A novel pathogenic MYH3 mutation in a child with Sheldon–Hall syndrome and vertebral fusions

Abstract

Sheldon-Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non-progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman-Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3-related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders.

Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3

“…A recent report that adds to this evolving understanding of genotype-phenotype correlations in this disorder described an individual with DA2B and partial fusions of cervical, thoracic, and lumbar vertebrae. 23 All mutations described in DA1, DA2A, and DA2B are missense or in-frame deletions, which is consistent with a dominant-negative effect or gain-of-function mechanism underlying these disorders.…”

Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant

“…According to the radiological tests, we could identify the distinctive skeletal changes from our proband such as flattened thoracolumbar vertebral bodies, the rough edges of vertebra, endplate bone defects, and the narrow intervertebral space. These radiological findings helped to distinguish MBTPS1 -related SEDKF from other very rare skeletal disorders, like Spondylocostal dysostosis 6 which showed complex vertebral segmentation defects in the cervico-thoracic spine ( 14 ) and MYH3-related arthrogryposis which displayed unilateral carpal bone fusion and multiple vertebral fusions ( 15 ). Moreover, all of them had their own distinctive facial features and responsible genes.…”

Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome

“…Missense mutations in MYH3, the earliest expressed embryonic myosin heavy chain gene that is predominantly expressed in myotubes destined to become fast-twitch myofibers [9], are strongly associated with DA clinically, and contribute to multiple subtypes including DA1, DA2A, and DA2B with varying degrees of severity [7][8][9]59,60]. MYH3associated DA is almost always caused by single missense variants, as frameshift knockout or premature stop mutations are frequently observed in healthy population controls [9].…”

“…Clinically, the lower extremity manifestations commonly include clubfoot and vertical talus. There are currently 10 classifications of DA, including Sheldon-Hall syndrome (DA2B) and Freeman-Sheldon syndrome (DA2A) [6][7][8][9]. Freeman-Sheldon syndrome is considered the most severe form of DA, and also presents with facial contractures [9].…”