The musculoskeletal phenotype of the RASopathies

Abstract

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.

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

“…In 17 adults ranging from age 16 to 40 years, all eight individuals who had a bone density measurement had abnormal results that suggested osteoporosis or osteopenia; three had bone pain, vertebral fractures, and height loss. 39,40 Adult-onset gastroesophageal reflux was present in four individuals in the series of White et al 39 ; additional cases are known (personal observation). The reported adult height range is 135-150 cm.…”

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

“…This idea is based on the observation that orthopedic manifestations are a common feature of Rasopathies. In the case of NS, scoliosis and other spinal deformities are frequently encountered [49,50] and it was recently reported that NS children may have decreased bone mineralization [51], even though this study was performed on a limited number of patients. This hypothesis is also based on a recent report showing that PTPN11 disruption causes severe skeletal defects in mice [52].…”

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

“…1,58,59 This is not surprising since the Ras/MAPK pathway plays a major role in mediating the intracellular signaling of Insulin-like Growth Factor (IGF-1), which mediates postnatal growth effects of growth hormone (GH). In addition, MAPK activation is important in regulating the proliferation of pituitary somatotrophs that synthesize and release GH.…”

“…59 It is estimated that two-thirds of children with CFC have short stature. 1,3,4,58,61,62 The exact cause of short stature is not well established; some individuals may have GH deficiency, whereas some may have GH resistance. In addition, inadequate nutrition, due to the high prevalence of feeding problems in CFC, might contribute to failure to thrive, poor growth, and possibly IGF-1 deficiency.…”

“…Osteopenia has been anecdotally reported, and there is biochemical evidence of increased bone resorption in several RASopathies, including CFC; however, the clinical consequence of increased bone resorption in this population is not yet known. 58 …”