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Keywords:

  • orthopedic manifestations;
  • Costello syndrome;
  • HRAS;
  • hip dysplasia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. 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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. 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. [2005] 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.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

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.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

Demographics

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.

Table I. Demographic Findings of Costello Syndrome Cohort
ManifestationNumber of patients (%, rounded)
  1. Demographic information on 43 patients used to determine overall orthopedic manifestations and surgical histories seen in individuals with costello syndrome.

Total patients43
Assessed by M.M.T.36 (84%)
Conference attendance34 (79%)
Medical records only7 (16%)
Sex
Female26 (60%)
Male17 (40%)
Age range (years)
0–516 (37%)
6–107 (16%)
11–153 (7%)
16–209 (21%)
≥218 (19%)
Genotype
p.G12S32 (74%)
p.G13C6 (14%)
p.G12A3 (7%)
p.G13D1 (2%)
p.A146V1 (2%)

Orthopedic Manifestations

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.

Table II. Percent of Costello Individuals With Specific Orthopedic Manifestations
Orthopedic manifestationIndividuals with manifestationTotal individuals assessed for manifestationPercent affected with manifestation (%, rounded)
General
Osteopenia143441
Osteoporosis2336
Fractures53813
Hypotonia333887
Joint laxity354185
Pectus124030
Spinal
Scoliosis254036
Kyphosis234058
Cervical1403
Thoracic54013
Lumbar114028
Unspecified74018
Lordosis63219
Thoracic53216
Unspecified1323
Upper extremities
Characteristic hand333985
Ulnar deviation264163
Elbow contracture213855
Shoulder contracture243765
Lower extremities-leg
Hip contracture123931
Hip dysplasia173845
Hamstring contracture134033
Genu valgum72825
Tight Achilles tendon304173
Tight tibialis anterior3398
Lower extremities-foot
Vertical talus74117
Bilateral talipes equinovarus1412
Pes planus193653
Pes cavus3408
Overriding toes114127
Hallux valgus3398
image

Figure 1. A: Individual presenting with hands characteristic of Costello syndrome (short, broad, hyperextensible digits) and bilateral ulnar deviation. B: Individual presenting with tight Achilles tendon of the right leg.

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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.

Table III. Surgical Intervention and Age of Utilization
SurgeryNumber of individuals affected (%, rounded)Number of individuals undergoing two proceduresAge range of surgery (mean age)
  1. ND, no data available.

  2. For those surgical interventions that had age range data, mean age of the individual when undergoing surgery was calculated.

  3. Surgical information obtained on 41 participants and percent affected was calculated out of 41 participants.

  4. a

    Hip reconstruction includes acetabular osteotomy, adductor tenotomy, femoral osteotomy.

  5. b

    Missing two data points for age values.

  6. c

    Missing one data point for age values.

Achilles lengthening17 (41)32–19 (7.8)b
Hip reconstructiona6 (15)31.5–12 (6.7)c
Spinal fusion4 (10)19–19 (14.3)c
Tension band plate construct1 (2)09 (9)
Hamstring lengthening1 (2)14–11.5 (7.8)
Vertical talus correction3 (7)02–11 (5.7)
Clubfoot correction1 (2)0ND
Tibial tendon transfer4 (10)16–12 (8.8)c
Plantar tendon release1 (2)03 (3)
Foot osteotomy3 (7)03–10 (6.5)c
Hallux osteotomy1 (2)09 (9)
Foot lengthening1 (2)0ND
Toe adduction correction2 (5)012 (12)c
Wrist tendon transfer1 (2)0ND
Wrist carpal removal1 (2)0ND

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.

Table IV. Overall Hip Measurements and Impression of 19 Individuals Determined by M.M.T.
PatientAge for image study (years)HRAS mutationSexAcetabular indicesa R/LFemoral head coverage R/L (%)Overall impression
  1. ND, no data.

  2. An increased acetabular index value and decreased femoral head coverage value indicate abnormal hips.

  3. a

    Individual considered skeletally mature by imaging (≥20) were measured for Sharp's angle.

  4. b

    Measurement taken after an individual underwent hip reconstruction surgery.

  5. c

    Measurement taken after an individual utilized abduction bracing.

1913p.G12SFND100/100Normal
298p.G12SM21/1965/65Left hip dislocation, right hip subluxation
 9  23/3765/20 
 9b  20/3165/55Bilateral hip subluxation
 10  20/3265/53 
 11  20/3064/33Left hip dislocation, right hip subluxation
436p.G12SM15/17100/100Normal
 8.5  12/17100/100 
473p.G12SM24/1975/80Bilateral coxa valga
 3.5  27/1980/72 
 4.5  21/1978/75 
 5.5  23/2570/75 
 7.5  26/2075/75 
 9  27/2275/75 
5322p.G12SM56/400/90Right hip dislocation
6720p.G12AF38/4290/90Normal
7115p.G12SF41/4280/87.5Right hip subluxation
14114p.G12SFND95/95Normal
2131.5p.A146VF30/2766/70Bilateral coxa valga
 4  26/21ND 
2421p.G12AF37/33NDRight hip dislocation, left hip subluxation
 1.3c  31/31NDRight hip normal, left hip subluxation
 1.8b  23/26NDNormal
2834.75p.G12AM25/2465/50Bilateral hip subluxation
2951p.G13CM16/20100/100Normal
2981 monthp.G12CF28/29NDNormal
3081.5p.G12SM26/24100/100Normal
3171.3p.G12SF31/33100/100Normal
3241p.G12SF27/26100/100Normal
3400.5p.G12SM23/29100/100Normal
3431p.G12SF30/2695/90Normal
35811p.G12SM7/2490/90Bilateral coxa valga
 16  16/1290/90 
image

Figure 2. A: Pelvic image of Patient CS#29 taken at age 9 years showing left hip dislocation and right hip subluxation after an acetabular osteotomy. B: Pelvic image of Patient CS#29 at 10 years showing bilateral hip subluxation after a femoral osteotomy. C: Pelvic image of Patient CS#53 taken at 22 years of age showing right hip dislocation.

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image

Figure 3. Figure demonstrates how acetabular index and femoral head coverage were measured [adapted from Scrutton and Baird, 1997]. Femoral head coverage equals BC × 100/AB.

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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.

Table V. Overall Spine Measurements and Impression of 23 Individuals Determined by M.M.T.
Costello syndrome ID#Age for image studyHRAS mutationSexScoliosis (curvature °)Scoliosis apexKyphosis (curvature °)LordosisCNS concernsTreatment for spinal concernOverall impression
  1. Curvature location and curvature degree were obtained by directly assessing the imaging studies and were not available for all cases.

418p.G12SFDextrothoracic (40)T9NoneNoneChiari/syrinx/tethered cordNoneScoliosis
1913p.G12SFNone NoneNoneNoneNoneNormal
436p.G12SMSlightNDNoneNoneNoneNoneNormal
477.5p.G12SMDextrothoracic (25)T9NoneNoneNoneBracingSlight scoliosis and curve reversal
 8  Dextrothoracic (24)T9NoneNoneBorderline ChiariBracing 
 9  Dextrothoracic (30)T9NoneNoneBorderline ChiariBracing 
 10  Dextrothoracic (20)T9NoneNoneBorderline ChiariBracing 
5316p.G12SMLevothoracic (7)L2–3Thoracolumbar junction (53)ThoracicBorderline ChiariNoneCurvature reversal
 20  Levothoracic (13)L2–3Thoracolumbar junction (36)ThoracicNoneNone 
678p.G12AFLevothoracic (10)L2Thoracolumbar (75)NoneNoneNoneSevere kyphosis
 10  Levothoracic (10)L2Thoracolumbar (75)NoneNDNone 
7115p.G12SFLevothoracic (44)T7NoneNoneNDNoneScoliosis
14112p.G12SFLevothoracic (20)NDJunctional (65)ThoracicNoneNoneScoliosis and curvature reversal
 14  Levothoracic (28)NDJunctional (65)ThoracicNoneNone 
 15  Levothoracic (38)NDJunctional (65)ThoracicNoneNone 
 15.5  Levothoracic (26)NDJunctional (65)ThoracicNoneNone 
 16  Levothoracic (23)NDJunctional (65)ThoracicNoneNone 
 17  Levothoracic (20)NDJunctional (65)ThoracicNoneNone 
 20  Levothoracic (17)NDJunctional (65)ThoracicChiari/severe syrinx/tethered cardNone 
2139p.A146VFNone NoneNoneChiariNoneNormal
2384p.G12SFDextrothoracolumbar (61)T11–12LumbarThoracicChiariNoneScoliosis and curvature reversal
2421p.G12AFLevothoracolumbar (ND)T12NoneNoneChiariNoneScoliosis and flattening
 1.3  Levothoracolumbar (19)T12NoneNoneNoneNone 
 1.8  Levothoracolumbar (20)T12NoneNoneNone  
25833p.G12SMLevothoracolumbar junction (43)T12Thoracic (110)NoneChiari/syrinx/tethered cardNoneSevere kyphosis and scoliosis, nonambulatory
2771p.G13CFNone NoneNoneNoneNoneNormal
3171p.G12SFNone PosterialNoneNoneNoneNormal
3431 monthp.G12SFNone NoneNoneNoneNoneNormal
35811p.G12SMLevothoracic (9)L3NoneNoneNoneNoneMild scoliosis
 14  Levothoracic (8)L3NoneNoneNoneNone 
 15.5  Levothoracic (10)L3NoneNoneNoneNone 
image

Figure 4. Photographic radiographic images of Patient CS#53. A,B: Mild levothoracic scoliosis. C: Curvature reversal of the spine (lumbar kyphosis and thoracic lordosis).

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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).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

Lower Extremity Findings and Implications

Hip manifestations

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. [2003] 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.

Table VI. Comparison of Selected Orthopedic Manifestations Seen in the Present Study and in Yassir et al. [2003]
Orthopedic manifestationPercent affected (%)
Current studyYassir et al.
Ligamentous laxity85100
Characteristic hand8575
Elbow contracture5563
Shoulder contracture6594
Tight Achilles tendon7372
Vertical talus1728
Hip subluxation4517
Kyphosis5817
Scoliosis6317
Pectus306

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. [2003]. 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. [2003] (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. [2003]. 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. [2003], 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. [2011] 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.

Conclusions

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

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.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

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.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information
  • Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. 2005. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37:10381040.
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Conclusions
  8. ACKNOWLEDGMENTS
  9. REFERENCES
  10. Supporting Information

Additional supporting information may be found in the online version of this article at the publisher's web-site.

FilenameFormatSizeDescription
ajmga36047-sm-0001-SupFig5-S1.tif37K

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 [1976], and end at 11 years of age.

ajmga36047-sm-0002-SupFig6-S2.tif35K

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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