Best Practice & Research Clinical RheumatologyVol. 22, No. 1, pp. 3–18, 2008doi:10.1016/j.berh.2007.12.008

available online at http://www.sciencedirect.com

1

Achondroplasia

Genevieve Baujat MD

Laurence Legeai-Mallet PhD

Georges Finidori MD

Valerie Cormier-Daire MD, PhD

Martine Le Merrer* MD, PhD

Hopital Necker-Enfants Malades, 149 rue de Sevres, 75743 Paris Cedex 15, France

Achondroplasia (MIM 100800) is the most common non-lethal skeletal dysplasia. Its incidence isbetween 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 lumbarspine, associated with normal cognitive development.

This autosomal-dominant disorder is caused by a gain-of-function mutation in the geneencoding 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 bydifferent age-related radiological features. Management care by a multidisciplinary team will pre-vent and treat complications, including cervical cord compression, conductive hearing loss andthoracolumbar gibbosity. Weight counselling, psychosocial guidance and professional integrationprogrammes 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, PierreMarie described the main features in children and adults. However, this conditionwas recognized earlier, as demonstrated in art from Egypt, Greece and Rome. Asachondroplasia is the most common condition associated with disproportionateshort 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 withenlarged head, depressed nasal bridge, short stubby trident hands, lordotic lumbarspine, 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 childhoodand 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 andone in 30 0002–5, affecting more than 250 000 individuals worldwide. It is one of themost common types of non-lethal skeletal chondrodysplasia. Earlier ascertainmentsof frequency were probably overestimates because, before involvement of theFGFR3 gene was identified, achondroplasia was often confused with various otherchondrodysplasias.1 There is no racial predisposition. With prenatal ultrasound be-coming routine in developed countries, many affected fetuses are recognized in thethird trimester of pregnancy. The consequence of legal late termination of pregnancyon birth rates, in such countries as France, is unknown. This prevalence may also bemodulated 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 bothclinically 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 thirdtrimester by abnormal ultrasound findings, namely foreshortening of the limbs(<3rd percentile), increased biparietal diameter (>95th percentile) and low nasalbridge.7,8 This can lead to intra-uterine imaging. Antenatal radiographic features ofachondroplasia 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 featuresare 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, showingslightly flat vertebral bodies with medial spurs extending from the anterior face,pointed femora with proximal extremity on profile (Figure 1), and round and squareilia with an oval radiolucent area in the proximal femur on face.9,10

After birth, achondroplasia is clinically characterized by short limbs, especially theproximal segment, with a long trunk and a narrow thorax. Birth height is generallypreserved (mean birth lengths are 47.7 cm for males and 47.2 cm for females). Thehead is large with frontal bossing, possibly leading to obstetric difficulties. The midfaceis 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 inabilityto fully oppose the third and the fourth digits.

In infancy, early motor milestones are delayed because of muscular hypotonia, butpsychomotor development is normal. Dorso-lumbar kyphosis in a seated position iscommon in early childhood but disappears with improving muscle tone. Excessive

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.

Achondroplasia 5

sudation is often noted. Hyperextensibility of the distal joints with limitations of elbowextension 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 beenproduced.11,12 Final adult height is approximately 125 cm for males and 120 cm forfemales. Mean adult weights are 55 kg for males and 46 kg for females, with an evidenttendency for obesity. The proximal segment of upper extremities, especially humeri,are relatively shorter than the middle and distal segments. The trunk is relativelylong 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 pelvisshows small and square iliac wings, the acetabular roof is horizontalized, and tubularbones are short and large with enlarged metaphyses (‘pagode roof’). Proximal femoraand, to a lesser extent, humerus are radiolucent because of the obliquity of the growthcartilage (Figure 2a). This is particularly evident on the femur profile, showing a sharp-pointed extremity specific for achondroplasia (Figure 2b). Decreased size of the baseof the skull and prominent frontal bones are noted.13

Later in infancy, epiphysis development is delayed but their appearance is quitenormal. The pedicles show a shortened antero-posterior diameter, and the posterioraspect 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

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.

6 G. Baujat et al

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 bowingaspect, associated with elongated fibula (Figure 3a). The growth plate of the distalfemur extremity is concave, with an impaction of the epiphysis into the cartilage cen-tre. Shortening femoral neck is associated with frequent vertical orientation. Femoracondyles are often asymmetrical. Progressively downward diminishing interpediculatedistances 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 bodydeformities (Figure 3b). The lumbar spine appears to have an acute articulation withthe sacrum, which is narrow and horizontally oriented. Narrowing of the pelvis inlet

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.

Achondroplasia 7

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

DIFFERENTIAL DIAGNOSIS

Achondroplasia belongs to a group of short-stature osteochondrodysplasias that havesome clinical features in common, such as postnatal dwarfism, micromelia, short handsand 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 beeasily excluded on the bases of their major clinical and radiological features. Severeforms of hypochondroplasia, associated with different mutations in FGFR3, may overlapclinically with achondroplasia.1

8 G. Baujat et al

COMPLICATIONS AND MANAGEMENT

In achondroplasia, complications are consequences of the abnormal linear bonegrowth. Many appear at predicted ages including adulthood. They can often be mini-mized if detected early. Indeed, guidelines for patients with achondroplasia havebeen 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 ortreat early neurological and respiratory complications, which arise particularly duringthe first year of life and in adults. This specific follow-up has to be settled with thecollaboration of the local medical team.

Neurology

Hydrocephalus

In the newborn with achondroplasia, the cranial-cervical junction is small, leading tofrequent dilated ventricles and excessive extra-axial fluid, without active hydrocepha-lus, which stabilize during the second year of life. Later, true internal hydrocephalusmay 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 earlyyears. A rapid increase or symptoms of increased pressure must be considered bypaediatric neurosurgeons familiar with achondroplasia. Some studies suggest that asmany 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 worsecomplications.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, magneticresonance imaging (MRI) of the brain, the cervical junction and the spinal cord shouldbe 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 medullarydecompression surgery.23,24 Somatosensory-evoked potential results, correlatedwith clinical status and MRI results, can help in childhood, especially in the presenceof 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 duringinfancy.

Spinal stenosis

In adults, leg and lower back pain are reported in half of patients15, revealing the firstsigns 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 roleand have to be minimized by adequate physiotherapy against lumbar lordosis and/or

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

pression with medullar suffering.

Achondroplasia 9

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 requirelumbar 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 firstyear of life, but should be tipped back in an infant seat to avoid aggravation of thegibbus. This gibbus may resolve spontaneously; however, in some severe cases, thesedeformities 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 (andcareful) muscular physiotherapy, with postural exercises in a ventral position. Insome 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 untilwalking.

Physiotherapy with stretching of the hip and correction of lumbar hyperlordosis isindicated to limit hip flexum and vicious attitude of the joints. Precocious training withsuch physiotherapy and muscular work is very effective and has to be carried outthroughout the growth period. In case of failure, pelvis deflexion osteotomy may besuggested.

Tibial bowing is often considered to be a hallmark of achondroplasia, and may beassociated 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 in10% of patients at 5 years of age and in 42% of adult patients.15 Osteotomy to correctbowing 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 causesof sleep apnoea are multiple. During childhood, they have been linked to brain stemspinal cord compression, and later, they are also due to midfacial hypoplasia, leadingto narrow upper airways and obstructive sleep apnoea. Tasker et al identified threedistinct aetiologic groups of cardiorespiratory dysfunction in achondroplasia: Group1 had mild midfacial hypoplasia resulting in relative adenoid and tonsil hypertrophy;Group 2 had jugular foramen stenosis resulting in muscular upper airway obstructionand progressive hydrocephalus due to jugular venous hypertension; and Group 3 hadmuscular upper airway obstruction without hydrocephalus resulting from hypoglossalcanal stenosis. Group 1 responded to adenoid-tonsillectomy, Group 2 responded tosurgical 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 problemduring the first year, particularly in cases of infection or asthma.

Otolaryngology

Due to midface underdevelopment, the Eustachian tubes are short, the pharynx issmall, and the tonsils and adenoids are large for the available space. Recurrent otitismedia is common in childhood (89% in the large survey by Horton et al12) and needsto 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 withachondroplasia.15 Conductive hearing screening should be excluded if speech is de-layed or recurrent otitis media occurs. Speech delay and articulation problems arefound 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 reducethe 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, especiallyjoint problems.33 It can contribute to the potential early cardiovascular mortality in thiscondition. 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 beensuggested, including the lack of physical activity, the persistence of an age-related appe-tite, and psychological weakness. It is unknown whether achondroplasia is associatedwith 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-termfollow-up and, if necessary, diet coaching.

Neurocognitive development and quality of life

Achondroplasia is associated with normal intelligence. However, during the first 2years of life, children affected by this condition present delayed motor milestonesdue to the neuromuscular transitory hypotonia. Chronic upper airway obstruction,middle ear dysfunction, craniocervical junction stenosis, thoracolumbar kyphosisand bowing of the lower legs may induce serious developmental consequences.11 Pre-vention of these complications is the major part of management. A previous longevitystudy 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 withcounselling for appropriate adaptations in daily life has to be provided for parentsand affected children.11 Genetic counselling with information on prenatal diagnosisshould be discussed. Women with achondroplasia are fertile and require consultationwith 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. Spinalanaesthesia 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 harbournew mutations. The mutation rate is estimated to be between 1.4� 10�5� 0.5 and1.93� 10�5� 0.43.2,35

The achondroplasia locus was mapped to chromosome 4p16.3 in 199436,37, anda recurrent heterozygous mutation of FGFR3 was identified soon after.38–40 Almostall 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 intheir 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 bymolecular analysis. All new mutations occur on the paternal allele46, suggestingincreased mutability of FGFR3 during spermatogenesis or, as demonstrated for theFGFR2 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, iscaused 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 theseonly account for a few cases, raising the question of possible genetic heterogeneityfor hypochondroplasia.38,52

Figure 5. FGFR3 mutations in chondrodysplasia.

12 G. Baujat et al

Several mutations in the extracellular domain or the stop codon53 are associatedwith thanotophoric dysplasia type I (MIM 187600), while a mutation in tyrosine kinasedomain 2 (Lys650Glu) is associated with thanatophoric dysplasia type II (MIM 187601),which is also lethal but less severe. A severe form of achondroplasia with acanthosisnigricans and mental retardation54 is associated with the Lys650Met mutation55. Otherphenotypes, not clearly related to these chondrodysplasias, are associated with differ-ent FGFR3 mutations: coronal craniosynostosis (Pro250Arg, MIM 602849)56; theBeare-Stevenson cutis gyrata syndrome (MIM 123790); and lacrimo-auriculo-dento-digital syndrome (Asp513Asn, MIM 149730). Interestingly, FGFR2 mutations, causingvarious forms of syndromic craniosynostosis (including Crouzon, Apert, Pfeiffer, andJackson-Weiss syndromes), are preferentially found in the extracellular domain ofthe 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 cytoplasmictyrosine 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 heparansulphate proteoglycans induces receptor dimerization and transautophosphorylation

Achondroplasia 13

of tyrosine kinase subdomains in the cytoplasmic domain. Phosphorylated residuesserve as docking sites for the adaptor proteins and effectors that propagate FGFreceptor signals via different signalling pathways, resulting in the regulation of manycellular processes, including proliferation, differentiation and survival (Figure 6). Chon-drocyte proliferation and differentiation are known to require activation of varioussignalling proteins, including STATs, MAPK ERK1/2, phospholipase C, protein kinaseC 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 CNPreceptor, namely natriuretic peptide receptor B (NPR-B), are responsible for Maro-teaux type acromesomelic dysplasia (MIM 602875), and that its disruption was recentlyshown 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, Gly380CysFGFR3 mutations have been assumed to induce constitutive activation of the receptorby 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 freecysteine 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 threedifferent phenotypes of increasing severity depending on the substituting amino acid.Recent results indicate that receptors are constitutively phosphorylated to variableextents, 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, characterizedby receptor retention at the plasma membrane, excessive ubiquitination and reduceddegradation, results from mutations that affect the extracellular domain or the stopcodon.14,59

The activating mutation may also occur in other non-chondrocyte cell types. Forexample, they promote mitosis in colon or bladder carcinoma, multiple myeloma orbenign dermoid keratosis.60

Genetic counselling and prenatal diagnosis

Fifty percent of the offspring of patients with achondroplasia will be affected. Geneticcounselling has been completely modified by the possibility of early detection of themutation during pregnancy. FGFR3 testing for the homozygous lethal form, in thecase 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 thecondition.61 As most cases of achondroplasia are sporadic, they are associatedwith de-novo mutation and no familial history. When a skeletal dysplasia is suspectedin utero (see above), molecular diagnosis may be discussed. Confirmation of diagno-sis can be provided by FGFR3 testing of prenatal specimens. This situation occurslater in pregnancy (27–32 weeks), increasing the difficulty of the situation. Thislate 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 ora geneticist who will discuss the diagnosis (natural history, prognosis, currently avail-able treatments) and the options available, including pregnancy termination andadoption, according to the law of the country. Patients’ associations (‘Little PeopleAssociation’ in the USA, ‘Association des Personnes de Petite Taille’ in France)may be very helpful. Psychological support will be proposed if a termination ischosen.

THERAPEUTIC STRATEGIES

Human growth hormone therapy in children with achondroplasia has been proposedthrough several trials, with pharmacological doses comparable to those used in Turnersyndrome.62–64 Long-term results are not conclusive; an increased growth rate wasreported 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 orthopaedicappliances. Expected lengthening is important (5–10 cm in long bones), but thisprocedure remains arduous for the patient, with a high risk of infection and jointand soft tissue damage, and may result in a poorer quality of life.65–68

Practice points

� diagnosis of achondroplasia is based on specific clinical and radiological charac-teristics. Confirmation of the FGFR3 gene abnormality is not necessary for thediagnosis� preventive care has to be directed to prevent serious damage:

– during the 2 first years of life: head circumference monitoring; MRI (toexplore the cervical medullar junction) polysomnography (to detectsleep apnoea); orthopaedic follow-up (to prevent thoracolumbar gibbusand hyperlodosis)

– during childhood: dietary management to prevent obesity; otorhinolar-yngology follow-up; psychological guidance for parents and affectedchild; growth hormone therapy is not recommended

– during adolescence and adulthood: genetic counselling; appropriate con-traception; information about prenatal diagnosis; management of narrowlumbar 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 thesame FGFR3 mutations are also involved in different tumoural processes, thereduction of excessive tyrosine kinase activity could be helpful for both growththerapy and cancer.14 These recently developed approaches are inhibition ofthe FGFR3 tyrosine kinase with small and new chemical molecules, tested oncell lines, especially human chondrocyte lines; generation of highly specificantibodies to block FGFR3 activation69,70; and activation of the NPR-B signallingpathway to block the excessive FGFR3 signals70

� these therapeutic developments require experimentation on animal and humancell lines, especially immortalized chondrocytes with and without FGFR3mutations,71 and several animal models. However, no results of in-vivo studiesare available to date, and the procedure to deliver the potential drug into thetarget tissue has not yet been elucidated

Achondroplasia 15

ACKNOWLEDGEMENTS

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

REFERENCES

*1. Maroteaux P, Le Merrer M. L’achondroplasie. In: Maladies Osseuses de l’Enfant. Fammarion Medecine

Science. 4th edn. Paris, 2002, pp. 56–65.

16 G. Baujat et al

2. Oberklaid F, Danks DM, Jensen F et al. Achondroplasia and hypochondroplasia. Comments on fre-

quency, mutation rate, and radiological features in skull and spine. Journal of Medical Genetics 1979;

16: 140–146.

3. Orioli IM, Castila EE, Scarano G & Mastroiacovo P. Effect of paternal age in achondroplasia, thana-

tophoric dysplasia, and osteogenesis imperfecta. American Journal of Medical Genetics 1995; 59:

209–217.

4. Stoll C, Dott B, Roth MP & Alembik Y. Birth prevalence rates of skeletal dysplasias. Clinical Genetics

1989; 35: 88–92.

5. Martinez-Frias ML, Cereijo A, Bermejo E et al. Epidemiological aspects of Mendelian syndromes in

a Spanish population sample: II. Autosomal dominant malformation syndromes. American Journal of

Medical Genetics 1991; 38: 622–625.

6. Dakouane Giudicelli M, Serazin V, Le Sciellour CR et al. Increased achondroplasia mutation frequency

with advanced age and evidence for G1138A mosaicism in human testis biopsies. Fertility and Sterility

2007; 11.

7. Cordone M, Lituania M, Bocchino G et al. Ultrasonographic features in a case of heterozygous achon-

droplasia at 25 weeks’ gestation. Prenatal Diagnosis 1993; 13: 395–401.

8. Mesoraca A, Pilu G, Perolo A et al. Ultrasound and molecular mid-trimester prenatal diagnosis of de

novo achondroplasia. Prenatal Diagnosis 1996; 16: 764–768.

*9. Krakow D, Williams 3rd J, Poehl M et al. Use of three-dimensional ultrasound imaging in the diagnosis

of prenatal-onset skeletal dysplasias. Ultrasound in Obstetrics & Gynecology 2003; 21: 467–472.

10. Ruano R, Molho M, Roume J & Ville Y. Prenatal diagnosis of fetal skeletal dysplasias by combining two-

dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer

tomography. Ultrasound in Obstetrics & Gynecology 2004; 24: 134–140.

*11. Trotter TL & Hall JG. American Academy of Pediatrics Committee on Genetics. Health supervision for

children with achondroplasia. Pediatrics 2005; 116: 771–783.

*12. Horton WA, Rotter JI, Rimoin DL et al. Standard growth curves for achondroplasia. The Journal of

Pediatrics 1978; 93: 435–438.

*13. Taybi H & Lachman R. Achondroplasia. In: Radiology of syndromes, metabolic disorders and skeletal

dysplasias. 4th edn. St Louis: CV Mosby, 2000, pp. 749–755.

*14. Horton WA, Hall JG & Hecht JT. Achondroplasia. Lancet 2007; 370: 162–172.

*15. Hunter AGW, Bankier A, Rogers JG et al. Medical complications of achondroplasia: a multicentre

patient review. Journal of Medical Genetics 1998; 35: 705–712.

*16. Carter EM, Davis JG & Raggio CL. Advances in understanding etiology of achondroplasia and review of

management. Current Opinion in Pediatrics 2007; 19: 32–37.

17. Bruhl K, Stoeter P, Wietek B et al. Cerebral spinal fluid flow, venous drainage and spinal cord compres-

sion in achondroplastic children: impact of magnetic resonance findings for decompressive surgery at

the cranio-cervical junction. European Journal of Pediatrics 2001; 160: 10–20.

18. Hecht JT, Horton WA, Reid CS et al. Growth of the foramen magnum in achondroplasia. American

Journal of Medical Genetics 1989; 32: 528–535.

19. Pierre-Kahn A, Hirsch JF, Renier D et al. Hydrocephalus and achondroplasia. A study of 25 observa-

tions. Child’s Brain 1980; 7: 205–219.

20. Reid CS, Pyeritz RE, Kopits SE et al. Cervicomedullary compression in young patients with achondro-

plasia: value of comprehensive neurologic and respiratory evaluation. The Journal of Pediatrics 1987; 110:

522–530.

21. Ryken TC & Menezes AH. Cervicomedullary compression in achondroplasia. Journal of Neurosurgery

1994; 81: 43–48.

*22. Bagley CA, Pindrik JA, Bookland MJ et al. Cervicomedullary decompression for foramen magnum

stenosis in achondroplasia. Journal of Neurosurgery 2006; 104: 166–172.

23. Rimoin DL. Cervicomedullary junction compression in infants with achondroplasia: when to perform

neurosurgical decompression. American Journal of Human Genetics 1995; 56: 824–827.

24. Ho NC, Guarnieri M & Brant LJ. Living with achondroplasia: quality of life evaluation following cervico-

medullary decompression. American Journal of Medical Genetics. Part A 2004; 131: 163–167.

25. Boor R, Fricke G, Bruhl K & Spranger J. Abnormal subcortical somatosensory evoked potentials

indicate high cervical myelopathy in achondroplasia. European Journal of Pediatrics 1999; 158:

662–667.

Achondroplasia 17

26. Sciubba DM, Noggle JC, Marupudi NI et al. Spinal stenosis surgery in pediatric patients with achondro-

plasia. Journal of Neurosurgery 2007; 106: 372–378.

27. Pauli RM, Breed A, Horton VK et al. Prevention of fixed, angular kyphosis in achondroplasia. Journal of

Pediatric Orthopedics 1997; 7: 726–733.

28. Kopits SE. Correction of bowleg deformity in achondroplasia. The Johns Hopkins Medical Journal 1980;

146: 206–209.

29. Pauli RM, Scott CI, Wassman Jr. ER et al. Apnea and sudden unexpected death in infants with achon-

droplasia. The Journal of Pediatrics 1984; 104: 342–348.

30. Hecht JT, Francomano CA, Horton WA & Annegers JF. Mortality in achondroplasia. American Journal of

Human Genetics 1987; 41: 454–464.

31. Waters KA, Everett F, Sillence DO et al. Treatment of obstructive sleep apnea in achondroplasia: eval-

uation of sleep, breathing, and somatosensory-evoked potentials. American Journal of Medical Genetics

1995; 59: 460–466.

32. Tasker RC, Dundas I, Laverty A et al. Distinct patterns of respiratory difficulty in young children with

achondroplasia: a clinical, sleep, and lung function study. Archives of Disease in Childhood 1998; 79: 99–108.

33. Hecht JT, Hood OJ, Schwartz RJ et al. Obesity in achondroplasia. American Journal of Medical Genetics

1988; 31: 597–602.

34. Wynn J, King TM, Gambello MJ et al. Mortality in achondroplasia study: a year follow-up. American Jour-

nal of Medical Genetics. Part A 2007; 143: 2502–2511.

35. Gardner RJM. A new estimate of the achondroplasia mutation rate. Clinical Genetics 1977; 11: 31–38.

36. Le Merrer M, Rousseau F, Legeai-Mallet L et al. A gene for achondroplasia-hypochondroplasia maps to

chromosome 4p. Nature Genetics 1994; 6: 318–321.

37. Velinov M, Slaugenhaupt SA, Stoilov I et al. The gene for achondroplasia maps to the telomeric region of

chromosome 4p. Nature Genetics 1994; 6: 314–317.

*38. Rousseau F, Bonaventure J & Legeai-Mallet L. Clinical and genetic heterogeneity of hypochondroplasia.

Journal of Medical Genetics 1996; 33: 749–752.

39. Shiang R, Thompson LM, Zhu YZ et al. Mutations in the transmembrane domain of FGFR3 cause the

most common genetic form of dwarfism, achondroplasia. Cell 1994; 78: 335–342.

40. Bellus GA, Hefferon TW, Ortiz de Luna RI et al. Achondroplasia is defined by recurrent G380R

mutations of FGFR3. American Journal of Human Genetics 1995; 56: 368–373.

41. Opitz JM. Editorial comment: unstable premutation in achondroplasia: penetrance vs phenotrance.

American Journal of Medical Genetics 1984; 19: 251–254.

42. Philip N, Auger M, Mattei JF & Giraud F. Achondroplasia in sibs of normal parents. Journal of Medical

Genetics 1988; 5: 857–859.

43. Fryns JP, Kleczkowska A, Verresen H & van den Berghe H. Germinal mosaicism in achondroplasia:

a family with 3 affected siblings of normal parents. Clinical Genetics 1983; 24: 156–158.

44. Mettler G & Fraser FC. Recurrence risk for sibs of children with ‘sporadic’ achondroplasia. American

Journal of Medical Genetics 2000; 90: 250–251.

45. Murdoch JL, Walker BA, Hall JG et al. Achondroplasia, a genetic and statistical survey. Annals of Human

Genetics 1970; 33: 227–244.

46. Wilkin DJ, Szabo JK, Cameron R et al. Mutations in fibroblast growth-factor receptor 3 in sporadic

cases of achondroplasia occur exclusively on the paternally derived chromosome. American Journal of

Medical Genetics 1998; 63: 711–716.

47. Goriely A, McVean GA, van Pelt AM et al. Gain-of-function amino acid substitutions drive positive

selection of FGFR2 mutations in human spermatogonia. Proceedings of the National Academy of Sciences

of the United States of America 2005; 102: 6051–6056.

48. Bellus GA, McIntosch I, Smith AE et al. A recurrent mutation in the tyrosine kinase domain of fibroblast

growth factor receptor 3 causes hypochondroplasia. Nature Genetics 1995; 10: 357–359.

49. Grigelioniene G, Eklof O, Laurencikas E et al. L.Asn540Lys mutation in fibroblast growth factor recep-

tor 3 and phenotype in hypochondroplasia. Acta Paediatrica 2000; 89: 1072–1076.

50. Bellus GA, Spector EB, Speiser PW et al. Distinct missense mutations of the FGFR3 lys650 codon

modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. American Jour-

nal of Human Genetics 2000; 67: 1411–1421.

51. Winterpacht A, Hilbert K, Stelzer C et al. A novel mutation in FGFR-3 disrupts a putative N-glycosylation

site and results in hypochondroplasia. Physiological Genomics 2000; 2: 9–12.

18 G. Baujat et al

52. Stoilov I, Kilpatrick MW & Tsipouras P. A common FGFR3 gene mutation is present in achondroplasia

but not in hypochondroplasia. American Journal of Human Genetics 1995; 55: 127–133.

53. Vajo Z, Francomano CA & Wilkin DJ. The molecular and genetic basis of fibroblast growth factor

receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and

Crouzon syndrome with acanthosis nigricans. Endocrine Reviews 2000; 21: 23–39.

54. Rousseau F, Bonaventure J, Le Merrer M et al. Mutations of FGFR3 gene cause 3 types of nanisms with

variably severity: achondroplasia, thanatophoric nanism and hypochondroplasia. Annales d’endocrinologie

(Paris) 1996; 57: 153.

55. Tavormina PL, Bellus GA & Webster MK. A novel skeletal dysplasia with developmental delay and acan-

thosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.

American Journal of Human Genetics 1999; 64: 722–731.

56. Muenke M, Gripp KW, McDonald-McGinn DM et al. A unique point mutation in the fibroblast growth

factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. American Journal of Human

Genetics 1997; 60: 555–564.

57. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.

58. Pejchalova K, Krejci P, Wilcox WR. C-natriuretic peptide: an important regulator of cartilage. Molecular

Genetics and Metabolism 2007;92: 210–215.

59. Gibbs L & Legeai-Mallet L. FGFR3 intracellular mutations induce tyrosine phosphorylation in the Golgi

and defective glycosylation. Biochimica Et Biophysica Acta 2007; 1773(4): 502–512.

60. Hafner C, van Oers JM, Tb Vogt et al. Mosaicism of activating FGFR3 mutations in human skin causes

epidermal nevi. The Journal of Clinical Investigation 2006; 116: 2201–2207.

61. Gollust SE, Thompson RE, Gooding HC & Biesecker BB. Living with achondroplasia: attitudes toward

population screening and correlation with quality of life. Prenatal Diagnosis 2003; 23: 1003–1008.

62. Horton WA, Hecht JT, Hood OJ et al. Growth hormone therapy in achondroplasia. American Journal of

Medical Genetics 1992; 42: 667–670.

63. Shohat M, Tick D, Barakat S et al. Short-term recombinant human growth hormone treatment in-

creases growth rate in achondroplasia. Journal of Clinical Endocrinology & Metabolism 1996; 81: 4033–

4037.

64. Seino Y, Yamanaka Y, Shinohanora M et al. Growth hormone therapy in achondroplasia. Hormone

Research 2000; 533: 53–56.

65. Aldegheri R, Trivella G, Renzi-Brivio L et al. Lengthening of the lower limbs in achondroplastic patients.

A comparative study of four techniques. The Journal of Bone and Joint Surgery 1988; 70B: 69–73.

66. Lavini F, Renzi-Brivio L & de Bastiani G. Psychologic, vascular, and physiologic aspects of lower limb

lengthening inachondroplastics. Clinical Orthopaedics and Related Research 1990; 250: 138–142.

67. Ganel A, Horoszowski H, Kamhin M, Farine I. Leg lengthening in achondroplastic children. Clinical

Orthopaedics 1979; 144: 194–197.

68. Ganel A & Horoszowski H. Limb lengthening in children with achondroplasia. Differences based on

gender. Clinical Orthopaedics and Related Research 1996; 332: 179–183.

69. Rauchenberger R, Borges E, Thomassen-Wolf E et al. Human combinatorial Fab library yielding specific

and functional antibodies against the human fibroblast growth factor receptor 3. The Journal of Biological

Chemistry 2003; 278: 194–205.

70. Yasoda A, Komatsu Y, Chusho H et al. Overexpression of CNP in chondrocytes rescues achondroplasia

through a MAPK-dependent pathway. Natural Medicines 2004; 101: 80–86.

71. Benoist-Lasselin C, Gibbs L, Heuertz S, Odent T, Munnich A & Legeai-Mallet L. Human immortalized

chondrocytes carrying heterozygous FGFR3 mutations: an in vitro model to study chondrodysplasias.

FEBS Letters 2007; 581: 2593–2598.