General information about the condition
Achondroplasia is an autosomal dominant condition caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The most salient clinical features include disproportionate short stature (adult height is approximately 4 feet), long-bone shortening that predominantly affects the proximal aspects of the upper and lower extremities (rhizomelic shortening), and macrocephaly. Patients with achondroplasia may have delayed motor development early on, but cognition is normal.
People with achondroplasia (as well as other conditions causing short stature) are often referred to as little people. Dwarf-derived names are not preferred.
Approximately 80 percent of cases are the result of new (de novo) mutations, while the remaining are inherited.
Occurrence
Patients with achondroplasia have gain-of-function mutation in the FGFR3 gene. Two specific mutations in the FGFR3 gene account for almost all cases of achondroplasia. These mutations occur at the same nucleotide in the FGFR3 gene, 1138G>A (98 percent) and 1138G>C (1 percent), in both cases resulting in a glycine-to-arginine substitution in amino acid 380 (p.Gly380Arg) in the transmembrane domain of the FGFR3 gene. This mutation permanently activates the FGFR3 receptor, inhibiting chondrocyte proliferation, which ultimately leads to impaired endochondral bone formation, growth restriction, bone shortening, and other skeletal anomalies
Manifestations of the condition
The craniofacial features and bone shortening are clearly present at birth. The craniofacial features include macrocephaly, frontal bossing, and midface retrusion. The nose is flattened out, often referred to as saddle nose deformity. The kyphoscoliosis can be seen from birth through infancy and typically decreases once the child starts to bear weight and ambulate. The lumbar lordosis is typically seen after ambulation starts at approximately 1.5 years of age.
Achondroplasia is associated with slow motor development. These children hold their head at approximately 4 to 7 months of age, sit alone at 9 to 11 months, crawl at 9 to 10 months, and walk alone by 16 to 22 months. The delay in these motor milestones is the result of a combination of joint laxity and a large head to support . These delays resolve by age two to three years provided no other medical problems exist. Persons with achondroplasia have normal intellectual development and satisfactory life adjustments
Diagnosis
The diagnosis of achondroplasia is based upon clinical manifestations, radiographic findings, and molecular results.
Prenatally, achondroplasia is suspected when shorter long bones and macrocephaly are present. Fetuses affected with achondroplasia born to average-stature women may sometimes require cesarean delivery due to cephalopelvic disproportion. Affected females with achondroplasia require a cesarean delivery when pregnant due to pelvic abnormalities
Postnatally, a radiographic skeletal survey is strongly advised if achondroplasia is suspected based upon clinical manifestations, including distinct craniofacial features and bone shortening.
The diagnosis is confirmed by molecular testing. Most laboratories offer targeted testing for classical 1138 mutation in the FGFR3 gene. Broader sequencing of the FGFR3 gene, including multiple exons or the full gene, is suggested if the clinical diagnosis is in doubt and other conditions such as hypochondroplasia are suspected. Parents should consult with a geneticist during the initial evaluation to discuss diagnosis, recurrence risk, and prenatal testing, when applicable.
Management of Achondroplasia
The management of achondroplasia focuses on maximizing functional capacity and monitoring, preventing, and treating complications.
Developmental delay – Physical therapy is appropriate for those children who present with delayed motor milestones in the first two years of life.
Activities of daily living – The limb shortening can interfere with daily self-care tasks such as reaching out, feeding, bathing, dressing, and independent toileting and self-care. Thus, adaptive arrangements are very important. An example is adapting furniture used in the home and school environment, such as using lower chairs and desks or using stools to reach the toilet seat or sink. In addition, hand extenders can be used for reaching objects or self-cleaning. Occupational therapy is also important for individuals with achondroplasia to achieve their best functional potential.
Growth Use of growth hormone is not recommended and can potentially worsen the disproportion seen in these patients. Vosoritide, a recombinant C-type natriuretic peptide analog that stimulates endochondral ossification, a process that is normally inhibited in patients with achondroplasia, is under investigation. In a phase-II study, 35 children with achondroplasia aged 5 to 11 years were enrolled… The annualized height growth velocity in all cohorts increased by 1.10 to 2.34 cm per year from baseline and was sustained during the treatment period… A phase-III randomized trial and open-label extension study are ongoing and include children as young as six months of age.
Limb-lengthening surgery – Limb-lengthening surgeries have been used in the past and are resurging due to emerging surgical techniques. However, these therapies have a high financial and social cost.
Weight management – Avoiding obesity should be discussed early on.
Otitis media – An aggressive approach to preventing and treating otitis media in infancy and childhood is required to avert problems related to speech development.
Leg bowing – The initial leg bowing due to joint laxity is addressed by physical therapy and rarely braces. Leg bowing after five to six years of age due to tibial bowing and fibular overgrowth requires frequent monitoring and, if needed, surgical intervention that may include osteotomies of the proximal fibula and epiphysiodesis
Cervical medullary compression – Neurosurgical referral is indicated in children with suspected compression of the cervical medullary junction. Patients with cervical medullary compression should avoid contact sports, trampoline use, diving, and gymnastic exercises or other athletic activities that could aggravate the compression.