Achondroplasia

Roshni Sonawane
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Achondroplasia - Treatment
A) Short stature: Surgical: Limb lengthening procedures have demonstrated an increment in the height by 12-14 inches. These, however, need to be opted for in the light of the involved risk of significant surgical complications and financial issues. Overall surgical procedures rely on highly specialized surgical expertise in addition to the need for multidisciplinary allied health teams. On a positive note, limb lengthening procedures using intramedullary skeletal kinetic distractor (ISKD) mechanism distraction devices and external fixation have shown promising results with minimal or no side effects in few case studies. The recommended age for surgery has two schools of thoughts. One group suggests early surgical intervention by 6-8 years of age while many experts recommend delaying the decision until the young person is competent to contribute to the decision-making process. Nonsurgical: Recombinant Growth Hormone (rhGH) treatment has not been very promising in increasing the final height.

B) Disease Surveillance and Management of the complications: The natural trajectory can be modified by preventive management strategies thus decreasing the potential morbidity and mortality and improving the life expectancy and quality.

Care during pregnancy: The large head of the Achondroplastic fetus is speculated to increase a risk of intracranial bleeding during delivery. An elective cesarean section is recommended to avoid complications related to cephalopelvic disproportion. General anesthesia is preferred over spinal or epidural anesthesia due to the risk of lumbar spinal stenosis. Monitoring respiratory function especially in the last trimester has also been stated.

Craniocervical junction compression: Regular clinical assessments including neurologic history and examination, computerized tomography of the craniocervical junction, and polysomnography should be performed. Also, baseline computerized tomography of the brain should be done. Referral to Pediatric neurosurgeon if above assessment suggests symptomatic suboccipital decompression in the form of lower limb hyperreflexia (clonus), central hypopnea (polysomnography) and CT indicating formanina magnum stenosis. They may consider foramen- magnum decompression.

Hydrocephalus: Clinical and radiological surveillance for symptomatic hydrocephalus include monitoring head circumference:
a) Every monthly in the first year
b) Every three monthly in the second year and
c) Every six monthly after that.
It also includes regular neurodevelopmental assessments. If there is abnormal rise in the head circumference or abnormalities on neurodevelopmental evaluations, cranial ultrasound should be organized at two monthly intervals starting when the infant is two month old, to monitor the ventricular size, look for the presence or absence of hydrocephalus, and possible intracranial bleed. Neuroimaging can be requested after six months of age (baseline CT scan of the brain). Achondroblasts may have isolated megalencephaly or associated communicating hydrocephalus or have dilated ventricles without hydrocephalus. Evidence of an elevated intracranial pressure on above clinical and radiological evaluation warrants an urgent referral to a neurosurgeon. Ventriculo-peritoneal shunt procedures may be performed if required.

Growth and Physical Activities: Regular monitoring of height, weight, and head circumference in childhood using growth curves standardized for achondroplasia can support early detection of obesity commonly presenting during childhood. Education of families regarding avoidance of activities placing child at risk of neck and back injury and compression of spinal cord while providing information about alternative options for recreation.

Obstructive Sleep Apnoea (OSA): Common in the first five years of life. If the patient has severe nocturnal or daytime symptoms, polysomnography should be organized. In cases of severe OSA, pediatric ENT referral is needed for contemplating adenotonsillectomy. Also, management obesity should be planned. In the case of worsening of symptoms, respiratory support like Continuous positive airway pressure (CPAP) may be required. Tracheostomy has been offered in very extreme circumstances.

Hearing and language development: Preventive strategies that should be adopted are, appropriate management of the recurrent otitis media and early detection by auditory screening at one year for hearing impairment. Also important to monitor for age-appropriate development of expressive language.

Dentition: Bracing or tooth extraction are the options for the defect in dental alignment noticed in older children.

SPINE: Kyphosis: Family should be educated to provide back support to the affected child during the first year of life and to avoid curled up position. Twice yearly clinical surveillance until the child is three years old helps in an early pick up of clinical worsening. If the kyphosis persists after ambulation, bracing can be used to stop its progress. If it continues in extreme cases, radiological evaluation and consideration of spinal surgery to prevent neurological sequelae is required.

Lumbar stenosis: Detailed neurological assessment in adults every 3 to 5 years can assist in early detection of lumbar stenosis.

Therapeutic interventions: Multiple treatment strategies have been attempted to target the growth faltering effect of FGFR3 signaling by either blocking receptor activation or inhibiting downstream signals, since the late 1990s. Initially, these were adapted from oncologic biology based on comparisons between FGFR3 in Achondroplasia and oncogenic kinase at molecular levels. An FGFR3 inhibitor was developed based on the chemical kinase inhibitors used in cancer therapy. It demonstrated a selective preference for FGFR3 and successful growth stimulation in experimental animals. However, it was never explored further due to unclear reasons. Also an analog of C-type natriuretic peptide (CNP) that antagonizes the mitogen-activated-protein (MAP) downstream the FGFR3 signaling has been utilized. CNP is also evidenced to act independently. A significant increment in the growth rate of children with achondroplasia has been shown with six-month therapy with CNP in the preliminary results of phase 2 studies that were accompanied by minimal side effects. Statins and Meclizine are two recognized medications that have also demonstrated improvement in growth in experimental animals. Challenges of current therapeutic approaches: FGFR3 is expressed in other organs like brain, gastrointestinal system, pancreas and adrenal glands as well. Prevailing treatment strategies are systemic which means that adverse effects may occur in the other tissues with systemic administration of these therapeutic agents. There is an increasing need to target the therapeutic agents to the growth plate and or cartilage to minimize the associated side effects in other systems. Role of gene therapy in achieving these ‘targeted therapeutic measures’ is being explored.

Genetic implications: The risk of disease transmission from affected parent to offspring is 50 % for each pregnancy for either sex of the resulting child. The risk remains the same for each future pregnancy. Also, when both parents are affected, offsprings have 50% risk to have achondroplasia and 25 % risk to have lethal homozygous achondroplasia. The de novo mutations in patients with unaffected parents are known to arise from paternal germinal cells. There have been reports of recurrences of achondroplasia in siblings born to patients with unaffected progenitors. It is estimated to originate likely from germinal mosaicism in father. Recurrence risk in such situations is estimated to be very low at <1 %

Disease Prevention: Achondroplasia cannot be prevented in the majority of cases, as new spontaneous mutations occur. However, prenatal diagnosis and pre-implantation genetic diagnosis (PGD) can be offered when parents are affected, and it has been possible to identify the mutation present in the family members.


References
Achondroplasia Achondroplasia 04/04/2016
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