AUTHOR INFORMATION

Section 1 of 12

Authored by Joo-Hee Grace Park, DO, Department of Emergency Medicine, Assistant Professor of Emergency Medicine, Division of Pediatric Emergency Medicine, University of New Mexico

Coauthored by Robert Wallerstein, MD, Chief, Genetics Service, Department of Pediatrics, Hackensack University Medical Center

Joo-Hee Grace Park, DO, is a member of the following medical societies: American Academy of Pediatrics

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; 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; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Joo-Hee Grace Park, DO
Editor's Email:	James Bowman, MD

eMedicine Journal, April 4 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 12

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:

• In the US: Frequency has not been documented in the United States.

• Internationally: 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

Section 3 of 12

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.

DIFFERENTIALS

Section 4 of 12

Other Problems to be Considered:

Clinical and radiologic features of achondroplasia are distinctive; identification of affected children should not be confusing. Genetic studies can assist identification.

Hypochondroplasia (milder form of achondroplasia)

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

One case report described an infant with both achondroplasia and hypochondroplasia. The infant had skeletal manifestations similar to those found in patients with achondroplasia. Severe motor and, possibly, mental delays were present.

WORKUP

Section 5 of 12

Lab Studies:

• Commercially available direct DNA analysis of FGFR3 mutations identifies the G1138 (G380R) mutation, a novel missense mutation (Lys650Met) in tyrosine kinase, and the Gly380Arg mutation. Direct DNA analysis of FGFR3 mutations can be used for prenatal screening in families at risk (ie, parents who are heterozygous for either the G1138A or the G1138C mutation).



• Epiphyseal growth plate cartilage findings are histologically, immunohistochemically, biochemically, and electron microscopically normal.

Imaging Studies:

• Diagnosis is based on typical clinical and radiologic features. Radiologic features confirm the diagnosis of achondroplasia and exclude other conditions.


• • Radiography
    • Perform a skeletal survey. Plain x-ray films obtained at birth can identify achondroplasia. Features include a contracted skull base, square-shaped long bones, trident hands, normal trunk length, proximal femoral radiolucency, and chevron-shaped distal femoral epiphysis. Growth plates are shortened.

    • When disproportionately short limbs are observed in the fetus on ultrasonography, plain film radiography performed after delivery may distinguish achondroplasia from other conditions.
  
  
  
  • MRI: MRI findings combined with somatosensory-evoked potentials can reveal spinal stenosis in the lumbar spine or foramen magnum.
  
  
  
  • Ultrasound
    • Perform head ultrasonography at birth and at ages 2 months, 4 months, and 6 months to monitor ventricular size for possible hydrocephalus and possible intracranial bleeding. In addition, perform ultrasonography if the fontanel is unusually large, the occipitofrontal circumference increases disproportionately, or symptoms of hydrocephalus develop.

    • Routine fetal ultrasonography is performed during prenatal visits of most pregnancies, even in low-risk pregnancies. In achondroplasia, ultrasonography is recommended for prenatal diagnosis if requested. Perform fetal ultrasonography to evaluate skeletal anomalies and to measure the long bones for size, shape, bowing, symmetry, and quality of calcification. Obtain serial ultrasonographs at the beginning of the second trimester to plot the femoral length growth curves to distinguish individuals with homozygous (lethal) and heterozygous (nonlethal) achondroplasia from unaffected individuals, since the characteristic features of heterozygous achondroplasia may not manifest until the second trimester. In addition, use fetal ultrasonography to evaluate the skull for size and shape.
  
  
  

TREATMENT

Section 6 of 12

Medical Care:

• Monitor growth.


• • Weight, head circumference, and occipitofrontal circumference monthly during the first year

  • Length and upper-to-lower segment ratio

  • Delay in motor milestones but speech is normal
  
  
  
• Perform careful neurologic examinations.

• Manage frequent middle ear infections and dental crowding.

• Control weight to prevent obesity.

• Therapy using growth hormone is described as follows:


• • The usefulness of growth hormone (GH) therapy in patients with achondroplasia need to be studied further.

  • Effects of GH therapy appear to continue to the second year of treatment.

    Many practitioners do not recommend growth hormone because of concern about increased deposition of abnormal bone and worsening of orthopedic issues such as kyphoscoliosis.

  
  
  
• Therapy using insulinlike growth factor (IGF)–1 or IGF-2 (single study/investigational) is described as follows:
  • No catabolic or anti-insulin effects are observed.

  • The ubiquity of the IGFs and their receptors is a disadvantage.

  • A future goal is to modify access of the appropriate ligand to the target tissue.



• Anti-inflammatory agents are useful in patients with degenerative joint disease.

• Transgenic mice with achondroplasia have been developed, which can potentially speed the research and development of drugs and provide animal models for gene therapy trials.

Surgical Care:

• Leg lengthening procedures using distraction osteogenesis have been performed successfully. Better outcomes are reported with the use of the Orthofix Garches lengthening device along with tenotomy of the Achilles tendon and syndesmosis, which provide the fewest complications with healing indices similar to those of other operative protocols. Another procedure associated with fewer complications in children and adolescents younger than 14 years is tibia, rather than femur, lengthening.



• In children with signs of craniomedullary compression, surgical treatment to release the compression can improve neurologic, cognitive, and respiratory functions. Indications for the possible need for suboccipital decompression include lower limb hyperreflexia or clonus on examination, central hypopnea demonstrated by polysomnography, and foramen magnum measurements lower than the mean.



• A lumbar laminectomy can be performed for spinal stenosis, which typically manifests in early adulthood.



• A spinal fusion can be performed for persistent kyphosis despite bracing and sitting modification.

Consultations:

• Refer the infant to a pediatric neurologist or pediatric neurosurgeon for reflex asymmetry, extreme hypotonia, early hand preference, or excessive head growth.



• Refer the infant to an ear, nose, and throat (ENT) specialist; orthopedist; pulmonologist; or physical therapist as needed.



• Refer to geneticists and genetic counselors for prenatal consultations.

Diet: Hunter et al recommend that children with achondroplasia remain within 1 standard deviation (SD) of the mean W/H curve for people with achondroplasia.

MEDICATION

Section 7 of 12

All of the medical treatments used in children with achondroplasia, including GH, have produced variable results.

Drug Category: Hormones -- GH stimulates growth of linear bone, skeletal muscle, and organs. It also stimulates erythropoietin, which increases RBC mass.

Drug Name	Growth hormone, human (Nutropin, Genotropin, Humatrope) -- Study results have been contradictory regarding usefulness in achondroplasia. One study of 35 children with achondroplasia showed an increase in growth velocity in the first 2 y of treatment and safety of growth hormone use for 5 y.
Adult Dose	0.1-0.3 mg/d SC initially
Pediatric Dose	GH deficiency: 0.15-0.3 mg/kg/wk SC divided into daily or 6 times/wk injections Achondroplasia: 0.04 mg/kg/d or 0.1 IU/kg/d SC
Contraindications	Documented hypersensitivity; closed epiphyses, actively growing intracranial tumor, any underlying intracranial lesion
Interactions	Glucocorticoids may decrease growth-promoting effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in diabetes; reconstitute with sterile water for injection if administering to newborns; rotate injection sites to avoid lipodystrophy

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• The following recommendations for the follow-up care in patients and the management of achondroplasia were presented at the first international symposium on achondroplasia:


• • Growth and head circumference measurements plotted on growth curves standardized for achondroplasia
  
  
  
  • Neurologic examinations, including CT scan, MRI, somatosensory-evoked potentials, and polysomnography
  
  
  
  • Management of frequent middle ear infections and dental crowding
  
  
  

Complications:

• Complications include cervicomedullary compression, spinal stenosis, restrictive and obstructive lung disease, otitis media, and tibial bowing. Other possible complications include development of thoracolumbar kyphosis, symptomatic hydrocephalus, or symptomatic upper cord compression.

Prognosis:

• Most individuals with achondroplasia are expected to have normal intelligence and a normal life expectancy.

Patient Education:

• Genetic counseling: Discuss the genetics of cause, recurrence risk, and prenatal diagnosis with families.



• Support groups may help in the following ways:


• • Provide practical information regarding solutions to problems in daily living, such as clothing and furniture resources
  
  
  
  • Provide emotional support
  
  
  
• The following information is adapted from “Health Supervision for Children with Achondroplasia” by the American Academy of Pediatrics Committee on Genetics:


• • Prenatal visits - Geneticists, obstetricians, and/or pediatricians to educate parents regarding the disorder, inheritance, and prognosis for offspring
  
  
  
  • Infants
    • Review the personal support available to the family.

    • Review contact with support groups.

    • Review the increased risk of serous otitis media because of short eustachian tubes. Indicate that an ear examination is needed with any upper respiratory tract infection.

    • Avoid infant carriers that place the infant in a curled-up position. This does not apply to car safety seats, which should always be used during automobile travel.
  
  
  
  • Early childhood (1-5 y)
    • Discuss adapting the home so the child can become independent (lower light switches and faucets and supply step stools).

    • Discuss adapting age-appropriate clothing with snapless easy-opening fasteners and tuckable loops.

    • Discuss adaptation of toys, especially tricycles, to accommodate short limbs.

    • Discuss adaptation of toilets to allow comfortable independent use, with an extended wand for wiping.

    • Discuss the use of a stool during sitting so that the child's feet are not hanging. Feet need support while the child is sitting in a chair. A cushion behind the child's back may be required for good posture.

    • Discuss orthodontic bracing in the future and the possible need for braces in children older than 5 years.

    • Encourage the family to develop activities in which the affected child can take part; avoid gymnastics, high diving, acrobatics, and collision sports.

    • Discuss how to talk with the child, friends, and family members about short stature.

    • Encourage preschool attendance so that the child can learn to socialize in an age-appropriate way, and work with parents to prepare the teacher and other children so that the child does not receive unnecessary special privileges.

    • Discuss toileting procedures and special preparations needed because of the child's short stature with school staff.

    • Discourage the child from jumping to decrease unnecessary stress on joints, particularly the joints of the spine.
  
  
  
  • Late childhood (5-13 y)
    • Discuss preparation of school personnel and furnishings to accommodate the child’s stature.

    • Prepare the child for psychosocial situations, and teach the child how to discuss issues.

    • Be sure children can explain their short stature and can ask for help in an appropriate way.

    • Children with achondroplasia usually are included in the regular education program.

    • Suggest adaptive aids in the school to help the child cope with heavy doors, high doorknobs, blackboard use, and a regular-sized desk, and ask the school to provide foot support. In addition, be sure that the child can use the restroom independently.
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Preventing serious complications involves taking a careful history and promptly referring the patient to appropriate subspecialists.


• • Suspect possible cervicomedullary compression with a history of pain, ataxia, incontinence, and apnea. Evaluate the patient for brisk reflexes, a small foramen magnum, and central hypopnea, which are indications for surgery to release cord compression. Failure to recognize severe compression and to take appropriate measures thereafter can result in respiratory arrest and progressive quadriparesis.
  
  
  
  • Patients with frequent otitis media may need evaluation for possible language development delays secondary to deafness.
  
  
  
  • A history of sleep disturbances and an increased head size may alert physicians to the presence of neurologic and respiratory complications.
  
  
  

Special Concerns:

• Pregnancy: Radiographic evaluation of the pelvis of a woman with achondroplasia is recommended before pregnancy to assess for narrow pelvis and difficulties with vaginal delivery.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A concerned mother who has just been informed that achondroplasia is suspected in her fetus asks her physician about the disorder, the inheritance, and the prognosis for offspring. Which of the following responses is most appropriate?

A: At least 50% of cases of achondroplasia are caused by a de novo mutation.
B: Diagnosis of the disorder is confirmed with certainty using radiograph findings obtained late in the pregnancy.
C: Most individuals with achondroplasia are expected to have normal intelligence and a normal life expectancy.
D: The child is expected to achieve a normal stature with administration of growth hormone.
E: Achondroplasia is caused by mutations in the FGFR3 gene, which is located on chromosome band 8p16.3.

The correct answer is C: At least 75-80% (not 50%) of cases of achondroplasia are due to a de novo mutation. In most fetuses, the diagnosis is not confirmed with certainty until after birth. Most individuals with achondroplasia are expected to have normal intelligence and a normal life expectancy. The child is not expected to achieve a normal stature with administration of growth hormone. The results of growth hormone administration have not been satisfactory. Achondroplasia is caused by mutations in the FGFR3 gene, which is located on band 4p16.3, not 8p16.3.

CME Question 2: Which of the following recommendations is appropriate for supervising the health of children with achondroplasia?

A: Perform head ultrasound at birth and at age 2 months, 4 months, and 6 months to monitor ventricular size, possible hydrocephalus, and possible intracranial bleed.
B: Measure occipitofrontal circumference monthly during the first year of life.
C: Assess growth and development in relation to age-appropriate growth charts for the general population.
D: A and B are correct.
E: A and C are correct.

The correct answer is D: A and B are correct. C is incorrect because the growth of children with achondroplasia should be plotted on growth curves standardized for achondroplasia, not age-appropriate growth charts for the general population.

Pearl Question 1 (T/F): Cesarean delivery is required in women with achondroplasia.

The correct answer is True: As a result of a narrow pelvis, women with achondroplasia must undergo cesarean delivery.

Pearl Question 2 (T/F): Tonsillectomy is the treatment of choice for sleep apnea in children with achondroplasia.

The correct answer is False: Results of tonsillectomy and adenectomy in these children compare poorly with results 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 patients with achondroplasia.

Pearl Question 3 (T/F): Indications for surgical correction of cervicomedullary compression include brisk reflexes, a small foramen magnum, central hypopnea, and hydrocephalus.

The correct answer is False: Indications for surgical correction of cervicomedullary compression include brisk reflexes, a small foramen magnum, and central hypopnea, but not hydrocephalus.

Pearl Question 4 (T/F): Parents with normal height cannot have a child with achondroplasia.

The correct answer is False: Achondroplasia is transmitted as an autosomal dominant trait with complete penetrance; however, 75-80% of cases are the result of de novo mutations.

PICTURES

Section 11 of 12

Caption: Picture 1. Height for females with achondroplasia (mean\standard deviation [SD]) compared to normal standard curves. The graph is based on information from 214 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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Caption: Picture 2. Height for males with achondroplasia (mean\2 standard deviations [SDs]) compared to normal standard curves. The graph is based on information from 189 males. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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Caption: Picture 3. Mean growth velocities (solid line) for males (top) and females (bottom) with achondroplasia compared to normal growth velocity curves. Dashed lines indicate 3rd percentile, mean, and 97th percentile. Data are from 26 males and 35 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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Caption: Picture 4. Upper and lower segment lengths for males (top) and (bottom) with achondroplasia (mean\standard deviation [SD]). Data are from 75 males and 95 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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Caption: Picture 5. Head circumference for females with achondroplasia compared to normal curves (dashed lines). Data are from 145 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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Caption: Picture 6. Head circumference for males with achondroplasia compared to normal curves (dashed lines). Data are from 114 females. Adapted from Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978 Sep; 93(3): 435-8.
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