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Genetics of Congenital Hand Anomalies

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Genetics of Congenital Hand Anomalies G. C. Schwabe1 S. Mundlos2 Genetics of Congenital Hand Anomalies Die Genetik angeborener Handfehlbildungen Original Article Abstract Zusammenfassung Congenital limb malformations exhibit a wide spectrum of phe- Angeborene Handfehlbildungen sind durch ein breites Spektrum notypic manifestations and may occur as an isolated malforma- an phänotypischen Manifestationen gekennzeichnet. Sie treten tion and as part of a syndrome. They are individually rare, but als isolierte Malformation oder als Teil verschiedener Syndrome due to their overall frequency and severity they are of clinical auf. Die einzelnen Formen kongenitaler Handfehlbildungen sind relevance. In recent years, increasing knowledge of the molecu- selten, besitzen aber aufgrund ihrer Häufigkeit insgesamt und lar basis of embryonic development has significantly enhanced der hohen Belastung für Betroffene erhebliche klinische Rele- our understanding of congenital limb malformations. In addi- vanz. Die fortschreitende Erkenntnis über die molekularen Me- tion, genetic studies have revealed the molecular basis of an in- chanismen der Embryonalentwicklung haben in den letzten Jah- creasing number of conditions with primary or secondary limb ren wesentlich dazu beigetragen, die genetischen Ursachen kon- involvement. The molecular findings have led to a regrouping of genitaler Malformationen besser zu verstehen. Der hohe Grad an malformations in genetic terms. However, the establishment of phänotypischer Variabilität kongenitaler Handfehlbildungen er- precise genotype-phenotype correlations for limb malforma- schwert jedoch eine Etablierung präziser Genotyp-Phänotyp- tions is difficult due to the high degree of phenotypic variability. Korrelationen. In diesem Übersichtsartikel präsentieren wir das We present an overview of congenital limb malformations based Spektrum kongenitaler Malformationen, basierend auf einer ent- 85 on an anatomic and genetic concept reflecting recent molecular wicklungsbiologischen, anatomischen und genetischen Klassifi- and developmental insights. kation unter Berücksichtigung der Bedeutung neuerer molekula- rer und entwicklungsbiologischer Erkenntnisse. Key words Limb development ´ malformation ´ syndactyly ´ polydactyly ´ Schlüsselwörter brachydactyly ´ genetics Angeborene Handfehlbildungen ´ Genetik ´ Embryologie ´ Syn- daktylie ´ Polydaktylie ´ Brachydaktylie Introduction of manifestations, phenotypic variability and genetic hetero- geneity. For a review on skeletal malformations see Kornak and Congenital hand malformations are a genetically and clinically Mundlos [30]. They are individually rare, but due to their overall heterogeneous group of disorders which present as an isolated frequency and severity they are of clinical relevance. Congenital trait or as part of a syndrome. They exhibit a wide spectrum limb malformations may be caused by genetic or environmental Affiliation 1 Max-Planck-Institut für Molekulare Genetik, Berlin, Germany 2 Institut für Medizinische Genetik, Humboldt-Universität, CharitØ, Berlin, Germany Correspondence Prof. Dr. med. Stefan Mundlos ´ Institut für Medizinische Genetik ´ Humboldt-Universität, CharitØ ´ Augustenburger Platz 1 ´ 13353 Berlin ´ Germany ´ E-mail: [email protected] Received: 11. 9. 20 03 ´ Accepted: 2.11. 2003 Bibliography Handchir Mikrochir Plast Chir 2004; 36: 85±97 Georg Thieme Verlag KG Stuttgart ´ New York ´ ISSN 0722-1819 ´ DOI 10.1055/s-2004-817884 factors disturbing the regular developmental program during embryogenesis. The study of the molecular mechanisms under- lying human genetic diseases, the analysis of animal model or- ganisms and the use of transgenic mouse technology have con- siderably helped elucidate the genetic basis of limb development and malformation in the last years. These findings have strongly influenced the genetic classification of congenital limb malfor- mations (see Glossary). In addition, a number of non-genetic conditions exist that are mainly caused by external factors such as amniotic bands, vascular disruptions or teratogens. In this ar- ticle we present an overview covering hand malformations in an isolated form or as part of a syndrome, based on anatomic and genetic observations and taking into account the significance of Original Article recent molecular and developmental data (see Fig.1 and Table 1). Accordingly, we will focus on conditions with known molecular and genetic causes, refraining from a surgical classification. Embryonic Limb Development During development, the limb forms as a result of a dual contri- bution from the lateral plate and the somitic mesoderm (Fig. 2; [28,35]). The limb buds of the embryo are formed at the lateral flank by proliferation of cells from the lateral plate. Shortly thereafter, cells from the lateral edges of adjacent somites invade the limb bud to form limb muscles, nerves and vessels. The limb bud increases in size and the individual skeletal elements are laid down in a proximodistal fashion. Different signaling centers control the outgrowth and patterning of the limbs in three di- mensions (Fig. 2). The outgrowth of the limb along the proximo- distal axis is directed by signals from the overlying ectoderm Fig.1 Congenital limb anomalies and their anatomic basis. Sche- which forms a specialized epithelial structure at its distal tip, matic representation of congenital limb malformations appearing as 86 the apical ectodermal ridge (AER). Experimental removal of the an isolated trait or in association with a syndrome. Abbreviations: AER leads to limbs with different severities of truncations, de- BDA ± Brachydactyly Type A;BDB ± Brachydactyly Type B;BDC ± Bra- pending on the time of removal. Subsequently, it has been shown chydactyly Type C;BDD ± Brachydactyly Type D;BDE ± Brachydactyly that fibroblast growth factors (Fgfs) represent key factors that Type E;CG ± Chondrodysplasia Grebe;GCPS ± Greig cephalosynpoly- dactyly;HFGS ± Hand-foot-genital syndrome;HOS ± Holt-Oram syn- mediate the outgrowth of the limb. drome;NPS ± Nail-patella syndrome;PAPA ± Postaxial polydactyly; PHS ± Pallister-Hall syndrome;PPD ± Preaxial Polydactyly;SD ± Syn- The anteroposterior patterning of the limb is controlled by the dactyly;SHFM ± Split-hand/-foot malformation;SLOS ± Smith-Lemli- zone of polarizing activity (ZPA), consisting of mesenchymal cells Opitz syndrome;SYM ± proximal symphalangism;TBS ± Townes- at the posterior margin of the limb bud. Experimental grafting of Brocks syndrome, UMS ± Ulna-mammary syndrome. the ZPA to the anterior margin of the limb bud leads to mirror image duplications of skeletal elements. Sonic hedgehog (Shh), a secreted molecule related to Drosophila Hedgehog (Hh), has been Despite our knowledge of outgrowth and patterning, the mecha- identified as the molecule responsible for the morphogenetic nisms underlying the specification of cells in the early limb bud properties of the ZPA. Shh regulates its target genes by control- remain unclear. In order to form distinct skeletal elements, the ling the balance of Gli3 repressor and activator. cells in the early limb bud are specified and receive positional in- formation during development. Two models, the ªprogress zone Dorsoventral patterning results in the formation of the dorsal modelº and the ªearly specification modelº, have been proposed versus the palmar side of the hand including the formation of to explain the underlying developmental mechanisms (Fig. 2). an ordered structure of muscles, tendons and nails. Originally, The progress zone model suggests that cells acquire their posi- surgical manipulations involving rotation of the chick limb bud tional information progressively in a proximodistal manner. In ectoderm suggested that the non-AER ectoderm is responsible this model, the AER facilitates specification by maintaining the for specifying the fate of cells along the dorsoventral axis. Subse- cells in the underlying progress zone in an immature condition. quent findings now indicate that the dorsal identity of the limb The cells are specified as they leave the PZ, indicating that cells is controlled by the genes Wnt7a and Lmx1, whereas En1 is re- that leave the PZ late will acquire a more distal fate. According sponsible for the ventral identity [43]. to the early specification model, a specified cell population ex- pands as the limb grows and is determined in a proximodistal fashion in response to cell-cell interactions [15]. Schwabe GC, Mundlos S. Genetics of Congenital ¼ Handchir Mikrochir Plast Chir 2004; 36: 85±97 Table 1 Congenital limb anomalies and their molecular basis Classification Disorder Genomic locus Gene Classification Disorder Genomic locus Gene Polydactylies ± preaxial Nager Preaxial LADD Fanconi anemia ± isolated PPD I TAR PPD II/TPT 7q36 C7orf2/ZRS Baller-Gerold PPD III Holt-Oram 12q24.1 TBX5 PPD IV 7p13 GLI3 HFGS 7p14.2-p15 HOXA13 ± associated Carpenter ± postaxial Cornelia de Lange 3q26 OFD II FFU SRPS II UMS 12q24.1 TBX3 Townes-Brocks 16q12.1 SALL1 Original Article Postaxial ± isolated PAPA1 7p13 GLI3 Brachydactylies PAPA2 13q21-q32 ± isolated BDA1 2q35 IHH PAPA3 19p13.2-p13.1 BDA2 4q23-q24 BMPR1B PAPB 7p13 GLI3 BDB 9q34 ROR2 ± associated Ellis van Creveld 4p16 EVC BDC 20q11.2 CDMP1 Smith-Lemli-Opitz 11q12-q13 DHCR7 BDD 2q31 HOXD13 McKusick-Kaufmann 20p12 BBS6 BDE 2q31 HOXD13 SRPS I ± associated Robinow 9q34 ROR2 OFD III Grebe 20q11.2 CDMP1 BBS1 11q13 BBS1 Rubinstein-Taybi 16p13.3 CREBBP BBS2 16q21 BBS2 ± associated Turner 45X0 BBS3 3p13 BDE Albright HO 20q13.2 GNAS BBS4 15q22 BBS4 Albright-like HO 2q37 BBS5 2q31 BCNS 9q22.3
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