Open Access

A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012

  • Yazhou Cui1, 2,
  • Heng Zhao1, 2,
  • Zhenxing Liu1, 2,
  • Chao Liu1, 2,
  • Jing Luan1, 2,
  • Xiaoyan Zhou1, 2 and
  • Jinxiang Han1, 2Email author
Orphanet Journal of Rare Diseases20127:55

https://doi.org/10.1186/1750-1172-7-55

Received: 27 March 2012

Accepted: 20 August 2012

Published: 22 August 2012

Abstract

Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically reviewed GSDs as defined in “Nosology and Classification of genetic skeletal disorders (2010 version)” using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% (12,312 cases) of the total cases. Five groups (group 8, 12, 14, 18, 21) defined by “Nosology and Classification of genetic skeletal disorders” have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%). In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.

Keywords

Rare diseases Genetic skeletal diseases China Bibliographic study

Introduction

Genetic skeletal disorders (GSDs) arise from disturbances of the complex processes of skeletal development, growth, and homeostasis caused by gene mutations. These disorders represent a challenge in terms of diagnosis and treatment due to their rarity and variety[1, 2]. The recently published “Nosology and Classification of Genetic skeletal disorders (2010 version)” listed 456 GSDs that were classified into 40 groups by clinical, radiographic, and molecular criteria; of these, 316 conditions were associated with mutations in 226 different genes[3]. The Nosology not only provides a guideline for the diagnosis of the patients and the recognition of the novel disorders for clinicians, but also is helpful for better understanding the mechanisms of genes, proteins and pathways involved in skeletal biology.

Until now, population-based studies to determine the prevalence of GSDs have been not been performed in China. Most GSDs have been reported in “case reports” in Chinese biomedical literature, but these sources are usually not available to international readers. Therefore, an introduction to the published literature on GSDs in China would enrich our knowledge on the prevalence and molecular characteristics of these rare diseases.

This study systematically reviewed GSDs reported in Chinese biomedical literature published over the past 34 years from January 1978 to January 2012. This study also analyzed the current state and specific challenges in diagnosing and treating rare diseases in China.

Methods

Rare diseases covered

This bibliographic study covered a total of 456 GSDs in 40 groups defined in “Nosology and Classification of GSDs (2010 version).” This study has been performed with the approval of the ethics committee of Shandong Academy of Medical Science.

Selection of database sources

A literature search was conducted using China Biomedical Database (CBM) (http://sinomed.imicams.ac.cn) and covered sources from January 1978 to January 2012. The CBM is the largest Chinese biomedical bibliographic database[4], and includes a total of 6,840,907 articles from more than 1,600 biomedical journals published in Chinese prior to January 12, 2012.

Search strategy

The CBM database and public web search engines were first used to search for alternative Chinese terms for the English terms describing each disorder, and then all the terms for the disorder (both in English and Chinese) were used to search for publications in the CBM database. English terms for disorders were included since most Chinese biomedical articles contain an English abstract. The following search algorithm was used: “English disorder terms OR Chinese disorder terms [fulltext]”. For diseases with different subtypes (for example, Osteogenesis Imperfecta, types I–V), only the main term (“Osteogenesis Imperfecta”) was used in the search, and information on the type was gleaned from the text.

Inclusion and exclusion criteria

Clinical data and diagnostic information were gleaned from the abstract or full text of the articles searched for in the CBM database. Cases of GSDs with a confirmed diagnosis were included. Detailed clinical, imaging, and laboratory data needed to be described for case reports. Exact diagnostic criteria had to be included for research reports involving multiple cases or families. For each study included, informed consent to publication was obtained from the patient. Patient medical information was carefully compared for series of reports on the same disorders by the same authors or institutions, and redundant cases were excluded.

Results

According to our criteria 3,208 Chinese reports were qualified for inclusion. A total of 16,099 cases of GSDs in 35 groups of the “Nosology and Classification of Genetic Skeletal Disorders (2010 version)” was reported in the literature. The number of published cases is listed in Table1. The 10 most frequently reported GSDs were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% of cases (12,312 cases). Five groups (group 8 TRPV4 group, group 12 spondylometaphyseal dysplasias, group 14 severe spondylodysplastic dysplasias, group 18 bent bones dysplasias, and group 21 chondrodysplasia punctata) described in the Nosology have not been reported yet by Chinese biomedical literature.
Table 1

Number of published cases of genetic skeletal diseases in Chinese and Europe biomedical literature listed in alphabetical order of diseases*

Diseases or group of diseases

Number of Cases reported in Chinese biomedical literature

Number of published cases in Europe[8]

Estimated prevalence in Europe (/100,000)[8]

Achondroplasia

685

 

4.5

Acrofacial dysostosis, Nager type

3

90

 

alpha-Mannosidosis

1

 

0.1

Apert syndrome

16

 

1.25

Asphyxiating thoracic dysplasia

45

150

 

Brachydactyly

88

80

 

Caffey disease

280

N.A.

 

Calcium pyrophosphate deposition disease (familial chondrocalcinosis) type 2

1

N.A.

 

Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia,McKusick type)

3

N.A.

 

Cherubism

105

N.A.

 

Chondrodysplasia punctata

7

 

0.5

Chondroectodermal dysplasia (Ellis–van Creveld)

11

150

 

Cleidocranial dysplasia

260

N.A

 

Congenital contractural arachnodactyly

7

N.A.

 

Craniofrontonasal syndrome

1

3

 

Craniometaphyseal dysplasia

4

70

 

Craniostenosis (Craniosynostosis)

302

72

 

Crouzon syndrome

161

 

2

Currarino triad

31

 

1

de Lange syndrome

7

 

1.9

Diaphyseal dysplasia Camurati-Engelmann

14

200

 

Dysplasia epiphysealis hemimelica (Trevor)

53

N.A.

 

Ectrodactyly-ectodermal dysplasia cleft-palate syndrome

5

N.A.

 

Ehlers–Danlos syndrome

57

 

0.2

Enchondromatosis (Ollier)

369

600

 

Enchondromatosis with hemangiomata (Maffucci)

80

250

 

Endosteal hyperostosis, van Buchem type

8

N.A.

 

Familial expansile osteolysis

1

N.A.

 

Familial hip dysplasia (Beukes)

45

N.A.

 

Familial osteochondritis dissecans

1

N.A.

 

Fanconi anemia

107

 

0.3

Fibrous dysplasia, polyostotic form

982

 

<50

Frontometaphyseal dysplasia

1

<30

 

Frontonasal dysplasia

4

N.A.

 

Fucosidosis

1

100

 

Fuhrmann syndrome

1

11

 

GM1 Gangliosidosis, several forms

7

N.A.

 

Grebe dysplasia

2

N.A.

 

Greig cephalopolysyndactyly syndrome

2

100

 

Hajdu–Cheney syndrome

7

N.A.

 

Hallermann–Streiff syndrome

32

<100

 

Hanhart syndrome(hypoglossia-hypodactylia)

1

<50

 

Holt-Oram syndrome

218

 

1

Hypertrophic osteoarthropathy

36

N.A.

 

Hypochondroplasia

3

 

3.3

Hypophosphatasia, perinatal lethal and infantile forms

19

N.A.

 

Hypophosphatemic rickets

43

<100

 

Idiopathic juvenile osteoporosis

1

5

 

Immuno-osseous dysplasia (Schimke)

3

50

 

Infantile systemic hyalinosis/Juvenile hyaline fibromatosis (ISH/JHF)

3

N.A.

 

Klippel-Feil anomaly with laryngeal malformation

318

 

2

Kniest dysplasia

1

2

 

Langer type (Homozygous dyschondrosteosis)

2

N.A.

 

Larsen syndrome

9

100

 

Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu–Hakola)

2

 

0.15

Mandibulo-facial dysostosis(Treacher-Collins, Franceschetti-Klein)

198

 

6

Marfan syndrome

5064

 

20

Marshall syndrome

2

63

 

Meckel syndrome

35

 

2.5

Melorheostosis

153

300

 

Melorheostosis with osteopoikilosis

6

N.A.

 

Mesomelic dysplasia

4

2

 

Metaphyseal dysplasia, Jansen type

3

16

 

Metaphyseal dysplasia, Schmid type (MCS)

53

N.A.

 

Mucolipidosis II (I-cell disease),alpha/beta type

2

 

0.15

Mucopolysaccharidosis

958

 

3.56

Multicentric carpal-tarsal osteolysis with and without nephropathy

2

<10

 

Multiple cartilaginous exostoses

911

 

2

Multiple epiphyseal dysplasia

122

 

5

Multiple sulfatase deficiency

1

50

 

Multiple synostoses syndrome

1

20

 

Nail-patella syndrome

61

 

2

Neonatal hyperparathyroidism, severe form

4

N.A.

 

Neurofibromatosis type 1 (NF1)

881

 

25

Oculodentoosseous dysplasia

8

243

 

Omodysplasia

1

30

 

Oral-facial-digital syndrome

15

 

1.2

Osteoectasia with hyperphosphatasia (juvenile Paget disease)

4

50

 

Osteogenesis imperfecta

1314

 

6.5

Osteopetrosis

810

 

1.75

Osteopoikilosis

338

300

 

Pachydermoperiostosis (hypertrophic osteoarthropathy,primary, autosomal dominant)

25

204

 

Pallister-Hall syndrome

1

100

 

Parietal foramina

11

 

5

Pfeiffer syndrome

4

 

1

Poland anomaly

27

3

 

Preaxial polydactyly

16

 

25

Progeria, Hutchinson–Gilford type

20

 

0.005

Progressive osseous heteroplasia

20

N.A.

 

Progressive pseudorheumatoid dysplasia (PPRD; SED with progressive arthropathy)

6

N.A.

 

Proteus syndrome

22

200

 

Proximal symphalangism

15

N.A.

 

Pseudoachondroplasia (PSACH)

51

 

1.6

Pyknodysostosis

14

 

0.13

Pyle disease

2

<30

 

Radio-ulnar synostosis

55

<20

 

Saethre–Chotzen syndrome

1

 

3

Schwartz–Jampel syndrome (myotonic chondrodystrophy)

4

100

 

SED tarda, X-linked (SED-XL)

156

 

0.55

SED, Wolcott–Rallison type

1

<60

 

Short rib-polydactyly syndrome

57

N.A.

 

Shprintzen-Goldberg syndrome

1

<50

 

Sotos syndrome

38

 

7

Split hand-foot malformation

25

 

1.1

Spondylocostal dysostosis

1

4

 

Spondyloepiphyseal dysplasia congenita (SEDC)

50

 

0.34

Spondylometaphyseal dysplasia

6

 

1

Spondylometaphyseal dysplasia, Kozlowski type

2

 

0.1

Sterile multifocal osteomyelitis,periostitis, and pustulosis (CINCA/NOMID-like)

1

N.A.

 

Stickler syndrome

7

 

13.5

Syndactyly type 5 (HOXD13)

7

N.A.

 

Thanatophoric dysplasia

28

 

3.5

Thrombocytopenia-absent radius

1

N.A.

 

Tibial hemimelia

2

 

0.1

Trichorhinophalangeal dysplasia

15

>100

 

*: Different types belong to one diseases have been combined as one item when the typing information was not provided in literature.

The geographic distribution of cases is shown in Figure1. GSDs have been reported in all of China’s provinces and province-level municipalities. However, the number of cases varied geographically. More patients were reported in the East and South of China, which have a higher population density and better medical services than other areas. Beijing, Guangdong, Shandong, Shanghai and Jiangsu ranked among the top 5 provinces or province-level municipalities where disorders were reported.
Figure 1

Geographic distribution of reported cases of genetic skeletal disorders (GSDs) in Chinese biomedical literature. The number of cases reported varied geographically, and focused in the East and South of China. Beijing, Guangdong, Shandong, Shanghai and Jiangsu ranked among the top 5 provinces or province-level municipalities where GSDs were reported.

As shown in Figure2, the number of patients with GSDs reported each year in the CBM database increased gradually since 1978 and rapidly increased starting in 1994. Most GSD cases were reported by pediatricians, radiologists, and orthopedists. 49.0% of the cases were diagnosed at a university hospital,10.8% were diagnosed at a provincial hospital, 32.7% were diagnosed at a municipal hospital, and the remainder (7.5%) was diagnosed at hospitals on country level or even from smaller communities. (Figure3).
Figure 2

Case number of genetic skeletal disorders reported in Chinese biomedical literatures from 1978 to 2011. The number of GSDs reported each year in the CBM database increased gradually since 1978 and rapidly increased starting in 1994. 1,057 cases were reported annually in recent 5 years.

Figure 3

Hospital distribution of reported cases of genetic skeletal disorders in Chinese biomedical literatures. Most of the GSDs were diagnosed in hospitals in cities including university hospitals (49.0%), provincial hospitals (10.8%), and municipal hospital (32.7%). Only 7.5% of GSD cases were reported by hospitals on country level and below, which account for about 70% of the medical resources in China.

Gene mutations were evaluated in 187 cases or families out of 16,099 total reported cases, accounting for only a minor portion (1.16%). As shown in Table2, a total of 37 genes for 41 different GSDs were reported, including 43 novel mutations that have not been reported before. The EXT1 and EXT2 genes (30 cases) for multiple cartilaginous exostoses, the FBN1 gene for Marfan syndrome (24 cases), and the FGFR3 gene for achondroplasia (22 cases) were most frequently reported in Chinese biomedical literature from the CBM database. Compared to the reported geographic distribution of GSDs (Figure2), genetic testing was only performed at university hospitals in a few areas (Figure4). Affiliated hospitals of Shanghai Jiaotong University, Chinese Academy Of Medical Science & Peking Union Medical College, Zhongshan University, Central South University, and Peking University rank the top 5 University hospitals which performed most gene testing of GSDs.
Table 2

Gene mutation of genetic skeletal disorders published in Chinese biomedical literature from 1978 to 2012*

Gene

Name of disorder

MIM No.

No. of case reported*

Mutation

Location

Type

Novel

ACVR1

Fibrodysplasia ossificans progressiva (FOP)

135100

2

c.617 G > A (p.R206H)

exon 4

missense

 
   

1

c.1067 G > A (p.G356D)

exon 7

missense

 

ALPL

Hypophosphatasia, infantile forms

241500

1

c.18delA and c.G407C (p.V7Yfs18X and p.R136P)

exon 2 and 5

nonsense and missense

yes

ALPL

Hypophosphatasia, adult form

146300

1

c.1366 G > A (p.G456R)

exon 12

missense

 
   

1

c.1581C > G (p.P446G)

exon 12

missense

yes

   

1

c.583 G > A (p.R136H)

exon 5

missense

 

CLCN5

Dent’s disease

300554

1

p.L594fsX595

exon 10

nonsense

yes

   

1

p.R637X

exon 10

nonsense

 
   

1

p.R467X

exon 9

nonsense

 
   

1

p.IVS4-2A > G

exon 4

splicing

yes

   

1

c.1022C > T (p.S244L)

exon 7

missense

 
   

1

c.1805 T > G (p.V505G)

exon 9

missense

yes

CLCN7

Osteopetrosis, late-onset form type 2 (OPTA2)

166600

1

c.C856T (p.R286W)

exon 10

missense

 

COL1A2

Osteogenesis imperfecta

 

1

c.A3350G (p.Y1117C)

exon 49

missense

 
   

1

c.G3305C (p.G1102A)

exon 49

missense

 

COL1A1

Osteogenesis imperfecta

166220

1

c.1678 G > A (p.G560S)

exon 25

missense

 
  

166200

1

p.Gly632x

exon 28

nonsense

yes

  

166200

1

p.D1441H

exon 52

missense

yes

  

166200

1

c.1875 + 1 G > A (IVS 27 + 1 G > A)

intron 27

splicing

yes

  

166200

1

IVS8-2A > G

intron 8

splicing

yes

   

1

c.2461 G > A (p.G821S)

exon 36

missense

 
   

1

c.3470 G > A (p.G1157D)

 

missense

yes

COL2A1

Spondyloepiphyseal dysplasia congenita (SEDC)

183900

1

c.1510 G > A (p.G504S)

 

missense

 
   

1

c.2401 G > A (p.G801S)

 

missense

 

EFNB1

Craniofrontonasal Syndrome

304110

1

c.161C > G (p.P54R)

exon 2

missense

yes

COMP

Pseudoachondroplasia

177170

1

c.815 T > C (p.L272P)

exon 8

missense

 

EIF2AK3

SED, Wolcott–Rallison type

226980

1

c.1408-1409insT and c.1596 T > A (p.S470FfsX7 and p.C532X)

exon 8 and 9

nonsense

 

EXT1

Multiple cartilaginous exostoses 1

133700

1

c.1564-7delC

exon 7

frameshift

yes

   

1

I8 + 2 T > G

intron 8

splicing

yes

   

1

c.651_664delinsTTT (p.K218fsX220)

exon 1

nonsense

 
   

1

c.680delG (p.R227fs)

exon 1

frameshift

 
   

1

c.1182delG (p.Arg394SerfsX9)

exon 4

nonsense

yes

   

1

c.1108 G > T (p.E370X)

exon 3

nonsense

yes

   

1

c.335delA (p.Asn112ThrfsX24)

exon 1

nonsense

yes

   

1

c.361C > T (p.Q121X)

exon 1

nonsense

yes

   

1

c.1879_1881delCAC (p.His627del)

exon 9

In frame deletion

yes

   

1

c.651_664delinsTTT (p.K218fsX220)

exon 1

frameshift

 
   

1

1633-26(C > A)

intron 7

splicing

 
   

1

c.2120delT

exon 6

frameshift

 
   

1

c.811 T > C (p.Y271H)

exon 1

missense

yes

EXT2

Multiple cartilaginous exostoses 2

133701

1

c.668 G > C (p.Arg223Pro)

exon 2

missense

 
   

1

c.950delT (p.Phe317SerfsX15)

exon 6

nonsense

yes

   

3

c.1016 G > A (p.Cys339Tyr)

exon 6

missense

 
   

1

c.398 T > G (p.L133R)

exon 2

missense

 
   

1

c.751C > T (p.Q251X)

exon 5

missense

 
   

1

c.544C > T (p.R182X)

exon 3

missense

 
   

1

c.536 G > A (p.Arg179Lys)

exon 2

missense

 
   

1

c.1006C > T (p.G1n336X)

exon 6

nonsense

yes

   

1

IVS2 + 1 G > A

intron 2

splicing

 
   

1

IVS7 + 1 G > T

intron 7

splicing

 
   

1

c.789-796delTGTT

exon 5

frameshift

yes

   

1

c.637 G > A

exon 4

nonsense

 
   

1

c.313A > T (p.Lys105X)

exon 2

nonsense

 
   

1

319insGT

exon 2

frameshift

 
   

1

536 + 1 G > A (IVS2 + 1 G > A)

intron 2

splicing

 

FBN1

Marfan syndrome

154700

1

c.3463 G > A (p.Asp1155Asn)

exon 27

missense

yes

   

1

c.5015 G > C (p.C1672S)

exon 40

missense

 
   

3

c.5309 G > A (p.C1770Y)

exon 43

missense

 
   

2

c.7241 G > A (p.R2414Q)

exon 58

missense

 
   

2

c.7769 G > A (p.C2590Y)

exon 62

missense

 
   

2

c.2261A > G (p.Y754C)

exon 18

missense

 
   

1

c.[6862_6871delGGCTGTGTAG;6871 + 1_6871 + 11delGTAAGAGGATC] (p.Gly2288MetfsX109)

exon 55

nonsense

yes

   

1

c.2462 G > A (p.Cys821Tyr)

exon 20

missense

yes

   

1

c.5015 G > C (p.C1672S)

exon 40

missense

 
   

1

c.3295 G > T (p.E1099X)

exon 26

nonsense

 
   

2

c.4307insTCGT (p.G1441X)

exon 34

nonsense

yes

   

1

c.4621C > T (p.R1541X)

exon 37

nonsense

 
   

1

c.8080C > T (p.A2694X)

exon 64

nonsense

 
   

2

IVS29 + 4A > T

intron 29

splicing

 
   

1

IVS50 + 1 G > A

intron 50

splicing

 
   

1

c.3069 G > T (p.Lys1023Asn)

exon 24

missense

yes

   

1

c.3243-3256delGCCTCTGCACCCA

exon 25

frameshift

 

FGFR1

Pfeiffer syndrome

101600

1

c.755C > G (p.Pro252Arg)

exon 5

missense

 

FGFR2

Pfeiffer syndrome

101600

1

IVS8 A > G

exon 8

splicing

 
   

1

p.Asp321Ala

exon 9

missense

 
 

Apert syndrome

101200

1

c.934C > G (p.S252W)

exon 7

missense

 
 

Crouzon syndrome

123500

1

c.833 G > T (p.C278F)

exon 8

missense

 
   

1

p.Tyr340His

exon 9

missense

 
   

1

p.Cys342Trp

exon 9

missense

yes

   

1

p.Cys342Tyr

exon 9

missense

 
   

1

p.Ala344Ala

exon 9

missense

 
   

1

p.Gly338Arg

exon 9

missense

 
   

1

p.Ala344Gly

exon 9

missense

 
   

1

p.Gln289Pro

exon 7

missense

 

FGFR3

Achondroplasia

100800

21

c.1138 G > A (p.G380R)

exon 10

missense

 
   

1

p.Ser217Cys

exon 5

missense

 

FGFR3

Thanatophoric dysplasia

187600

1

c.742C > T (p.R248C)

exon 7

missense

 

GALNS

Mucopolysaccharidosis type 4A

253000

1

c.1567 T > G and c.374C > T

exon 14 and 4

nonsense and missense

yes

GDF5

Multiple synostoses syndrome type 2

186500

2

c.1471 G > A (p.E491K)

exon 2

missense

 

GNAS1

Albright hereditary osteodystrophy

103580

1

1-bp (C) deletion at codon 291

exon 11

frameshift

 

HLXB9

Currarino triad

176450

2

c.552C > G (p.Tyr184X)

 

nonsense

 

TP63

Split hand-foot malformation, isolated form, type 4 (SHFM4)

605289

1

c.956 G > A (p.R280H)

exon 7

missense

 

HOXD13

Synpolydactyly

186000

1

c.32 G > C (p.G11A)

exon 1

missense

 
   

1

c.64 G > T (p.A22S)

exon 1

missense

yes

   

3

9-residue polyalanine expansion

exon 1

  
 

yes

      
   

1

8-residue polyalanine expansion

exon 1

  
   

1

7-residue polyalanine expansion

exon 1

  

IDS

Mucopolysaccharidosis type 2

309900

1

c.892C > T (p.Q298X)

exon 7

nonsense

 
   

1

c.1468delA

exon 9

frameshift

 
   

1

c.263 G > A (p.Arg88His)

exon 3

missense

 
   

1

1103_1123del19

exon 8

frameshift

 

IHH

Brachydactyly type A1

112500

1

c.G298A (p.D100N)

exon 1

missense

 

NF1

Neurofibromatosis type 1

162200

1

c.1009 G > T

exon 7

nonsense

yes

   

1

c.3443-3444delCA

exon 20

frameshift

yes

   

1

c.4339C > T (p.G1336X)

 

nonsense

 
   

1

c.5839C > T (p.R1947X)

exon 31

nonsense

 
   

1

p.Leu1141Arg

exon 20

missense

 

TP63

Ankyloblepharon-ectodermal dysplasia-cleft lip/palate

106260

1

c.838C > T (p.R280C)

exon 7

missense

 
 

Limb-mammary syndrome (including ADULT syndrome)

603273

1

c.893 G > A (p.R298Q)

exon 8

missense

 

PHEX

Hypophosphatemic rickets, X-linked dominant

307800

1

IVS20-1 G > T

intron 20

splicing

 
   

1

c.1861C > T (p.GIn621X)

exon 18

missense

yes

PTPN11

Baller–Gerold syndrome

218600

1

IVS11-1 G > A and c.3401A > T

intro 11 and exon 10

splicing and nonsense

 

ROR2

Brachydactyly type B

113000

1

c.2265C > A (p.Y755X)

exon 9

nonsense

 
   

1

c.1398-1399insA

exon 9

nonsense

 

RUNX2

Cleidocranial dysplasia

119600

1

c.346 T > A (p.W116R)

exon 1

missense

 
   

1

c.610A > T (p.K204X)

exon 3

nonsense

 
   

1

c.346 T > A (p.W116R)

exon 1

missense

 
   

1

c.475 G > C (p.G159R)

exon 2

missense

yes

   

1

c.673C > T (p.R225W)

exon 3

missense

 
   

1

c.1171C > G (p.R391X)

exon 7

nonsense

 
   

1

c.674 G > A (p.R225Q)

exon 3

missense

 

SALL1

Townes–Brocks syndrome (Renal-Ear-Anal-Radial syndrome)

107480

4

c.1792 G > C

exon 2

missense

 

SEDL

SED tarda, X-linked (SED-XL)

313400

1

c.218C > T (p.S73L)

exon 4

missense

 
   

1

c.370-371insA (p.S124fsX127)

exon 6

nonsense

yes

   

1

c.218C > T (p.S73L)

exon 4

missense

 
   

1

c.239A > G (p.H80R)

exon 4

missense

 
   

1

c.G209A

exon 4

nonsense

 
   

1

c.262-266delGACAT

exon 5

frameshift

 
   

1

D109-S123del (p.S124fsX126)

intron 5-exon 6

nonsense

 
   

1

IVS5-2-1delAG322-332delTTTTCAATGAA

intron 5-exon 6

splicing

yes

   

1

IVS2-2A > C

intron 2

  

SH3BP2

Cherubism

118400

5

c.1505 G > C (p.Arg415Pro)

exon 9

missense

 
   

2

c.G1520A (p.Gly420Glu)

exon 9

missense

 

SHOX

Dyschondrosteosis

127300

1

c.115 T > G

exon 2

  
   

1

c.1171-1172insA

exon 3

frameshift

 
   

1

c.996A > T (p.E102V)

exon 3

missense

 

SOX9

Campomelic dysplasia (CD)

114290

1

p.R178L

exon 2

missense

yes

TBX5

Holt-Oram syndrome

142900

1

c.416delC

exon 4

frameshift

 
   

1

c.145C > A

exon 2

missense

 
   

1

c.161 T > C

exon 2

missense

 

TGFbeta1

Diaphyseal dysplasia Camurati-Engelmann

131300

1

p.R218H

exon 4

missense

 

WISP3

Progressive pseudorheumatoid dysplasia

208230

1

c.624-625insA and c.729-735delGAGAAAA

exon 4 and exon 4

frameshift and frameshift

yes

   

1

c.624-625insA and c.866-867insA

exon 4 and exon 5

frameshift and frameshift

yes

   

1

c.866_867insA and c.866-867insA

exon 5 and exon 5

frameshift and frameshift

yes

   

1

c.589 + 2 T > C and c.624dupA

intro 3 and exon 4

splicing and nonsense

yes

*: “Pedigree mutation”, that is an identical mutation has been reported in more than one affected siblings in a family, was counted as one case. Mutation information was extracted from the full text, as its original description, all the novel mutations were claimed in the papers by the authors, and then were confirmed by searching the previous literature and the Human Gene Mutation Database.

Figure 4

Geographic distribution of reported genetic skeletal disorders with gene mutation testing in Chinese biomedical literature. Genetic testing for GSDs was only performed at university hospitals in a few areas, far less than the regions where GSDs were reported.

Discussion

As the world’s most densely populated nation, China has the world’s largest number of rare disease groups[5]. In 1984, the concept of rare diseases was introduced in China. Until recently, however, the problem presented by rare diseases has received little attention[6]. Currently, there is no case registration system for most rare diseases, so there is very little documented information on the epidemiology of those diseases in China[7]. China still lacks an official definition and spectrum of rare diseases.

A bibliographic study will help to estimate the prevalence of rare diseases[8]. Most rare diseases have been reported in Chinese biomedical publications. Presently, only 86 Chinese biomedical journals have abstracts in English included in Pubmed[9]. Therefore, most reports on rare diseases in China are unavailable to international readers. To our knowledge, the current study is the first systematic review of the Chinese biomedical literature on rare disease groups.

GSDs are representative for many other groups of rare diseases. The current systematic review found that the number and type of GSDs reported in Chinese biomedical literature increased gradually over the past 30 years. In the last 5 years in particular, there were 1,057 cases reported annually, which is due to the rapid improvement of general healthcare and increasing attention to the medical problems caused by rare diseases in China. Although most genetic skeletal disease groups have been reported in Chinese biomedical literature, but only a small portion of patients were exactly molecularly characterized. For example, 1,314 cases of osteogenesis imperfecta were reported in the CBM database but in only 5% the exact type has been determined. This situation might be mainly due to the fact that most of these patients were diagnosed based on clinical and radiographic criteria and because gene mutation testing has been unavailable at most hospitals until now. In only 1% of all cases with GSDs a causative gene mutation was identified. Among these reported mutations, there is a relatively high frequency of novel mutations. These novel variations may also lead to a better understanding of the mutation spectrum and impact of genes associated with GSDs. For example, 5 cases of novel mutations in COL1A1 have been reported in Chinese biomedical literature. Among them, 4 cases belong to glycine single base substitution mutations in the triple-helical region (p.G632x, p.G1157D) and splicing sites (IVS27 + 1 G > A, IVS8-2A > G), which are the most and second common mutation types in COL1A1 gene. Mutations in the C-propeptide coding region have been identified less frequent than other forms of mutation. D1441 is one of a few residues absolutely conserved in this region, a previous study reported a defect in this site (D1441Y) resulting in a lethal variant of osteogenesis imperfecta with features of dense bone diseases[10], however, a novel mutation in this site described in a Chinese family (D1441H) led to only mild osteogenesis imperfecta (type 1), which suggesting mutations in this region show great heterogeneity in clinical outcome.

This systematic review of genetic skeletal diseases also revealed that reporting of rare diseases varies significantly in different regions and medical resources available in China. Cases of rare diseases were more frequently reported in large municipalities such as Beijing and Shanghai instead of areas with a larger population but a relatively lower level of development such as Sichuan and Henan Provinces. Country level hospitals and below are mainly responsible for treating rural residents and represent more than 70% of the medical resources in China[11]. In this review, we found that only 7.5% of the cases of rare diseases were diagnosed by these hospitals, which is significantly lower than that diagnosed by urban hospitals. In actuality, there are also significant disparities in health care between university hospitals and provincial and municipal hospitals. Currently, gene mutation testing for genetic rare diseases in China is done only by university hospitals in several key municipalities.

We further compared the number of GSD cases reported in Chinese biomedical literature with those of published cases or estimated prevalence of these diseases in Europe from bibliographic data issued by Orphanet[8] (Table1). Generally, the number of GSDs reported in Chinese biomedical literatures is lower than in Europe, but, with some exceptions, the proportions between the different entities are similar. One of these exceptions are the multiple epiphyseal dysplasias, whose frequency in Europe is 5/100,000, while only a total of 122 cases were reported in Chinese biomedical literature in the past 34 years. Although publication bias and genetic differences between Caucasian and Asian people may exist, we think this discrepancy is mainly due to the fact that China is still lagging behind Europe in terms of the medical resources for these rare diseases, especially in the widespread underdeveloped regions and hospitals on basic levels, therefore, many patients with genetic skeletal disorders could not acquire proper and timely diagnosis in China.

Creating a network for rare diseases is an important medical policy that should significantly reduce misdiagnosis and improve the level of treatment. A network for collaboration with national medical resources has been set up in countries and regions such as Europe, North America, and Japan[12, 13]. A number of centers offering counseling on rare diseases have been established in major Chinese cities and several provinces, but a national network has yet to be created. Given the fact that there is a huge gap in terms of medical services in different areas and hospital levels of China, a stronger network of diagnosis and treatment including all levels of hospitals across the country should be created to improve healthcare for rare diseases in the future.

Conclusion

In conclusion, this systematic review summarized the number, geographic and genetic characteristics of GSDs in Chinese biomedical publications. Analyzing number of the diseases revealed an imbalance in the distribution of areas and hospitals diagnosing rare diseases, which suggests that a multi-level network should be created to meet the specific challenge of healthcare for rare diseases in China.

Declarations

Authors’ Affiliations

(1)
Shandong Academy of Medical Sciences, Shandong Medical Biotechnological Center
(2)
Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease Research of Shandong Province

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Copyright

© Cui et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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