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Genetic disorders, skeletal dysplasias and malformations
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Fergal Monsell, Martin Gargan, Deborah Eastwood, James Turner, Ryan Katchky
Diastrophic dysplasia is an autosomal recessive disorder, occurring secondary to a mutation in the SLC26A2 gene. This results in defective production of a sulphate transporter protein, resulting in abnormalities of cartilage proteoglycan. The genetic mutation is present in approximately 1 in 70 in the indigenous population of Finland, but is rare in the rest of the world, with an estimated incidence of 1:1000000.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: autosomal recessive, caused by mutations in SLC26A2 or DTDST (diastrophic dysplasia sulphate transporter gene), encoding a sulphate transporter involved in the sulphation of proteoglycans in cartilage matrix. Mutations in the same gene have also been associated with diastrophic dysplasia (DTD), autosomal recessive multiple epiphyseal dysplasia and achondrogenesis type 1B (ACG1B). A genotype-phenotype correlation exists: mutations in the transmembrane domain or nonsense usually result in achondrogenesis type 1B, the most severe associated phenotype, whereas ‘milder’ mutations (missense, located outside the transmembrane domain) or combinations of one severe and one milder mutation cause less severe phenotypes such as atelosteogenesis type 2, diastrophic dysplasia and recessive multiple epiphyseal dysplasia.
Fetal Skeletal Dysplasias: Radiologic-Pathologic Classification of 72 Cases
Published in Fetal and Pediatric Pathology, 2022
Sulfation disorders are associated with DTDST/SLC26A2 deficiency, a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfoconjugation of proteoglycans and normal cartilage development. This sulfate transporter is a key limiting factor in the bone growth because of the low capacity of sulfate endogenous synthesis. The lethal form, achondrogenesis type 1B, is associated with lesser capacity of the chondrocyte to incorporate the sulfate, resulting in lack of the ground glass appearance and rarefaction of the cartilage matrix which tends to form dense collagenous rings around chondrocytes, and in severe defects in the intramembranous and endochondral ossifications [24]. These severe histologic alterations are correlated with the significant phenotypic and radiologic anomalies that associate extreme micromelia, short trunk with narrow chest, and diffuse severe ossification defects encompassing lucent skull, thin and short ribs with flared and cupped ends, extremely short long bones with flared, irregular and cupped metaphyses, delayed ossification of the vertebral bodies and sacrum and small square-shaped iliac wings. The cartilage matrix displays in the moderate form, diastrophic dysplasia, variable amount of matrix with pale areas, related to undersulfation of proteoglycans, interspersed with normal areas, along with disruption of the proliferative and hypertrophic zones due to irregular invasion of the metaphyseal capillaries and fibrosis [25]. Consistent with these moderate alterations, micromelia is less severe and the long bones have a normal tubular shape with enlarged metaphyses.
Prenatal genetic diagnosis of omphalocele by karyotyping, chromosomal microarray analysis and exome sequencing
Published in Annals of Medicine, 2021
Xiaomei Shi, Hui Tang, Jian Lu, Xiue Yang, Hongke Ding, Jing Wu
DTD (OMIM 222600) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2. The variant c.1020_1022delTGT (p.Val341del) has been previously reported and classified as pathogenic. The deletion of exon 2–3 has not been reported, but was predicted to be a disease-causing variant by in-silico prediction tools and classified as likely-pathogenic. Finally, the foetus was diagnosed with DTD by combined prenatal ultrasonography and whole exome sequencing (WES).