Congenital Joint Dislocations Caused by Carbohydrate Sulfotransferase 3 Deficiency in Recessive Larsen Syndrome and Humero-Spinal Dysostosis

Abstract

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.

Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis

“…All were characterized by normal hands, apart from advanced carpal ossification. CHST3 mutations have been reported in spondyloepiphyseal dysplasia with congenital joint dislocations and in one case of DD type 2 [Hermanns et al, 2008]. Our DD type 2 case harbored an homozygous p.Leu259Pro mutation previously reported in spondyloepiphyseal dysplasia with congenital joint dislocations.…”

Craniosynostosis

“…The pinched upper ear helix in this child appears similar to the images of patients with mutations in CHST3 described by Tuysuz et al (2009). In addition birth length is usually normal (Bicknell et al, 2007;Hermanns et al, 2008;Unger et al, 2010). In addition birth length is usually normal (Bicknell et al, 2007;Hermanns et al, 2008;Unger et al, 2010).…”

“…Sulphation of glycoaminoglycans is essential to the function of proteoglycans, which have roles in development and maintenance of the skeleton (Hermanns et al, 2008;Van Roij et al, 2008). CHST3 encodes chondroitin-6-sulphotransferase (C6ST), which catalyses sulphate transfer to chondroitin sulphate in cartilage extracellular matrix (Van Roij et al, 2008).…”

Paediatric Orthopaedic Diagnosis

“…One form of skeletal dysplasia that is associated with congenital hip and knee dislocation is spondyloepiphyseal dysplasia with congenital joint dislocation (Hermanns et al 2008 ). In addition to the dislocations, short stature and progressive kyphosis are characteristic features of the condition.…”