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Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis |
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| Authors: | Hermanns Pia Unger Sheila Rossi Antonio Perez-Aytes Antonio Cortina Hector Bonafé Luisa Boccone Loredana Setzu Valeria Dutoit Michel Sangiorgi Luca Pecora Fabio Reicherter Kerstin Nishimura Gen Spranger Jürgen Zabel Bernhard Superti-Furga Andrea |
| Affiliation: | 1 Center for Pediatrics and Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany 2 Institute for Human Genetics, University of Freiburg, 79106 Freiburg, Germany 3 Department of Biochemistry, University of Pavia, 27100 Pavia, Italy 4 Hospital Infantil “La Fe,” 46000 Valencia, Spain 5 Division of Molecular Pediatrics, CHUV, University of Lausanne, 1011 Lausanne, Switzerland 6 U.O. Genetica Clinica e Malattie Rare, Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, 09100 Cagliari, Italy 7 Medical Genetic Unit, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy 8 Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, 204-8567 Tokyo, Japan |
| 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. |
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