You are in: eMedicine Specialties > Radiology > PEDIATRICS AchondroplasiaArticle Last Updated: Jul 22, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia Ali Nawaz Khan is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the United States, Royal College of Radiologists, and Royal College of Surgeons of England Coauthor(s): Rumana Rahim, MBBS, MRCS, Staff Physician, Department of Radiology, North Manchester General Hospital; Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute Editors: Lori Lee Barr, MD, FACR, FAIUM, Clinical Associate Professor of Radiology, University of Texas Health Science Center in San Antonio; Clinical Assistant Professor of Radiology, University of Texas Medical Branch at Galveston; Member, Board of Directors, Austin Radiological Association; Consulting Staff, Seton Health Network, Columbia/St David's Healthcare System, Healthsouth Rehabilitation Hospital of Austin, Georgetown Hospital, St Mark's Medical Center, Cedar Park Regional Medical Center; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Felix S Chew, MD, MBA, EdM, Professor, Department of Radiology, Vice Chairman for Radiology Informatics, Section Head of Musculoskeletal Radiology, University of Washington Author and Editor Disclosure Synonyms and related keywords: achondroplasia, osteochondrodysplasia, short-limb dwarfism, dwarfism, inborn genetic disease, bone growth disorder, bone disease, developmental bone disease, chondrodystrophia fetalis, hypoplastic chondrodystrophy, chondrodystrophies, achondroplastic dwarfism, Parrot's disease, rickets fetal, ACH, metatrophic dwarfism II, Kniest syndrome, Kniest's syndrome, pseudoachondroplasia, PSACH, FGFR3 gene INTRODUCTIONSection 2 of 11
  BackgroundAchondroplasia is an inherited disorder of bone growth that causes the most common type of dwarfism. It is 1 of the groups of disorders collectively called chondrodystrophies. Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head with frontal bossing, a narrow thorax, a waddling gait, and characteristic facial features. Intelligence and life span are usually normal, though the risk of infant death from compression of the cervical spinal cord and/or upper airway obstruction is increased. Achondroplasia is inherited as an autosomal dominant trait. However, approximately 80% of cases appear to be the result of spontaneous mutations. If 1 parent has achondroplasia, there is a 50% likelihood of the infant's inheriting the disorder. If both parents have the condition, the likelihood increases to 75%. Achondroplasia can be diagnosed on the basis of characteristic clinical and radiographic findings in most affected individuals. In infants, in whom the diagnosis can be difficult, and with individuals with atypical findings, molecular genetic testing can be used to detect a mutation in the FGFR3 gene (locus 4p16.3). Such testing detects mutations in 99% of affected individuals and is available in clinical laboratories.1, 2 PathophysiologyAchondroplasia is a genetic disorder of endochondral bone with an autosomal dominant mode of inheritance. Achondroplasia may be inherited in a homozygous or heterozygous manner. Heterozygous disease is a common skeletal dysplasia, with a rate of 1 case per 26,000 births. Approximately 80% of all cases of achondroplasia are the result of a spontaneous mutation that causes rhizomelic shortening, a large head with frontal bossing, depressed nasal bridge, short trident hands, and lumber lordosis. Mental and sexual development and life span are normal. Homozygous disease is lethal because of respiratory difficulties resulting from thoracic constriction. It is important that homozygous disease be distinguished from heterozygous disease prenatally so that an informed decision can be made regarding continuation of the pregnancy. Penetrance of the gene is 100%, which means that all individuals who have a single copy of the altered FGFR3 gene have achondroplasia. The risk of achondroplasia is low when 1 parent is heterozygous; in such cases, the rate is 1 case per 50,000, or 0.002%. When both parents are heterozygous, the rate is 25%. The skeletal changes in achondroplasia reflect retarded endochondral bone formation. The major defect occurs at the epiphyseal osteochondral junction and is associated with loss of the palisade of growing cartilaginous spicules. It is this palisade of spicules that undergoes provisional calcification and eventually ossification. Premature ossification results in a transverse barrier at the osteochondral junction. The result of this anomaly is that the long bones are abnormally short; however, because appositional growth is not affected, the bones are usually wide. The skull, which does not depend on endochondral bone formation, is large. The length of the vertebral column is relatively normal, but there is some flattening of the vertebral bodies; because of other changes in the body habitus, kyphoscoliosis and other vertebral deformities are relatively common. The achondroplastic foramen magnum is small at birth. During the first year, its rate of growth is severely impaired, especially in the transverse dimension. This markedly diminished growth results not only from abnormal endochondral bone growth but also from abnormal placement and premature fusion of the synchondroses. The most important complications in people with achondroplastic dwarfism are neurologic problems related to a narrowed spinal canal. Stenosis of the spinal canal is secondary to abnormalities of endochondral ossification with premature synostosis of the ossification centers of the vertebral body and the posterior arch. This results in thickening of the laminae, shortening of the pedicles, and a reduction in the height of the vertebral bodies. Additional factors, such as prolapsed intervertebral disks, osteophytes, and progressive thoracolumbar kyphosis, contribute to the narrowing of the spinal canal.3 Patients with achondroplasia undergo dynamic changes in brain morphometry, resulting in a rostral displacement of the brainstem with gradual compression of the frontal lobes. This is the result of enlargement of the supratentorial ventricular spaces, commensurate with an increase in venous sinus distention.4 The amount of blood flow in the superior sagittal sinus is correlated with brain maturation. Hydrocephalus associated with achondroplasia is closely related to reduction in blood flow in the superior sagittal sinus — a finding that supports the hypothesis that in patients with achondroplasia, hydrocephalus results from a restriction of venous outflow. FrequencyUnited StatesAchondroplasia is the most common inherited disorder involving disproportionate shortness of stature. It occurs in 1 in 15,000-40,000 live births. InternationalNo data suggest that the incidence of achondroplasia in other countries differs from that in the United States. Mortality/Morbidity
RaceNo racial predilection is known for achondroplasia. SexA minor male preponderance is observed in achondroplasia. AgeAchondroplasia can be detected antenatally. Complications from achondroplasia affect all age groups. Patients with the homozygous type of achondroplasia seldom survive infancy. AnatomySkeletal anomalies associated with achondroplasia reflect retarded endocardial bone formation. Therefore, the long bones are short but wide because appositional bone growth is unaffected. The skull is not dependent on endocardial bone; therefore, it is generally large. The spinal column is of relatively normal length but becomes kyphotic as a result of vertebral anomalies and body habitus. Clinical DetailsClinical featuresThe features of achondroplasia are usually apparent at birth. These include typical facial features, disproportionate short stature, and rhizomelic shortening (ie, shortening of the proximal ends of the limbs). Most affected individuals develop normal intelligence. Motor delays are not unusual in infants, but cognitive function develops normally. In infancy, mild to moderate hypotonia is typical, and the acquisition of developmental motor milestones is often delayed. Infants have difficulty supporting their heads because of both hypotonia and the large size of the head. Special developmental charts are available for assessing the development of children with achondroplasia; these charts show growth curves typical of children with achondroplasia. The final adult height is in the range of 4 feet. The characteristic feature is a large head with frontal bossing. The midface is often small; the nasal bridge is flat, and the nostrils are narrow. Middle ear infections are common in infancy and childhood because of the small size of the nasal passages and because of dysfunction of the eustachian tubes. Persistent ear infections may result in hearing loss. The mandible is large relative to the rest of the face; this may give rise to dental crowding. Respiratory problems may occur in infants and children. Airway obstruction may be either central in origin (owing to compression of the foramen magnum) or obstructive in origin (owing to narrowing of nasal passages). Symptoms of airway obstruction include snoring and sleep apnea. Affected individuals tend to sleep with the neck in a hyperextended position. Dwarfism associated with achondroplasia is primarily the result of rhizomelic shortening of the limbs. The legs are usually straight in infancy, but valgus knees develop when the child starts walking. As the child continues to walk, the knees acquire a varus position. The fingers and toes are short. Infants have a thoracolumbar kyphosis in the sitting position. Infants with achondroplasia often have reduced muscle tone. Some children and some affected adults develop neurologic complications. Infants may develop hydrocephalus. Infants should be monitored regularly by means of measurements of head circumference. Symptoms of cord compression may occur at the level of the foramen magnum. Symptoms of cord compression at the foramen magnum include apnea and cervical myelopathy. The risk of lumbar spinal canal stenosis is increased; stenosis is associated with compromise of the spinal cord or the exiting nerve root. Symptoms of such compromise include weakness, paresthesias, and pain that radiates to the lower limbs. One characteristic feature of stenosis of the spinal canal is the relief of pain when the patient assumes a squatting position. As the condition worsens, pain in the low back or buttocks occurs. The clinical features of achondroplasia can be summarized as follows:
ComplicationsPeople with achondroplasia seldom grow taller than 5 feet in height. Complications include hydrocephalus, spinal stenosis, and club feet. The most common cause of medical complaint in adulthood is symptomatic spinal stenosis involving L1-4.8 Low lumbar levels are usually not involved. Fowler and associates described 8 cases of communicating hydrocephalus in children with genetic metabolic disorders: 1 case of mucopolysaccharidosis I (MPS I or Hurler syndrome); 1 case of MPS II (Hunter disease); 4 cases of MPS III (Sanfilippo syndrome, 2 of which affected siblings); and 2 cases of achondroplasias.9 The authors recommended surgical treatment of the latter but were doubtful about treatment of the former, in which case hydrocephalus was only a contributing cause to severe dementia. Mantle and Kingsnorth described an unusual cause of back pain in a 47-year-old man with achondroplasia who presented with lower back pain that radiated to his left loin.10 An intravenous urogram (IVU) showed hydronephrosis on the left side and a dilated left ureter passing down into the left inguinal region. A CT scan confirmed the presence of a left inguinal hernia, which contained the left ureter and caused ureteric obstruction. The hernia was repaired and the ureter replaced retroperitoneally. A postoperative IVU indicated recovery of renal function; however, the left ureter remained persistently dilated, although it was not obstructed. The large head of the newborn with achondroplasia increases the risk of intracranial bleeding during vaginal delivery. Hydrocephalus may be caused by an increase in intracranial venous pressure that is a result of stenosis of the sigmoid sinus at the level of the narrowed jugular foramina. Recurring otitis media is frequently a problem. Approximately 7.5% of infants with achondroplasia die in the first year of life from obstructive apnea or central apnea.6 Obstructive apnea may result from midface hypoplasia. Brainstem compression is common and may cause abnormalities of respiratory function, including central apnea. In 1 study, 10% of infants had craniocervical junction (CCJ) compression with abnormality of the cervical spinal cord.11 All children who underwent surgical decompression of the CCJ had marked improvement of neurologic function. Obesity is a major problem in patients with achondroplasia. Excessive weight gain is manifest in early childhood. Until a height of about 75 cm is reached, the mean weight-to-height ratios for children with average stature and for children with achondroplasia are virtually identical. Above a height of 75 cm, the weight-to-height ratio for patients with achondroplasia exceeds that of the general population.12 In adults, obesity may increase the morbidity associated with lumbar stenosis; in addition, it may contribute to nonspecific joint problems and possibly to early mortality from cardiovascular complications.6 Limited elbow extension occurs in about 70% of patients and is primarily caused by posterior bowing of the distal humerus; posterior dislocation of the radial head (about 20% of patients) results in greater loss of elbow extension.13 The incidence of neurologic deficits in patients with achondroplasia is by no means negligible. Morphologic abnormalities of the spinal canal exist from birth, and signs of cervical cord involvement are not uncommon in children. The delayed occurrence of clinical symptoms related to narrowing of the thoracolumbar canal may be explained by other acquired abnormalities, such as kyphosis, disk prolapse, and degenerative spondylosis. The clinical history usually indicates an insidious onset. The most frequent symptoms are motor weakness of the lower limbs (82.8%) and low back pain (77.1%). Sensory and/or sphincter disturbances appear to be less frequent (about 40%). The incidence of neurologic complications in patients with achondroplasia is 20-47%. Symptoms are often subtle, though they are associated with serious conditions such as cervicomedullary compressive syndromes, syringomyelia, or hydrocephalus. Therefore, the early identification of this disorder is important. Ruiz-Garcia et al prospectively examined 39 patients (20 female, 19 male; age range, 3 mo to 17 y; mean, 4 y 6 mo).14 All patients had hypotonia and psychomotor delay; 3 had recurrent apnea; 1 developed radicular syndrome; and 1 had leg paresthesias. For 5 patients, CT scans were normal; 20 patients had cortical atrophy; and 18 patients had communicating hydrocephalus. The authors identified foramen magnum abnormalities in 28 patients and reduced CCJ with cervicomedullary compression in 6. Myelography and myelotomography demonstrated spinal compression in 12 patients. MRI showed cervicomedullary infarct in 1, syringomyelia in 2, and diastematomyelia in 1. In this study, somatosensory evoked responses (SSERs) were useful in the early identification of brainstem and spinal abnormalities. The authors concluded that the neurologic manifestations of pediatric patients with achondroplasia are frequent and important. Such neurologic findings require comprehensive clinical evaluation, especially in patients with severe hypotonia or alterations in SSERs, although such evaluation is required even in asymptomatic patients. Differential diagnosis and other problems to be consideredAlthough more than 100 skeletal dysplasias that cause short stature are recognized, many are extremely rare, and all have clinical and radiographic features that readily distinguish them from achondroplasia. In contrast to many of the other skeletal dysplasias, the findings of achondroplasia are present at birth, but they are not associated with respiratory insufficiency. Results on antenatal sonograms either suggest or confirm most skeletal dysplasias. Conditions that may be confused with achondroplasia include the conditions discussed below. Achondrogenesis Achondrogenesis (Parenti type I, Fraccara type 1A, Houston-Harris, Fraccara type 1B; 20%) is a lethal autosomal recessive dwarfism. Both endochondral ossification and membranous ossification are affected; the calvaria, spine, and long bones may be involved, with frequent rib fractures. Short-limbed dwarfism is severe. The skull and the rest of the skeleton are poorly ossified. Chest narrowing is marked, but the head is not enlarged relative to the trunk. Polyhydramnios is usually present. Langer-Saldino syndrome (80%) is also autosomal recessive. It is less severe than type 1 endochondral ossification. This syndrome involves variable calcification of calvaria and spine, with no rib fractures; it is a lethal short-limbed dwarfism of the long-bone type. The head is large relative to the rest of the body. Prominent skin folds are present over a short neck, small chest, and distended abdomen, with fetal hydrops. The patients' short limbs are extended away from the body. Chondroectodermal dysplasia Chondroectodermal dysplasia, or Ellis-van Creveld syndrome, is an autosomal recessive disorder with variable expression. The ribs are severely shortened. This disease is associated with short limbs, narrow thorax, polydactyly, postaxial hexadactyly, and congenital heart disease; approximately 50% of patients have a large atrial septal defect. The size of the thorax is particularly striking when compared with the abdomen and head. Asphyxiating thoracic dystrophy Asphyxiating thoracic dystrophy (Jeune syndrome) is an autosomal recessive disorder. Patients present with an extremely narrow thorax, rhizomelic short-limb dwarfism, polydactyly, and renal dysplasia (renal cysts). Osteogenesis imperfecta Osteogenesis imperfecta type IIa is a lethal autosomal dominant condition. Patients present with a thin skull vault that may collapse and with short limbs that are thickened and angulated because of multiple fractures. Osteogenesis imperfecta types I, III, and IV are autosomal dominant or sporadic disorders. Patients have normal body proportions and fractures with normal bone lengths. Congenital hypophosphatasia Congenital hypophosphatasia is an autosomal recessive disorder; the homozygous type is associated with severe deficiency of alkaline phosphatase and increased excretion of phosphoethanolamine. Severe demineralization of the bones is present. The incidence is 1 case per 100,000 births. Four types are described: neonatal (congenital), juvenile, adult, and latent. The last is a mild form thought to be autosomal dominant. Sonography shows short-limbed dwarfism characterized by thin, delicate bones with reduced echogenicity. First-trimester chorionic sampling with alkaline phosphatase assay may establish the diagnosis. Metatrophic dysplasia Metatrophic dysplasia has varied inheritance; it is associated with a narrow thorax, kyphoscoliosis, relatively long trunk, and a tail-like appendage over the sacrum. Roberts syndrome Roberts syndrome, or pseudothalidomide syndrome, is autosomal recessive with variable expression. Patients usually present with tetraphocomelia and a midline facial cleft. Chromosomal analysis shows a classic abnormality in which the centromere region is fluffy. Diastrophic dysplasia Diastrophic dysplasia is an autosomal recessive disorder with multiple contractures and hitchhiker's thumb (ie, more muscle mass than arthrogryposis). Short rib–polydactyly syndrome types I, II, and III Type I disease, or Saldino-Noonan disease, is autosomal recessive; it is characterized by severely shortened ribs and/or narrow thorax; short limbs; polydactyly; cardiovascular and genital anomalies; polycystic kidneys; and pointed metaphysis (an important differentiating feature). Type II disease, or Majewski disease, is associated with short limbs, narrow thorax, polydactyly, cardiovascular anomalies, polycystic kidneys, genital anomalies, disproportionately short tibia, and cleft lip and palate. The short tibia and cleft lip and palate are important differentiating features. Type III disease, or Naumoff disease, is associated with short limbs, narrow thorax, polydactyly, and cardiovascular and genital anomalies. The metaphysis may be wide, with marginal spurs. Nephroblastomatosis Large polycystic kidneys, occipital encephalocele, microcephaly, or polydactyly may be associated with any type of short rib-polydactyly syndrome. Spondyloepiphyseal dysplasia congenita (camptomelic dysplasia) Spondyloepiphyseal dysplasia congenita (camptomelic dysplasia) is autosomal dominant. This disease has variable expression. It is associated with short and bowed femora, a short spine and trunk (delayed ossification centers, calcaneus and talus), anterior bowing of the long bones of the lower extremities, anomalies of cervical and thoracic spine with spinal scoliosis, and hypoplastic or absent scapulas. Thanatophoric dysplasia Thanatophoric dysplasia occurs sporadically and represents the most common lethal skeletal dysplasia. About 14% of patients have a cloverleaf skull. This disease may be transmitted in an autosomal recessive manner. It is characterized by marked narrowing of the thorax and marked micromelia; enlargement of the head (with a prominent forehead); occasional hydrocephalus; and polyhydramnios. The soft tissues of the limbs may be thickened. Thanatophoric dysplasia is more common in male fetuses than in female fetuses. Fibrochondrogenesis Fibrochondrogenesis is an autosomal recessive disorder associated with a thin skull vault, which may be poorly echogenic and difficult to identify. Collapsed sutures are occasionally seen. The limbs are short and thin, and the ribs are thin and poorly visualized. The spine is poorly mineralized and poorly visualized, and the metaphyses are widened. Chondrodysplasia punctate (rhizomelic type) Chondrodysplasia punctate (rhizomelic type) is associated with severe micromelia of the humeri and femora; multiple joint contractures; and dorsal and ventral ossification of the vertebral body, which is separated by a cartilaginous bar. Kniest dysplasia Kniest dysplasia is an autosomal dominant disease associated with kyphoscoliosis, short trunk, broad thorax, and widened metaphyses. The prognosis is usually good. Mesomelic and acromesomelic dysplasia Mesomelic and acromesomelic dysplasia are autosomal recessive or autosomal dominant conditions associated with micromelia of the middle or distal segments. The distribution of shortening differentiates these conditions from other lethal syndromes. Hypochondroplasia Hypochondroplasia is characterized by phenotypic and genetic heterogeneity. It is often difficult to differentiate hypochondroplasia from other conditions involving disproportionate short stature. Prinster and associates examined 21 patients with suspected hypochondroplasia on the basis of radiologic criteria most often reported in the literature on this disease.15 The object was to determine the reliability of radiologic interpretation in the diagnosis of hypochondroplasia and to evaluate the most typical skeletal abnormalities. The data were correlated with molecular findings. Radiographs of the lumbar spine, left leg, pelvis, and left hand were obtained. The presence of the N540K mutation in the FGFR3 gene was verified by means of restriction enzyme digestion. The selection of patients was made on the basis of a review of all radiographs by 2 pediatric radiologists; a second selection was made in blinded fashion, and the results were compared. Both radiologists confirmed the diagnosis in 10 of 21 patients; with regard to the other patients, the disease was excluded; there was uncertainty as to the findings; or there was disagreement as to the final interpretation of the data. The best agreement rate was obtained in the evaluation of cases involving the lumbar spine and the legs. Radiologic features of 9 patients (43%) with the N540K substitution were not remarkably different from the features reported in the patients without this mutation. The authors concluded that, with regard to the diagnosis of hypochondroplasia, the crucial skeletal regions to focus on are the lumbar spine and legs; findings in the pelvis and hands seem to be less characteristic than those in these crucial regions. To reduce the risk of misdiagnosis, accurate radiologic and clinical evaluations are needed, especially in patients who do not have a defined genetic defect. Pseudoachondroplasia Pseudoachondroplasia (PSACH) is a spondyloepimetaphyseal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity, and precocious osteoarthritis. Autosomal dominant inheritance has been demonstrated in many families. Stoll described a boy with PSACH who appeared healthy at birth.16 However, by 3 years of age, the patient's height was below the fifth percentile. At age 6.5 years, he was 99 cm tall (-3.5 standard deviations), and he had bowing of the lower extremities and limitations of movement at the elbows and knees. Radiographs showed features of PSACH. Later, the patient developed kyphoscoliosis with anterior beaking of the vertebrae. Cerebral CT scanning showed a large frontal cyst communicating with the third ventricle. MRI confirmed the frontal cyst and showed dilatation of the third ventricle and the occipital horns of the lateral ventricles, as well as right frontoparietal hemispheric atrophy. At age 26 years, the patient had knee pain, difficulties with swallowing, and vertigo. Sonograms showed a large cortical cyst of the right kidney and smaller cysts in both kidneys. Double heterozygosity in bone growth disorders Because union between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. Flynn and Pauli summarized 7 occurrences of 4 combinations of double heterozygosity: chondroplasia/spondyloepiphyseal dysplasia congenita, achondroplasia/PSACH, achondroplasia/osteogenesis imperfecta type I, and achondroplasia/hypochondroplasia (non-FGFR3 disease).17 They also reviewed additional reports from the literature. Each of the 8 examples of double heterozygosity for bone growth disorders that were described are distinct with regard to phenotypic features, severity, and expectations. Prenatal testingPrenatal diagnosis for high-risk pregnancies is possible. A high-risk pregnancy is one in which 1 or both parents have achondroplasia. DNA extracted from fetal cells obtained by means of chorionic villus sampling (CVS) at about 10-12 weeks' gestation or amniocentesis at 16-18 weeks' gestation is analyzed.18, 19 The disease-causing allele or alleles in the affected parent or parents must be identified before prenatal testing can be performed. In low-risk pregnancies, routine prenatal sonography may reveal short fetal limbs and raise the possibility of achondroplasia in a fetus not known to be at increased risk. Such ultrasonographic findings are usually not apparent until the third trimester. DNA extracted from fetal cells obtained by means of amniocentesis can be analyzed. Genetic counseling Achondroplasia is inherited in an autosomal dominant manner. More than 80% of individuals with achondroplasia have genetically normal parents; in these individuals, achondroplasia occurs as a result of a de novo gene mutation. In such parents, the risk of having another child with achondroplasia is low. An individual with achondroplasia who has a partner of normal stature has a 50% risk of having a child with achondroplasia in each pregnancy. When both parents have achondroplasia, the likelihood of their offspring having normal stature is 25%, the risk of their offspring having achondroplasia is 50%, and the risk of their offspring having homozygous achondroplasia is 25%. When both parents have achondroplasia, they should be given the option of undergoing antenatal molecular genetic testing. Preferred ExaminationPrenatal diagnosis can be achieved with sonography. Antenatal, targeted ultrasonography is indicated in at-risk pregnancies. Conventional radiography remains the preferred modality for initial investigation for both children and adults. Myelography, CT, CT myelography, and MRI are added when indicated, as with compressive cord symptoms at the craniocervical and thoracolumbar junctions. Both CT and MRI can be used to examine the size of the foramen magnum, which is an important determinant of compressive myelopathy of the upper cervical cord. MRI has the added advantage of depicting posterior cranial fossa anatomy and other abnormalities, such as syringomyelia and hydrocephalus. MRI is the modality of choice in cases of suspected spinal stenosis; disk lesions; and compromise of the exiting nerve root in the lumbar region. Radiologic studies are indicated if the head circumference increases disproportionately or if symptoms of hydrocephalus develop. Ultrasonography provides a noninvasive and fairly reliable method of assessing the ventricles of infants before the fontanels close. Ultrasonography may be supplemented with CT and/or MRI of the head to monitor for compression of the foramen magnum.20 Limitations of TechniquesBoth false-positive and false-negative diagnoses may occur with antenatal ultrasonography of skeletal dysplasias. Heterozygous disease may not be recognized until late in the second trimester (>24-28 wk), because sonograms are normal early in the course of the disease. Ultrasonography remains operator dependent. Conventional radiography is good for depicting skeletal pathology, but it is poor at providing information on the brain and spinal cord. Myelography is invasive. Myelography has traditionally been the most useful examination in delineating the level of compression of the spinal cord or the cauda equina. However, in patients with achondroplasia, myelography is difficult because of stenosis of the lumber spine. When myelography is performed near the lumber root, there is a risk that the neurologic deficit will increase; this is particularly so in cases of kyphosis. Therefore, when myelography is necessary, the study is best performed by means of cisternal puncture; however, this step makes the procedure even more invasive than it otherwise would be. CT exposes the patient to ionizing radiation and is limited in its capacity to portray the spinal cord and to depict structures of the posterior fossa. With CT, infants and young children may need sedation or general anesthesia. MRI is expensive and creates problems for patients with claustrophobia. However, MRI can accurately depict anatomic encroachment on the CNS. MRI is frequently used to evaluate the brain and spinal cord in patients with achondroplasia. It cannot be performed in patients with cardiac pacemakers or in patients who have certain surgical clips or other foreign objects in the body. As with CT, young children may need sedation or general anesthesia to undergo MRI. DIFFERENTIALSSection 3 of 11
Spinal Stenosis Other Problems To Be ConsideredAchondrogenesis RADIOGRAPHSection 4 of 11
FindingsThe radiographic findings in achondroplasia are as follows (see Images 1-28):
Kitoh and associates examined 23 patients (41 elbows) with achondroplasia.13 The extension of the elbow was clinically assessed, and the angle of posterior bowing of the distal humerus was measured on lateral radiographs. Extension of the elbow was limited in 28 elbows(68%), and the mean loss of extension was 13.1°. Posterior bowing of the humerus was seen in all elbows, with a mean angle of 17.0°. The 2 measurements were positively correlated. Posterior bowing greater than 20° caused a loss of full elbow extension. Posterior dislocation of the radial head was seen in 9 elbows (22%). The mean loss of extension of the elbows was 28.7°; this loss of extension was significantly greater than the loss seen in elbows in which the head was not dislocated (8.7°), though posterior bowing was not significantly different between the groups (19.3° vs 16.3°). Posterior bowing of the distal humerus is a principal cause of loss of elbow extension. Posterior dislocation of the radial head caused further limitation of movement in the more severely affected joints. Thomeer and van Dijk described surgical treatment of lumbar stenosis in patients with achondroplasia that involved selective widening of the lumbar interapophyseolaminar diameter.8 They found that dynamic lumbar myelography was required for demonstrating the symptomatic level. Degree of ConfidenceConventional radiography is noninvasive, inexpensive, quick to perform, and fairly reliable. It is generally the first examination performed after birth to confirm the diagnosis of achondroplasia. It is also usually the first examination of choice for patients with a symptomatic spine. False Positives/NegativesConventional radiographs generally provide only bony detail and provide little information about the state of the brain and spinal cord. The cord is better depicted with myelography, though myelography provides little information about anomalies within the cord. CT SCANSection 5 of 11
FindingsAmong infants with achondroplasia and apnea, CT and MRI have repeatedly demonstrated cord compression resulting from direct impingement of the posterior rim of the foramen magnum and C1 arch. Sleep apnea responds well to decompression of the foramen magnum. CT shows that in virtually all children with achondroplasia, there is some degree of compromise of the foramen magnum. In about 96% of such children, the foramen magnum is smaller than 3 standard deviations of the mean. CT and/or MRI can depict this change. A small spinal canal is present in the cervical region from birth, but symptoms of cervical canal stenosis generally do not occur until middle age or later. If neurologic deficit occurs and does not resolve through conservative measures, laminectomy at multiple levels may be required. Preoperative imaging with CT, CT myelography, and/or MRI is vital for successful surgery. Preoperative and intraoperative myelography, CT, or MRI defines the level of cord and/or root compression caused by dorsolumbar spinal stenosis. Although MRI has largely replaced conventional myelography, CT myelography and intraoperative myelography may still play a role. Otitis media is a relatively common complication of achondroplasia. To best define the changes affecting the temporal bone that might predispose patients with achondroplastic dwarfism to otitis media, Cobb et al evaluated 9 subjects referred because of hearing loss.21 Patients underwent high-resolution CT of the temporal bone; their results were compared with those of subjects without achondroplasia. A number of morphologic changes were seen: (1) poor development of mastoid air cells, (2) shortening of the carotid canals, (3) narrowing of the skull base, (4) towering petrous ridges, and (5) relative rotation of the cochlea and other structures of the temporal bone. The most notable change was the rotational effect, which was most pronounced medially and which resulted in abnormal orientations of inner-ear structures relative to middle-ear structures and of middle-ear structures relative to the external auditory canal. The investigators also noted a lack of evidence of otitis media or its sequelae in any of the patients with achondroplasia. Audiograms were obtained in 2 adults and 4 children. The results showed evidence of mixed hearing loss in the 4 children but only of sensorineural hearing loss in the adults. The authors concluded that the persistent hearing loss in patients with achondroplasia is not a sequela of otitis media, as others have suggested. Intrinsic vestibulocochlear changes below the limits of resolution of high-resolution CT scanning may be responsible. Degree of ConfidenceThe sensitivity of CT myelography is greater than that of conventional myelography. CT depicts bone detail better than MRI. MRI has an obvious advantage of being radiation free, but many clinicians believe that the degree of stenosis is usually best demonstrated with myelography. False Positives/NegativesDetails of the posterior fossa brain and cord are better depicted on MRI than on CT. Cord edema and changes associated with myelomalacia usually cannot be seen with CT. CT also provides only indirect evidence of associated anomalies, such as syringomyelia, whereas MRI shows such features directly and clearly. MRISection 6 of 11
FindingsCraniocervical MRI findings may include narrowing of the foramen magnum and C1 canal, effacement of the subarachnoid spaces at the cervicomedullary junction, abnormal intrinsic cord signal intensity, and mild to moderate ventriculomegaly. In the spinal canal, associated anomalies such as syringomyelia and changes of myelomalacia are well depicted on MRI. In addition to depicting spinal canal stenosis, MRI also demonstrates disk protrusions and osteophytes that cause compromise (see Image 29). Brühl et al studied the CSF flow, venous drainage, and spinal cord compression in achondroplastic children and the impact of MRI findings for decompressive surgery at the craniocervical junction (CCJ).22 They examined 25 patients with conventional morphologic imaging and with functional imaging of CSF flow with magnetic resonance angiography (MRA) of the veins and sinuses at the cranial base by using a special protocol. The results were compared with those from age-matched control subjects and were correlated with each other and with the neurologic findings. Distances and angulations at the CCJ on MRIs were similar to those measured on conventional radiographs and CT scans. Therefore, these measures may be used without correction for spatial distortion. Signs of cervical medullary compression, myelomalacia, and intramedullary cyst formation were found in 6, 7, and 3 children, respectively. These alterations were significantly correlated with each other (P <.05). Semiquantitative evaluation of CSF flow demonstrated interruption of CSF pathways at the CCJ, which was correlated with CCJ narrowing (P <.05). MRA showed significant narrowing of the jugular foramina, with a variable compensatory enlargement of the emissary veins and a significant reduction of the total outflow area (P <.01). These MRI changes were not significantly correlated with neurologic deficits. The authors concluded that, because of this unexpectedly poor correlation between MRI and clinical findings in children with achondroplasia, the present role of MRI in the clinical setting is limited to the demonstration of spinal-cord compression in individual patients. In 3 patients with prominent neurologic abnormalities, the severe changes demonstrated on MRI strongly supported the indication for surgical decompression. Yamashita et al evaluated 29 patients with atlantoaxial subluxation using MRI. The atlantoaxial subluxation was related to a variety of pathologies, but 1 patient had achondroplasia. Cord compression was classified into 4 grades according to the degree on MRI. Seven patients had no thecal sac compression (grade 0), 10 had a minimal degree of subarachnoid space compression without cord compression (grade 1), 7 had mild cord compression (grade 2), and 5 had severe cord compression or cord atrophy (grade 3). Although the severity of myelopathy was poorly correlated with the atlantodental interval on conventional radiography, MRI grade and the degree of myelopathy were highly correlated. T2-weighted images showed hyperintense foci in 7 of 12 patients with cord compression (grades 2 and 3). Kao et al performed MRIs of the craniovertebral junction, cranium, and brain in 10 patients (aged 3 mo to 16 y) with achondroplasia.23 All had narrowing of the subarachnoid space at the level of the foramen magnum, and 5 had compressive deformities of the cervicomedullary junction. Apparent upward displacement of the brainstem and a relatively vertical course of the optic nerve were seen in all patients. Dilated lateral and third ventricles were seen in 5 patients, and bifrontal widening of the subarachnoid space was evident in 4. Skull asymmetry was seen in 2 patients, and an empty sella (confirmed on metrizamide cisternography) was present in 1. In 1 patient, foci of abnormal signal intensity were seen in the cervicomedullary region. The authors indicated that MRI is useful in delineating the many abnormalities of the cranial, cerebral, and cervicomedullary junction present in children with achondroplasia. Degree of ConfidenceMRI is a noninvasive technique and is ideal for children because it does not use ionizing radiation. MRI has an advantage over CT in the degree of detail of the posterior cranial fossa cord that it provides. Early clinical and MRI evaluations are necessary to determine whether infants with achondroplasia have cervicomedullary compression. With early recognition, an immediate decompression can be performed safely to avoid serious complications associated with cervicomedullary compression, including sudden death. False Positives/NegativesCT depicts details of bone and the degree of spinal stenosis better than MRI. Claustrophobia may limit the quality of MRI, and motion artifacts may produce false-negative and/or false-positive results. ULTRASOUNDSection 7 of 11
FindingsUltrasonography is generally performed in the antenatal setting and in pregnant women who are at risk for achondroplasia. Homozygous achondroplasia results in rhizomelic micromelia, normal trunk length, and cloverleaf skull. These cases are lethal. Lung hypoplasia is a major cause of mortality (associated with thoracic narrowing). There is a noticeable disproportion between skull dimensions and/or biparietal diameter (BPD) and limb lengths. The discrepancy between femoral length and BPD is noted as early as 13 weeks' gestation. The femoral length decreases to below the third percentile at 14.0-16.5 weeks' BPD age (mean, 15.6 weeks; 95% confidence interval: 13.4, 17.8). Therefore, femoral growth curves are established in the second trimester. Serial sonography enables prenatal distinction between homozygous and heterozygous disease. The changes in heterozygous achondroplasia are relatively mild and include short limbs, narrow thorax and abdomen, increased fetal head circumference and BPD, a protuberant forehead, and a diminished interpediculate distance in the spine. Heterozygous disease may not be recognized until late in the second trimester (>24-28 wk); early in the course of disease, sonograms are normal. Rhizomelic limb shortening that predominantly affects the proximal long bones is observed. Krakow and associates found that 3-dimensional (3D) imaging in the prenatal-onset diagnosis of skeletal dysplasia had advantages over 2-dimensional (2D) imaging in the evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements, and the hands and feet.24 Of most importance, the patient and referring physician appreciated the 3D images of the abnormal findings more readily than other images; this advantage aided in patient counseling and in managing the pregnancy.25 Degree of ConfidencePatel and Filly retrospectively reviewed serial sonograms of 15 fetuses at 25% risk of homozygous achondroplasia.26 Femoral growth curves were established and were compared with published standards to determine the gestational age. They were calculated according to BPD, at which femoral length crossed below the third percentile. The presence and severity of achondroplasia were clinically determined after birth. Their results showed that the femoral length crossed the third percentile at 14.0-16.5 weeks BPD age (mean, 15.6 wk) in the 4 homozygous fetuses and at 18.2-26.2 weeks BPD age (mean, 21.5 wk) in the 8 heterozygous fetuses. In the 3 unaffected fetuses, femoral length did not cross percentiles as gestational age increased. The authors concluded that the establishment of a femoral growth curve in the second trimester with serial sonograms enables prenatal distinction between homozygous, heterozygous, and unaffected fetuses, when both parents have heterozygous achondroplasia. False Positives/NegativesParilla and associates reviewed 37 cases of skeletal dysplasia diagnosed antenatally over 8 years.27 Complete follow-up was available in 31 cases. The mean gestational age at diagnosis was 22.7 weeks (range, 14-32.3 wk). In 21 cases, the diagnosis was made before the 24th week. A final diagnosis was obtained in 80% of cases. The antenatal diagnosis was correct in 20 (65%) of 31 cases. Two false-positive diagnoses occurred. Specific final diagnoses included thanatophoric dysplasia (n = 8), osteogenesis imperfecta (n = 6), Roberts syndrome (n = 2), achondroplasia (n = 3), Ellis-van Creveld syndrome (n = 1), metaphyseal dysplasia (n = 1), spondyloepiphyseal dysplasia (n = 1), distal arthrogryposis (n = 1), caudal regression (n = 1), and glycogen storage disorder (n = 1). The condition was correctly thought to be lethal in 16 of the fetuses on the basis of early, severe long-bone shortening (n = 13), femur length–abdominal circumference ratio of less than 0.16 (n = 12), hypoplastic thorax (n = 10), marked bowing or fractures (n = 4), short ribs (n = 4), caudal regression (n = 1), and cloverleaf skull (n = 1). The ability to predict lethality was 100%. No false-positive findings with respect to lethality occurred. The authors concluded that antenatal diagnosis of skeletal dysplasias is problematic. In their series, only 20 of 31 cases were correctly diagnosed. However, the antenatal prediction of lethality was highly accurate. The most common predictors of lethal skeletal dysplasias included early and severe shortening of the long bones, femur length–abdominal circumference ratio of less than 0.16, hypoplastic thorax, and certain distinguishing characteristics. NUCLEAR MEDICINESection 8 of 11
FindingsIsotopic cisternography with an intrathecal injection of indium-111 diethylenetriamine pentaacetic acid (DTPA) was commonly used in the past to assess hydrocephalus. It is rarely used now, because it does not increase accuracy in predicting favorable responses to shunting, relative to CT and clinical evaluation. INTERVENTIONSection 9 of 11
There is no specific treatment of achondroplasia. Associated orthopedic abnormalities, such as club feet, should be corrected. Recommendations of the American Academy of Pediatrics Committee on Genetics The American Academy of Pediatrics Committee on Genetics outlined recommendations for the treatment of children with achondroplasia in 1995. Their recommendations are meant to supplement guidelines available for treating children of average stature. The recommendations include but are not limited to the following:
Treatment of obstructive sleep apnea Treatment of obstructive sleep apnea may include adenotonsillectomy, weight reduction, continuous positive airway pressure (CPAP) by means of a nasal mask, and, in extreme cases, tracheostomy. Improvement in disturbed sleep and some improvement in neurologic function may result from these interventions.28 Growth hormone therapy Growth hormone (GH) therapy has been proposed as a possible treatment of the short stature of achondroplasia. Initial skepticism about the utility of this approach was based on normal GH levels in children with achondroplasia and reflected a concern that the abnormal growth-plate cartilage would not improve with GH therapy. However, growth velocity increases with GH therapy, especially during the first year of treatment. Data from a number of studies suggest that growth rate increases with treatment of 1-2 years.29, 30, 31, 32, 33 The usefulness of GH treatment in achondroplasia will be known only when patients in the current studies achieve their adult height. Surgical limb lengthening Early experience with surgical limb-lengthening procedures resulted in a high incidence of complications, including pain, pin infections, and neurologic and vascular compromise resulting from rapid lengthening. However, recent experience shows improvement, with increases in height of up to 12-14 inches. The best predictors of the need for suboccipital decompression include lower-limb hyperreflexia or clonus; central hypopnea, as demonstrated by polysomnography; and a reduction in foramen magnum size, as determined by means of CT of the CCJ and by comparison with the norms for children with achondroplasia. Thomeer and van Dijk determined that in about 70% of symptomatic patients with spinal stenosis, total relief of symptoms was achieved after decompression without laminectomy.8 The L2-3 level most commonly required decompression. Other surgical treatment Other surgical treatment consists of anterior decompression with fusion when thoracolumbar kyphosis is prevalent, and/or posterior decompression when the symptoms are mainly caused by canal stenosis. From the prognostic point of view, 2 groups of patients are recognized in relationship to the presence of marked dorsal kyphosis. Those with kyphosis almost invariably have poor functional results. In the remaining patients, the results are satisfactory, provided that the clinical history is less than 3 years and the symptoms are not already too advanced. Labor and delivery Women may have difficulty during labor. It is generally recommended that infants with achondroplasia be born by means of cesarean delivery to reduce the risk of possible CNS complications with vaginal delivery. Socialization Because of the highly visible nature of the short stature associated with achondroplasia, affected persons and their families may encounter difficulties in socialization and adjustment in school. Support groups can assist families with these issues through peer support, personal example, and social awareness programs. Patients and families may benefit from information about employment, education, disability rights, adoption of short-statured children, medical issues, suitable clothing, adaptive devices, and parenting; such information is available through a national newsletter, seminars, and workshops. Special Concerns
MULTIMEDIASection 10 of 11
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