eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Achondroplasia

Author: Joo-Hee Grace Park, DO, Assistant Professor, Department of Emergency Medicine, Division of Pediatric Emergency Medicine, University of New Mexico
Coauthor(s): Robert Wallerstein, MD, Chief, Genetics Service, Department of Pediatrics, Hackensack University Medical Center
Contributor Information and Disclosures

Updated: Apr 4, 2006

Introduction

Background

Achondroplasia is a common, nonlethal form of chondrodysplasia. It is transmitted as an autosomal dominant trait with complete penetrance. De novo mutations cause 75-80% of cases. The mutation rate is estimated to be 0.000014 per gamete per generation. Cardinal features include short stature, rhizomelic shortening of the arms and legs, a disproportionately long trunk, trident hands, midfacial hypoplasia, prominent forehead (frontal bossing), thoracolumbar gibbus, true megalencephaly, and caudal narrowing of the interpedicular spaces.

Pathophysiology

Achondroplasia is caused by mutations in the gene for fibroblast growth factor receptor-3 (FGFR3). The gene has been mapped to band 4p16.3. The common mutations cause a gain of function of the FGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production. G1138A and G1138C mutations account for approximately 99% of the mutations resulting in a specific amino acid substitution (G380R). A rare mutation is the novel missense mutation (Lys650Met) in the tyrosine kinase region, which results in a disorder termed severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Another mutation, Gly380Arg, has been reported in a Spanish population.

Frequency

United States

Frequency has not been documented in the United States.

International

Frequency is believed to be 1 case per 15,000-40,000 births worldwide. In 1986, Orioli et al reported the incidence rate to be 0.5-1.5 cases per 10,000 births. They assessed the prevalence of all skeletal dysplasias in their study population of 349,470 live births and stillbirths. The mutation rate was estimated to be 1.72-5.57 x 10-5 per gamete per generation.

Mortality/Morbidity

  • Sudden death in the first year of life is attributed to abnormalities at the craniocervical junction causing spinal cord compression. The rate of unexpected death in infants with achondroplasia is less than 3%.
  • Angular deformities of the extremities, premature degenerative joint disease, and spinal disorders are common clinical features.
  • Cervical instability, a potentially life-threatening dysplasia, occurs in a large percentage of patients.
  • Obesity, when present, aggravates the morbidity related to lumbar stenosis, nonspecific joint problems, and cardiovascular risks. According to the weight/height (W/H) curves developed by Hunter et al, the mean W/H curve in children with achondroplasia matches the control curve until the children reach 75 cm in height. Beyond 75 cm, the weight in children with achondroplasia increases disproportionately to height. The Quetelet index can be used to estimate weight excess in children aged 3-6 years; after that, the Rohrer index can be used in children and adolescents aged 6-18 years.
  • Respiratory disorders are seen frequently, including apnea and abnormalities of gas exchange. Studies report that as many as 75% of children with achondroplasia have a pathologic apnea index (>30 episodes).
    • Brainstem compression may contribute to central apnea, and obstructive apnea may be related to midface abnormalities.
    • The rate of severe upper airway obstruction is less than 5% in children with achondroplasia.
    • Restrictive pulmonary disease, with or without restrictive airway disease, occurs in fewer than 5% of children younger than 3 years.
    • Tonsillectomy and adenectomy do not yield satisfactory results in these children as in other children, possibly because in addition to adenotonsillar hypertrophy, hypotonicity and a narrowed body confining the airway may contribute to upper airway obstruction in children with achondroplasia.
    • As seen in other children with obstructive sleep apnea (OSA), in children with achondroplasia, respiratory dysfunction detected in polysomnograms is associated with cognitive deficits.
  • One study of school-aged children with achondroplasia reported CT findings of kinking of the medulla and neuroanatomic abnormalities consistent with arrested hydrocephalus, including enlarged ventricles and hypoplasia of the corpus callosum. These CT findings are similar to those seen in children with compensated and unshunted hydrocephalus. The hydrocephalus may be due to increased intracranial venous pressure secondary to stenosis of the sigmoid sinus at the level of the narrowed jugular foramina. Although their cognitive scores are average, children with achondroplasia show mild deficits in visual-spatial tasks, similar to children with arrested hydrocephalus.
  • Motor milestones usually are delayed, possibly secondary to hypotonia, but speech is normal.

Race

No documented race predilection exists.

Sex

Males and females are affected equally.

Clinical

History

Although achondroplasia often is caused by a de novo mutation, it may be helpful to identify families at risk, such as parents who are heterozygous for either the G1138A or G1138C mutation.

  • After diagnosis, obtain the following history to prevent serious complications:
    • Suspect possible cervicomedullary compression with a history of pain, ataxia, incontinence, and apnea. Cord compression may result in respiratory arrest and progressive quadriparesis. Indications for surgery to release the compression include brisk reflexes, a small foramen magnum, and central hypopnea.
    • Obtain a careful history of frequent otitis media to prevent possible deafness and language development delays.
    • A history of sleep disturbances and increased head size may alert physicians to neurologic and respiratory complications.

Physical

  • Head and neck - Characteristic facies with frontal bossing and midface hypoplasia
  • Skeletal features
    • Contracted skull base
    • Average adult male height of 131 cm; average adult female height of 124 cm
    • Normal trunk length
    • Rhizomelic shortening of the limbs with trident hands and brachydactyly
    • Thoracolumbar gibbus in infancy, which usually disappears with walking and is replaced by an exaggerated lumbar lordosis
    • Large calvarial bones in contrast to the small cranial base and facial bones
    • Progressive interpedicular narrowing at the lumbar spine
    • Limited elbow extension
    • Genu varum
    • Short pedicles, which can cause spinal stenosis; short femoral neck; metaphyseal flaring; dysplastic ilium; narrow sacroiliac groove; and flat-roofed acetabula

Causes

Advanced paternal age is identified as a risk factor in sporadic cases of achondroplasia, suggesting that factors influencing DNA replication or repair during spermatogenesis may predispose men to the occurrence of G1138 FGFR3 mutations.

More on Achondroplasia

Overview: Achondroplasia
Differential Diagnoses & Workup: Achondroplasia
Treatment & Medication: Achondroplasia
Follow-up: Achondroplasia
Multimedia: Achondroplasia
References
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Further Reading

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Keywords

achondroplasia, short stature, chondrodystrophy, skeletal dysplasia, osteochondrodysplasia, disproportionately short stature, dwarfism, rhizomelic shortening of limbs, disproportionately long trunk, trident hands, midfacial hypoplasia, prominent forehead, frontal bossing, thoracolumbar gibbus, megalencephaly, caudal narrowing of interpedicular spaces, chondrodysplasia

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Contributor Information and Disclosures

Author

Joo-Hee Grace Park, DO, Assistant Professor, Department of Emergency Medicine, Division of Pediatric Emergency Medicine, University of New Mexico
Joo-Hee Grace Park, DO is a member of the following medical societies: American College of Osteopathic Pediatricians, American Medical Association, and American Osteopathic Association
Disclosure: Nothing to disclose.

Coauthor(s)

Robert Wallerstein, MD, Chief, Genetics Service, Department of Pediatrics, Hackensack University Medical Center
Disclosure: Nothing to disclose.

Medical Editor

James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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