Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: Congenital dislocations and vertebral changes as principal diagnostic features

Abstract

We recently reported on the deficiency of carbohydrate sulfotransferase 3 (CHST3; chondroitin-6-sulfotransferase) in six subjects diagnosed with recessive Larsen syndrome or humero-spinal dysostosis [Hermanns et al. (2008); Am J Hum Genet 82:1368-1374]. Since then, we have identified 17 additional families with CHST3 mutations and we report here on a series of 24 patients in 23 families. The diagnostic hypothesis prior to molecular analysis had been: Larsen syndrome (15 families), humero-spinal dysostosis (four cases), chondrodysplasia with multiple dislocations (CDMD "Megarbane type"; two cases), Desbuquois syndrome (one case), and spondylo-epiphyseal dysplasia (one case). In spite of the different diagnostic labels, the clinical features in these patients were similar and included dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The most useful radiographic clues were the changes of the lumbar vertebrae. Twenty-four different CHST3 mutations were identified; 16 patients had homozygous mutations. We conclude that CHST3 deficiency presents at birth with congenital dislocations of knees, hips, and elbows, and is often diagnosed initially as Larsen syndrome, humero-spinal dysostosis, or chondrodysplasia with dislocations. The incidence of CHST3 deficiency seems to be higher than assumed so far. The clinical and radiographic pattern (joint dislocations, vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance) is characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations such as filamin B-associated dominant Larsen syndrome and Desbuquois syndrome.

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

“…Biochemical analysis showed the majority of these mutations result in loss-of-function or severe reduction in the enzymatic activity (31,(33)(34)(35)(36). Recessive inheritance would be consistent with most rare mutations that affect enzymes.…”

“…Rare mutations in CHST3 that disrupt its enzymatic activity have been reported in patients with recessive skeletal abnormalities, including spondyloepiphyseal dysplasia Omani type, Larsen syndrome, humerospinal dysostosis, and chondrodysplasia with multiple dislocation (31)(32)(33)(34)(35)(36). Despite the different diagnostic labels, patients with CHST3 mutations have similar clinical characteristics and can be generally classified as spondyloepiphyseal dysplasia with congenital joint dislocation and vertebral changes as the principal features (OMIM 603799).…”

Insights in the etiopathology of galactosyltransferase II (GalT-II) deficiency from transcriptome-wide expression profiling of skin fibroblasts of two sisters with compound heterozygosity for two novel B3GALT6 mutations

“…Furthermore, CHST3 mutations were disclosed in a number of patients who have presented with various diagnoses, i.e., recessive Larsen syndrome, chrondrodysplasia with multiple dislocations, humerospinal dysostosis, and Desbuquois syndrome [15], [16]. Mutations in CHSY1 cause Temtamy pre-axial brachydactyly syndrome [17], and defects in HS synthesis ( EXT1 and EXT2 ) are linked with hereditary multiple exostosis types 1 and 2 [18].…”

Novel and recurrent COL2A1 mutations in Chinese patients with spondyloepiphyseal dysplasia

“…The SED spectrum ranges in severity from lethal SED, including achondrogenesis type II and hypochondrogenesis (ACG2 and HCG, MIM 200610), through SED congenita (SEDC, MIM 183900) to late-onset SED (SED tarda or SEDT, MIM 184100) (Nishimura et al, 2005). SED is a genetically heterogeneous disorder, most often inherited in an autosomal dominant manner, but autosomal recessive (Omani type, MIM 608637) and X-linked forms (MIM 313400) have been reported (Bar-Yosef et al, 2004;Nishimura et al, 2005;Unger et al, 2010). To date, at least eight related causative genes have been identified, including COL2A1 (collagen II α-1), TRAPPC2 (trafficking protein particle complex 2), CHST3 [carbohydrate (chondroitin 6) sulfotransferase 3], PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2), WISP3 (WNT1-inducible signaling pathway protein 3), ACAN (aggrecan), TRPV4 (transient receptor potential cation channel, subfamily V, member 4), and MATN3 (matrilin 3) (Faiyaz ul Haque et al, 1998;Fiedler et al, 2003;Borochowitz et al, 2004;Liao et al, 2004;Thiele et al, 2004;Gleghorn et al, 2005;Nishimura et al, 2005Nishimura et al, , 2010.…”