Diego Vélasquez, don Sebastian de Morra

ACHONDROPLASIA

Geert Mortier, MD, PhD Department of Medical Genetics

Antwerp University Hospital University of Antwerp

GENOMED Centre of Excellence

•  autosomal dominant condition •  recurrent mutation (p.G380R) in FGFR3 gene •  most common form of short limb dwarfism (1/10.000-1/30.000)

•  major clinical features: - prenatal onset of disproportionate short stature - macrocephaly, low nasal bridge, frontal bossing - short limbs with redundant skin folds, trident hand - ligamentous laxity in knees, genua vara - normal intelligence - adult height: males 131 ± 5,6 cm females 124 ± 5,9 cm

•  major radiographic features:

- shortening of tubular bones (all segments involved) -  platyspondyly, bullet-shaped vertebrae, posterior scalloping -  interpedicular narrowing -  abnormal pelvis with small iliac wings, flat acetabular roofs (trident) -  lumbar hyperlordosis

Achondroplasia

Radiographic features of achondroplasia

Radiographic features of achondroplasia

Short-limbdwarfism

Short-trunkdwarfism

Differential diagnosis

Hypochondroplasia

clinical photos deleted

thanatophoric dysplasia

achondroplasia hypochondroplasia

FamilyofFGFR3disorders

FGFR3

cell

mem

bran

e

intracellular extracellular

SP: signal peptide Ig: immunoglobuline-like domain TM: transmembrane domain

Structure of the FGFR3 protein

p.G380R mutation in achondroplasia

Activation of the fibroblast growth factor receptors

cell membrane

(Fibroblast growth factors)

Effect of the mutations on FGFR signal transduction

Current care and management

•  no cure •  genetic counseling •  growth hormone treatment: effect on adult height?1 •  limb lengthening: final height up to + 20 cm •  new drugs in the pipeline •  now mainly prevention and treatment of complications •  lack of evidence-based guidelines •  need for multidisciplinary approach!

1 Miccoli M et al. Horm Res Paediatr 2016;86:27-34

Growth and development should be monitored according to norms for achondroplasia

Pediatrics 2005;116:771-783

males

Monitor neuromotor development

•  key concerns in the infant and toddler: - ventriculomegaly/true hydrocephaly (very rare) - spinal cord compression at cervicomedullary junction (small foramen magnum)

- sudden infant death (rare) - thoracolumbar kyphosis - middle ear effusions and infections - sleep apnea (obstructive and/or central)

•  key concerns in the older child:

- upper airway and ENT infections - sleep apnea - obesity - angular deformities of the lower limb (genua vara)

•  key concerns in the adolescent and adult

- lumbar spinal stenosis - back pain - peripheral nerve compression

Areas of concern in achondroplasia

Femoral Lengthening in Achondroplasia

• Correct Coxa vara • Correct FFD hip • Decrease hyperlordosis

•  Pharma-ledcurrentstudies–  Biomarin901–naturalhistorystudy–  Biomarin301–RCTofvosori@de(C-nature@cpep@de)in5-18yearagegroup

–  Therachon–TA-46(FGFR3ligandtrap)–phase1started•  Pharma-ledindevelopment

–  Biomarin205-RCTofvosori@dein2-5yearagegroup–  Ascendis–TransConCNP–sustainedreleaseCNP–  Ribomic–RBM007–an@-FGF2aptamer

•  Inves@gator-ledstudies

–  Meclozine(preclinical)

Clinical trials in achondroplasia

Courtesy N Bishop

From: Klag KA & Horton WA. Hum Mol Genet 2015

Interaction between FGF and CNP signaling

Natriure@cpep@desystem

cGKII (cGMP dependent kinase II) �  Acts downstream of cGMP �  cGKII-/- mice

�  Dwarfism

�  Inhibits the MAPK pathway �  Overactivation in achondroplasia

�  Caused by gain-of-function mutations in FGFR3 �  Short-limb dwarfism

è CNP possible therapeutic target

BMN-111

Yasoda A et al. Endocrinology 2009;150:3138-3144

https://globenewswire.com/news-release/2015/06/17/745424/10138876/en/BMN-111-vosoritide-Improves-Growth-Velocity-in-Children-With-Achondroplasia-in-Phase-2-Study.html

https://globenewswire.com/news-release/2015/06/17/745424/10138876/en/BMN-111-vosoritide-Improves-Growth-Velocity-in-Children-With-Achondroplasia-in-Phase-2-Study.html

From: Unger S et al. Curr Osteoporos Rep 2017;15:53-60

Use of a FGFR3 decoy receptor

Garcia S et al. Sci Transl Med 2013;5:203ra124

Take home messages

•  frequent skeletal dysplasia •  significant morbidity (more than being short…) •  need for close follow-up early on in life •  multidisciplinary approach •  use of achondroplasia-specific charts (growth and development) •  need for good (evidence-based) clinical guidelines •  new drugs maybe promising (not only for stature?)