Sudden death in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type

Dias, Cristina; Cairns, Robyn; Patel, Millan S.

doi:10.1097/mcd.0b013e3283186907

Cited by 10 publications

(10 citation statements)

References 9 publications

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“…CNS: Compression of the cervical spinal cord due to foramen magnum stenosis in about 50% of the patients. 117 Additionally, hypomyelination in 1 patient. 118 Osteodysplasty Melnick-Needles (OMIM: 309350) General information: Less than 70 patients reported.…”

Section: Spondylo-epi-metaphyseal Dysplasia Short Limb-abnormal Calcmentioning

confidence: 97%

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Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review

Wagner

Poretti

Benson

et al. 2016

Journal of Neuroimaging

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Genetic skeletal disorders (GSDs) are a heterogeneous group characterized by an intrinsic abnormality in growth and (re-)modeling of cartilage and bone. A large subgroup of GSDs has additional involvement of other structures/organs beside the skeleton, such as the central nervous system (CNS). CNS abnormalities have an important role in long-term prognosis of children with GSDs and should consequently not be missed. Sensitive and specific identification of CNS lesions while evaluating a child with a GSD requires a detailed knowledge of the possible associated CNS abnormalities. Here, we provide a pattern-recognition approach for neuroimaging findings in GSDs guided by the obvious skeletal manifestations of GSD. In particular, we summarize which CNS findings should be ruled out with each GSD. The diseases (n = 180) are classified based on the skeletal involvement (1. abnormal metaphysis or epiphysis, 2. abnormal size/number of bones, 3. abnormal shape of bones and joints, and 4. abnormal dynamic or structural changes). For each disease, skeletal involvement was defined in accordance with Online Mendelian Inheritance in Man. Morphological CNS involvement has been described based on extensive literature search. Selected examples will be shown based on prevalence of the diseases and significance of the CNS involvement. CNS involvement is common in GSDs. A wide spectrum of morphological abnormalities is associated with GSDs. Early diagnosis of CNS involvement is important in the management of children with GSDs. This pattern-recognition approach aims to assist and guide physicians in the diagnostic work-up of CNS involvement in children with GSDs and their management.

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Section: Spondylo-epi-metaphyseal Dysplasia Short Limb-abnormal Calcmentioning

confidence: 97%

“…CNS: Compression of the cervical spinal cord due to foramen magnum stenosis in about 50% of the patients . Additionally, hypomyelination in 1 patient …”

Section: Glossarymentioning

confidence: 99%

Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review

Wagner

Poretti

Benson

et al. 2016

Journal of Neuroimaging

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“…A previous study [5] suggested that SMED-SL should be included in the list of genetic disorders causing death. In genetic diseases caused by the impaired function of a single gene, various interconnected pathways are affected, making the identification of relevant pharmaceutical targets difficult.…”

Section: Discussionmentioning

confidence: 99%

“…This bone dysplasia is progressive, with serious complications leading to death in some cases. Atlantoaxial instability resulting in cord damage has been the most reported cause of death [2,5]. Homozygous mutations occurring in the Discoidin domain receptor 2 gene ( DDR2 , MIM 191311) have been identified as the cause for this severely dwarfing condition [6,7].…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking

Al-Kindi

Kizhakkedath

et al. 2014

BMC Med Genet

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BackgroundThe rare autosomal genetic disorder, Spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL), is reported to be caused by missense or splice site mutations in the human discoidin domain receptor 2 (DDR2) gene. Previously our group has established that trafficking defects and loss of ligand binding are the underlying cellular mechanisms of several SMED-SL causing mutations. Here we report the clinical characteristics of two siblings of consanguineous marriage with suspected SMED-SL and identification of a novel disease-causing mutation in the DDR2 gene.MethodsClinical evaluation and radiography were performed to evaluate the patients. All the coding exons and splice sites of the DDR2 gene were sequenced by Sanger sequencing. Subcellular localization of the mutated DDR2 protein was determined by confocal microscopy, deglycosylation assay and Western blotting. DDR2 activity was measured by collagen activation and Western analysis.ResultsIn addition to the typical features of SMED-SL, one of the patients has an eye phenotype including visual impairment due to optic atrophy. DNA sequencing revealed a novel homozygous dinucleotide deletion mutation (c.2468_2469delCT) on exon 18 of the DDR2 gene in both patients. The mutation resulted in a frameshift leading to an amino acid change at position S823 and a predicted premature termination of translation (p.S823Cfs*2). Subcellular localization of the mutant protein was analyzed in mammalian cell lines, and it was found to be largely retained in the endoplasmic reticulum (ER), which was further supported by its N-glycosylation profile. In keeping with its cellular mis-localization, the mutant protein was found to be deficient in collagen-induced receptor activation, suggesting protein trafficking defects as the major cellular mechanism underlying the loss of DDR2 function in our patients.ConclusionsOur results indicate that the novel mutation results in defective trafficking of the DDR2 protein leading to loss of function and disease. This confirms our previous findings that DDR2 missense mutations occurring at the kinase domain result in retention of the mutant protein in the ER.

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“…The presence of chondral calcification was emphasized by Langer et al [] who proposed the name SMED, SL‐AC. The lack of soft tissue and chondral calcification on first examination cannot exclude the diagnosis of SMED, SL‐AC since these findings may appear later in life [Al‐Gazali et al, ; Dias et al, ]. The loss of function of DDR2 (Discoidin domain receptors 2) is responsible of this disease [Bargal et al, ].…”

Section: Introductionmentioning

confidence: 99%

Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo‐meta‐epiphyseal dysplasia, short limb‐abnormal calcification type

Mansouri

Kayserili

Elalaoui

et al. 2015

American J of Med Genetics Pt A

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Spondylo-meta-epiphyseal dysplasia (SMED), short limb-abnormal calcification type (SMED, SL-AC), is a very rare autosomal recessive disorder with various skeletal changes characterized by premature calcification leading to severe disproportionate short stature. Twenty-two patients have been reported until now, but only five mutations (four missense and one splice-site) in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene has been identified. We report here a novel DDR2 missense mutation, c.370C > T (p.Arg124Trp) in a Moroccan girl with SMED, SL-AC, identified by whole exome sequencing. Our study has expanded the mutational spectrum of this rare disease and it has shown that exome sequencing is a powerful and cost-effective tool for the diagnosis of clinically heterogeneous disorders such as SMED.

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Sudden death in spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type

Cited by 10 publications

References 9 publications

Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review

Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review

A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking

Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo‐meta‐epiphyseal dysplasia, short limb‐abnormal calcification type

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