Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, is a rare autosomal recessive disorder of the skeleton characterized by disproportionate short stature with narrow chest and dysmorphic facial features. The skeletal manifestations include platyspondyly, short flared ribs, short tubular bones with abnormal metaphyses and epiphyses, severe brachydactyly, and premature stippled calcifications in the cartilage. The abnormal calcifications are so distinctive as to point to the definitive diagnosis. However, they may be too subtle to attract diagnostic attention in infancy. Homozygous variants in DDR2 cause this disorder. We report on a 5-year-old girl with the classic phenotype of SMED, SL-AC in whom a novel homozygous nonsense mutation in DDR2 was detected using exome sequencing.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Borochowitz Z, Langer LO Jr, Gruber HE, Lachman R, Katznelson MB, Rimoin DL. Spondylo-metaepiphyseal dysplasia (SMED), short limb-hand type: a congenital familial skeletal dysplasia with distinctive features and histopathology. Am J Med Genet. 1993;45:320–6.
Langer LO Jr, Wolfson BJ, Scott CI Jr, Reid CS, Schidlow DV, Millar EA, Borns PF, Lubicky JP, Carpenter BL. Further delineation of spondylometa-epiphyseal dysplasia, short limb-abnormal calcification type, with emphasis on diagnostic features. Am J Med Genet. 1993;45:488–500.
Al-Gazali LI, Bakalinova D, Sztriha L. Spondylo-metaepiphyseal dysplasia, short limb, abnormal calcification type. Clin Dysmorphol. 1996;5:197–206.
Rozovsky K, Sosna J, LeMerrer M, Simanovsky N, Koplewitz BZ, Bar-Ziv J, CormierDaire V, Raas-Rothschild A. Spondyloepimetaphyseal dysplasia, short limb-abnormal calcifications type: progressive radiological findings from fetal age to adolescence. Pediatr Radiol. 2011;41:1298–1307.
Smithson SF, Grier D, Hall CM. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. Clin Dysmorphol. 2009;18:31–35.
Bargal R, Cormier-Daire V, Ben-Neriah Z, Le Merrer M, Sosna J, Melki J, Zangen DH, Smithson SF, Borochowitz Z, Belostotsky R, Raas- Rothschild A. Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. Am J Hum Genet. 2009;84:80–84.
Dias C, Cairns R, Patel MS. Sudden death in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type. Clin Dysmorphol. 2009;18:25–29.
Fano V, Lejarraga H, Barreiro C. Spondylo-metaepiphyseal dysplasia, short limbs, abnormal calcification type: a new case with severe neurological involvement. Pediatr Radiol. 2001;31:19–22.
Al-Kindi A, Kizhakkedath P, Xu H, John A, Al Sayegh A, Ganesh A, Al-Awadi M, AlAnbouri L, Al-Gazali L, Leitinger B, Ali BR. A novel mutation in DDR2 causing spondylometa-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking. BMC Med Genet. 2014;15:42–52.
Ali BR, Xu H, Akawi NA, John A, Karuvantevida NS, Langer R, Al-Gazali L, Leitinger B. Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Hum Mol Genet. 2010;19:2239–2250.
Tuysuz B, Gazioglu N, Ungur S, Aji DY, Türkmen S. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type. Pediatr Radiol. 2009;39:84–89.
Mansouri M, Kayserili H, Elalaoui SC, Nishimura G, Iida A, Lyahyai J, Miyake N, Matsumoto N, Sefiani A, Ikegawa S. Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo‐meta‐epiphyseal dysplasia, short limbabnormal calcification type. Am J Med Genet A. 2016;170:460–5.
Guo L, Girisha KM, Iida A, Hebbar M, Shukla A, Shah H, Nishimura G, Matsumoto N, Nismath S, Miyake N, Ikegawa S. Identification of a novel LRRK1 mutation in a family with osteosclerotic metaphyseal dysplasia. J Hum Genet. 2017;62:437–41.
Wang Z, Horemuzova E, Iida A, Guo L, Liu Y, Matsumoto N, Nishimura G, Nordgren A, Miyake N, Tham E, Grigelioniene G, Ikegawa S. Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. J Hum Genet. 2017;62:503–6.
Labrador JP, Azcoitia V, Tuckermann J, Tuckermann J, Lin C, Olaso E, Manes S, Bruckner K, Goergen JL, Lemke G, Yancopoulos G, Angel P, Martınez C, Klein R. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO Rep. 2001;2:446–452.
Leitinger B, Kwan APL. The discoidin domain receptor DDR2 is a receptor for type X collagen. Matrix Biol. 2006;25.6:355–364.
We thank the family for participating in the study. This study is supported by KAKENHI for Scientific Research (Wakate B) (ZW, No.17K16710), RIKEN-MOST (SI), and Japan Agency For Medical Research and Development (AMED) (SI, NM, No. 17ek0109280h0001), the National Key Research and Development Program of China, RIKEN-MOST (SI, ZW, 2016YFE0128400).
Conflict of interest
The authors declare that they have no conflict of interest.