Achondroplasia

Roshni Sonawane
Consultant Pediatrician
Rockingham General Hospital Western Australia

First Created: 02/20/2001  Last Updated: 02/20/2001

What is Achondroplasia?

Achondroplasia is the prototype and most common of the human chondrodysplasias. Chondrodysplasias are human bone genetic disorders causing a defect in the endochondral ossification at the growth plate (formation of bone from cartilage), resulting in skeletal malformations. Achondroplasia is the most frequent cause of short-limb dwarfism. It occurs in 1 out of every 10,000-30,000 live births.

How does Achondroplasia Occur?

Mutations in the Genes that are expressed in the cartilaginous growth plates are responsible for the occurrence of various chondrodysplasias. These genes normally play a fundamental role in the utilization of the cartilage for bone growth. Mutations in these genes compromise both the degree and quality of skeletal growth. Achondroplasia, in particular, is caused by heterozygous mutation in the fibroblast growth factor receptor-3 gene (FGFR3) on chromosome 4p16.3. It occurs as a spontaneous (de novo) mutation in almost 90% of cases, which means that parents are not affected. Advanced paternal age is considered a predisposing factor in these instances. Less commonly, familial cases have been reported. Here it is inherited as an autosomal dominant disease with virtually complete penetrance. In over 98% of patients with a mutation, the glycine residue replaces arginine at position 380 (Gly 380 Arg). It is described as a gain-of-function mutation that exaggerates the signal output of the FGFR3. FGFR3 is a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. FGFR3 seems to inhibit the proliferation and hypertrophy of growth plate chondrocytes.

Clinical Features of Achondroplasia

It does not have any predilection for any race or gender. The characteristic features at birth are macrocephaly, frontal bossing, midface retrusion, depressed nasal bridge, rhizomelic limb shortening, narrow trunk, and trident hand. The FGFR3 gene abnormality confirmation is not necessary for the diagnosis. Infants present with mild to moderate hypotonia and delayed motor developmental milestones. They have difficulty holding head due to the combination of macrocephaly and hypotonia.

Rest of the clinical spectrum evolves secondary to the abnormal linear growth as follows:
Extremities: Hyper-extensibility occurs in most joints, especially the knee joints. However, there is a restriction of extension and rotation of the elbow. There is a characteristic trident deformity of the hand. Also, genu varum deformity is seen in many adults.

Spine: Various deformities of the spine can be seen in patients with Achondroplasia. Thoracolumbar gibbus is commonly present at birth. In a few cases, it may fail to resolve spontaneously and lead to progressive neurologic sequelae in adulthood. Child carriers where sitting is unsupported, mechanical swings, jumpers, and umbrella-style strollers are suspected to enhance the risk of gibbus. Exaggerated lumbar lordosis develops with the onset of ambulation. Patients may complain of back pain and muscle fatigue. Finally, worsening upper lumbar spinal stenosis presents in adulthood with intermittent back pain, sciatica, radical claudication, and in extreme cases, loss of continence and lower limb function.

Growth: It is recommended to plot the growth parameters plotted on Achondroplasia-specific growth charts. These charts guide to identify individuals who vary from the norms for this population. Arm span, total body length, upper to lower body segment ratio, head circumference, and weight can be observed. Body mass index is not a reliable parameter. Growth disorders associated with Achondroplasia are

  • Short stature: The short stature progressively predominates during childhood and later adulthood. The average adult height is 131+/-5.6 cm for men and 124 +/- 5.9 cm for women.
  • Obesity: Mean weight in adults is 55 kg for males and 46 kg for females with a predisposition to obesity, which is a major problem in Achondroplasia. Excessive weight gain manifests since early childhood. In adulthood, obesity may worsen the aforementioned musculoskeletal problems like lumbar stenosis and the occurrence of non-specific joint pains, increasing the disease morbidity.
  • Failure to thrive: May occur in infants and children with respiratory compromise.

Neurological:

  • Megalencephaly and Macrocephaly: Both true megalencephaly and macrocephaly are features of Achondroplasia. There is also a narrowing of the foramen magnum which results in stenosis of the sigmoid sinus. This can elevate the intracranial venous pressure level and cause internal hydrocephalus.
  • Abnormalities at the craniocervical junction: Narrow craniocervical junction can also cause cervical cord compression. It may present with severe hypotonia, clonus, lower limb hyperreflexia, and central apnoea (confirmed on sleep studies).
  • Intelligence: It is unaffected in achondroplasia per se. However, it may be affected secondary to hydrocephalus or other central nervous system complication.

Respiratory problems secondary to the skeletal abnormalities in Achondroplasia:

These can be categorized as:

  • Relative adenoid and tonsillar hypertrophy due to mild mid-facial hypoplasia.

  • Muscular upper airway obstruction associated with progressive hydrocephalus due to jugular foramen stenosis.

  • Muscular upper airway obstruction due to hypoglossal canal stenosis (not associated with hydrocephalus).

  • Chronic recurrent otitis media, predisposed by multiple anatomical factors like midfacial hypoplasia, eustachian tubes shortening, small pharynx, and relative enlargement of tonsils and adenoids.

  • Central apnoea from brainstem compression.

  • Restrictive and obstructive pulmonary disease can also occur.

  • Obstructive sleep apnoea is frequently seen in pediatric as well as adult age groups. It occurs secondary to the anatomical changes leading to the shortening of upper airways.

Diagnosis

Antenatal diagnosis: In the antenatal period, the diagnosis is suspected on fetal ultrasound by the 3rd trimester. It can be confirmed with DNA testing if parents are affected, as homozygosity can be lethal in the antenatal period or the immediate postnatal period. Serial antenatal ultrasound scans may be useful to monitor the fetal growth in these situations.

Postnatal diagnosis: The distinctive clinical and radiological features support the diagnosis of achondroplasia at birth.

Typical Radiological features include:

  • Enlarged skull vault with small skull base

  • Short, thick long bones, especially in the proximal aspects

  • Flaring and cupping appearance of the metaphysics

  • Ball and socket or Chevron deformity of metaphysis- (appearance of the Epiphysis being encompassed by the two arms of the "V" shaped epiphysis).

  • Short hands with Trident pattern (increased distance between the 2nd and 3rd digits)

  • Coxa vara and genu varum deformity

  • The lumbosacral angle worsens with a gradual reduction in the interpedicular distance in the lumbar spine

  • ‘Vertical' appearance of squared iliac wings

  • Horizontal acetabulum and narrow sacroiliac notch

  • Proximal femoral radiolucency

Genetic tests: A genetic confirmation is only required if there is ambiguity in clinical diagnosis or for genetic counseling. Initially, Targeted mutation analysis for the two common mutations is tested. If it is negative and there is a high index of suspicion, a Sequence analysis can be performed.

Differential Diagnosis

  • Other conditions related to FGFR3 mutation:

    • Hypochondroplasia (shares the clinical and radiological features of Achondroplasia. The only difference is that it is milder. Molecular testing for the common FGFR3 mutation can assist with the definitive diagnosis of Achondroplasia.

    • Thanatophoric dysplasia - It is nearly always a lethal disorder. There is severe limb shortening, significant macrocephaly, and extreme chest constriction in addition to typical radiological features.

    • Homozygous Achondroplasia presents clinically similar to Thanatophoric dysplasia. Radiological features differentiate it from both, heterozygous Achondroplasia as well as Thanatophoric dysplasia.

    • Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN). Skeletal abnormalities are as grave as in thanatophoric dysplasia, however, it is accompanied by developmental retardation and acanthosis nigricans. Before the diagnosis of developmental retardation, during the early years, SADDAN can be differentiated from achondroplasia and thanatophoric dysplasia only by molecular testing.

    • FGFR-related craniosynostosis

  • Other skeletal dysplasias with similar dwarfism:

    • Cartilage-hair hypoplasia

    • Pseudoachondroplasia.

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 a few case studies. The recommended age for surgery has two schools of thought. 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 life expectancy and quality.

Care during pregnancy: The large head of the Achondroplastic fetus is speculated to increase the 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 the 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 month in the first year

b) Every three months in the second year and

c) Every six months after that.

It also includes regular neurodevelopmental assessments. If there is an 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 months 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 elevated intracranial pressure on the above clinical and radiological evaluation warrants an urgent referral to a neurosurgeon. Ventriculoperitoneal 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 the child at risk of neck and back injury and compression of the 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, a pediatric ENT referral is needed for contemplating adenotonsillectomy. Also, management of 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 of 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 the 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. The 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 a 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 the 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 preimplantation genetic diagnosis (PGD) can be offered when parents are affected, and it has been possible to identify the mutation present in the family members.

Complications of Achondroplasia

Achondroplasia is a non-lethal condition and Life expectancy remains overall unaffected. Also, they can function independently in the community to a large extent with appropriate adaptations. However, certain complications can increase the morbidity and mortality of the disease as follows:
A) During infancy, the risk of death is significantly increased due to central apnoea secondary to compression effects of the craniocervical junction.

B) Cardiovascular complications secondary to obesity can increase the prospect of death in young adults with achondroplasia.

C) Recurrent otitis media can cause hearing deficits which may compromise language development.

D) Also, fatal sudden upper airway obstruction can occur secondary to the anatomical changes as discussed above.

E) Neurological complications of symptomatic hydrocephalus during infancy and worsening lumbar spinal stenosis (cord compression) during adulthood can be debilitating sequelae.


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