X-linked spondyloepiphyseal dysplasia tarda: Identification of a TRAPPC2 mutation in a Korean pedigree

Abstract

Spondyloepiphyseal dysplasia (SED) comprises a heterogeneous group of skeletal dysplasias that primarily affect the epiphyses and vertebral bodies. Patients affected by SED usually exhibit short stature and experience early development of degenerative osteoarthritis. SED is subdivided into congenita and tarda forms according to the age at onset and clinical severity, and further subdivided into genetically different forms according to the mode of inheritance and the gene involved. We report a 14-yr-old Korean male who presented with a disproportionately short stature and a short trunk. A pedigree analysis of 3 generations with 6 affected persons revealed an X-linked recessive mode of inheritance. Mutation analysis of the TRAPPC2 (previously called SEDL) gene, the only gene associated with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT; MIM 313400), was performed, and a splice-donor site mutation in intron 3 of the TRAPPC2 gene (c.93+5G>A) was identified in the proband and in his unaffected mother (a heterozygote). This mutation is one of the 2 most frequent mutations reported in the medical literature, and is known to result in exon 3 skipping. This is the first report of a genetically confirmed X-linked SEDT case in Korea and highlights the importance of recognizing the mode of inheritance in the diagnosis of X-linked SEDT.

Keywords: SEDL; Spondyloepiphyseal dysplasia; TRAPPC2; X-linked spondyloepiphyseal dysplasia tarda.

Fig. 1

Family pedigree indicating X-linked recessive inheritance of the disease. The arrow indicates the proband. All open boxes represent healthy males and open circles represent healthy females. Black boxes represent affected males. Boxes or circles with a diagonal line indicate that the person has already died. Circles with a dot in the middle indicate the status of carrier.

Fig. 2

Radiographs of the lateral lumbosacral spine (left) and pelvis (right) of the proband at age 13. Note the diagnostic features of platyspondyly with superior and inferior bony 'humps', as well as irregular hip-joint surfaces and short femoral heads.

Fig. 3

Sequencing chromatograms revealed hemizygosity for a splice-donor site mutation in intron 3 of the TRAPPC2 gene (c.93+5G>A) in the proband (A, red arrow) and heterozygosity for the same mutation in his unaffected mother (B, blue arrow).