Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with "corner fractures"

被引：15

作者：

Costantini, Alice ^{[1
,2
]}

Valta, Helena ^{[3
,4
]}

Baratang, Nissan Vida ^{[5
]}

Yap, Patrick ^{[6
]}

Bertola, Debora R. ^{[7
,8
]}

Yamamoto, Guilherme L. ^{[7
,8
]}

Kim, Chong A. ^{[8
]}

Chen, Jiani ^{[9
]}

Wierenga, Klaas J. ^{[10
]}

Fanning, Elizabeth A. ^{[9
,11
]}

Escobar, Luis ^{[12
]}

McWalter, Kirsty ^{[13
]}

McLaughlin, Heather ^{[13
]}

Willaert, Rebecca ^{[13
]}

Begtrup, Amber ^{[13
]}

Alm, Jessica J. ^{[1
,2
]}

Reinhardt, Dieter P. ^{[14
,15
]}

Makitie, Outi ^{[1
,2
,3
,4
,16
,17
,18
]}

Campeau, Philippe M. ^{[5
]}

机构：

[1] Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden

[2] Karolinska Inst, Ctr Mol Med, S-17176 Stockholm, Sweden

[3] Univ Helsinki, Childrens Hosp, FIN-00290 Helsinki, Finland

[4] Helsinki Univ Hosp, Helsinki 00290, Finland

[5] Univ Montreal, CHU St Justine, Res Ctr, Montreal, PQ H3T 1C5, Canada

[6] Genet Hlth Serv New Zealand Northern Hub, Auckland 1023, New Zealand

[7] Univ Sao Paulo, Ctr Pesquisa Genoma Humane & Celulas Tronco, Inst Biociencias, BR-05508090 Sao Paulo, SP, Brazil

[8] Univ Sao Paulo, Fac Med, Hosp Clin, Clin Genet Unit,Inst Crianca, BR-05403000 Sao Paulo, SP, Brazil

[9] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA

[10] Mayo Clin Florida, Jacksonville, FL 32224 USA

[11] Childrens Hosp Philadelphia, Div Genom Diagnost, Philadelphia, PA 19104 USA

[12] St Vincent Hlth, Payton Manning Childrens Hosp, Indianapolis, IN 46260 USA

[13] GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA

[14] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 0G7, Canada

[15] McGill Univ, Fac Dent, Montreal, PQ H3A 0G7, Canada

[16] Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden

[17] Univ Helsinki, Folkhalsan Inst Genet, Helsinki 00290, Finland

[18] Univ Montreal, Dept Pediat, Montreal, PQ H3T 1C5, Canada

来源：

BONE | 2019年 / 121卷

基金：

瑞典研究理事会; 巴西圣保罗研究基金会; 加拿大健康研究院; 芬兰科学院;

关键词：

FN1; Fibronectin; Skeletal dysplasia; Corner-fracture; Coxa vara; Mutation; OSTEOBLAST DIFFERENTIATION; MATRIX; BONE; GLOMERULOPATHY; PROTEIN; RESORPTION;

D O I：

10.1016/j.bone.2018.12.020

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with "corner fractures" (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of "corner fractures". An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extracellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys23ITrp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and "corner fracture" appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.

引用

页码：163 / 171

页数：9

共 51 条

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