)||T9||None||None||Borderline Chiari||Bracing|
|53||16||p.G12S||M||Levothoracic (7)||L2–3||Thoracolumbar junction (53)||Thoracic||Borderline Chiari||None||Curvature reversal|
|20||Levothoracic (13)||L2–3||Thoracolumbar junction (36)||Thoracic||None||None|
|67||8||p.G12A||F||Levothoracic (10)||L2||Thoracolumbar (75)||None||None||None||Severe kyphosis|
|10||Levothoracic (10)||L2||Thoracolumbar (75)||None||ND||None|
|141||12||p.G12S||F||Levothoracic (20)||ND||Junctional (65)||Thoracic||None||None||Scoliosis and curvature reversal|
|14||Levothoracic (28)||ND||Junctional (65)||Thoracic||None||None|
|15||Levothoracic (38)||ND||Junctional (65)||Thoracic||None||None|
|15.5||Levothoracic (26)||ND||Junctional (65)||Thoracic||None||None|
|16||Levothoracic (23)||ND||Junctional (65)||Thoracic||None||None|
|17||Levothoracic (20)||ND||Junctional (65)||Thoracic||None||None|
|20||Levothoracic (17)||ND||Junctional (65)||Thoracic||Chiari/severe syrinx/tethered card||None|
|238||4||p.G12S||F||Dextrothoracolumbar (61)||T11–12||Lumbar||Thoracic||Chiari||None||Scoliosis and curvature reversal|
|242||1||p.G12A||F||Levothoracolumbar (ND)||T12||None||None||Chiari||None||Scoliosis and flattening|
|258||33||p.G12S||M||Levothoracolumbar junction (43)||T12||Thoracic (110)||None||Chiari/syrinx/tethered card||None||Severe kyphosis and scoliosis, nonambulatory|
|358||11||p.G12S||M||Levothoracic (9)||L3||None||None||None||None||Mild scoliosis|
Neurologic abnormalities, including Chiari I malformation, syrinx and tethered cord, were seen with normal (1/6) and abnormal spinal (4/10) evaluations. There was insufficient data to determine if neurological abnormalities were associated with spinal abnormalities.
Of the six individuals with scoliosis and multiple data points, two had no change in their spinal curvature severity over time. Two individuals had increasing spinal curvature and two had increasing curvature followed by a decrease, which dropped below their starting curvature value. The decrease of curvature for the younger individual (Patient CS#47) may be attributed to corrective bracing. However, there was no intervention for the older individual (Patient CS#141) with a decreasing curve. All but one of the scoliosis patients had involvement of the thoracic spine. Also, both left and right sided curves were present.
One individual with kyphosis had only one data point (Patient CS#258). This individual had the highest degree of kyphosis, 110°, isolated to the thoracic spine. The remaining three individuals all had thoracolumbar involvement. Two had unchanging curvature values over time and one showed significant decrease in his curve during his teens to early adulthood despite no stated intervention.
A flattening or more pronounced reversal of the normal curvature of the spine was seen in five individuals. Two of the five had hypokyphosis of the thoracic spine without pronounced lumbar kyphosis. The remaining three individuals had noteworthy lumbar kyphosis along with thoracic lordosis (Fig. 4C).
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Lower Extremity Findings and Implications
Bilateral and unilateral subluxation and dysplasia on either side were seen and six individuals (15%) underwent corrective surgery. Three required a second hip operation. Therefore, it appears that for many individuals surgical intervention does not resolve the hip issues. Patient CS#29 (Fig. 2A,B) exemplifies this because he has undergone two hip surgeries and maintained his ambulatory status, however, he still had persistent dysplasia and most likely will require more surgical intervention. However, as demonstrated by Patient CS#53 (Fig. 2C), the lack of surgical intervention can lead to complete hip dislocation and have a great impact on the ambulatory status. Appropriate management of the hips in this patient population is complicated and requires a greater understanding of the mechanism for abnormal hip development, as well as finding appropriate and effective interventions.
Review of imaging data and surgical history support contributions of both, congenital and acquired hip dysplasia, to the resulting complications. Therefore, it appears that there are multiple ways for individuals with Costello syndrome to develop hip abnormalities. The congenital hip abnormalities, especially as seen in Patient CS#242, suggest a potential for developmental hip dysplasia. Individuals also acquired hip abnormalities during childhood and adolescence. This could indicate that hip dysplasia is secondary to hypotonia and joint laxity, or central nervous system abnormalities including tethered cord, Chiari I malformation and syrinx. We recommend that hip imaging studies be performed during infancy and, because of these potential mechanisms for acquired hip dysplasia, repeated throughout childhood to adolescence.
Leg, ankle, and foot manifestations
Leg manifestations included hamstring contractures and genu valgum, which were present in 33% and 25% of individuals, respectively. The most notable lower extremity finding affected the ankle. A tight Achilles tendon (Fig. 1B) was seen in 73% and resulted in 41% receiving corrective surgery, with 7% experiencing a recurrence requiring a second procedure. This complication causes individuals to ambulate via toe-walking. Routine stretching, physical therapy, and orthotics are recommended as needed. Surgical intervention is frequently utilized, but may still result in a recurrence. Although individual foot deformities and complications were not highly prevalent, combined they accounted for 34% of all orthopedic surgeries. Lower extremity manifestations may affect ambulation and quality of life and should be properly assessed and addressed. The cause is not well understood and may be a result of a central nervous system abnormality, hypotonia or other intrinsic muscle abnormality [Van der Burgt et al., 2007; Tidyman et al., 2011], or a combination thereof.
Spine Findings and Implications
Scoliosis was seen in 63% of the individuals and kyphosis in 58%. Although scoliosis and kyphosis affected more individuals than hip dysplasia, its impact appeared less significant. Only 10% of individuals needed corrective spinal surgery, compared to 15% needing corrective hip surgery.
Imaging data showed that 5 of 16 patients with adequate full spine imaging data had lumbar kyphosis along with thoracic lordosis or hypokyphosis (flattening), resulting in reversal of the normal spinal curvature (Fig. 4C). This finding differs from many of the more typical spinal abnormalities seen in other conditions. Although scoliosis and kyphosis are found in the other rasopathies, curvature reversal seems particular to Costello syndrome. The limited number of affected individuals makes it difficult to understand the etiology, as well as its full impact. All individuals with curvature reversal were ambulatory, except for one with a dislocated hip, and did not need intervention, such as bracing or surgery, to correct their spine. Therefore, this finding seems to have a limited functional impact.
Kyphosis was not limited to the lumbar region. One individual (Patient CS#23) presented with exaggerated thoracic kyphosis measuring 110°.
The causes of these spinal abnormalities are not fully understood. However, some curvature may be caused by osteoporosis, hypotonia, and joint laxity. Other causes could include central nervous system abnormalities such as Chiari I malformation, tethered cord and syrinx. Although CNS abnormality data were collected for those with imaging studies, there was not enough information to draw conclusions. Better understanding between the relationship of CNS and orthopedic abnormalities could be attained through future studies. This study confirms previous work demonstrating that spinal abnormalities are a concern for this population and lifelong screening should be strongly considered.
Upper Extremity Findings and Implications
Upper extremity findings included characteristic hands, ulnar deviation, elbow and shoulder contractures and overall joint laxity, which is most notable in the hands. Interestingly, Costello syndrome is the only rasopathy with a high incidence of ulnar deviation (63%). Perhaps this is due to an HRAS-specific mechanism.
Costello syndrome is a rare genetic condition that is characterized by multisystem abnormalities including the musculoskeletal system. This is the largest study of orthopedic manifestations in individuals with Costello syndrome. Previously, Yassir et al.  evaluated 16 individuals, ranging in age from 3 to 23 years, at the International Costello Syndrome Conference for orthopedic manifestations, and their results can be compared to our data (Table VI). However, the limited number of participants in both studies may mean that the differences seen are not statistically significant. Further, it is likely that there is some overlap in the cohorts as each was largely ascertained through participation at an International Costello syndrome conference, albeit at different times, in 1999 and 2011, respectively. Of note, molecular confirmation of the clinical diagnosis was not available when the earlier cohort was ascertained, possibly allowing for a more heterogeneous cohort.
|Orthopedic manifestation||Percent affected (%)|
|Current study||Yassir et al.|
|Tight Achilles tendon||73||72|
Both studies confirm the almost universal ligamentous laxity, and high prevalence of hand and upper extremity abnormalities as well as Achilles tightness. The current study had 43 patients compared to 16 seen by Yassir et al. . We found a lower incidence of vertical talus (17% vs. 28%), possibly related to sample size. We also found a much higher prevalence of hip dysplasia and spine involvement compared to Yassir et al.  (Table VI). Hip dysplasia is very common in Costello syndrome and screening is warranted. In order to identify the most appropriate screening protocol, we need to understand the genesis of the hip dysplasia. The second surgical procedure rate for hip dysplasia in our cohort parallels that reported by Yassir et al. . Given the high failure rate of current primary surgical treatment, improved treatment protocols should be developed. Also, we identified a higher rate of spine abnormalities than Yassir et al. , and this should be screened for as well. Due to the high prevalence of orthopedic issues, it would be reasonable to involve an experienced orthopedic surgeon early in the care of individuals with Costello syndrome. We suggest a consultation at diagnosis, and annually thereafter.
Orthopedic Manifestations of Rasopathies
Syndromic conditions resulting from dysregulation of the Ras-mitogen activated protein (Ras/MAPK) pathway due to germline mutations are collectively referred to as rasopathies. The rasopathies affect multiple organ systems, including the musculoskeletal system [for review see Stevenson and Yang, 2011]. Neurofibromatosis type 1 (NF1) is a common rasopathy, and its musculoskeletal complications include generalized abnormalities such as short stature and osteopenia, as well as localized bony dysplasia predisposing to pseudarthrosis or scoliosis. While the progressive scoliosis in some individuals with NF1 results from dysplastic vertebral elements, often no primary osseous abnormality is found. Similarly, scoliosis and kyphoscoliosis are common in cardio-facio-cutaneous (CFC) syndrome [Armour and Allanson, 2008; Reinker et al., 2011].
Costello syndrome shares some features with other rasopathies. Reinker et al.  highlighted the high prevalence of foot deformities and hip dysplasia in CFC and Noonan syndrome. This is also similar to our observations in the Costello population. One may speculate that similar mechanisms result in the orthopedic manifestations seen in NF1, CFC, Noonan, and Costello syndrome, and that these are related to the effects of Ras/MAPK dysregulation on muscle fibers, osteoclasts, and osteoblasts.
Future Research Direction
This study furthered understanding of orthopedic manifestations in individuals with Costello syndrome. However, the contributing factors for these manifestations remain unclear. We think that it is important to obtain further insight into the mechanisms, and to identify appropriate treatment protocols. It will be important to determine if these features are primary manifestations of Costello syndrome, or if they are secondary to another complication. Detailed studies found that HRAS mutations can affect the muscle fibers, including causing an excess of muscle spindles, abnormality and variability in muscle fiber size and the predominance of type 2 muscle fibers [Van der Burgt et al., 2007; Tidyman et al., 2011]. These findings are suggestive of a true myopathy and are thought to contribute to hypotonia, joint contractures and muscle weakness [Van der Burgt et al., 2007; Tidyman et al., 2011]. These studies begin to shed light on the HRAS mutations impact on the musculoskeletal system and, along with future studies, will hopefully contribute to understanding the etiology of the orthopedic manifestations in Costello syndrome.
Other research directions include a more detailed review of the hip and spine changes over time. While the current study reviewed serial imaging studies as available, most data was based on a single evaluation. The overall goal of our work is to improve the quality of life for these individuals by providing them the best medical management. In order to accomplish this, we plan to focus on tracking the outcome of orthopedic surgeries, bracing, and physical therapy.
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Orthopedic manifestations are common in individuals with Costello syndrome and result in significant morbidity. We recommend that orthopedic management be part of the routine medical care for individuals with Costello syndrome. Spinal deformity screening should be strongly considered due to the high prevalence of scoliosis, kyphosis, and curvature reversal. Lastly, we strongly advocate that screening for hip dysplasia begin during infancy and extend into adolescence.
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The authors want to give a heartfelt thanks to the individuals who participated in this study as well as their families, and to the Costello Syndrome Family Network and the Ellington Beaver Award for Intellectual Inquiry from Arcadia University.
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Additional supporting information may be found in the online version of this article at the publisher's web-site.
FIG. 5. Left and Right Acetabular Index Distribution by Age. Acetabular index values were assessed by M.M.T. All values obtained are represented in this figure with some individuals having multiple values. Normal acetabular index values as obtained from Harris , and end at 11 years of age.
FIG. 6. Left and Right Femoral head Coverage Distribution by Age. Femoral head coverage values were assessed by M.M.T. All values obtained are represented in this figure with some individuals having multiple values. Values below 66% are considered abnormal.
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