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Ophthalmic Molecular Genetics |

New Phenotype Associated With an Arg116Cys Mutation in the CRYAA Gene Nuclear Cataract, Iris Coloboma, and Microphthalmia FREE

Francis Beby, MD; Claire Commeaux; Muriel Bozon; Philippe Denis, MD, PhD; Patrick Edery, MD, PhD; Laurette Morlé, PhD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology (Drs Beby and Denis) and Service de Cytogénétique Constitutionnelle (Dr Edery), Edouard Herriot Hospital, Place d’Arsonval, and Equipe d’Acceuil 3739, Université Claude Bernard Lyon 1 (Dr Edery), Lyon, France; and Molecular and Cellular Genetic Center, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5534, University of Lyon, Villeurbanne, France (Mss Commeaux and Bozon and Dr Morlé).


Section Editor: Janey L. Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2007;125(2):213-216. doi:10.1001/archopht.125.2.213.
Text Size: A A A
Published online

Objective  To describe a new phenotype with an arginine-to-cysteine mutation at position 116 (Arg116Cys) in the CRYAA gene.

Methods  We investigated a 4-generation French family with autosomal dominant cataract and performed a genetic linkage analysis using microsatellite DNA markers encompassing 15 known cataract loci. Exons 1, 2, and 3 and flanking intronic sequences of the CRYAA gene were amplified and analyzed using direct sequencing.

Results  All of the affected individuals had nuclear cataract and iris coloboma.Genetic analysis revealed the previously described Arg116Cys mutation in the CRYAA gene in the heterozygous state in all of the affected members of the family but not in unaffected individuals.

Conclusion  To our knowledge, this is the first case to date in which an Arg116Cys mutation in the CRYAA gene was associated with nuclear cataract and iris coloboma.

Clinical Relevance  This study indicates that an Arg116Cys mutation in the CRYAA gene could be associated with an unusual phenotype in affected individuals. In this family, the clinical observation of iris coloboma allows for the possibility of identifying individuals carrying the mutation. Iris coloboma is particularly important in terms of perinatal diagnosis because its detection in the newborn requires a careful and regular examination of the lens.

Figures in this Article

Congenital cataracts are a common cause of visual impairment in children.1,2 Approximately 30% of nonsyndromic congenital cataracts have a genetic origin.3 To date,22 independent autosomal dominant cataract loci have been mapped and 14 genes have been identified, including 8 genes coding for crystallins.15 Here we report the first case in which an arginine-to-cysteine mutation at position 116 (Arg116Cys) in the CRYAA gene was associated with autosomal dominant nuclear cataract and iris coloboma.

A full ophthalmological examination was performed in 16 members of a 4-generation French family with autosomal dominant cataract. Twelve affected and 4 unaffected members were studied. The onset of the cataract was determined by medical documentation and surgical records of cataract extraction. For each individual, ocular axial length was determined by A-scan ultrasonography.A diagnosis of microphthalmia was based on a total axial length less than 20 mm. All of the affected patients had a bilateral early-onset cataract.The lens opacity appeared at birth or developed during the first years of life. The cataract consisted of a single dense axial opacity of 3 mm confined to the embryonic and fetal nuclei of the lens. In all of the affected individuals,the bilateral nuclear cataract was also associated with bilateral iris coloboma (Figure 1). Two affected individuals (II:7 and III:5) (Figure 2) had congenital microphthalmia in conjunction with cataract. Physical examination of the affected individuals did not reveal any dysmorphic facial features, mental retardation,or developmental malformations that could indicate that the cataract was syndromic.The power to detect a linkage in this family was estimated using the SLINK simulation program6 (Rockefeller University,New York, NY) and assuming an autosomal dominant model of inheritance, a 95%penetrance, and a gene frequency of 0.00015. We performed a genetic linkage analysis using microsatellite DNA markers7 encompassing 15 known cataract loci: 1q21-q25 (CX50); 2q33-q35(CRYGB); 3p22.1-3p21; 3q21.3-22.3 (BFPS2); 9q13-q22; 11p13 (PAX6); 11q22.3-q23.1(CRYAB); 12q13-q14 (MIP);13q11-q13 (CX46); 14q24 (CHX10); 15q21-q22; 16q22 (HSF4); 17q11.2-q12 (CRYBA1); 20q12-p12; and 21q22.3 (CRYAA). Logarithm of odds (LOD) scores were calculated using the LINKAGE version 5.2 package8 (Université Paris 7, Paris, France) and the parameters described for the SLINK program. Exons 1, 2, and 3 and flanking intronic sequences of the CRYAA gene were amplified as previously described9 and analyzed using direct sequencing.

Place holder to copy figure label and caption
Figure 1.

Slitlamp photograph of the left eye of an affected individual (III:9) showing an iris coloboma (arrows) and a nuclear cataract. The lens opacity is located in the embryonal and fetal nucleus of the lens (dilated pupil).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Pedigree of the family. cM indicates centimorgans; open circles, unaffected females; filled circles, females with both a nuclear cataract and an iris coloboma; open squares, unaffected males;filled squares, males with both a nuclear cataract and an iris coloboma; asterisks,individuals with microphthalmia. The numbers below the symbols indicate the genotypes for 3 markers, and the disease-associated haplotypes appear in bold numbers.

Graphic Jump Location

All of the affected individuals had an autosomal dominant bilateral nuclear cataract with bilateral iris coloboma. A microphthalmia also appeared in 2 of 14 affected members. A SLINK simulation calculation yielded expected LOD scores of 3.5 at θ = 0, 3.2 at θ = 0.05,and 2.9 at θ = 0.01, indicating a high probability of finding a linkage in this family. Although we were able to exclude 14 of 15 candidate loci, we detected positive LOD scores with markers D21S1912 (LOD score = 2.6 at θ = 0) and D21S1890 (LOD score = 1.9 at θ = 0). Haplotype analysis indicated that a specific haplotype segregates with the disease (Figure 2). The CRYAA gene,which lies within the D21S1260-D21S1890 interval and encodes a crystallin protein, was considered to be a good candidate. Sequence analysis of the 3 CRYAA exons revealed the previously described Arg116Cys mutation9 in the heterozygous state in all of the affected members of this family but not in unaffected individuals. In addition, a synonymous change at the third base of codon 2 (GAC→GAT) (single nucleotide polymorphism rs872331, http://www.ncbi.nih.gov/SNP/) was observed on the CRYAA mutated allele. This polymorphism was found in the homozygous state in the 2 affected individuals (II:7 and III:5) who have both cataract and microphthalmia and in 5 of 12 other affected patients who have normal eye size. This frequent polymorphism was also observed in the heterozygous state in 5 of 12 patients with cataract and in 3 unaffected members of the family. Thus, its occurrence in the homozygous state did not correlate with microphthalmia and iris coloboma.

An Arg116Cys mutation of the CRYAA gene was identified in all of the affected members from the family with autosomal dominant cataract described here. This mutation was previously reported in 1 family9 with isolated autosomal dominant cataract but no iris coloboma. The preservation of a positive charge at position 116 was found to be critical for the structural and functional integrity of the αA-crystallin.10 Indeed, Bera et al10 have demonstrated that the Arg116 residue can be replaced by another positively charged amino acid, Lys, without any effect on protein structure and function.Moreover, mutation of Arg116 to Cys or to another neutral amino acid, Gly,showed very similar changes in structure, oligomerization, and chaperone function.This suggests that an extra Cys residue per se is not the cause of the changes.In contrast, the replacement of the Arg116 residue by a negatively charged amino acid, Asp, has a devastating effect on the secondary and tertiary protein structures.10 The αA-crystallin Arg116Cys mutant forms larger oligomerized heteroaggregates with αB-crystallin11 whereas its interaction with the βB2- and γC-crystallins is decreased.12 In addition, the mutant Arg116Cys protein has reduced chaperone activity.13,14

In this study, an iris coloboma was observed in all of the patients with cataract, and 2 individuals have microphthalmia in addition to cataract and iris coloboma. Two families with different CRYAA mutations have been described.15,16 An Arg49Cys mutation was previously reported in a family with isolated autosomal dominant cataract15 whereas a Trp9Xaa mutation was identified in a family with autosomal recessive cataract.16 No iris coloboma was described in these 2 families. Litt et al9 noted that 5 of 13 individuals with the Arg116Cys mutation had microphthalmia in addition to their cataract. In contrast, no ocular abnormality aside from cataract was found either in the family with autosomal dominant cataract with a missense Arg49Cys mutation of the human CRYAA gene15 or in the family with autosomal recessive cataract with a nonsense Trp9Xaa mutation of the CRYAA gene.16

Coloboma may be caused by a defect in the closure of the optic fissure or by an abnormal development of the iris stroma and epithelium.17 Although some CRYAA transcripts have been detected in an iris complementary DNA library (National Eye Institute NEIBank library NbLib0016, http://neibank.nei.nih.gov), a direct implication of CRYAA in iris development remains to be demonstrated. Nevertheless,investigators1820 have previously demonstrated that the lens produces growth factors and influences the development of the ciliary body and iris. Based on the features found,our results also indicate that CRYAA protein is probably involved in choroidal development. In the family we have described, the occurrence of an iris coloboma could be related to a higher expression level of the Arg116Cys αA-crystallin mutant allele compared with the previously described family.9 Indeed,polymorphisms in the CRYAA promoter region appear to influence transcriptional activity21 and may be responsible for a different expression level of the mutant protein.

In a family with autosomal dominant cataract with a mutation in MAF, a lens developmental gene that is expressed in early eye development, 1 of 5 affected patients had iris coloboma and 2 of 5 had microcornea.22 Ogino and Yasuda23 suggested that MAF may have a role in the embryogenesis of the eye and in the maintenance of lens clarity through its known role in crystallin gene regulation. Recently, a CRYBB1 mutation was found to lead to cataract and microcornea in 8 of 10 affected individuals.Willoughby et al24 identified a novel mutation in the CRYBB1 gene and provided the first molecular basis for cataract with microcornea in the absence of microphthalmia or coloboma.Thus, CRYBB1 also plays a role in early ocular development.Altogether, these results provide evidence for an early expression of MAF, CRYBB1, and CRYAA in the embryogenesis of the eye and confirm that mutations in each of these genes can result not only in a phenotype restricted to the lens but also in a complex variety of ocular phenotypes combining cataract, microphthalmia,and anterior segment dysgenesis such as microcornea or iris coloboma.

Mouse mutants with the Val142Glu CRYAA mutation25 or with a CRYAA gene homozygous invalidation26 have both microphthalmia and cataract. In the family described here, we suggest the possibility that the Arg116Cys mutation acting in combination with a trans genetic modifier such as a polymorphic allele of a gene involved in eye development may be responsible for the occurrence of microphthalmia in 2 individuals.

Autosomal dominant cataract is phenotypically and genetically highly heterogeneous, making it a major obstacle to the phenotype-genotype relationship and direct linkage of congenital cataract genes.15 We describe in this study a new phenotype associated with an Arg116Cys mutation of the CRYAA gene in a French family. In this family,all of the affected individuals had nuclear cataract and iris coloboma.

Correspondence: Francis Beby, MD, 30 rue du Professeur Florence, 69003 Lyon, France (beby.francis@neuf.fr).

Submitted for Publication: March 13, 2006;final revision received June 14, 2006; accepted June 22, 2006.

Author Contributions: Dr Beby had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This work was supported by contracts HCL 1999 and HCL 2001 from the Hospices Civils de Lyon, by the Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5534),and by the Claude Bernard Lyon 1 University. Dr Beby is the recipient of a grant from the Fondation pour la Recherche Médicale.

Acknowledgment: We are grateful to the family members in this study. We thank the Développements Techniques pour l’Analyse Moléculaire de la Biodiversité for their technical support.

Reddy  MAFrancis  PJBerry  VBhattacharya  SSMoore  AT Molecular genetic basis of inherited cataract and associated phenotypes. Surv Ophthalmol 2004;49300- 315
PubMed Link to Article
Graw  J Congenital hereditary cataracts. Int J Dev Biol 2004;481031- 1044
PubMed Link to Article
He  WLi  S Congenital cataracts: gene mapping. Hum Genet 2000;1061- 13
PubMed Link to Article
Francis  PJMoore  AT Genetics of childhood cataract. Curr Opin Ophthalmol 2004;1510- 15
PubMed Link to Article
Nandrot  ESlingsby  CBasak  A  et al.  Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts. J Med Genet 2003;40262- 267
PubMed Link to Article
Ott  J Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci U S A 1989;864175- 4178
PubMed Link to Article
Dib  CFauré  SFizames  C  et al.  A comprehensive genetic map of the human genome based on 5 264microsatellites. Nature 1996;380152- 154
PubMed Link to Article
Lathrop  GMLalouel  JM Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 1984;36460- 465
PubMed
Litt  MKramer  PLaMorticella  DMMurphey  WLovrien  EWWeleber  RG Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum Mol Genet 1998;7471- 474
PubMed Link to Article
Bera  SThampi  PCho  WJAbraham  EC A positive charge preservation at position 116 of alpha A-crystallin is critical for its structural and functional integrity. Biochemistry 2002;4112421- 12426
PubMed Link to Article
Bera  SAbraham  EC The alphaA-crystallin R116C mutant has a higher affinity for forming heteroaggregates with alphaB-crystallin. Biochemistry 2002;41297- 305
PubMed Link to Article
Fu  LLiang  JJ Alteration of protein-protein interactions of congenital cataract crystallin mutants. Invest Ophthalmol Vis Sci 2003;441155- 1159
PubMed Link to Article
Shroff  NPCherian-Shaw  MBera  SAbraham  EC Mutation of R116C results in highly oligomerized alpha A-crystallin with modified structure and defective chaperone-like function. Biochemistry 2000;391420- 1426
PubMed Link to Article
Andley  UPPatel  HCXi  JH The R116C mutation in alpha A-crystallin diminishes its protective ability against stress-induced lens epithelial cell apoptosis. J Biol Chem 2002;27710178- 10186
PubMed Link to Article
Mackay  DSAndley  UPShiels  A Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q. Eur J Hum Genet 2003;11784- 793
PubMed Link to Article
Pras  EFrydman  MLevy-Nissenbaum  E  et al.  A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family. Invest Ophthalmol Vis Sci 2000;413511- 3515
PubMed
Onwochei  BCSimon  JWBateman  JBCouture  KCMir  E Ocular colobomata. Surv Ophthalmol 2000;45175- 194
PubMed Link to Article
Collinson  JMQuinn  JCBuchanan  MA  et al.  Primary defects in the lens underlie complex anterior segment abnormalities of the Pax6 heterozygous eye. Proc Natl Acad Sci U S A 2001;989688- 9693
PubMed Link to Article
de Iongh  RMcAvoy  JW Spatio-temporal distribution of acidic and basic FGF indicates a role for FGF in rat lens morphogenesis. Dev Dyn 1993;198190- 202
PubMed Link to Article
Beebe  DCCoats  JM The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Dev Biol 2000;220424- 431
PubMed Link to Article
Buckland  PRColeman  SLHoogendoorn  BGuy  CSmith  SKO’Donovan  MC A high proportion of chromosome 21 promoter polymorphisms influence transcriptional activity. Gene Expr 2004;11233- 239
PubMed Link to Article
Jamieson  RVMunier  FBalmer  AFarrar  NPerveen  RBlack  GC Pulverulent cataract with variably associated microcornea and iris coloboma in a MAF mutation family. Br J Ophthalmol 2003;87411- 412
PubMed Link to Article
Ogino  HYasuda  K Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science 1998;280115- 118
PubMed Link to Article
Willoughby  CEShafiq  AFerrini  W  et al.  CRYBB1 mutation associated with congenital cataract and microcornea. Mol Vis 2005;11587- 593
PubMed
Graw  JLoster  JSoewarto  D  et al.  Characterization of a new, dominant V124E mutation in the mouse alphaA-crystallin-encoding gene. Invest Ophthalmol Vis Sci 2001;422909- 2915
PubMed
Brady  JPGarland  DDuglas-Tabor  YRobison  WG  JrGroome  AWawrousek  EF Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin. Proc Natl Acad Sci U S A 1997;94884- 889
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Slitlamp photograph of the left eye of an affected individual (III:9) showing an iris coloboma (arrows) and a nuclear cataract. The lens opacity is located in the embryonal and fetal nucleus of the lens (dilated pupil).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Pedigree of the family. cM indicates centimorgans; open circles, unaffected females; filled circles, females with both a nuclear cataract and an iris coloboma; open squares, unaffected males;filled squares, males with both a nuclear cataract and an iris coloboma; asterisks,individuals with microphthalmia. The numbers below the symbols indicate the genotypes for 3 markers, and the disease-associated haplotypes appear in bold numbers.

Graphic Jump Location

Tables

References

Reddy  MAFrancis  PJBerry  VBhattacharya  SSMoore  AT Molecular genetic basis of inherited cataract and associated phenotypes. Surv Ophthalmol 2004;49300- 315
PubMed Link to Article
Graw  J Congenital hereditary cataracts. Int J Dev Biol 2004;481031- 1044
PubMed Link to Article
He  WLi  S Congenital cataracts: gene mapping. Hum Genet 2000;1061- 13
PubMed Link to Article
Francis  PJMoore  AT Genetics of childhood cataract. Curr Opin Ophthalmol 2004;1510- 15
PubMed Link to Article
Nandrot  ESlingsby  CBasak  A  et al.  Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts. J Med Genet 2003;40262- 267
PubMed Link to Article
Ott  J Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci U S A 1989;864175- 4178
PubMed Link to Article
Dib  CFauré  SFizames  C  et al.  A comprehensive genetic map of the human genome based on 5 264microsatellites. Nature 1996;380152- 154
PubMed Link to Article
Lathrop  GMLalouel  JM Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 1984;36460- 465
PubMed
Litt  MKramer  PLaMorticella  DMMurphey  WLovrien  EWWeleber  RG Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum Mol Genet 1998;7471- 474
PubMed Link to Article
Bera  SThampi  PCho  WJAbraham  EC A positive charge preservation at position 116 of alpha A-crystallin is critical for its structural and functional integrity. Biochemistry 2002;4112421- 12426
PubMed Link to Article
Bera  SAbraham  EC The alphaA-crystallin R116C mutant has a higher affinity for forming heteroaggregates with alphaB-crystallin. Biochemistry 2002;41297- 305
PubMed Link to Article
Fu  LLiang  JJ Alteration of protein-protein interactions of congenital cataract crystallin mutants. Invest Ophthalmol Vis Sci 2003;441155- 1159
PubMed Link to Article
Shroff  NPCherian-Shaw  MBera  SAbraham  EC Mutation of R116C results in highly oligomerized alpha A-crystallin with modified structure and defective chaperone-like function. Biochemistry 2000;391420- 1426
PubMed Link to Article
Andley  UPPatel  HCXi  JH The R116C mutation in alpha A-crystallin diminishes its protective ability against stress-induced lens epithelial cell apoptosis. J Biol Chem 2002;27710178- 10186
PubMed Link to Article
Mackay  DSAndley  UPShiels  A Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q. Eur J Hum Genet 2003;11784- 793
PubMed Link to Article
Pras  EFrydman  MLevy-Nissenbaum  E  et al.  A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family. Invest Ophthalmol Vis Sci 2000;413511- 3515
PubMed
Onwochei  BCSimon  JWBateman  JBCouture  KCMir  E Ocular colobomata. Surv Ophthalmol 2000;45175- 194
PubMed Link to Article
Collinson  JMQuinn  JCBuchanan  MA  et al.  Primary defects in the lens underlie complex anterior segment abnormalities of the Pax6 heterozygous eye. Proc Natl Acad Sci U S A 2001;989688- 9693
PubMed Link to Article
de Iongh  RMcAvoy  JW Spatio-temporal distribution of acidic and basic FGF indicates a role for FGF in rat lens morphogenesis. Dev Dyn 1993;198190- 202
PubMed Link to Article
Beebe  DCCoats  JM The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye. Dev Biol 2000;220424- 431
PubMed Link to Article
Buckland  PRColeman  SLHoogendoorn  BGuy  CSmith  SKO’Donovan  MC A high proportion of chromosome 21 promoter polymorphisms influence transcriptional activity. Gene Expr 2004;11233- 239
PubMed Link to Article
Jamieson  RVMunier  FBalmer  AFarrar  NPerveen  RBlack  GC Pulverulent cataract with variably associated microcornea and iris coloboma in a MAF mutation family. Br J Ophthalmol 2003;87411- 412
PubMed Link to Article
Ogino  HYasuda  K Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science 1998;280115- 118
PubMed Link to Article
Willoughby  CEShafiq  AFerrini  W  et al.  CRYBB1 mutation associated with congenital cataract and microcornea. Mol Vis 2005;11587- 593
PubMed
Graw  JLoster  JSoewarto  D  et al.  Characterization of a new, dominant V124E mutation in the mouse alphaA-crystallin-encoding gene. Invest Ophthalmol Vis Sci 2001;422909- 2915
PubMed
Brady  JPGarland  DDuglas-Tabor  YRobison  WG  JrGroome  AWawrousek  EF Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin. Proc Natl Acad Sci U S A 1997;94884- 889
PubMed Link to Article

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