Current Care and Investigational Therapies in Achondroplasia
Current Care and Investigational Therapies in Achondroplasia
Sheila Unger 0 1 2
Luisa Bonafé 0 1 2
Elvire Gouze 0 1 2
0 Service of Genetic Medicine, Lausanne University Hospital (CHUV) , Av. Pierre-Decker 2, 1011 Lausanne , Switzerland
1 Institute de Biologie Valrose, University. Nice Sophia Antipolis, Batiment Sciences Naturelles; UFR Sciences , Parc Valrose, 28 avenue Valrose, 06108 Nice, Cedex 2 , France
2 Center for Molecular Diseases, Service of Genetic Medicine, Lausanne University Hospital (CHUV) , Av. Pierre-Decker 2, 1011 Lausanne , Switzerland
Purpose of Review The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Recent Findings Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. Summary In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications.
Achondroplasia; FGFR3; Treatment; Biotherapies; Clinical management
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Achondroplasia is a rare genetic disorder for which no cure is
available. This skeletal dysplasia is the most common form of
short limb dwarfism and was first reported in 1878 [1]. It is
estimated that it affects approximately 250,000 people
worldwide [2 , 3, 4]. The incidence is estimated to be 1 in 10,000 to
30,000 live births per year [5], affecting both males and
females with equal frequency.
Achondroplasia is characterized by prenatal onset of
disproportionate short stature [6, 7]. Most affected children and
adults enjoy good general health, but numerous neurological,
orthopedic, and otolaryngologic complications can occur in
this disorder, and an association with sudden infant death
has been reported [8]. The phenotype of achondroplasia is
caused by abnormal endochondral bone development, thus
mainly affecting the growth of the long bones; the vertebrae;
and several bones in the skull, including the temporal,
occipital, sphenoid, and ethmoid bones. The trunk is narrow but of
normal size. Adult height is 131 ± 5.6 cm in males and
124 ± 5.9 cm in females [7, 9].
Achondroplasia is caused by a single point
gain-offunction mutation in the gene coding for fibroblast growth
factor receptor 3 (FGFR3) [10]. It follows an autosomal
dominant inheritance; though in 80% of the cases, it is a de novo
mutation [11] associated with increased paternal age, relative
to the general population [12–15]. In 90% of the cases, the
mutation is a Gly380Arg substitution (the most common
mutation is 1138G > A transition; a G > C transversion has been
reported in 20% of the cases) [11, 16, 17]. Diagnosis can be
suspected in utero by ultrasound and/or clinical and
radiological features at birth but should be confirmed by molecular
testing [18]. To help with diagnosis of skeletal dysplasia
including achondroplasia, non-invasive prenatal testing is being
developed [19]. The penetrance is 100% and the phenotype is
already apparent at birth. Infants with achondroplasia present
characteristic features with macrocephaly with frontal
bossing, midface hypoplasia, and flat nasal bridge. They have
short limbs with predominantly proximal (rhizomelic)
shortening of the upper limbs [20], joint laxity, and a trident hand
[21]. Intellect is not affected and their lifespan is close to that
of the general population. Children with achondroplasia
present motor delays notably to acquire standing position and
walking due to muscle hypotonia and ligamentous laxity.
More than 50% of the patients develop an early obesity that
augments the morbidity associated with lumbar lordosis as
well as the severity of sleep apnea or orthopedic complications
such as genua vara.
Achondroplasia is a short stature condition compatible with
good general health and normal life expectancy. Besides the
burden of short stature, health issues may arise from
complications, due to the particular anatomical features of
achondroplasia.
Current Care and Management
Recommendations for management of children with
achondroplasia have been proposed and updated over time [2 , 22,
23]. However, these guidelines are mainly based on personal
experience of the authors and not on clinical studies.
Treatments aimed at correcting growth have been tried;
growth hormone therapy has no significant effect on adult
stature [24]. Surgical limb lengthening can improve body
proportions and final height up to 20 cm but requires multiple
surgeries with high rate of complic (...truncated)