Current Care and Investigational Therapies in Achondroplasia

Current Osteoporosis Reports, Feb 2017

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 is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. 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. 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.

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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 - 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)


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Sheila Unger, Luisa Bonafé, Elvire Gouze. Current Care and Investigational Therapies in Achondroplasia, Current Osteoporosis Reports, 2017, pp. 53-60, Volume 15, Issue 2, DOI: 10.1007/s11914-017-0347-2