Achondroplasia

Achondroplasia is a common type of dwarfism.

The disease is related to the following processes:  congenital and has an incidence of about  0 / 100.000.

Overview

Achondroplasia is the most common type of short-limb skeletal dysplasia [1] [2]. It is a form of dwarfism characterized by intrinsic abnormalities in the growth of cartilage and bone [3] [4]. It causes short stature (dwarfism) with a standing height below the third percentile for age [4]. Achondroplasia accounts for 80% of all individuals recognized as "little people" [3]. It has an estimated worldwide prevalence of 250,000 [4] [5].

Achondroplasia is a genetically inherited disease caused by a gene mutation of the fibroblast growth factor receptor 3 (FGFR3) [6]. This gene mutation affects the cartilaginous growth plate of the growing skeleton [3] [7]. It can result in a variety of deformities and complications [3].

The disorder can be transmitted as an autosomal dominant disease from either or both parents [3] [7]. However, in 80% of affected infants it occurs as a new sporadic mutation, the highest incidence of which occur with fathers over 40 years of age [3].

The life expectancy of individuals with achondroplasia is significantly lower than those not affected [3] [4]. Achondroplasia is associated with a number of life-threatening complications related to its skeletal abnormalities [4] [8]. Early mortality is the result of complications due to skeletal deformities causing restrictive respiratory disease, neurologic deficits, and cardiovascular problems [4] [9].

Etiology

The term achondroplasia, though inaccurate, means absence of cartilage. It was first used by Parrot in 1878 [3]. Achondroplasia is the most common osteochondrodysplasia, a genetic disorder which is associated with abnormal bone growth at the growth plates [3] [7] [8]. The mode of inheritance is autosomal dominance, however, most cases represent as a new mutation [6] [8].

The genetic defect responsible for achondroplasia has been known for over a decade [3]. More than 95% of patients have a mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) [3] [7]. This gene is responsible for the transmission of the signal to stimulate bone growth. Without this activation, individuals with achondroplasia fail to grow, particularly, the long bones of the proximal extremities [7].

Achondroplasia is associated with a number of life-threatening complications [8] [9]. No effective treatments to stimulate bone growth have been found [3] [6]. Life-expectancy for those with achondroplasia continues to be 10 or more years shorter than the general population [4]. The causes of death for these individuals are related to the complications associated with the skeletal deformities and their impact on the neurologic and cardiovascular systems [3] [4] [9].

In children younger than 4 years, brain stem compression is the most common cause of death [4]. In those 5-24 years of age, the common causes of mortality are central nervous system and respiratory problems [4]. In persons aged 25-54 years, cardiovascular problems are the most frequent causes of death [4].

The complexity of the condition led to the development of Heath Supervision Guidelines published by the American Academy of Pediatrics in 1995 and revised in 2005 [8] [10].

Epidemiology

The prevalence of achondroplasia is estimated to be approximately 10,000 individuals in the United States and 150,000 to 250,000 worldwide [3]. The incidence of achondroplasia is 5–15 per 100 000 live births [2] [4].

Achondroplasia affects all races [2]. It occurs with equal frequency in males and females [2].
More than 95% of patients have a mutation in the gene for fibroblast growth factor receptor 3 [3]. 

Higher death rates when adjusted for age are seen in the affected population [4]. Heart disease-related mortality, between ages 25 and 35, is more than 10 times higher than the general population [4].

Sex distribution
Age distribution

Pathophysiology

The skeleton is divided into 2 parts, the axial skeleton, or central core unit, and the appendicular skeleton, the bones of the extremities [11]. The primary defect of achondroplasia is abnormal endochondral ossification of the appendicular skeleton [8] [11].

The molecular basis for achondroplasia is related to the fibroblast growth factors which are stimulate cell growth and migration, wound healing, and angiogenesis [7]. The cause of the disorder is a mutation of the fibroblast growth factor receptor 3 (FGFR3) [7] [3] located on the fourth chromosome [2]. The primary function of fibroblast growth factor receptor 3 is to limit osteogenesis [2] [7]. Fibroblast growth factor receptors transmit a mitogenic signal that is unique to growth plate chondrocytes [3] [7]. The mutation negatively regulates chondrocyte production and differentiation by suppressing mitogenic activity [9]. Recent research suggests that the disorder is due to increased signal transduction from the mutant receptor resulting in the failure of cell production and growth at the growth plate [2] [3].

The genetic abnormality responsible for achondroplasia is a single gene mutation on the short arm of the fourth chromosome [2]. It can be transmitted as an autosomal dominant trait or as a new random mutation [2] [3]. Eighty percent of cases are the result of a new mutation which is linked to a paternal age over 36 years [2] [7]. Most parents are of normal size with no family history of a dwarfism [2].

Prognosis

Overall survival and the average life expectancy for those with achondroplasia are decreased by approximately 10 years from the general population, despite advances in the knowledge of and health care needs [4] [10]. Early mortality generally results from the effects of skeletal and neurologic deformities, and is due to respiratory or cardiovascular complications [9].

The risk of producing a second affected child is negligible with a 1 in 443 risk of recurrence in the siblings of an affected child with unaffected parents [3] [7]. Normal sized siblings have no increased risk of producing a child with achondroplasia [7].

When both parents have achondroplasia [3] [7]:

  • 50% of their offspring are heterozygous and affected
  • 25% are homozygous which is usually fatal in the first few months of life
  • 25% are unaffected

If DNA testing shows the gene mutation present in both parents their infants have a 50% risk of inheriting affected genes from both parents (double homozygous). They are either stillborn or die shortly after birth [7].

Presentation

Achondroplasia is present at birth and is seen as disproportionately short-limbs, and specific facial features due to abnormal bone growth. Infants with achondroplasia suffer a high rate of apnea and sudden death in the neonatal period [12]. The principle features of achondroplastic dwarfism include [2] [7] [11] [13]:

  • Rhizomelic (proximal) shortening of the extremities with normal trunk size
  • Decreased growth of the long bones of the proximal extremities (humerus and femur)
  • Macrocephaly 
  • Abnormal development of the base of the skull with narrowing of the foraman magnum
  • Under-development of the mid-face
  • Stenosis of the spinal canal and intervertebral foramen
  • Genu varum

Macrocephaly is often present due to triventricular enlargement and hydrocephalus may result [8] [11]. However, intracranial pressure is not elevated significantly [8] [9]. The distinctive facial features include [3] [11]:

  • Frontal bossing 
  • Flattened nasal bridge
  • Hypoplasia of the mid-face
  • Prominent mandible

Achondroplasia is a short-limb dwarfism. These individuals have a sitting height that is normal, while standing height is below the third percentile. The mean adult standing height for men is 132 cm (52 in), and that for women is 125 cm (49 in) [3] [11]. The upper arms and thighs are more severely involved than the forearms, legs, hands, and feet [3]. There is normal development of clavicle and musculature resulting in broad, strong shoulders. The anterior-posterior chest diameter is flattened, lower ribs flared, and the abdomen protrudes [3] [11].

Complications associated with achondroplasia include [3] [9] [11] [14]:

  • Neurologic complications due to cervicomedullary compression: quadriparesis, paresthesia, paraparesis, incontinence, and sudden death
  • Respiratory complications: restrictive respiratory disease, respiratory insufficiency, apnea, pneumonia
  • Obstructive respiratory complications: upper airway obstruction, apnea, cyanotic episodes, feeding problem
  • Recurrent otitis media with subsequent hearing loss
  • Hydrocephalus
  • Spinal deformities: kyphosis, lordosis, scoliosis
  • Developmental delays
  • Obesity
  • Spinal stenosis
  • Genu varum
  • Cardiovascular complications

Respiratory complications

The most serious complications of achondroplasia are restrictive respiratory disease, apnea, pneumonia, and sudden infant death resulting from compression of the medulla oblongata [3] [12]. The prevalence of respiratory complications in this population is reported to be 12% versus 0.92% in the general population [12]. Pneumonia remains a primary cause of death [12].

Neurologic complications

Half of the patients with achondroplasia show neurological complications [2] [9]. Abnormal development of the base of the skull results in compression of the cervicomedullary region. Affected individuals also have smaller foramen magnum dimensions and abnormal shape [9] [11] [13]. These two conditions may cause respiratory insufficiency, apnea, cyanotic episodes, feeding problems, quadriparesis, and sudden death [9].

Spinal deformities are the most common and potentially disabling problems seen in achondroplasia [9] [11]. Stenosis of the spinal canal and intervertebral foramen can result in sensory deficits, lower and upper motor neuron involvement which result in low back pain, leg pain, dysesthesia, paresthesia, paraparesis, and incontinence [9]. 

Narrowing of the foramen magnum may result in a variety of neurologic problems in the first several years of life particularly [4] [9] [11]. It is the primary factor responsible for respiratory problems and sudden infant death of infants with achondroplasia in the neonatal period [4].

Abnormal curvature of the spine (kyphosis, lordosis, scoliosis) is present in 33-50% of adults with achondroplasia [9] [11]. It may cause back pain, respiratory dysfunction, neurologic deficits, or symptoms of spinal stenosis [9]. These abnormalities generally do not require treatment [10].

Developmental issues

In achondroplasia children milestones are delayed across all ages and domains compared with the general population [3] [14]. Children up to 7 years of age have a greater need for caregiver assistance in all areas [14]. Functional delays are related to musculoskeletal impairments [3] [14]. Head control, sitting, standing, and ambulation may lag by 3-6 months [8][14]. Children with achondroplasia show improvement in functioning with physical therapy between the ages of 3 and 5 years, but not after this [14].

Speech and language problems are common with achondroplasia. They are caused by tongue thrust that usually resolve spontaneously [8] [14]. Cognitive development and the intelligence levels in these children are generally normal [8] [14].

Recurrent otitis media is common due to poor drainage of the Eustachian tubes from underdevelopment of the mid-face. This may result in moderate to severe hearing loss [3] [10].

Obesity is a lifelong issue for affected individuals. As a result these individuals are at higher risk of chronic diseases such as diabetes and cardiovascular disease [3] [10]. These conditions have a direct causal relationship with early mortality rates due to stroke and myocardial infarction [10].

Workup

Diagnosis of achondroplasia is made based on physical examination and genetic testing [3] [10]. Early identification of the disorder is generally made either prenatally or in early infancy by the presence of the distinctive features of the disease [3]. These clinical findings include: shortened limbs especially of upper arms and legs, macrocephaly, abnormally shaped skull, flat face and abnormal maxilla [2]. The particular pattern of long-bone growth is specific to achondroplasia [2] [11].

Diagnosis of achondroplasia may also be made using prenatal ultrasonography to detect the skeletal abnormalities. However changes in limb lengths do not occur until 20-24 weeks’ gestation, after this time the growth rate decreases [2] [3].

Laboratory studies

Recent advances in molecular biology has made cell free fetal deoxyribonuleic acid (DNA) analysis allows genetic diagnosis of this condition using a maternal blood sample [2]. Analysis of plasma for the fibroblast growth factor receptor 3 (FGFR3) mutation in the mother can be done when a short-limb skeletal dysplasia is diagnosed prenatally on ultrasound [3] [7].

Imaging studies [10] [11]

  • Radiography: X-rays of individuals with achondroplasia show the characteristic features of the disease.
  • Ultrasonography of brain in the neonate can detect ventricle size and other abnormalities [9].
  • Computed tomography of brain, skull, trunk,and rib cage.
  • Magnetic resonance imaging evaluation is needed in any patient with neurological symptoms [9] [10]. A baseline scan is strongly recommended in infancy to evaluate potential problems [10]. 

Other tests when indicated [9] [10]:

  • Pulmonary function tests are indicated when respiratory symptoms are present. These show the vital capacity decreased by 68% for males and 72% for females.
  • Sleep apnea studies are useful in those with sleep hypoxia. 
  • Intracranial pressure monitoring with moderate ventriculomegaly. Treatment is recommended when the ICP is greater than 15 mm. 
  • Somatosensory evoked potential (SSEP) as abnormalities have been reported in 44% of patients with Achondroplasia.

Further evaluation of individuals with achondroplasia should include consultation by [8] [10]:

  • Geneticist
  • Neurologist, neurosurgeon
  • Pulmonary specialist
  • Orthopedist
  • Rehabilitation physiatrist
  • Speech therapist

Treatment

There is no specific treatment for achondroplasia at this time. Prenatal gene therapy is still in the future. Current therapy is essentially supportive to prevent the common complications associated with the disease [3] [10]. Therapeutic strategies are aimed at reducing fibroblast growth factor receptor 3 signals, such as kinase inhibitors and neutralizing antibodies [3] [6]. Administration of C-type natriuretic peptide is currently in the early stages of development. Further research into long-term effectives and safety of this drug is needed [3] [6].

Growth hormone is used to increase the height of patients with achondroplasia. There is no long-term data about the routine use of growth hormone and it remains controversial [3] [6]. There may be metabolic effects on the patient's lipid profile, bone mineral density, and muscle mass, and cardiovascular risk [6]. Somatotropin, a recombinant human growth hormone, for the treatment of short stature has shown acceleration in growth, particularly in the first year of treatment. It is recommended that therapy be started between age 1 to 6 years for maximum benefits [6].

Early identification and immediate cervicomedulary decompression procedure are needed to prevent serious neurological complications occurring in achondroplasia. These complications include respiratory failure, apnea and sudden death [9] [10].

Neurosurgical symptoms that may indicate the need for corrective surgery include back pain, muscle weakness, incontinence, hypotonia, psychomotor delay, apnea, and respiratory arrest [9][10].

Surgical procedures [3] [9] [10]:

  • Foramen magnum decompression and C1 laminectomy.
  • Ventriculoperitoneal shunts are indicated for patients with progressive hydrocephalus, increased intracranial pressures, and Chiari malformation.
  • Limb lengthening of the upper and lower extremities is controversial.
  • Surgical correction of genu varum.

Children with achondroplasia require more assistance for self-care and mobility skills. Interventions in this area should include physical therapy, occupational therapy, and speech therapy [8][14].

Obesity is a common complication in individuals with achondroplasia [15]. Obesity increases the risk for health problems such as cardiovascular disease and diabetes [5].

Prevention

Most serious complications of achondroplasia can be prevented or reduced by anticipation and early treatment [3] [10]. Early neurological evaluation and intervention when indicated are required to prevent the high morbidity and mortality in infancy and childhood [9].

Little People of America is an excellent resource for individuals with achondroplasia. This national organization deals with the social, physical, and medical needs of this population.

Patient Information

What is achondroplasia?

Achondroplasia is a form of dwarfism characterized by shortened extremities with near normal trunk length. It is accompanied by a larger than normal head and specific, distinctive facial features. It is present at birth and accounts for a high rate of deaths in the neonatal period and early infancy. In those individuals with Achondroplasia, who survive early childhood, life expectancy is generally shorter due to cardiovascular and respiratory complications.

What causes achondroplasia?

Achondroplasia is a genetically inherited disorder due to a mutation on the gene that controls bone growth at the growth plates of the long bones. It affects primarily the long bones of the upper arms and legs, the rib cage, and the bones of the base of the skull and face.

What are the symptoms?

Decreased growth of the long bones of the extremities ( humerus and femur),

  • Abnormal development of the base of the skull
  • Narrowing of the spinal canal
  • Under-development of the mid-face with characteristic features
  • Macrocephaly (enlarged head)

Who gets Achondroplasia?

Achondroplasia is an inherited genetic disorder. Individuals with this disease inherit it from either one or both of their parents. The majority inherit it due to a new, mutation in the gene from one parent (paternal age over 40 years has been associated with a high incidence of achondroplasia).
Parents generally are of normal height.

How is it diagnosed?

Achondroplasia is usually diagnosed by its characteristic skeletal features seen at birth or on prenatal ultrasound. Definitive diagnosis is made by the presence of the gene mutation on DNA analysis.

What are the complications?

The complications of achondroplasia are related to the skeletal deformities associated with the disease and include:

  • Neurologic complications: motor and sensory deficits, incontinence, and sudden death
  • Respiratory complications: apnea, pneumonia
  • Obstructive respiratory complications: upper airway obstruction, apnea, feeding problems
  • Hydrocephalus
  • Recurrent otitis media with subsequent hearing loss
  • Spinal deformities: kyphosis, lordosis, scoliosis
  • Developmental delays
  • Obesity
  • Genu varum (bowing of lower legs)
  • Cardiovascular complications and diabetes

How is achondroplasia treated?

There is no specific treatment at this time. Research is being done on genetic interventions to overrule the effects of the gene mutation. The individual with achondroplasia is currently treated to prevent the life threatening complications of the disease. Early intervention and treatment to prevent neurologic and respiratory defects and prevention of obesity will hopefully extend the life expectancy of these individuals.

How can achondroplasia be prevented?

Achondroplasia cannot be prevented currently, however, research is being done involving gene therapy. Genetic counseling and prenatal testing can predict the disorder. Most serious complications can be prevented or reduced by anticipation and early treatment. Early neurological evaluation and intervention, when indicated, can prevent the high morbidity and mortality in infancy and childhood.

Search symptoms now!

References

  1. Achondroplasia. (2015). In Encyclopædia Britannica. 
  2. Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, J. Cole T. New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol . 2011; 37: 283–289.
  3. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-72. 
  4. Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT. Mortality in achondroplasia study: A 42-year follow-up. Am J Med Genet A. 2007;143(21):2502-11. 
  5. Hoover-Fong JE, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr. 2008;88(2):364-71. 
  6. Mehta A, Hindmarsh PC. The use of somatropin (recombinant growth hormone) in children of short stature. Paediatr Drugs. 2002;4(1):37-47. 
  7. Wang Q, Green RP, Zhao G, Ornitz DM. Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development. 2001;128(19):3867-76. 
  8. Ireland PJ, Johnson S, Donaghey S, Johnston L, Ware RS, Zankl A, et al. Medical management of children with achondroplasia: Evaluation of an Australasian cohort aged 0-5 years. J Paediatr Child Health. 2012:48(5);443-9. 
  9. Gil Z, Tauman R, Sivan J, et al. Neurosurgical aspects in achondroplasia: evaluation and treatment. Harefuah. 2001;140(11):1026-31, 1118.
  10. American Academy of Pediatrics Committee on Genetics. Health supervision for children with achondroplasia. Pediatrics. 1995;95(3):443-51. 
  11. Smoker WR, Khanna G. Imaging the craniocervical junction. Childs Nerv Syst. 2008;24(10):1123-45.

  • A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia - A Superti-Furga, B Steinmann, R Gitzelmann - European journal of , 1995 - Springer
  • A Case of Recurrent Craniopharyngioma - G Gayen, NC Mahapatra - 30th WB State PEDICON 2011, 2011 - iapwb.in
  • Anaesthesia for the achondroplastic dwarf - JF Mayhew, J Katz, M Miner, B Leiman - Canadian Journal of , 1986 - Springer
  • Achondroplasia and hydrocephalus A computerized tomographic, roentgenographic, and psychometric study - SM Mueller, W Bell, S Cornell, K deS HAMSHER - Neurology, 1977 - AAN Enterprises
  • 'Short stature in children-a questionnaire for parents': a new instrument for growth disorder-specific psychosocial adaptation in children - F Haverkamp, M Noeker - Quality of Life Research, 1998 - Springer
  • And genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome - Z Vajo, CA Francomano, DJ Wilkin - Endocrine reviews, 2000 - Endocrine Soc
  • A gene for achondroplasia–hypochondroplasia maps to chromosome 4p - M Le Merrer, F Rousseau, L Legeai-Mallet - Nature , 1994 - nature.com
  • Achondroplasia - LO LANGER, PA BAUMANN - American Journal of , 1967 - Am Roentgen Ray Soc
Search symptoms now!