Clinical Features Patient Report Introduction Skeletal Dysplasia With
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Skeletal Dysplasia with short stature and a Larsen-like Phenotype due to a homozygous mutation in B3GAT3 Elisabeth Steichen-Gersdorf, Department of Pediatrics 1, Medical University of Innsbruck Franco Laccone, Institute of Medical Genetics, Vienna, Austria E-mail: Elisabeth.steichen@i- med.ac.at Introduction Patient Report Clinical features Proteoglycans are We report on a girl with important components of disproportionate short stature cell plasma membranes and joint laxity with pes planus and extracellular matrices and radial head dislocation. The of connective tissues. girl is the 1st child of a The basic structure of each consanguinous turkish mating, proteoglyan consists of a born at 37 weeks, BW 2140g, L gylcosaminoglycan side 43cm (<P3rd), mildly delayed chain attached to a core motor devellopement and normal protein via a intelligence. She was previously Patient at 13 years, dysproportionate short Hypermobile finger joints, spatulate tetrasaccharide linker assigned to Spondylo- stature, round flat face, prominent eyes, distal phalages, pes planus, halux region . The first sugar is a epimetaphyseal dysplasia with radial head dyslocation, genu valgum valgus Xylose unit enzymatically joint laxity type 1 (SEMDJL1), a added onto the serine similar phenotype with residue of the core protein. progressive severe Subsequent addition of two kyphoscoliosis, thoracic galactose and one asymmetry, and respiratory glucuronic acid completes compromise resulting in early the process. The specific death. A novel homozygous enzymes that catalyze each mutation in B3GAT3 was Short femoral neck, radial head dyslocation, subluxation of knee of the steps have well been detected by whole-exome- joint, irregular carpal bones, halux valgus characterized and defects sequencing causing a Larsen-like Fig.1 have been asigned to a phenotype with skeletal pleiotropic spectrum of involvement including elbow connective tissue disorders deformities with radial head (Fig2). Most of them with dislocation, genu valgum, Glycosaminoglycan Synthesis short stature, dislocation of hypermobile joints, flat feet, and large joints, joint laxity tapered fingers with spatulate and/or skoliosis. distal phalanges. The girl had a B3GAT3- c.416C>T, B3GAT3 mutations are round face, bifid uvula, high p.Thr139Met Glucoronyltransferase 1 rare and have been arched palate, flat midface, deficiency reported previously in two prominent eyes with blue sclerae, Arabian families with short and a long philtrum. Bone density stature and joint laxity. The (BMD) at the age of 18 years was female patient with a novel low with L1-4 ,Z score-1,8. Final homozygous mutation height was 129,5 cm (-5,3 expands the spectrum of SDS),weight 37kg (<3rd centile) the impaired proteoglycan synthesis. Malfait et al Am J Hum Genet 2013 Fig. 2 Whole Exome Sequencing Discussion Whole Exome Sequencing by SOLID 5500 We add an additional case with a spondyloepimetaphyseal (ThermoFIsher) revealed a homozygous dysplasia to a group of patients with features of Ehlers-Danlos or missense mutation in B3GAT3-gene Larsen-like phenotype with a unique combination of multiple coding for Glucoronyl-transferase I dyslocations and joint laxity, caused by mutations in the linker (enzymatic step in the Golgi apparatus for region of glycosaminoglycans (GAG). This includes syndromes with a linkage region synthesis of proteoglycans mutations of enzymes in the GAG side chain polymerization such i.e heparan sulfate) c.416C>T, as B3GAT3, B3GALT6 (Ehlers-Danlos- like), B4GALT6 (Ehlers- p.Thr139Met. (Fig2): This residue is highly Danlos-like syndrome with kyphoskoliosis), B4GALT7 (Larsen of conserved and predicted as pathogenic by Reunion Island Syndrome) and XYLT1 (Desbuquois Dysplasia Type Polyphen-2 and MutationTaster. 2). Glucoronosyl-transferase deficiency 1, encoded by B3GAT3 is References: supposed to result in defects in collagen supramolecular organisation, which is responsible for several of the observed 1. Von Oettingen J, Tan WH, Dauber A. 2014: Am.J. Med. Genet clinical features. Bone mineral density was in the lower range, 164A,1580-6 however compared to Galactosyl-transferase II (B3GALT6) 2. Baasanjav S, Al-Gazali L, Hashiguchi T et al. , Am J Hum Genet 89:15-27 mutations, early onset fractures did not occur in this patient. 3. Malfait F, Kariminejad A, Van Damme T et al 2013, Am J Hum Genet 92,935-45 The authors declare no conflict of interests 452-P2 Growth Poster presented at: Elisabeth Steichen-Gersdorf DOI: 10.3252/pso.eu.54espe.2015 ESPE 2015 ESPE.