Achondroplasia

What is achondroplasia?¹

Achondroplasia is the most frequent form of short-limb dwarfism.² As well as short stature due to shortening of limbs, affected individuals have characteristic facies with frontal bossing and mid-face hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum and trident-like hands. Incidence increases with paternal age.

99% of patients have the heterozygous c.1138G>A variant and 1% the c.1138G>C variant in the fibroblast growth factor receptor 3 (FGFR3) gene. The pattern of inheritance is autosomal dominant, with a penetrance of 100%.

In 80% of cases, the disease is caused by a de novo variant, not inherited from the parents, and associated with advanced paternal age (generally over 35 years).

FGFR3 is also important in craniofacial, vertebral and neurological development such that this mutation has multiple effects in an affected individual.³

How common is achondroplasia? (Epidemiology)

• Achondroplasia is apparent at birth and has a birth prevalence of 1 in 20,000-30,000 live-born infants. Although it is inherited as an autosomal dominant condition, 80% of cases occur sporadically.⁴

• Incidence increases with paternal age.⁵

• For couples of average stature who have a child with achondroplasia, the risk of recurrence is less than 1%, reflecting the risk of germline mosaicism.⁶

Symptoms of achondroplasia (presentation)⁷

• In the homozygous form the condition is severe and lethal.

• At birth or within the first year of life, with disparity between large skull, normal length trunk and short arms and legs.

• The chest is usually very narrow.

• Fingertips may only come down to the iliac crest.

• Shortness is particularly evident in the proximal segments of limbs.

• Limbs appear very broad with deep creases and trident-like hands with short fingers.

• There is often increased joint laxity.

• Skull shows a bulging vault, small face and a flat nasal bridge or 'scooped out' glabella.

• Spine shows marked lumbar lordosis.

• Frontal bossing, depressed nasal bridge.

Differential diagnosis

• Hypochondroplasia: less pronounced skeletal disproportion and spinal abnormalities with the skull unaffected.

• Achondroplasia-like dwarfism (distinguish radiologically).

• Spondyloepiphyseal dysplasias: the spine is mainly affected, with the trunk short as well as the limbs.

• Proportionate dwarfism.

Diagnosing achondroplasia (investigations)

• The diagnosis is based on the typical clinical and X-ray features.

• Prenatal diagnosis is by ultrasound. However, prenatal sonographic diagnosis often fails as limb length is preserved until around 22 weeks of gestation, after the time of the routine fetal anomaly scan.⁸

• The use of MRI in the prenatal diagnosis of skeletal dysplasia has also been researched and has been shown to confirm the diagnosis in 82% of cases.⁹

• Prenatal diagnosis of homozygous achondroplasia is also available in families at risk and in which the parents are heterozygous for either the 1138A or 1138C allele.

• Plasma can be analysed for the FGFR3 mutation in the mother when a short-limb skeletal dysplasia is diagnosed prenatally on ultrasound.¹⁰

• A full skeletal survey should be undertaken if there is clinical suspicion of skeletal dysplasia, such as disproportionate short stature, limb malalignment or specific dysmorphic features.¹¹

• Confirmatory molecular analysis to detect the recurrent G380R FGFR3 mutations may be helpful where there is residual doubt about the diagnosis.¹²

• X-rays show metaphyseal irregularity, flaring in the long bones, and late-appearing irregular epiphyses. The pelvis is narrow in anteroposterior diameter with deep sacroiliac notches and short iliac wings. The spine shows progressive narrowing of the interpedicular distance from top to bottom (reverse of normal).

• Investigation of possible cranial abnormalities and hydrocephalus includes ultrasound, and CT and MRI scans. Detailed imaging of the craniocervical junction is particularly important in infants in order to rule out spinal cord compression (see 'Complications', below).

• However, one recent study has shown that cervical cord lesions are observed in around 40% of people with achondroplasia and this are actually not associated with any clinical symptoms.¹³

• Molecular genetic testing is the gold standard. Whilst clinical and X-ray features will identify the majority of patients, this is the only means of differentiating achondroplasia from the other forms of skeletal dysplasias. It is also a helpful investigation prior to considering therapeutic options and genetic counselling.²

Management of achondroplasia

• It is recommended that all people with achondroplasia be followed up regularly to detect the significant complications that occur in approximately 10% of these children.¹¹

• There are condition-specific centile charts available to monitor the growth of children with achondroplasia.¹⁴

• Upper to lower segment ratio should be monitored.

• Dental treatment for crowding of teeth.

• Management of frequent middle ear infections. Treatment of obstructive sleep apnoea - eg, adenotonsillectomy, weight loss and continuous positive airway pressure.

• As excess weight gain is often a significant issue for many affected children, regular height and weight measurement later in childhood and an emphasis on maintaining weight gain within acceptable limits from an early age are very important.¹¹

• Recombinant human growth hormone possibly enables better growth pattern in children with achondroplasia, especially in combination with l-thyroxine and surgical elongation of tibia and/or femur, but there is a theoretical possibility of the appearance of acromegaly, and an increase in foramen magnum narrowing with spinal cord compression.⁹

• Anti-inflammatory drugs may be helpful in patients with degenerative joint disease.

• Surgical intervention includes enlargement of the foramen magnum in cases of severe stenosis, lengthening of the limb bones, tibial osteotomy or epiphysiodesis of the fibular growth plate to correct bowing of the legs, and lumbar laminectomy for spinal stenosis (typically presents in early adulthood).

Complications of achondroplasia

The degree of complications and disability is variable:

• Gross motor skills in particular develop later in the child with achondroplasia; approximately 50% of children will sit alone by 9 months and just over 50% will walk alone by 18 months.¹¹

• Short arms, limited elbow and hip extension, and knee and leg deformities can cause disabilities in arm function and locomotion.

• A progressive, unresolving thoracolumbar kyphosis can occur.

• Hydrocephalus, a narrow foramen magnum, spinal deformity, and spinal canal stenosis can cause neurological problems (eg, progressive quadriparesis, pain, ataxia, incontinence) leading to disabilities in locomotion, communication, and learning.

• Skeletal disproportion can lead to early osteoarthritis, problems with childbirth in women, hydrocephalus and paraplegia.

• Narrowing of the spinal canal causes symptoms of spinal stenosis.

• Obesity is common; once the child has reached 75 cm there tends to be a disproportionate increase in weight compared with height.

• Ear, nose and throat abnormalities such as recurrent otitis media, upper respiratory tract obstruction, deafness, speech delay, and jaw malocclusion can also lead to disabilities in communication and learning.¹¹

• Respiratory complications may include apnoea (including obstructive sleep apnoea) and abnormalities of gas exchange.¹⁵ Children with respiratory dysfunction may be associated with cognitive deficit.

• The most severe complication results from craniocervical stenosis and medullary and upper spinal cord compression, which can have devastating and even lethal sequelae during early childhood.⁴

Prognosis

• Life expectancy is normal in the majority of cases.

• Overall cognitive scores are normal but some children may exhibit mild deficits in visual-spatial tasks.

• Final height varies between 80 cm and 150 cm.

• Death in the first year of life can occur due to pressure on the spinal cord, caused by abnormalities at the craniocervical junction.