Musculoskeletal publications

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Musculoskeletal publications

Orthopedic Manifestations and Implications for Individuals With Costello Syndrome


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,b]. 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, butWhite et al. [2005] assessed bone mineral density for eight adultswithCostello 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 [Yassiret 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 inscreening and treatment.

Skeletal Muscle Pathology in Costello and Cardio-Facio-Cutaneous Syndromes: Developmental Consequences of Germline Ras/MAPK Activation on Myogenesis


Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. All of the RASopathies exhibit some degree of hypotonia, but CS and CFC are more severe. To determine if individuals with CS and CFC have an underlying skeletal myopathy, we systematically evaluated skeletal muscle pathology in both conditions.Wereviewed pathology reports from six individuals who had undergone a skeletal muscle biopsy, and we reviewed histology slides on two cases with CS and one case with CFC. All patients in the cohort had histopathologic findings, and two consistent abnormalities were identified. The first was the presence of abnormal muscle fiber size and variability, and the second was the presence of type 2 fiber predominance. Given the degree of hypotonia typically present in these patients, the overall architecture of the muscle was relatively normal, without showing indications of severe structural histopathology or metabolic abnormalities. Because the Ras/MAPK pathway is vital for skeletal myogenesis, we evaluated the effects of CS and CFC mutations on myogenesis using C2C12 myoblasts. All CS/CFC mutations inhibited myoblast differentiation as indicated by fewer myosin heavy chain expressing cells and a decrease in the number of myotubes as compared to controls. These findings indicate that CS and CFC may have a true myopathy related to an inherent dysregulation of skeletal myogenesis, which further expands our understanding of the consequences of germline Ras/MAPK mutations

Craniofacial and dental malformations in Costello syndrome: A detailed evaluation using multi-detector row computed tomography

Masashi Takahashi1 and Hirofumi Ohashi2

1 Department of Pediatric Dentistry, Nihon University Graduate School of Dentistry at Matsudo, Matsudo, and 2Division of Medical Genetics, Saitama Children’s Medical Center, Saitama, Japan


Costello syndrome is a rare multiple congenital anomaly syndrome caused by heterozygous germline HRAS mutations, which is characterized by intellectual disability, growth retardation, distinctive facies, loose skin, cardiomyopathy and a preposition to malignancies. Although teeth abnormalities have been encountered in nearly two-thirds of the patients in literature, the evaluation tended to be limited to the extent which can be obtained from physical examination. We investigated detailed craniofacial, oral and dental findings in four patients with Costello syndrome. In this study, images reconstructed by multi-detector row computed tomography (MDCT) were used as substitutes for dental cast study and panoramic and lateral cephalometric radiograph studies to evaluate dental arches, tooth size, relationships between craniofacial and dental structures, and hypodontia.

All four patients showed true/relative macrocephaly with facial bone hypoplasia and gingival hypertrophy. Occlusal attrition, malocclusion, small dental arches, microdontia, and convex face were noted in three patients. In addition, one patient showed dental caries, conic tooth and gingivitis, and another patient showed hypodontia. Our study suggests that craniofacial and dental abnormalities are common in Costello syndrome patients and comprehensive dental care should be provided from early infancy. To our knowledge, this is the first study of thorough craniofacial and dental evaluation by using MDCT in Costello syndrome. MDCT is a useful tool for precise evaluation of craniofacial and oral manifestations in patients with congenital anomaly/intellectual disability syndromes.

Costello Syndrome: Orthopaedic Manifestations and Functional Health

Walid K. Yassir, M.D., †Brian E. Grottkau, M.D., and ‡Michael J. Goldberg, M.D.

Study conducted at The Department of Orthopaedics, Tufts-New England Medical Center, Tufts University School of Medicine,Boston, Massachusetts, U.S.A.


Sixteen individuals with Costello syndrome underwent a complete history, physical examination, and medical record review. Medical history and record review were performed for two additional children with Costello syndrome. 

The POSNA Functional Health Outcome Questionnaire Baseline Assessment was completed by the parents of all 18 children. All the children were below the fifth percentile for height and all had ligamentous laxity. All children demonstrated delayed walking and none was able to run. Orthopaedic problems included tight heel cords, congenital vertical talus, planovalgus feet, hip subluxation, kyphosis, scoliosis, radial head subluxation, elbow flexion deformity, reduced shoulder range of motion, and limitation of overhead activity. Foot problems were most frequently encountered. Two children had no orthopaedic symptoms.

All children with Costello syndrome had poor scores on the POSNA Functional Health Outcome Questionnaire. Orthopaedic problems are a significant part of Costello syndrome, and affected individuals should be evaluated and followed-up regularly by an orthopaedic surgeon.



1 University of Utah, Division of Medical Genetics, 2C412 SOM, Salt Lake City, Utah 84132

2 Department of Orofacial Science, University of California San Francisco, San Francisco, California, USA

3 Department of Pediatrics, University of California San Francisco, San Francisco, California, USA

4 Department of Orthopedics, University of Texas Health Sciences Center, San Antonio, Texas, USA

5 Shriners Hospital for Children Salt Lake City, Salt Lake City, Utah, USA Accepted 22 January 2012


Introduction: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. Methods: Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. Results: Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). Conclusions: Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.

The Musculoskeletal Phenotype of the RASopathies


The Ras/MAPK signal transduction pathway is critical for the regulation of proliferation and differentiation of multiple cell types. Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in the NF1 gene resulting in an increased Ras signaling cascade. Subsequently, additional syndromes with some overlapping physical manifestations such as Noonan syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome were also shown to be due in many cases to mutations in genes encoding for proteins interacting with the Ras/MAPK pathway. Although neurocutaneous manifestations have been considered hallmark features for these disorders, multiple organ systems including the musculoskeletal system are affected. Some of the overlapping musculoskeletal phenotypes include scoliosis, kyphosis, anterior chest wall anomalies, pes planus, osteopenia, and hand anomalies. However, there are also discordant skeletal phenotypes such as sphenoid wing dysplasia and tibial pseudarthrosis seen only in NF1. We provide an overview of the concordant and discordant musculoskeletal manifestations in the RASopathies. 

Bone resorption in syndromes of the Ras/MAPK pathway

Short Report

Stevenson DA, Schwarz EL, Carey JC, Viskochil DH, Hanson H, Bauer S, Cindy Weng H-Y, Greene T, Reinker K, Swensen J, Chan RJ, Yang F-C, Senbanjo L, Yang Z, Mao R, Pasquali M.

Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and nurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. 

Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.