Best Practice & Research Clinical Rheumatology

Vol. 22, No. 1, pp. 3–18, 2008

doi:10.1016/j.berh.2007.12.008
available online at http://www.sciencedirect.com

Achondroplasia

Geneviève Baujat MD

Laurence Legeai-Mallet PhD

Georges Finidori MD

Valérie Cormier-Daire MD, PhD

Martine Le Merrer * MD, PhD

Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France

Achondroplasia (MIM 100800) is the most common non-lethal skeletal dysplasia. Its incidence is
between one in 10 000 and one in 30 000. The phenotype is characterized by rhizomelic dispro-
portionate short stature, enlarged head, midface hypoplasia, short hands and lordotic lumbar
spine, associated with normal cognitive development.
This autosomal-dominant disorder is caused by a gain-of-function mutation in the gene
encoding the type 3 receptor for fibroblast growth factor (FGFR3); in more than 95% of cases,
the mutation is G380R. The diagnosis is suspected on physical examination and confirmed by
different age-related radiological features. Management care by a multidisciplinary team will pre-
vent and treat complications, including cervical cord compression, conductive hearing loss and
thoracolumbar gibbosity. Weight counselling, psychosocial guidance and professional integration
programmes play an important role in the global quality of life of these patients and their families.

Key words: achondroplasia; clinical features; molecular pathogenesis; differential diagnosis;

management.

The term ‘achondroplasia’ was first used by Jules Parrot in 1878, and in 1900, Pierre
Marie described the main features in children and adults. However, this condition
was recognized earlier, as demonstrated in art from Egypt, Greece and Rome. As
achondroplasia is the most common condition associated with disproportionate
short stature, it is probably one of the best-known and -defined chondrodysplasias.

* Corresponding author. Tel.: 00 33 1 44 49 51 52; Fax: 00 33 1 44 49 51 50.

E-mail address: lemerrer@necker.fr (M. Le Merrer).
1521-6942/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
4 G. Baujat et al

Achondroplasia is characterized by disproportionate short stature associated with

enlarged head, depressed nasal bridge, short stubby trident hands, lordotic lumbar
spine, prominent buttocks and protuberant abdomen.1 This autosomal-dominant dis-
order is caused by mutations in the type 3 receptor for fibroblast growth factor
(FGFR3). The natural history and management rules are well established in childhood
and adolescence, but they are less fully delineated for adults, and several complica-
tions remain because of lack of preventative health.

EPIDEMIOLOGY

The birth incidence of achondroplasia is estimated to be between one in 10 000 and

one in 30 0002–5, affecting more than 250 000 individuals worldwide. It is one of the
most common types of non-lethal skeletal chondrodysplasia. Earlier ascertainments
of frequency were probably overestimates because, before involvement of the
FGFR3 gene was identified, achondroplasia was often confused with various other
chondrodysplasias.1 There is no racial predisposition. With prenatal ultrasound be-
coming routine in developed countries, many affected fetuses are recognized in the
third trimester of pregnancy. The consequence of legal late termination of pregnancy
on birth rates, in such countries as France, is unknown. This prevalence may also be
modulated by paternal age, which increases the incidence of de-novo gene mutation.6

CLINICAL AND RADIOLOGICAL DESCRIPTION:

NATURAL HISTORY

Features of achondroplasia are so distinctive that they can easily be identified both
clinically and radiologically. DNA testing for FGFR3 mutation is not systematically use-
ful for diagnosis.
During pregnancy, the diagnosis of achondroplasia may be suspected in the third
trimester by abnormal ultrasound findings, namely foreshortening of the limbs
(<3rd percentile), increased biparietal diameter (>95th percentile) and low nasal
bridge.7,8 This can lead to intra-uterine imaging. Antenatal radiographic features of
achondroplasia are shortened long bones with wide metaphyses, and a slim and radio-
lucent area in the proximal femur and horizontal acetabular roof.1 As these features
are not always detected by intra-uterine x rays, three-dimensional computed tomog-
raphy scan (3D CT scan) may be performed, after 30 weeks of gestation, showing
slightly flat vertebral bodies with medial spurs extending from the anterior face,
pointed femora with proximal extremity on profile (Figure 1), and round and square
ilia with an oval radiolucent area in the proximal femur on face.9,10
After birth, achondroplasia is clinically characterized by short limbs, especially the
proximal segment, with a long trunk and a narrow thorax. Birth height is generally
preserved (mean birth lengths are 47.7 cm for males and 47.2 cm for females). The
head is large with frontal bossing, possibly leading to obstetric difficulties. The midface
is hypoplastic resulting in an endochondral growth defect at the base of the skull.
Hands and fingers are short with a trident appearance in early life, due to inability
to fully oppose the third and the fourth digits.
In infancy, early motor milestones are delayed because of muscular hypotonia, but
psychomotor development is normal. Dorso-lumbar kyphosis in a seated position is
common in early childhood but disappears with improving muscle tone. Excessive
 Achondroplasia 5

Figure 1. Three-dimensional computed tomography scan of a fetus with achondroplasia. Note the pointed
aspect of the upper femoral metaphyse and the platyspondyly with high intervertebral distance.

sudation is often noted. Hyperextensibility of the distal joints with limitations of elbow
extension are common.1,12
In children and adults, short stature becomes gradually evident. Growth curves spe-
cific for achondroplasia for height, weight, head and chest circumference have been
produced.11,12 Final adult height is approximately 125 cm for males and 120 cm for
females. Mean adult weights are 55 kg for males and 46 kg for females, with an evident
tendency for obesity. The proximal segment of upper extremities, especially humeri,
are relatively shorter than the middle and distal segments. The trunk is relatively
long and is deformed by excessive lumbar lordosis.
Skeletal radiographs confirm the diagnosis with specific age-related criteria. Ante-
natal x rays and 3D CT scans are described above. In the newborn period, the pelvis
shows small and square iliac wings, the acetabular roof is horizontalized, and tubular
bones are short and large with enlarged metaphyses (‘pagode roof’). Proximal femora
and, to a lesser extent, humerus are radiolucent because of the obliquity of the growth
cartilage (Figure 2a). This is particularly evident on the femur profile, showing a sharp-
pointed extremity specific for achondroplasia (Figure 2b). Decreased size of the base
of the skull and prominent frontal bones are noted.13
Later in infancy, epiphysis development is delayed but their appearance is quite
normal. The pedicles show a shortened antero-posterior diameter, and the posterior
aspect of the vertebral bodies is concave. The interpediculate distances narrow pro-
gressively from the upper to the lower lumbar spine. The thoracic cage is relatively
6 G. Baujat et al

Figure 2. Radiographs of a newborn with achondroplasia. (a) Squared iliac wings with flat acetabula and
radiolucent aspect of the upper femoral metaphyse. (b) Platyspondyly and anterior wedging of the lumbar
vertebral bodies.

small. On lateral view, ribs are short with enlarged, cupuliform anterior extremities.
The proximal phalanges have a massive appearance, particularly the second phalanges.
In adult patients, tubular bones are short and thick. Tibia and radius may have a bowing
aspect, associated with elongated fibula (Figure 3a). The growth plate of the distal
femur extremity is concave, with an impaction of the epiphysis into the cartilage cen-
tre. Shortening femoral neck is associated with frequent vertical orientation. Femora
condyles are often asymmetrical. Progressively downward diminishing interpediculate
distances in the lumbar spine, and anterior wedging of the vertebral bodies, particu-
larly in the region of the thoracolumbar junction, may result in some vertebral body
deformities (Figure 3b). The lumbar spine appears to have an acute articulation with
the sacrum, which is narrow and horizontally oriented. Narrowing of the pelvis inlet
 Achondroplasia 7

Figure 3. Radiographs of an adult with achondroplasia. (a) Very short pedicle on lumbar spine on profile
with posterior scalloping. (b) Fibula overgrowth with stubby and bent tibia.

leads to obstetric difficulties in women. The enlarged aspect of the crest of muscle
insertion reinforces the massive aspect of the long bones.

DIFFERENTIAL DIAGNOSIS

Achondroplasia belongs to a group of short-stature osteochondrodysplasias that have

some clinical features in common, such as postnatal dwarfism, micromelia, short hands
and narrow thorax. However, the other entities, namely Ellis-van Creveld syndrome,
metatropic dysplasia, diastrophic dysplasia, thoracic dystrophy of Jeune, pseudoachon-
droplasia, various spondyloepiphyseal and spondylo-metaphyseal dysplasia, can be
easily excluded on the bases of their major clinical and radiological features. Severe
forms of hypochondroplasia, associated with different mutations in FGFR3, may overlap
clinically with achondroplasia.1
8 G. Baujat et al

COMPLICATIONS AND MANAGEMENT

In achondroplasia, complications are consequences of the abnormal linear bone

growth. Many appear at predicted ages including adulthood. They can often be mini-
mized if detected early. Indeed, guidelines for patients with achondroplasia have
been developed in several countries11,14–16 to aid physicians in such preventive care.
Regular follow-up by a trained multidisciplinary team may be essential to prevent or
treat early neurological and respiratory complications, which arise particularly during
the first year of life and in adults. This specific follow-up has to be settled with the
collaboration of the local medical team.

Neurology

Hydrocephalus
In the newborn with achondroplasia, the cranial-cervical junction is small, leading to
frequent dilated ventricles and excessive extra-axial fluid, without active hydrocepha-
lus, which stabilize during the second year of life. Later, true internal hydrocephalus
may occur because of increased venous pressure due to the narrowed jugular fora-
men.17 Head growth should be monitored carefully every 6 months during the early
years. A rapid increase or symptoms of increased pressure must be considered by
paediatric neurosurgeons familiar with achondroplasia. Some studies suggest that as
many as 10% of individuals have ventricle shunts14,18, but this is not the authors’
experience in France where shunting is rare in achondroplasia and may lead to worse
complications.19

Cervical cord compression

During the first months, cervical cord compression can occur due to the narrow cra-
nio-cervical junction. The best indicators are lower limb hyper-reflexes, clonus, aggra-
vation of severe hypotonia, and central apnoea demonstrated by polysomnography.20
As affected patients can be asymptomatic with significant medullar suffering, magnetic
resonance imaging (MRI) of the brain, the cervical junction and the spinal cord should
be done systematically between 6 and 12 months of age (earlier if necessary). Mod-
ification of the signal of the spinal cord (Figure 4) requires surgical decompres-
sion.21,22 Depending on the source of affected individuals for the studies,
approximately 5–10% of patients with achondroplasia have had cervical medullary
decompression surgery.23,24 Somatosensory-evoked potential results, correlated
with clinical status and MRI results, can help in childhood, especially in the presence
of symptoms if MRI is not easily available.25 In cases of occipital stenosis without med-
ullary suffering, clinical and MRI follow-up will be organized every year11 during
infancy.

Spinal stenosis
In adults, leg and lower back pain are reported in half of patients15, revealing the first
signs of spinal stenosis. These symptoms may appear early and are improved by anti-
inflammatory drugs, including periradicular corticosteroid injections for lumbar radi-
culopathy. A number of associated factors are considered to play an aggravating role
and have to be minimized by adequate physiotherapy against lumbar lordosis and/or
 Achondroplasia 9

Figure 4. Magnetic resonance imaging of a 6-month-old baby with achondroplasia. Note the cervical com-
pression with medullar suffering.

excess weight prevention. Neurological signs including paresthesia, weakness and al-
tered deep tendon reflexes, and later claudication, are associated with spinal stenosis,
especially in patients with persistent kyphosis. Nearly one-third of patients require
lumbar laminectomy, which has to be performed by surgeons familiar with this condi-
tion and before definitive damage to the spinal cord.26

Orthopaedic

Related to truncal hypotonia, a thoracolumbar gibbus is often present in childhood.

Children with achondroplasia should not be placed in a sitting position during the first
year of life, but should be tipped back in an infant seat to avoid aggravation of the
gibbus. This gibbus may resolve spontaneously; however, in some severe cases, these
deformities can lead to cuneiform deformity of some vertebral body.27 In the authors’
experience, these complications may be prevented in almost all cases by active (and
careful) muscular physiotherapy, with postural exercises in a ventral position. In
some pronounced cases, a slight surgical brace may be prescribed when a sitting po-
sition is acquired, and in the absence of breathing problems for a short period until
walking.
Physiotherapy with stretching of the hip and correction of lumbar hyperlordosis is
indicated to limit hip flexum and vicious attitude of the joints. Precocious training with
such physiotherapy and muscular work is very effective and has to be carried out
throughout the growth period. In case of failure, pelvis deflexion osteotomy may be
suggested.
Tibial bowing is often considered to be a hallmark of achondroplasia, and may be
associated with genu recurvatum and lateral torsion. Kopits reported that 50% of
10 G. Baujat et al

patients have bowing, but did not report patient ages.28 Hunter reported bowing in
10% of patients at 5 years of age and in 42% of adult patients.15 Osteotomy to correct
bowing is usually performed between 10 and 20 years of age.

Cardiorespiratory and sleep dysfunction

Apnoea is common during daytime and sleep. It may increase the risk of sudden un-
expected death in infants27,29,30 and neuropsychological deficits in adults.31 The causes
of sleep apnoea are multiple. During childhood, they have been linked to brain stem
spinal cord compression, and later, they are also due to midfacial hypoplasia, leading
to narrow upper airways and obstructive sleep apnoea. Tasker et al identified three
distinct aetiologic groups of cardiorespiratory dysfunction in achondroplasia: Group
1 had mild midfacial hypoplasia resulting in relative adenoid and tonsil hypertrophy;
Group 2 had jugular foramen stenosis resulting in muscular upper airway obstruction
and progressive hydrocephalus due to jugular venous hypertension; and Group 3 had
muscular upper airway obstruction without hydrocephalus resulting from hypoglossal
canal stenosis. Group 1 responded to adenoid-tonsillectomy, Group 2 responded to
surgical treatment of hydrocephalus; and Group 3 required multiple treatment modal-
ities including foramen decompression.32
Restrictive respiratory insufficiency linked to a small chest may only be a problem
during the first year, particularly in cases of infection or asthma.

Otolaryngology

Due to midface underdevelopment, the Eustachian tubes are short, the pharynx is
small, and the tonsils and adenoids are large for the available space. Recurrent otitis
media is common in childhood (89% in the large survey by Horton et al12) and needs
to be treated with tonsillectomy and ventilation tube (78% in study by Horton et al12)
to prevent conductive hearing loss, which is seen in nearly 40% of individuals with
achondroplasia.15 Conductive hearing screening should be excluded if speech is de-
layed or recurrent otitis media occurs. Speech delay and articulation problems are
found in approximately 25% of patients.

Dental

Orthodontic problems are found in more than half of cases, and are probably under-
reported in medical reports.15 Procedures to expand the maxillary area and to reduce
the number of teeth in the mandible are often needed to achieve dental alignment.

Obesity

Obesity is a major problem in achondroplasia leading to increased morbidity, especially

joint problems.33 It can contribute to the potential early cardiovascular mortality in this
condition. Hunter et al developed weight-for-height curves for these patients and sug-
gested a different specific index to estimate weight excess.15 Several reasons have been
suggested, including the lack of physical activity, the persistence of an age-related appe-
tite, and psychological weakness. It is unknown whether achondroplasia is associated
with some metabolic syndrome features (hyperlipidaemia, diabetes and hypertension).
However, it is interesting to note that a high rate of heart-disease-related deaths is
 Achondroplasia 11

reported in this condition.34 Dietary management has to begin early, with long-term
follow-up and, if necessary, diet coaching.

Neurocognitive development and quality of life

Achondroplasia is associated with normal intelligence. However, during the first 2

years of life, children affected by this condition present delayed motor milestones
due to the neuromuscular transitory hypotonia. Chronic upper airway obstruction,
middle ear dysfunction, craniocervical junction stenosis, thoracolumbar kyphosis
and bowing of the lower legs may induce serious developmental consequences.11 Pre-
vention of these complications is the major part of management. A previous longevity
study in the USA showed an increased mortality rate due to cardiovascular disease,
but without any correlation with the neurological sequelae.30
Adults with achondroplasia are able to lead a normal and productive life. Psycho-
logical difficulties are common and may interfere with neurocognitive development.
They need to be detected at an early stage. Age-adapted anticipatory guidance with
counselling for appropriate adaptations in daily life has to be provided for parents
and affected children.11 Genetic counselling with information on prenatal diagnosis
should be discussed. Women with achondroplasia are fertile and require consultation
with a knowledgeable gynaecologist to find appropriate long-term contraception.
Pregnancy is possible, but baseline respiratory function tests are required at the begin-
ning of the pregnancy and caesarean delivery is necessary due to the small pelvis. Spinal
anaesthesia is not recommended.11

GENETICS

Achondroplasia is an autosomal-dominant disorder with essentially complete pene-

trance. More than 85% of patients are born from unaffected parents and harbour
new mutations. The mutation rate is estimated to be between 1.4  10 5  0.5 and
1.93  10 5  0.43.2,35
The achondroplasia locus was mapped to chromosome 4p16.3 in 199436,37, and
a recurrent heterozygous mutation of FGFR3 was identified soon after.38–40 Almost
all patients with achondroplasia have the same amino acid substitution in the trans-
membrane domain of FGFR3 mutations (Gly380Arg). Further analyses showed (rare)
other mutations in the same domain. The penetrance of the mutation is complete,
and the exceptional affected siblings, with normal parents, are due to mosaicism in
their father’s sperm41–43, with a recurrence risk of less than 0.02%.44 Increased pater-
nal age in affected patients has been described45, and this was confirmed recently by
molecular analysis. All new mutations occur on the paternal allele46, suggesting
increased mutability of FGFR3 during spermatogenesis or, as demonstrated for the
FGFR2 gene, a selective advantage of this pathogenic mutation in the male cell line.47
Other FGFR3 mutations are associated with different skeletal disorders (Figure 5).
Hypochondroplasia, characterized by a mild clinical and radiological phenotype, is
caused by mutations in tyrosine kinase domains 1 (Asn540Lys) and 2 (Lys650Glu or
-Asn) (MIM 146000).48 Nevertheless, only 60–65% of clinically diagnosed hypochon-
droplasia patients carry these mutations. Additional substitutions at positions 538
(I538V), 650 (K650N, Q, T) and 328 (N328I) have been reported49–51, but these
only account for a few cases, raising the question of possible genetic heterogeneity
for hypochondroplasia.38,52
12 G. Baujat et al

Figure 5. FGFR3 mutations in chondrodysplasia.

Several mutations in the extracellular domain or the stop codon53 are associated
with thanotophoric dysplasia type I (MIM 187600), while a mutation in tyrosine kinase
domain 2 (Lys650Glu) is associated with thanatophoric dysplasia type II (MIM 187601),
which is also lethal but less severe. A severe form of achondroplasia with acanthosis
nigricans and mental retardation54 is associated with the Lys650Met mutation55. Other
phenotypes, not clearly related to these chondrodysplasias, are associated with differ-
ent FGFR3 mutations: coronal craniosynostosis (Pro250Arg, MIM 602849)56; the
Beare-Stevenson cutis gyrata syndrome (MIM 123790); and lacrimo-auriculo-dento-
digital syndrome (Asp513Asn, MIM 149730). Interestingly, FGFR2 mutations, causing
various forms of syndromic craniosynostosis (including Crouzon, Apert, Pfeiffer, and
Jackson-Weiss syndromes), are preferentially found in the extracellular domain of
the receptor.

FGFR3

FGFR3 belongs to the fibroblast growth factor receptor family. The four FGFR (1–4)
members share a common organization comprising three extracellular immunoglo-
bin-like loops (Ig I–III), one hydrophobic transmembrane domain and two cytoplasmic
tyrosine kinase subdomains TK1 and TK2, responsible for the catalytic activity.57 Bind-
ing of fibroblast growth factor (FGF) ligands in the presence of cell-surface heparan
sulphate proteoglycans induces receptor dimerization and transautophosphorylation
 Achondroplasia 13

of tyrosine kinase subdomains in the cytoplasmic domain. Phosphorylated residues

serve as docking sites for the adaptor proteins and effectors that propagate FGF
receptor signals via different signalling pathways, resulting in the regulation of many
cellular processes, including proliferation, differentiation and survival (Figure 6). Chon-
drocyte proliferation and differentiation are known to require activation of various
signalling proteins, including STATs, MAPK ERK1/2, phospholipase C, protein kinase
C and AKT. Other signalling pathways, such as C-type natriuretic peptide (CNP),
modulate the strength of FGFR3 signals. It is noteworthy that mutations of the CNP
receptor, namely natriuretic peptide receptor B (NPR-B), are responsible for Maro-
teaux type acromesomelic dysplasia (MIM 602875), and that its disruption was recently
shown to be associated with an overgrowth phenotype.58
FGFR3 mutations lead to gain of function and several mechanisms have been sug-
gested. Based on different studies (in vitro and in vivo) in achondroplasia, Gly380Cys
FGFR3 mutations have been assumed to induce constitutive activation of the receptor
by stabilizing ligand-induced dimers, resulting in prolonged signalling at the cell surface.
On the contrary, in thanathophoric dysplasia, the dimerization seems to be indepen-
dent of the FGFR3 ligand, but is caused by the disulphide bonds created by the free
cysteine residues introduced by the mutations.

Figure 6. FGFR3 signalling pathways. Four main signalling pathways are shown: STAT (signal trans-
ducer and activator of transcription), MAPK (mitogen-activated protein kinase), PLCg (phospholipase
C gamma) and PI3K-AKT (phosphatidylinositol phosphatase-3-kinase-serine/threonine kinase). It is
likely that other pathways are also involved in the control of chondrocyte proliferation and
differentiation.
14 G. Baujat et al

Moreover, the mechanisms responsible for the constitutive receptor phosphoryla-

tion of the highly conserved Lys650 mutations are complex, and can produce three
different phenotypes of increasing severity depending on the substituting amino acid.
Recent results indicate that receptors are constitutively phosphorylated to variable
extents, and are differentially processed at the intracellular level, depending on the do-
main in which the mutation arises. FGFR3 intracellular mutations induce tyrosine phos-
phorylation and defective glycosylation, whereas a different mechanism, characterized
by receptor retention at the plasma membrane, excessive ubiquitination and reduced
degradation, results from mutations that affect the extracellular domain or the stop
codon.14,59
The activating mutation may also occur in other non-chondrocyte cell types. For
example, they promote mitosis in colon or bladder carcinoma, multiple myeloma or
benign dermoid keratosis.60

Genetic counselling and prenatal diagnosis

Fifty percent of the offspring of patients with achondroplasia will be affected. Genetic
counselling has been completely modified by the possibility of early detection of the
mutation during pregnancy. FGFR3 testing for the homozygous lethal form, in the
case of two affected parents, allows them to consider having children.
Interest in and use of prenatal diagnosis in heterozygous achondroplasia are vari-
able, and have to be correlated with individual experiences and perceptions of the
condition.61 As most cases of achondroplasia are sporadic, they are associated
with de-novo mutation and no familial history. When a skeletal dysplasia is suspected
in utero (see above), molecular diagnosis may be discussed. Confirmation of diagno-
sis can be provided by FGFR3 testing of prenatal specimens. This situation occurs
later in pregnancy (27–32 weeks), increasing the difficulty of the situation. This
late diagnosis is always delicate for the parents. They usually have no previous infor-
mation about achondroplasia and their appreciation of the quality of life in this con-
dition is very variable. In this circumstance, the family should meet a paediatrician or
a geneticist who will discuss the diagnosis (natural history, prognosis, currently avail-
able treatments) and the options available, including pregnancy termination and
adoption, according to the law of the country. Patients’ associations (‘Little People
Association’ in the USA, ‘Association des Personnes de Petite Taille’ in France)
may be very helpful. Psychological support will be proposed if a termination is
chosen.

THERAPEUTIC STRATEGIES

Human growth hormone therapy in children with achondroplasia has been proposed
through several trials, with pharmacological doses comparable to those used in Turner
syndrome.62–64 Long-term results are not conclusive; an increased growth rate was
reported in some of the earliest trials. Consequently, this treatment is not recommen-
ded worldwide for achondroplasia.
Limb lengthening is often discussed, using several surgical and orthopaedic
appliances. Expected lengthening is important (5–10 cm in long bones), but this
procedure remains arduous for the patient, with a high risk of infection and joint
and soft tissue damage, and may result in a poorer quality of life.65–68
 Achondroplasia 15

Practice points

 diagnosis of achondroplasia is based on specific clinical and radiological charac-

teristics. Confirmation of the FGFR3 gene abnormality is not necessary for the
diagnosis
 preventive care has to be directed to prevent serious damage:
– during the 2 first years of life: head circumference monitoring; MRI (to
explore the cervical medullar junction) polysomnography (to detect
sleep apnoea); orthopaedic follow-up (to prevent thoracolumbar gibbus
and hyperlodosis)
– during childhood: dietary management to prevent obesity; otorhinolar-
yngology follow-up; psychological guidance for parents and affected
child; growth hormone therapy is not recommended
– during adolescence and adulthood: genetic counselling; appropriate con-
traception; information about prenatal diagnosis; management of narrow
lumbar spinal canal by specialist surgeons

Research agenda

 recent advances in knowledge on the molecular pathways of normal and mu-

tated FGFR3 genes have enabled the orientation of new therapeutic strategies,
including targeted constitutional activation of tyrosine kinase receptor. As the
same FGFR3 mutations are also involved in different tumoural processes, the
reduction of excessive tyrosine kinase activity could be helpful for both growth
therapy and cancer.14 These recently developed approaches are inhibition of
the FGFR3 tyrosine kinase with small and new chemical molecules, tested on
cell lines, especially human chondrocyte lines; generation of highly specific
antibodies to block FGFR3 activation69,70; and activation of the NPR-B signalling
pathway to block the excessive FGFR3 signals70
 these therapeutic developments require experimentation on animal and human
cell lines, especially immortalized chondrocytes with and without FGFR3
mutations,71 and several animal models. However, no results of in-vivo studies
are available to date, and the procedure to deliver the potential drug into the
target tissue has not yet been elucidated

ACKNOWLEDGEMENTS

This work was supported by the GIS-Maladies Rares 2002. The authors wish to thank
the Association des Personnes de Petite Taille for their collaboration.

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