CURRENT CONCEPTS REVIEW

GENES AND ORTHOPEDICS :

FROM GENE TO CLINIC AND VICE VERSA

Ph. DEBEER1,2,3, L. DE SMET1, W. J. M. VAN DE VEN3, G. FABRY1, J.-P. FRYNS2

Recent advances in molecular biology have greatly identify novel genes. Recent technical advances in
helped in understanding the mechanisms involved in molecular biology and the completion of the
normal skeletal morphogenesis. Multiple genes Human Genome Project (38, 61), which involved
involved in normal skeletal development have been sequencing the three million base pairs of the
identified, but several others still await discovery. human genome, have significantly facilitated the
Mutations in these genes are often responsible for the
possibility to locate and identify genes responsible
congenital skeletal malformations that we see in the
orthopedic clinics. In this overview we would like to
for normal skeletal development. Further characte-
emphasize the importance of the interaction between rization of these genes and elucidation of the func-
orthopaedic surgeons, molecular biologists and tion of the corresponding proteins will undoubted-
geneticists. ly provide us with more information regarding their
role in normal limb- and skeletal development.
Keywords : skeletal development ; congenital orthope-
In this review, we present a brief overview of the
dic malformations.
Mots-clés : développement du squelette ; malformations
current knowledge of the molecular aspects of
orthopédiques. skeletal disease and illustrate how the recent
advances in genetics may have practical implica-
tions for patients with orthopaedic problems.
INTRODUCTION
Etiology of congenital malformations
The embryonic development of the skeleton and
Over 6000 human disorders exhibit simple gene
limbs is an intriguing and complex process, which
unifactorial or Mendelian inheritance. A disorder
involves a cascade of molecular interactions. More
determined by a gene on an autosome is said to
specifically, differentiation, proliferation and pro-
show autosomal inheritance, whereas a disorder
grammed cell death play an important role. Much
determined by a gene on one of the sex chromo-
of what we know about the general mechanism
underlying skeletal morphogenesis is the result of
animal studies. The consequences of spontaneous ————————
or induced mutations in the fruitfly (Drosophila
1
Department of Orthopedics, University Hospital
Pellenberg, Weligerveld 1, B-3212 Lubbeek (Pellenberg),
melanogaster), worm (Caenorhabditis elegans), Belgium.
zebra fish (Danio rerio), frog (Xenopus laevis), 2
Centre for Human Genetics, Herestraat 49,
chicken and mouse have lead to the identification B-3000 Leuven, Belgium.
of a multitude of genes involved in normal skeletal 3
Laboratory for Molecular Oncology, Herestraat 49,
development (39, 41, 44, 45). Congenital deforma- B-3000 Leuven, Belgium.
Correspondence and reprints : Ph. Debeer, Department
tions in humans, isolated or as part of a syndrome,
of Orthopaedic Surgery, U.Z. Pellenberg, Weligerveld 1,
also provide us with the unique opportunity to B-3212 Lubbeek (Pellenberg), Belgium.

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

204 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

somes is said to show sex-linked inheritance. A tal malformation occasionally reveal a chromo-
dominant trait manifests itself in a heterozygote, a somal aberration. These include abnormalities in
person possessing both the abnormal or mutant chromosome number (aneuploidies, e.g. trisomy
allele and the normal allele. The clinical features in 13 and trisomy 21, which give rise to polydacty-
dominant traits can vary from person to person. ly and brachydactyly respectively) or abnormali-
This is known as variable expressivity. In some ties in chromosome structure (for example the
individuals of families with autosomal dominant ring chromosome 13 syndrome which is accom-
traits, the presence of the mutation can go unde- panied by absence of the thumb).
tected (‘skip a generation’), which is known as 4. The great majority of congenital malformations
reduced penetrance. In autosomal dominant disor- however, are caused by a combination of genetic
ders an affected person usually has an affected and environmental factors. In these cases
parent. Sometimes a disorder can appear in an indi- patients have a genetic liability to develop a
vidual whose parents (and all the previous genera- disease, but an environmental factor is also
tions) are unaffected. This sudden appearance of a necessary.
condition due to a mistake occurring in the trans-
We will further focus our attention on congenital
mission of a gene is called a new mutation (de novo
disorders with an underlying genetic defect.
mutation). Recessive disorders are only manifest
when the mutant allele is present in a double dose
How can we find novel genes involved in skeletal
(homozygosity). Both parents of the affected person
malformations ?
are obligate heterozygous for the mutation. They
are perfectly healthy carriers. Many disorders
Several approaches can be used in order to detect
demonstrate a type of inheritance that is not similar
genes involved in human disease (11, 12). Some-
to any recognised Mendelian pattern (for instance
times information about the underlying biochemi-
congenital dislocation of the hip). This pattern of
cal defect is used. Using a functional cloning
inheritance is referred to as multifactorial. Both
approach, the identification of a gene is based on
genes and environmental factors play a role in these
pre-existing information about the underlying bio-
disorders.
chemical defect. No reference is made to any chro-
When searching for the possible causes of con-
mosomal map position or sequence information.
genital malformations, four categories must be
Positional cloning assumes no functional informa-
considered.
tion and must locate the responsible genes on the
1. Sometimes, a clear exogenous insult can be basis of map position. In a first step, linkage analy-
identified as the main causative factor. Examples sis of multiple affected families can assist in map-
include the limb anomalies caused by thalido- ping the disease gene on a specific chromosome.
mide, congenital malformations caused by The identification of patients with chromosomal
maternal illness (infections, hypertension, dia- aberrations (chromosomal deletions, inversions,
betes, toxemia) and transverse limb deficiencies translocations, duplications,...) is often of great
caused by early chorion villus sampling with help. After mapping the cytogenetic aberration to
fetal vascular shock. Poland syndrome (unilater- its correct location on the chromosome, the candi-
al symbrachydactyly with ipsilateral aplasia of date interval is narrowed down until the gene is
the pectoralis major) is probably due to a prima- identified. The genetic tools used mainly consist of
ry defect in the development of the subclavian previously constructed chromosomal maps and
artery. sequence information. All these data can be found
2. In some Mendelian inherited conditions, a single at various sites on the World Wide Web. The com-
major gene can be identified, for example the pletion of the Human Genome Project greatly faci-
HOXD13 mutations in synpolydactyly (1, 47). litates the search for genes involved in human
3. Chromosome studies in patients with a congeni- disease. The candidate gene approach makes use of

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

 GENES AND ORTHOPEDICS 205

information of already known genes. Features of Foot-Genital-Syndrome (42, 43)). Figure 1 illus-
the disease are compared with those of the gene trates how currently all the available data and tech-
and, depending on the results of this comparison, a niques can be combined in searching for human
specific gene is considered a good candidate or not. disease genes. There is a clear interplay between
Mutation analysis of this gene in affected patients clinical work, computer analysis (“cyber cloning”)
may prove that this gene is indeed responsible for and laboratory benchwork. It is obvious that the
the observed phenotype. The positional candidate advances in the Human Genome Project greatly
gene approach combines the two latter methods. speed up this approach.
First the disease locus is mapped to the correct
chromosomal region, followed by a search of this Molecular genetics of skeletal disease : an
interval to see whether any functionally interesting overview
candidate genes have been positioned there. In our
search for genes involved in skeletal malforma- A detailed description of all the disorders given
tions, information derived from other species is below can be found in the OMIM database (Online
often of great help. Several mouse models with dis- Mendelian Inheritance in Man ; http://www.ncbi.
tinct phenotypes have been described (39, 41). nlm.nih.gov/Omim/). Table 1 gives an overview of
Sometimes a human limb deformity shows great some congenital malformations with orthopedic
resemblance with that of a previously described implications. The underlying genetic defect, if
mouse. If the genetic defect in the mouse is known, known, is indicated together with the mode of
identification of its human counterpart is possible inheritance (AD = autosomal dominant ; AR= auto-
(for example the identification of hoxa13 mutations somal recessive) and the OMIM number. Neuro-
in the hypodactyly mouse and the subsequent iden- muscular and metabolic disorders were not in-
tification of human HOXA13 mutations in Hand- cluded.

Fig. 1. — This flowchart illustrates the important interplay between clinical work, laboratory benchwork and computer analysis. The
key step is to arrive at the point where you can identify a suitable candidate gene (Step B3). This candidate gene can subsequently be
tested for mutations in other affected individuals. (Figure adapted with permission from Figure 15.1 in Tom Strachan & Andrew
P. Read, Human Molecular Genetics 2, Second edition, 1999, BIOS Scientific Publishers, Ltd).

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

206 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

Table 1

Disease Inheritance Causative gene OMIM

SKELETAL DYSPLASIAS
Achondrogenesis type I AR DTDST 600972
Achondrogenesis type II AR COL2A1 200610
Achondroplasia AD FGFR3 100800
Campomelic dysplasia AR SOX9 114290
Cleidocranial dysostosis AD RUNX2 119600
Diastrophic dysplasia AR DTDST 222600
Grebe chondrodysplasia AR CDMP1 200700
Hypochondroplasia AD FGFR3 146000
Leri-Weill dyschondrosteosis (Madelung) AD SHOX or SHOXY 127300
Metaphyseal chondrodysplasia Jansen type AD PTHR 156400
Metaphyseal chondrodysplasia Schmid type AD COL10A1 156500
Multiple epiphyseal dysplasia AD/AR COMP 132400
Nail-patella syndrome AD LMXB1 161200
Pseudoachondroplasia AD/AR COMP 177170
Spondyloepiphyseal dysplasia congenita AD COL2A1 183900
Spondyloepiphyseal dysplasia tarda AD/AR ? 184100
Spondyloepiphyseal dysplasia X-linked X-linked SEDL 313400
Spondylo-metaphyseal dysplasia AD COL2A1 184250
Stickler syndrome AD COL2A1-COL11A1-COL11A2 108300-
604841-
184840
Thanatophoric dwarfism AR FGFR3 187600
SYNDROMES
Apert syndrome AD FGFR2 101200
Crouzon syndrome AD FGFR2 123500
EEC syndrome (ectrodactyly-cleft palate) AD p63 129900
Ehlers-Danlos syndrome AD/AR COL5A1-COL5A2-COL1A1 130000
Greig syndrome AD GLI3 175700
Holt-Oram syndrome AD TBX5 142900
Jackson-Weiss syndrome AD FGFR2 123150
Marfan syndrome AD Fibrillin1 154700
McCune-Albright polyostotic fibrous dysplasia AD GNAS1 174800
Oro-facio-digital syndrome X-linked CXORF5 311200
Pfeiffer syndrome AD FGFR2 101600
Ulnar-mammary syndrome AD TBX3 181450
MISCELLANEOUS
Brachydactyly type A1 AD IHH 112500
Brachydactyly type B1 AD ROR2 113000
Brachydactyly type C AD CDMP1 113100
Hereditary multiple exostoses type 1 AD EXT1 133700
Hereditary multiple exostoses type 2 AD EXT2 133701
Hereditary multiple exostoses type 3 AD EXT3 600209
Melorheostosis Sporadic ? 155950
Multiple synostosis syndrome AD Noggin 186500
Neurofibromatosis AD NF1 162200
Osteogenesis imperfecta type 1 AD COL1A1-COL1A2 166200
Osteogenesis imperfecta type 2 AD/AR COL1A1-COL1A2 259400-
166210
Osteogenesis imperfecta type 3 AR COL1A1-COL1A2 259420
Osteogenesis imperfecta type 4 AD COL1A1-COL1A2 166220
Osteopetrosis congenita AR TCIRG1-CLCN7 259700
Osteopetrosis tarda AD ? 166600
Osteopoikilosis AD ? 166700
Parietal foramina AD MSX2 168500
Proximal symphalangism AD Noggin 185800
Pycnodysostosis AR cathepsin K 265800
Synpolydactyly AD HOXD13 186300

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

 GENES AND ORTHOPEDICS 207

ferentiated area of mesenchyme under the AER,

receives signals from both the AER and the ZPA.
When cells exit the progress zone, they have all the
necessary positional information along the three
axes. Cells that leave the PZ at an early stage will
develop into more proximal structures, whereas
cells that leave the PZ at a later stage will develop
in more distal structures.
Fibroblast growth factors (FGFs) are important
in limb bud initiation and outgrowth. Once formed,
further outgrowth of the limb bud is controlled by
the AER. Removal of the AER results in distal limb
truncations. The level of truncation depends on
Fig. 2. — Schematic representation of the three major regions
in the developing limb bud together with the most important when the AER is removed : early removals lead to
signaling molecules (transverse section at the left, sagittal sec- proximal truncations whereas later removals lead
tion at the right). The apical ectodermal ridge (AER), a spe- to more distal truncations. Sonic hedghog (Shh)
cialized epithelial structure covering the limb bud, controls the
proximo-distal outgrowth of the developing limb and is also
mediates the activity of the ZPA and is thus respon-
involved in dorso-ventral patterning. The zone of polarizing sible for antero-posterior patterning. Shh expres-
activity (ZPA), a region of posterior limb bud mesenchyme, sion is restricted to the ZPA, which is located in the
regulates the antero-posterior patterning. The progress zone posterior limb bud. Grafting of Shh expressing
(PZ) is the area of undifferentiated mesenchyme below the
AER. When cells leave the PZ, they have all the necessary cells along the anterior margin of the limb bud
positional information along the three axes. results in the formation of ectopic mirror-symme-
tric digits. Dorso-ventral patterning requires the
expression of several other signaling molecules.
a) Disorders of the limbs
Wnt7a is only expressed in the dorsal ectoderm and
Considerable advances have been made in induces the expression of the transcription factor
understanding the molecular mechanisms of verte- Lmx-lb in the underlying mesoderm. The homeo-
brate limb development (21, 34, 49, 60). The out- box-containing transcription factor Engrailed-1
growth and development of the limb is a complex (En-1) is expressed only in the ventral ectoderm.
process that occurs along three axes : the proximo- As mentioned before, the limb bud is the key
distal axis, the antero-posterior axis and the dorso- structure in upper and lower limb development.
ventral axis. Patterning along these axes is con- The outgrowth of the upper limb begins at day 24,
trolled by different signaling molecules. The key whereas outgrowth of the lower limb bud starts at
structure in the process of vertebrate limb develop- day 28. Morphologically, the differences between
ment is the limb bud. Each limb bud is composed the forelimb and hindlimb are very clear. Molecu-
of an outer ectodermal cap and an inner mesoder- larly, there are differences in the molecules that
mal core. Experiments in the chick embryo have specify the limb identity. In the developing embryo,
led to the identification of three major regions limb-specific expression of Pitx1, Tbx4, and Tbx5
within the developing limb bud (fig. 2). The apical regulates the determination of limb identity, but
ectodermal ridge (AER), a specialized epithelial there is strong evidence that several other genes
structure at the distal tip of the ectodermal jacket also play an important role (60, 41, 27).
overlying the limb bud, regulates the proper forma- All these signaling molecules make sure that
tion of structures along the proximo-distal axis of cells in the developing limb develop in the correct
the developing limb. The zone of polarizing acti- manner and give rise to a cartilaginous “Anlage”.
vity (ZPA), a region of posterior limb bud The “Anlagen” are formed in a proximal to distal
mesenchyme, is responsible for antero-posterior sequence : the humeral anlage is formed first, the
patterning and the progress zone (PZ), an undif- anlage for the digits is formed last. Joints and fin-

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

208 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

gers are subsequently formed through a process of other hand, mutations in TBX3, are responsible for
programmed cell death (apoptosis). Bone morpho- the ulnar-mammary syndrome (OMIM 181450) (2,
genetic proteins (BMPs), cartilage-derived- 3). Here, the limb malformations range from dupli-
morphogenetic proteins (CDMPs or growth and cation of the fifth digit to complete absence of hand
differentiation factors (GDFs)), and transcription and forearm. Additional features of this syndrome
factors like HOX (homeobox) and T-box genes play include defects of the teeth, genitals and apocrine
an important role in these processes. glands including the breasts. Mutations in MSX2,
The importance of all these signaling molecules another homeobox containing transcription factor,
is illustrated by the different congenital malforma- have been described in families with autosomal
tions in humans and mice, caused by mutations in dominant craniosynostosis and in patients with cra-
these genes. Mutations in GLI3, one of the tran- nial defects of the parietal bones (foramina parie-
scription factors involved in the Sonic hedghog talia permagna ; OMIM 168500) (33, 63). EEC
pathway, cause Greig cephalopolysyndactyly (skull syndrome (OMIM 129900) is an autosomal domi-
deformity associated with polysyndactyly of hands nant disorder characterized by ectrodactyly, ecto-
and feet ; OMIM 175700), Pallister Hall syndrome dermal dysplasia, and facial clefts. Recently, Celli
(hypothalamic hamartoma, anal defects, variable et al. (10) found that this syndrome is caused by
degree of syndactyly and postaxial polydactyly of mutations in the p63 gene. Mutations in this gene
hands and feet ; ONIM 146510) or postaxial poly- are also responsible for the split hand/split foot
dactyly type A (well formed, functional extra digit malformation (OMIM 605289) (32). Mutations in
that articulates with the 5th or extra metacarpal/ LMX1B are responsible for the patella-nail syn-
metatarsal or a pedunculated postminimus (OMIM drome (OMIM 161200) which is characterized by
174200)) (35, 52, 53, 62). In mice lacking Noggin, dysplasia of the nails and absent or hypoplastic
cartilage condensations initiated normally but patellae and in some cases nephropathy (20).
developed hyperplasia, and initiation of joint devel- b) Disorders of the axial skeleton
opment failed (6). Human NOG mutations were
Ribs and vertebrae are frequently involved in
found in families with multiple synostoses syn-
malformation syndromes. Both originate from the
drome (SYNS 1 ; OMIM 186500) and also in fami-
sclerotome, a structure composed by differentiation
lies with proximal synphalangism (SYM1 ; OMIM
of the somites. Somites are blocks of epithelial
185800) (27). Both SYM1 and SYNS1 have multi-
cells and they give rise to the development of ribs
ple joint fusion as their principal feature. Other
and vertebrae, the dermis of the dorsal skin, and the
examples are the mutations in HOXD13 which
skeletal muscles of the body wall and limbs (5, 19,
cause synpolydactyly (SPD ; OMIM 186300),
28). The Notch-Delta pathway is crucial in somito-
characterized by syndactyly between the third and
genesis as demonstrated by several knock-out
fourth fingers, with digit duplication in the syn-
mutations (Mesp2, Notch1, Dll1, lunatic fringe and
dactylous web combined with syndactyly of the
Dll3) in mice. Recently, mutations in the human
fourth and fifth toes. Mutations in CDMPI cause
homologue DLL3 were found to cause axial skele-
brachydactyly type C (OMIM 113100) (50). Here,
tal defects in spondylocostal dysostosis (SD ;
the anomalies of the digits are of many types :
OMIM 277300), a heterogenous group of disorders
brachydactyly of the middle phalanges of the index
characterized by multiple hemivertebrae, rib
and middle fingers, triangulation of the fifth middle
fusions and deletions with a non-progressive
phalanx, brachymetapody, hyperphalangy (more
kyphoscoliosis (9).
than 3 phalanges per finger), symphalangism. Holt-
Oram syndrome (OMIM 142900), caused by muta-
c) Disorders affecting the formation and growth of
tions in one of the T-box genes, TBX5, is charac-
bone and cartilage
terized by limb anomalies ranging from tripha-
langeal thumb to complete absence of the limb, Undifferentiated cells condensate according to a
together with cardiac malformations (4). On the pattern that outlines the future skeletal elements

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

 GENES AND ORTHOPEDICS 209

(‘Anlagen’). After condensation, these precursor bone, tendons and perichondrium. Mutations in
cells differentiate into chondrocytes or osteoblasts COL2A1, the gene encoding type II collagen, can
and produce their own specific extracellular matrix result in several types of dysplasia (achondrogene-
(ECM). Bones then develop either through a sis (OMIM 200610), Stickler syndrome (OMIM
process of intramembranous ossification (clavicle, 108300), spondyloepiphyseal dysplasia congenita
flat bones of the skull and the mandible) or through (OMIM 183900). Osteogenesis imperfecta types I-
a process of endochondral bone formation (a tem- IV (OMIM 166200/166210/166220/259420) is
porary cartilaginous template is subsequently caused by mutations in COL1A1 and COL2A2.
replaced by bone). Mutations in RUNX2, a gene Multiple epiphyseal dysplasia type 1 (OMIM
involved in intramembranous ossification, lead to 132400) and pseudoachondroplasia (OMIM
cleidocranial dysplasia (OMIM 119600) (46). 177170) are caused by mutations in COMP (carti-
Further longitudinal bone growth is achieved in the lage oligomeric protein), one of the non-collage-
growth plate of long bones through the prolifera- nous proteins in the ECM (6).
tion and differentiation of chondrocytes. The Apart from the collagen and the non-collagenous
growth plate consists of several zones and each proteins the ECM of chondrocytes also contains
zone is under the specific control of regulatory sulfated proteoglycans. Defects in the biochemical
genes (13). In this way, a tight control of prolifera- pathways that lead to sulfation of these proteo-
tion, differentiation, ECM production and cartilage glycans result in distinct chondrodysplasias like
removal is maintained. Several genes involved in diastrophic dysplasia (OMIM 222600) caused by
these processes have been identified. FGFR3 keeps mutations in the gene encoding a sulphate trans-
the chondrocytes undifferentiated in the resting porter (DTDST) (31).
zone of the growth plate. Mutations in FGFR3
cause achondroplasia (characterized by a long, nar- d) Disorders caused by abnormal matrix homeo-
row trunk, short extremities, particularly in the stasis
proximal (rhizomelic) segments, a large head with
frontal bossing, hypoplasia of the midface and a A continuous interaction between osteoclasts
trident configuration of the hands ; OMIM (bone resorption) and osteoblasts (deposition of
100800), hypochondroplasia (similar as achondro- new bone matrix) results in normal bone turnover
plasia but no involvement of the head ; OMIM and remodelling. In osteopetrosis or marble bone
146000), and thanatophoric dysplasia (lethal form disease (OMIM 259700) there is more bone pro-
of dwarfism ; OMIM 187600) (51, 56, 58). Diffe- duction than bone resorption. As a consequence of
rentiation of proliferating chondrocytes in the tran- this, very dense bone without trabeculation is pro-
sition zone into hypertrophic cells is controlled by duced and bone marrow becomes replaced by bone,
Indian hedghog and PTHrP. Mutations in the gene which may result in aplastic anaemia and death.
encoding Indian hedgehog are responsible for Frattini et al. (22) and Kornak et al. (37) showed
brachydactyly type Al (OMIM 112500) (25). In that TCIRG1, encoding the osteoclast-specific 116-
this type of brachydactyly, the middle phalanges of kD subunit of the vacuolar proton pump, was
all the digits are rudimentary or fused with the ter- mutated in 5 of 9 patients with infantile malignant
minal phalanges. In the lower part of the hyper- osteopetrosis. Recently Kornak et al. (36) demon-
trophic zone of the growth plate, chondrocytes pro- strated that loss of the ClC-7 chloride channel leads
duce collagen into their ECM which starts to calci- to osteopetrosis in mice and man. Pycnodysostosis
fy. The calcified cartilaginous matrix is removed by (OMIM 265800), a disorder characterized by
osteoclasts and replaced by bone. At the end of the deformity of the skull (including wide sutures),
normal growth period the growth plate is complete- maxilla and phalanges (acroosteolysis), osteoscle-
ly replaced by bone. The major components of the rosis, and fragility of bone, is caused by mutations
ECM of normal cartilage are aggrecan and collagen in the lysosomal enzyme cathepsin K (26). In
type II. Collagen type I is the major component of osteoporosis bone catabolism exceeds bone

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

210 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

anabolism, resulting in a generalized reduction in mode of inheritance and prognosis of the disorder,
bone mass. Polymorphisms in the COL1A1 gene, but will also aid in choosing the appropriate treat-
the IL-6 gene and in the genes for vitamin D and ment. In order to make a correct diagnosis several
the calcitonin receptor have been associated with classification systems have been proposed. Usually
osteoporosis (29, 40, 48, 54). Several mouse classification systems for congenital orthopedic
mutants exist that display osteoporosis as part of malformations are based on the clinical and radio-
their phenotype. For instance, mice deficient for logical appearance. In the past, various Greek and
the proteoglycan biglycan show a reduced growth Latin names were adopted to describe common
rate and decreased bone mass after birth (64). deficiencies (for example acheira, amelia, ectro-
This overview is certainly not meant to be melia, micromelia, peromelia, phocomelia,...).
exhaustive, since almost every week new scientific These terms often were very confusing to most
data from the field of skeletal development are clinicians. Therefore many authors have tried to
published. It merely illustrates that many orthope- develop a more useful classification system based
dic conditions have a genetic basis and that science on defects in normal embryologic development. In
is progressively unraveling the underlying causes. 1968, Swanson, Barsky and Entin proposed their
How can all this information be of any use in daily work “Classification of limb malformations on the
orthopedic practice ? Currently one of the limiting basis of embryological failures” (57). In this work,
factors to assign a gene to a disease is the availa- deformities were grouped according to the parts
bility of patients with these diseases. The orthope- that have been primarily affected by certain embry-
dic surgeon finds himself in a privileged position ological failures. The International Federation
since he is often one of the first to see patients with of Societies for Surgery of the Hand (IFSSH)
rare genetic diseases. Moreover he can provide proposed seven categories based upon the original
scientists with clinical samples like articular carti- classification of Swanson. Despite its usefulness,
lage, synovial tissue, bone, skin for further this classification system is not the ideal one as
research. Since abnormal genes are the basis of demonstrated by Buck- Gramcko (8) and De Smet
many orthopedic disorders, ranging from skeletal et al. (15). Other classification systems, like the
dysplasias to osteoarthrosis, orthopedic surgeons one described by Temtamy and McKusick (59), are
need to be aware of the data already available and based on anatomical and genetic grounds. This
of the increasing technical possibilities in molecu- classification system is still used by most clini-
lar biology. As will be demonstrated, understanding cians. The use of classification systems based
the genetic basis of inherited orthopedic malforma- on clinical appearance and skeletal radiology is
tions can help in making a correct diagnosis and frequently complicated by a large variation in
counsel patients and families. Eventually, it will expressivity and considerable overlap between
also provide the orthopedic surgeon with new apparently different malformation syndromes.
therapeutic tools. Finally, the identification of indi- Further understanding of the molecular pathways
viduals or patients with unique skeletal malforma- involved in normal skeletal and limb development
tions will help scientists to gain more insight into will lead to an entirely different classification
the complex mechanisms of skeletal development. system wherein the affected gene/or pathway can
be associated with its phenotypical spectrum. For
Diagnosis of inherited skeletal malformations instance, Greig cephalopolysyndactyly, Pallister
and counseling Hall syndrome and postaxial polydactyly type A1
are all caused by mutations in the GLI3 gene, but
When confronted with a congenital malforma- clinically and radiologically these three syndromes
tion, making the correct diagnosis is a first and are very distinct. When using the ‘classical’ classi-
important step in the further management of the fication systems they would fall into three separate
patient. Making a correct diagnosis is not only categories whereas molecularly they fall into one
helpful in determining the normal evolution, the single category.

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

 GENES AND ORTHOPEDICS 211

Inherited skeletal malformations are often asso- tions (55). Recombinant human OP-1 (BMP7) is
ciated with other visceral malformations. Mutati- already being used in clinical trials in the treatment
ons in TBX5 for instance, cause Holt-Oram syn- of tibial nonunions (23, 24). Increasing knowledge
drome. This syndrome is not only characterized by of the molecular pathways involved in the normal
hand malformations but is also associated with car- differentiation of osteoblasts and chondrocytes will
diac malformations. In these cases, counseling may allow us to modify progenitor cells so that they
not be limited to determining the possible recur- specifically produce the desired molecules when
rence risk of the limb deformity, but it must also administered to the patient, for example for the
include a screening for possible associated cardiac treatment of cartilage defects. Genes directly
malformations. Recently, we identified a girl with a involved in skeletal development can be used as
complex type of synpolydactyly associated with drug targets or as reagents for drug development.
urogenital problems. She was diagnosed as having For example, drugs that inhibit osteoclast activity
Hand-Foot-Genital-Syndrome (HFGS) associated could be very valuable in treating patients with
with synpolydactyly (SPD). Three other family Paget’s disease or osteoporosis. The discovery of
members on the maternal side of the family were novel molecules or the attribution of novel func-
also known to have SPD. In HFGS, (OMIM tions to already known molecules will also have its
140000) there is first digit and hallux hypoplasia, effect on orthopedic tissue engineering (for a
brachydactyly of second to fifth toes, clinodactyly review on tissue engineering see Clin. Orthop.
of the fifth finger and ulnar deviation of the second 1999 Oct ; 367 Suppl.) and on the possible applica-
finger. Males often have hypospadias. Müllerian tions of gene therapy in certain orthopedic disor-
duct fusion defects in females result in a vaginal ders (30).
septum, a double uterus with double cervix, and The following case is an illustration of how an
urinary abnormalities (ectopic ureteric orifices, orthopedic malformation can lead to the discovery
vesico-ureteral reflux, pelvi-ureteric junction of molecules possibly involved in normal limb
obstruction). SPD is caused by mutations in the development. All affected members in a family
HOXD13 gene whereas mutations in the HOXA13 with a complex type of synpolydactyly associated
gene cause HFGS. Mutation analysis in this patient with synostoses were found to have a balanced
revealed both mutations in HOXD13 and HOXA13 translocation t(12;22)(p11.2; q13.3) between chro-
(Debeer et al., manuscript in preparation). Further mosome 12 and chromosome 22 (14, 16). The co-
analysis within this family showed that the segregation of the phenotype with the translocation
HOXD13 mutation was present in all affected lead to the hypothesis that on one or on both chro-
members on the maternal side. The HOXA13 muta- mosomes a gene was located involved in normal
tion came from the paternal side but HFGS was not limb development. When disrupted by the translo-
previously diagnosed here. Upon further investiga- cation, it would give rise to the observed limb phe-
tion subtle urogenital problems were identified in notype. Detailed molecular analysis of this translo-
this side of the family. This example illustrates how cation resulted in the identification of two genes
genetic investigation of an orthopedic malforma- directly involved in the translocation (17, 18). One
tion clearly has implications in counseling other of these genes, Fibulin-1 turned out to be the ideal
family members. candidate for the phenotype since it is expressed in
the developing handplate. We were able to demon-
Therapeutic and scientific implications strate that fibroblasts in the synpolydactyly patients
produced significantly less Fibulin-1D protein as
Congenital orthopedic malformations provide a compared to normal skin fibroblasts. This finding
unique opportunity to identify novel molecules supports the hypothesis that haploinsufficiency for
involved in normal skeletal development. The iden- Fibulin-1D is the cause for this limb malformation
tification of such molecules offers potential for new and illustrates once more the importance of a nor-
therapeutic strategies in several orthopedic condi- mal ECM in skeletal development.

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

212 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

CONCLUSION trum of mutations in TBX3 : Genotype/Phenotype rela-

tionship in u1nar-mammary syndrome. Am. J. Hum.
Orthopedic surgeons need to be aware of the cur- Genet., 1999, 64, 1550-1562.
3. Bamshad M., Lin R. C., Law D. J., Watkins W. C.,
rent advances and possibilities in molecular biolo- Krakowiak P. A., Moore M. E., Franceschini P. et al.
gy and genetics. The increasing amount of infor- Mutations in human TBX3 alter limb, apocrine and genital
mation regarding skeletal development has not only development in u1nar-mammary syndrome. Nat. Genet.,
diagnostic but also possible therapeutic implica- 1997, 16, 311-315.
4. Basson C. T., Bachinsky D. R., Lin R. C., Levi T.,
tions. A good communication between orthopedic Elkins J. A., Soults J., Grayzel D. et al. Mutations in
surgeons, molecular biologists and geneticists is human TBX5 cause limb and cardiac malformation in
therefore essential. Holt-Oram syndrome. Nat. Genet., 1997, 15, 30-35.
5. Brand-Saberi B., Christ B. Evolution and development of
distinct cell lineages derived from somites. Curr. Top. Dev.
GLOSSARY
Biol., 2000, 48, 1-42.
6. Briggs M. D.., Hoffman S. M., King L. M., Olsen A. S.,
Haploinsufficiency : describes the case where a Mohrenweiser H., Leroy J. G., Mortier G. R. et al. Pseudo-
50% reduction in the level of gene function causes achondroplasia and multiple epiphyseal dysplasia due to
an abnormal phenotype. mutations in the cartilage oligomeric matrix protein gene.
Nat. Genet., 1995, 10, 330-336.
Homeobox : conserved DNA sequence that
7. Brunet L. J., McMahon J. A., McMahon A. P.,
encodes a DNA-binding motif famous for its Harland R. M. Noggin, cartilage morphogenesis, and joint
presence in genes that are involved in orchestrating formation in the mammalian skeleton. Science, 1998, 280,
development of a wide range of organisms. 1455-1457.
Knock-out mutation : the targeted inactivation of 8. Buck-Gramcko, D. Congenital malformations of the Hand
and Forearm. In : Livingston C. (ed). Harcourt Brace and
a gene in an intact cell. Company Limited, London, 1998.
Linkage : the tendency of genes or other DNA 9. Bulman M. P., Kusumi K., Frayling T. M., McKeown C.,
sequences at specific loci to be inherited together Garrett C., Lander E. S., Krumlauf R. et al. Mutations in
as a consequence of their physical proximity on a the human delta homologue, DLL3, cause axial skeletal
defects in spondylocostal dysostosis. Nat. Genet., 2000,
single chromosome. 24, 438-441.
Locus : unique chromosomal location defining 10. Celli J., Duijf P., Hamel B. C., Bamshad M., Kramer B.,
the position of an individual gene or DNA Smits A. P., Newbury-Ecob R. et al. Heterozygous
sequence. germline mutations in the p53 homolog p63 are the cause
of EEC syndrome. Cell, 1999, 99, 143-153.
Polymorphism : any sequence variant present at 11. Collins F. S. Positional cloning : let’s not call it reverse
a frequency > 1% in a population or any nonpatho- anymore. Nat. Genet., 1992, 1, 3-6.
genic sequence variant, regardless the frequency. 12. Collins F. S. Positional cloning moves from perditional to
Transcription factor : eukaryotic protein re- traditional. Nat. Genet., 1995, 9, 347-350.
13. de Crombrugghe B., Lefebvre V., Behringer R. R., Bi W.,
quired to initiate or regulate transcription (= copy- Murakami S., Huang W. Transcriptional mechanisms of
ing one strand of DNA into a complementary RNA chondrocyte differentiation. Matrix. Biol., 2000, 19, 389-
sequence by the enzyme RNA polymerase). 394.
14. De Smet L., Debeer P., Fryns J. P. Cenani-Lenz syndrome
Aknowledgments in father and daughter. Genet. Counsel., 1996, 7, 153-157.
15. De Smet L., Matton G., Monstrey S., Cambier E., Fabry G.
The authors wish to thank BIOS Scientific Publishers Ltd Application of the IFSSH(3)-classification for congenital
for permission to use an adapted version of figure 1. anomalies of the hand, results and problems. Acta Orthop.
Belg., 1997, 63, 182-188.
REFERENCES 16. Debeer P., Schoenmakers E. F., De Smet L., Van de
Ven W. J., Fryns J. P. Cosegregation of an apparently
1. Akarsu A. N., Stoilov I., Yilmaz E., Sayli B.S., balanced reciprocal t(12;22)(p11.2;q13.3) with a complex
Sarfarazi M. Genomic structure of HOXD13 gene : a nine type of 3/3’/4 synpolydactyly associated with metacarpal,
polyalanine duplication causes synpolydactyly in two metatarsal and tarsal synostoses in three family members.
unrelated families. Hum. Mol. Genet., 1996, 5, 945-952. Clin. Dysmorphol., 1998a, 7, 225-228.
2. Bamshad M., Le T., Watkins W .S., Dixon M. E., 17. Debeer P., Schoenmakers E. F., Thoelen R. Fryns J. P., Van
Kramer B. E., Roeder A. D., Carey J. C., et al. The spec- de Ven W. J. Physical mapping of the t(12;22) translocation

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

 GENES AND ORTHOPEDICS 213

breakpoints in a family with a complex type of 3/3’/4 syn- tion is caused by mutations in the p63 gene on 3q27. Am.
polydactyly. Cytogenet. Cell. Genet., 1998b, 81, 229-234. J. Hum. Genet., 2000, 67, 59-66.
18. Debeer P., Schoenmakers E. F., Thoelen R., Holvoet M., 34. Jabs E. W., Muller U., Li X., Ma L., Luo W., Haworth I. S.,
Kuittinen T., Fabry G., Fryns J. P. et al. Physical map of a Klisak I. et al. A mutation in the homeodomain of the
1.5 mb region on 12p11.2 harbouring a synpolydactyly human MSX2 gene in a family affected with autosomal
associated chromosomal breakpoint. Eur. J. Hum. Genet., dominant craniosynostosis. Cell., 1993, 75, 443-450.
2000, 8, 561-570. 35. Johnson R. L., Tabin C. J. Molecular models for vertebrate
19. Dockter J. L. Sclerotome induction and differentiation. limb development. Cell., 1997, 90, 979-990.
Curr. Top. Dev. Biol., 2000, 48, 77-127. 36. Kang S., Graham J. M., Jr., Olney A. H., Biesecker L. G.
20. Dreyer S. D., Zhou G., Baldini A., Winterpacht A., GLI3 frameshift mutations cause autosomal dominant
Zabel B., Cole W., Johnson R. L. et al. Mutations in Pallister-Hall syndrome. Nat. Genet., 1997, 15, 266-268.
LMX1B cause abnormal skeletal patterning and renal dys- 37. Kornak U., Kasper D., Bosl M. R., Kaiser E.,
plasia in nail patella syndrome. Nat. Genet., 1998, 19, 47-50. Schweizer M., Schulz A., Friedrich W. et al. Loss of the
21. Dudley A. T., Tabin C. J. Constructive antagonism in limb ClC-7 chloride channel leads to osteopetrosis in mice and
development. Cuff. Opin. Genet. Dev., 2000, 10, 387-392. man. Cell., 2001, 104, 205-215.
22. Frattini A., Orchard P. J., Sobacchi C., Giliani S., 38. Kornak U., Schulz A., Friedrich W., Uhlhaas S.,
Abinun M., Mattsson J. P., Keeling D. J. et al. Defects in Kremens B., Voit T., Hasan C. et al. Mutations in the a3
TCIRG1 subunit of the vacuolar proton pump are respon- subunit of the vacuolar H(+)-ATPase cause infantile malig-
sible for a subset of human autosomal recessive osteo- nant osteopetrosis. Hum. Mol. Genet., 2000, 9, 2059-2063.
petrosis. Nat. Genet., 2000, 25, 343-346. 39. Lander E. S., Linton L. M., Birren B., Nusbaum C.,
23. Friedlaender G. E. OP-1 clinical studies. J. Bone Joint Zody M. C., Baldwin J., Devon K. et al. Initial sequencing
Surg. Am., 2001, 83-A, S160-1. and analysis of the human genome. Nature, 2001, 409,
24. Friedlaender G. E., Perry C. R., Cole J. D., Cook S. D., 860-921.
Cierny G., Muschler G. F., Zych G. A. et al. Osteogenic 40. Li Y., Olsen B. R. Murine models of human genetic skele-
protein-1 (bone morphogenetic protein-7) in the treatment tal disorders. Matrix Biol., 1997, 16, 49-52.
of tibial nonunions. J. Bone Joint Surg. Am., 2001, 83-A, 41. Margulies E. H., Kardia S. L., Innis J. W. A comparative
S151-8. molecular analysis of developing mouse forelimbs and
25. Gao B., Guo J., She C., Shu A., Yang M., Tan Z., Yang X., hindlimbs using serial analysis of gene expression (sage).
et al. Mutations in IHH, encoding Indian hedgehog, cause Genome Res., 2000, 11, 1686-98.
brachydactyly type A-1. Nat. Genet., 2001, 28, 386-388. 42. Masi L., Becherini L., Gennari L., Colli E., Mansani R.,
26. Gelb B. D., Shi G. P., Chapman H. A., Desnick R. J. Falchetti A., Cepollaro C. et al. Allelic variants of human
Pycnodysostosis, a lysosomal disease caused by cathepsin calcitonin receptor : distribution and association with bone
K deficiency. Science, 1996, 273, 1236-1238. mass in postmenopausal Italian women. Biochem.
27. Gibson-Brown J. J., Agulnik S. I., Chapman D. L., Biophys. Res. Commun., 1998, 245, 622-626.
Alexiou M., Garvey N., Silver L. M., Papaioannou V. E. 43. McLean W., Olsen B. R. Mouse models of abnormal skele-
Evidence of a role for T-box genes in the evolution of limb tal development and homeostasis (review). Trends in
morphogenesis and the specification of forelimb/hindlimb Genetics, 2001, 17, S38-S43.
identity. Mech. Dev., 1996, 5 6, 93-101. 44. Mortlock D. P., Innis J. W. Mutation of HOXA13 in hand-
28. Gong Y., Krakow D., Marcelino J., Wilkin D., Chitayat D., foot-genital syndrome. Nat. Genet., 1997, 15, 179-180.
Babul-Hirji R., Hudgins L. et al. Heterozygous mutations 45. Mortlock D. P., Post L. C., Innis J. W. The molecular basis
in the gene encoding noggin affect human joint morpho- of hypodactyly (Hd) : a deletion in Hoxa 13 leads to arrest
genesis. Nat. Genet., 1999, 21, 302-304. of digital arch formation. Nat. Genet., 1996, 13, 284-290.
29. Gossler A., Hrabe de Angelis M. Somitogenesis. Curr. Top. 46. Mundlos S., Olsen B. R. Heritable diseases of the skeleton.
Dev. Biol., 1998, 38, 225-287. Part I : Molecular insights into skeletal development-
30. Grant S. F., Reid D. M., Blake G., Herd R., Fogelman I., transcription factors and signaling pathways. Faseb J.,
Ralston S. H. Reduced bone density and osteoporosis asso- 1997a, 11, 125-132.
ciated with a polymorphic Sp1 binding site in the collagen 47. Mundlos S., Olsen B. R. Heritable diseases of the skeleton.
type I alpha 1 gene. Nat. Genet., 1996, 14, 203-205. Part II : Molecular insights into skeletal development-
31. Hardouin P., Anselme K., Flautre B., Bianchi F., matrix components and their homeostasis. Faseb. J.,
Bascoulenguet G., Bouxin B. Tissue engineering and 1997b, 11, 227-233.
skeletal diseases. Joint Bone Spine, 2000, 67, 419-424. 48. Mundlos S., Otto F., Mundlos C., Mulliken J. B.,
32. Hastbacka J., de la Chapelle A., Mahtani M. M., Clines G., Aylsworth A. S., Albright S., Lindhout D. et al. Mutations
Reeve-Daly M. P., Daly M., Hamilton B. A. et al. The dia- involving the transcription factor CBFA1 cause cleido-
strophic dysplasia gene encodes a novel sulfate transporter, cranial dysplasia. Cell., 1997, 89, 773-779.
positional cloning by fine-structure linkage disequilibrium 49. Muragaki Y., Mundlos S., Upton J., Olsen B. R. Altered
mapping. Cell, 1994, 78, 1073-1087. growth and branching patterns in synpolydactyly caused
33. Ianakiev P., Kilpatrick M. W., Toudjarska I., Basel D., by mutations in HOXD13. Science, 1996, 272, 548-551.
Beighton P., Tsipouras P. Split-hand/split-foot malforma- 50. Murray R. E., McGuigan F., Grant S. F., Reid D. M.,

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002

214 PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G. FABRY, J.-P. FRYNS

Ralston S. H. Polymorphisms of the interleukin-6 gene are 65. Vortkamp A., Gessler M., Grzeschik K. H. GL13 zinc-
associated with bone mineral density. Bone, 1997, 21, 89- finger gene interrupted by translocations in Greig syn-
92. drome families. Nature, 1991, 352, 539-540.
51. Ng J. K., Tamura K., Buscher D., Izpisua-Belmonte J. C. 66. Wilkie A. O., Tang Z., Elanko N., Walsh S., Twigg S. R.,
Molecular and cellular basis of pattern formation during Hurst J. A., Wall S. A. et al. Functional haploinsufficiency
vertebrate limb development. Curr. Top. Dev. Biol., 1999, of the human homeobox gene MSX2 causes defects in
41, 37-66. skull ossification. Nat. Genet., 2000, 24, 387-390.
52. Polinkovsky A., Robin N. H., Thomas J. T., Irons M., 67. Xu T., Bianco P., Fisher L. W., Longenecker G., Smith E.,
Lynn A., Goodman F. R., Reardon W. et al. Mutations in Goldstein S., Bonadio I. et al. Targeted disruption of the
CDMP1 cause autosomal dominant brachydactyly type C. biglycan gene leads to an osteoporosis-like phenotype in
Nat. Genet., 1997, 17, 18-19. mice. Nat. Genet., 1998, 20, 78-82.
53. Prinos P., Costa T., Sommer A., Kilpatrick M. W.,
Tsipouras P. A common FGFR3 gene mutation in
hypochondroplasia. Hum. Mol. Genet., 1995, 4, 2097-
2101. SAMENVATTING
54. Radhakrishna U., Bornholdt D., Scott H. S., Patel U. C.,
Rossier C., Engel H., Bottani A. et al. The phenotypic PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN, G.
spectrum of GLI3 morphopathies includes autosomal FABRY, J.-P. FRYNS. Genes and orthopedics : from gene
dominant preaxial polydactyly type-IV and postaxial poly- to clinic and vice versa.
dactyly type-A/B ; No phenotype prediction from the posi-
tion of GL13 mutations. Am. J. Hum. Genet., 1999, 65,
De recente ontwikkelingen binnen de genetica en de
645-655.
55. Radhakrishna U., Wild A., Grzeschik K. H., moleculaire biologie zorgen voor een toenemende ken-
Antonarakis S. E. Mutation in GLI3 in postaxial poly- nis van de moleculaire mechanismen verantwoordelijk
dactyly type A. Nat. Genet., 1997, 17, 269-271. voor een normale skeletontwikkeling. Verschillende
56. Riggs B. L., Nguyen T. V., Melton L. J., 3rd, genen die hierbij betrokken zijn werden reeds geidenti-
Morrison N. A., O’Fallon W. M., Kelly P. J., Egan K. S. et ficeerd, doch vele moeten nog ontdekt worden. Mutaties
The contribution of vitamin D receptor gene alleles to the in dergelijke genen zijn vaak de oorzaak van de congeni-
determination of bone mineral density in normal and
tale skeletafwijkingen welke gezien worden binnen de
osteoporotic women. J. Bone Miner. Res., 1995, 10, 991-
996. orthopedie. In dit overzichtsartikel willen we het belang
57. Rodan G. A.,. Martin T. J. Therapeutic approaches to bone van een goede interactie tussen orthopedisten, genetici
diseases. Science, 2000, 289, 1508-1514. en moleculair biologen benadrukken.
58. Shiang R., Thompson L. M., Zhu Y. Z.,, Church D. M.,
Fielder T. J., Bocian M., Winokur S. T. et al. Mutations in
the transmembrane domain of FGFR3 cause the most com- RÉSUMÉ
mon genetic form of dwarfism, achondroplasia. Cell.,
1994, 78, 335-342.
59. Swanson A. B., Barsky A. J., Entin M. A. Classification of PH. DEBEER, L. DE SMET, W. J. M. VAN DE VEN,
limb malformations on the basis of embryological failures. G. FABRY, J.-P. FRYNS. La génétique et l’orthopédie :
Surg. Clin. North Am., 1968, 48, 1169-1179. du gène à la clinique et vice versa.
60. Szeto D. P., Ryan A. K., O’Connell S. M., Rosenfeld M. G.
P-OTX, a PIT-1-interacting homeodomain factor Les progrès récents de la génétique et de la biologie
expressed during anterior pituitary gland development. moléculaire ont beaucoup contribué à une meilleure
Proc. Natl. Acad. Sci. U.S. A., 1996, 93, 7706-7710.
compréhension des mécanismes qui sont impliqués dans
61. Tavormina P. L., Shiang R., Thompson L. M., Zhu Y. Z.,
Wilkin D. J., Lachman R. S., Wilcox W. R. et al. Thanato- la morphogenèse normale du squelette. On a identifié de
phoric dysplasia (types I and II) caused by distinct muta- nombreux gènes impliqués dans le développement nor-
tions in fibroblast growth factor receptor 3. Nat., 1995, 9, mal du squelette ; de nombreux autres gènes restent à
321-328. découvrir. Des mutations au niveau de ces gènes sont
62. Temtamy S. A., McKusick V. A. The genetics of hand mal- souvent à l’origine de malformations congénitales du
formations. Birth Defects Orig. Artic Ser., 1978, 14, 1-619. squelette, que les orthopédistes rencontrent en clinique.
63. Tickle C., Munsterberg A. Vertebrate limb development –
Dans cette revue générale, les auteurs soulignent l’im-
the early stages in chick and mouse. Cuff. Opin. Genet.
Dev., 2001, 11, 476-481. portance d’une interaction entre chirurgiens orthopé-
64. Venter J. C., Adams M. D., Myers E. W., Li P. W., diques, biologistes moléculaires et généticiens.
Mural R. J., Sutton G. G., Smith H. O. et al. The sequence
of the human genome. Science, 2001, 291, 1304-1351.

Acta Orthopædica Belgica, Vol. 68 - 3 - 2002