Neurologic Morbidity Associated With Achondroplasia Jacqueline T. Hecht, PhD;
Ian J. Butler, MD
Abstract
Neurologic morbidity has long been appreciated in adults with achondroplasia and has recently been recognized to be common in children. Neurologic complications result from bony stenosis involving the entire vertebral column and the base of the skull. These complications are reviewed with special attention to the findings in children. ( JChild Neurol 1990;5:84-97).
is the best known and most form of the congenital shortlimbed dwarfing conditions. The disorder has been recognized for more than 5000 years and is represented in Egyptian statues, in paintings by Valasquez, and in the literature of Charles Dickens. Individuals with achondroplasia were gladiators in Roman times, court jesters in medieval history, and wrestlers or circus clowns in modern times.’1 Achondroplasia is apparent at birth and has a birth incidence of 1 in 26,000 live-born infants.2 The disorder is inherited as an autosomal dominant condition, although 80% of cases occur sporadically as new mutations. ~ Dwarfs frequently marry other dwarfs and should both have achondroplasia, there would be a 25% risk of having an offspring with a severe and lethal form of homozygous achondro-
Achondroplasia common
4
plasia.
The defect in achondroplasia is thought to reside in endochondral ossification; however, the basic defect has been elusive. A defect in type 2 collagen
considered, but three linkage studies have excluded type 2 collagen as a candidate gene.5-’ The neurologic complications of achondroplasia have been recognized in adults for more than half a century8-10 and can usually be attributed to the defect in bone formation, connective tissue structures, or was
Received August 1, 1989. Received revised Sept 28, 1989. Accepted for publication Oct 5, 1989. From the Departments of Pediatrics and Neurology, University of Texas Medical School at Houston, Houston, Texas. Address correspondence to Dr Jacqueline T. Hecht, Univer-
sity
of Texas Medical School, TX 77225.
20708, Houston,
Department
of Pediatrics, P.O. Box -
both tissues. Recently, similar neurologic complications have been recognized in infants, young 2 children, and teenagers with achondroplasia. 11, 12 Defective endochondral ossification leads to a small, abnormally shaped foramen magnum, short vertebral pedicles, and narrow spinal carnal. 13 The narrowing of the spinal canal may be a particular problem in the cervical and lumbar regions. Various foramina may be narrowed and compress structures passing through the bone.’ A small jugular foramen at the base of the skull may compress the internal jugular veins and exiting cranial nerves. Occasionally, defective vertebral column alignment leads to scoliosis, kyphoscoliosis, lumbar gibbus deformity, and severe lordosis that can compress the spinal cord and cauda equina. Defective connective tissue elements in achondroplasia frequently lead to ligamentous laxity, which can aggravate the complications associated with bony stenosis. The bony abnormalities have been shown to be a cause of neurologic morbidity 11 , 12 and lead to a shortened life span. &dquo; Associated problems are shown in Table 1 and will be discussed in this format. This paper will review the newly described neurologic complications associated with achondroplasia in childhood and provide recommendations for evaluating these children.
Macrocephaly Macrocephaly or an enlarged head is an easily recognizable and common phenotypic feature of achondroplasia. The etiology of the head enlargement is of concern, particularly in young children under 2 years of age with delayed motor developmeant. 15 Earlier studies suggested that hydrocephalus
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TABLE 1
Neurologic Complications of Achondroplasia
the cause of that head enlargement.9 Other studies have suggested that the enlarged head was due to a large brain (megalencephaly) and that the ventricles were normal or only mildly dilated.l6 Subsequently, standard growth curves for achondroplasia were developed, including those for head circumference, height, and weight. 17 These growth curves indicated that head size in achondroplasia is larger than in the normal population, although there is some overlap. These charts should be used routinely to assess growth and particularly any variation in head circumference over a period of time that could suggest progressive hydrocephalus. Although hydrocephalus with dilated ventricles has been recognized for many decades in achondroplasia, the exact mechanism in any individual is not always certain and remains controversial.ls Ventricles in achondroplasia may be mildly dilated but may also show marked dilation (Figure 1). Noncommunicating hydrocephalus has been attributed to stenosis of the aqueduct of Sylvius. 19 Kinking of the aqueduct and compressive obliteration of the basal cisterns related to the small cranial base (basis cranii)
was
has been identified.
Communicating hydrocephalus frequently in achondroplasia and is often diagnosed as hydrocephalus ex vacuo, without clinical evidence of brain atrophy. Mild communicating hydrocephalus may be difficult to distinguish from mild ventricular dilation frequently observed in achondroplasia by computed tomography.2° Communicating hydrocephalus, including prominent subarachnoid spaces over the cortex (Figure 1), has been attributed to impaired absorption of cerebrospinal fluid via the arachnoid villi of the superior sagittal sinus. Pressure in the venous drainage of the brain, including the sagittal sinus, can be elevated by constriction of the jugular veins in the at the deformed base of the achonjugular foramina 16,21 A recent study showed reversal droplastic skull. of blood flow in the emissary veins connecting the is
seen
more
intracranial and extracranial venous systems, suggesting that this was due to raised venous pressure in the jugular veins.22 Clinically, this increased venous pressure may appear as prominent scalp veins. Hydrocephalus in achondroplasia may not be obvious clinically and frequently is discovered during routine
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FIGURE 1
Computed tomography scans showing mild (A),
moderate (B), and severe (C) ventricular dilation. Prominent subarachnoid space and sulci occur frequently in achondroplasia.
evaluation of macrocephaly or neurologic manifestations such as gait impairment or weakness of the limbs. Often during the first year of life, hydrocephalus may be suspected because of a bulging anterior fontanel. Although computed tomography will often demonstrate the degree of ventricular dilation, 20 magnetic resonance imaging will show more detailed anatomy (eg, aqueductal stenosis) and also the presence of subependymal fluid, indicating decompensation of the hydrocephalus and possible need for surgical shunting. It is usually possible with computed tomography to serially monitor for mild to moderate communicating type of ventricular dilation. In these cases, surgery can often be avoided. Neuropsychological testing and evaluation by a neurosurgeon are indicated before deciding to perform a shunting procedure for clinically significant ventricular dilation. 18 A few cases of ventricular dilation have been attributed to severe jugular venous outflow obstruction. In these cases, venous angiography with venous pressure gradient evaluations were necessary prior to venous graft anastomosis of an internal venous sinus to an external vein in order to improve collateral circulation and decrease venous backflow pressure.23 Raised jugular venous pressure may produce dilated ventricles in young children due to communicating hydrocephalus, whereas in older subjects, pseudotumor cerebri occurs, with small ventricles.’-3 The ability of the skull to expand in the young child prior to fusion of the sutures may account for the difference in outcome. Subdural hematomas have been observed in several children with achondroplasia without a his-
tory of sufficient head trauma (Figure 2). Spontaneous onset of subdural hematoma could be
a result of large subarachnoid spaces commonly observed in achondroplasia. Excessive movement of the brain within the relatively large skull could lead to rupture of veins bridging the subdural space. Other causes appear to be postoperative ventriculoperitoneal shunting or leakage from the posterior fossa decompression site, with decreased intracranial pressure and dynamic shifts of brain structures leading to rupture of bridging veins. Because of the relatively large volume
FIGURE 2 resonance imaging scan showing large subdural hematoma in the region of the occipital lobe in a 2-monthold boy with achondroplasia. Prominent subarachnoid space is evident.
Magnetic
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of the skull, the subdural collections may have minimal neurologic effects. However, these collections can be a prelude to further bleeding and increase in head circumference, necessitating neuro-
surgical decompression. Craniocervical Junction Anomalies The bones of the cranial base and neural arches enlarge by endochondral ossification. Anomalies of the craniocervical junction are frequent in achondroplasia and result from the defect in endochondral ossification. 11,24,25 The various components of the craniocervical junction in achondroplasia that can lead to neurologic complications include foramen magnum stenosis, upper cervical vertebral canal stenosis (Cl, C2), abnormal odontoid shape or posi-
tion, ligamentous laxity, and jugular foramen stenosis. The reduced growth of the occipital bones pro-
achondroplasia.2‘~
duces a small foramen magnum in This reduction in growth leads to an abnormally shaped foramen magnum (Figure 3) and a reduction in the transverse and sagittal dimensions of the foramen magnum as determined by computed tomography.24-26 At birth, the foramen magnum in achondroplasia is smaller than that in the nonachondroplastic population, particularly in the transverse diameter.25 Growth in this area is greatly diminished in both dimensions, especially during the first 18 months of life, when maximum growth is (Figure 4). Although symptomatic and asymptomatic individuals with achondroplasia had similar foramen magnum dimensions at birth, the symptomatic individuals showed a decreased mean rate of growth
expected25
FIGURE 3 Foramen magnum shapes in achondroplasia are shown in A through D. The normal foramen magnum shape (E) should be oval and four synchondroses can be seen. In contrast, the foramen magnum in achondroplasia has a keyhold appearance and synchondroses are often displaced medially into one growth center. (Reprinted from Hecht et al2s with permission.)
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(Figure 5). This hypertrophied margin has been implicated in the severe angulation and pressure necrosis of the brain stem at this level. Neurologic complications such as myelopathy, apnea, and sudden death, resulting from compression at the medullary level, were not appreciated until recently. The two vertebrae making up the atlantoaxial complex also contribute to the narrowing of the vertebral canal in the upper cervical region. Furtherstem
the posterior neural arch of the atlas may fuse with the posterior margin of the foramen magnum. Defects in the odontoid process can also contribute to the neurologic morbidity. The odontoid process tends to project posteriorly and superiorly into the small foramen magnum, and the medulla oblongata is anatomically draped over this protuberance (Figure 5). In particular, projection of the odontoid process into the anterior aspects of the medulla can lead to compression necrosis affecting the corticospinal tracts 12 and may damage the arterial supply (anterior spinal artery) to the medulla and cervical cord, leading to more widespread neurologic damage. A posteriorly dislocated bulbous odontoid process has been noted in a case presenting with more,
FIGURE 4 Foramen magnum growth curves for the transverse (A) and sagittal dimensions (B) for the normal and achondroplastic populations. The general population curves are above the achondroplastic growth curves. The growth curves include the mean ± 2 SEM (standard error of the mean). The foramen magnum in achondroplasia, particularly in the transverse dimensions, does not show the dramatic growth seen in the general population foramen magnum. (Reprinted from Hecht et a125 with permission.)
dimensions, although this decrease was not statistically significant.25 The average adult foramen magnum in achondroplasia was the size of that in average-stature newborns and 2-year-olds in the transverse and sagittal dimensions, respectively.25 The failure of foramen magnum growth has been attributed not only to the defect in bone developin both
ment, but also to premature fusion and aberrant development of the posterior synchondroses .2’ The posterior fusion defect may also contribute to the hypertrophied margin of the posterior aspect of the foramen magnum that appears as a shelf radiologically and surgically (M. E. Miner, personal communication, 1987) and projects into the posterior brain
FIGURE 5 Sagittal reconstruction of the foramen magnum (bone window, A; and soft-tissue window, B) in a 1-year-old showing the hypertrophied occipital shelf projecting into the posterior fossa and brain stem.
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intermittent quadriparesis. 12 Presumably, both odontoid process size and ligamentous laxity in this patient accounted for the problem. Bony stenosis and instability at the craniocervical junction can compress the cervicomedullary cord and upper spinal nerve roots. Serious complications associated with damage of the spinal cord at this high level include sudden infant death, sleep apnea syndrome, disorders of respiration, myelopathy, syringobulbia-myelia, and hydrocephalus.
Sudden Infant Death Sudden unexpected death has been described in infants with achondroplasia. Thirteen such cases were found and described by retrospective case ascertainment sturdy. 27 A cohort study of 781 individuals with achondroplasia confirmed that sudden death was significantly increased.14 The risk of dying suddenly for those less that 1 year of age was 7.5% (Figure 6). Surprisingly, there was a 2.5% risk of sudden death from 1 to 4 years of age. This finding suggested that sudden death in achondroplasia was different from sudden death in the general population. Indeed, it has been shown that compression at the level of the foramen magnum can interfere with the respiratory control centers, causing cessation of respiration that may result in death of the infant with achondroplasia. 12, 27, 28 This often occurs during
respiratory control centers during this particularly sensitive either to postural effects at the craniocervical junction (neck flexion) or changes in carbon dioxide and oxygen levels in blood have had during sleep. A few younger children recurrent diurnal apneic episodes, 12’29 some of which may be alarmingly prolonged and misdiagnosed as a seizure disorder. Gliosis, edema, and cystic myelo-
sleep,
time
since the
are
malacia at the level of the medulla noted at postmortem examination appear to be causes of disordered respiratory control centers.2’ Both acute and chronic compression of the spinal cord by constriction at the foramen magnum stenosis can cause these changes.
Sleep Apnea Syndrome Various sleep apnea syndromes have been recognized in achondroplasia.11,12 Commonly, children with achondroplasia will have a history of excessive snoring at night and this symptom may be a valuable clue to the need for further studies. Recurrent apneic episodes during sleep can cause multiple arousals, sleep walking, and enuresis. Lack of nocturnal sleep in these children can present with excessive daytime somnolence, excessive weight gain, poor linear growth, fluid retention, headache, and dyspnea. The latter problems are due to cor pulmonale with carbon dioxide retention during the apneic episodes, which causes reactive constriction of pulmonary vasculature. Sleep apnea syndromes in achondroplasia had previously been considered secondary to obstruction of the airway due to enlarged tonsils, glossoptosis, and pharyngolaryngeal wall laxity. Recent studies have shown that there is
a
neural basis for
some
cases.11,12 Polysomnography has demonstrated the presence of obstructive, central, and mixed (obstructive and central) forms of apnea during sleep.11,12
Improvement
in apnea, both obstructive and central
types, has been observed following decompression of the medulla oblongata by enlargement of the foramen magnum. Similar findings have been observed in other neurologic conditions having clinically significant obstructive apnea, including syringomyelia, poliomyelitis, and lateral medullary syndrome. 30 Presumably, foramen magnum stenosis causes damage to the medulla oblongata, impairing the respiratory control mechanisms and leading to apnea during either wakefulness or In addition, apnea can result from injury to the motor nuclei of the brain stem that control the reflex movements of the larynx and pharynx during respiration, and discoordinated movements of the upper airway muscle wall during inspiration can cause severe airway obstruction. This
sleep.12, 29
FIGURE 6 Survival curve for achondroplasia showing excessive mortality between birth and 4 years. Mean survival is 61 years for achondroplasia compared to 72 years in the general population. (Reprinted from Hecht et al 14 with permission of Arn J Hurn Gelled.)
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clinical picture presents as obstructive apnea but has a central brain stem etiology.
Disorders
of Respiration Respiratory dysfunction is estimated to occur in 10% to 85% of achondroplastic children. 11, 12,2&dquo; A number of factors have been implicated as having an etiologic role in impaired respiration and dyspnea in achondroplasia. A small chest circumference could restrict respirations; however, this does not12appear to be a factor in the sleep apnea syndrome. Chest circumference is small in achondroplasia, but catch-up growth in the first 2 years of life usually leads to a normal chest circumference.31 Chest size was not found to correlate with respiratory dysfunction in children less than 2 years of ague. 12 Following progressive cervical myelopathy or as a complication after surgical decompression of the cervical cord, there may be impairment of phrenic nerve control of the diaphragm or spinal tracts to the intercostal nerves. The effect on respiration would depend on the degree of involvement and, in particular, whether there was unilateral or bilateral spinal cord injury. Two children presenting with central respiratory abnormalities and marked foramen magnum compression initially had relief of respiratory problems after a suboccipital decompression. Later, they presented with a mixed obstructive and central apnea on polysomnography and cor pulmonale. Treatment with continuous positive airway pressure at night with resolution of all symptoms suggested that central respiratory drive abnormalities were presenting as obstructive apnea (J. T. H., unpublished
data).
Myelopathy
myelopathy of the medulla due to foramen magnum stenosis is well recognized in achondroplasia at all ages, although in our experience it is more frequently recognized in the young. There may be extreme hypotonia in the infant, progressing to hypertonia with increased reflexes and extensor plantar responses. Older children may have impaired dorsal column sensation with a positive Romberg sign and gait disturbances progressing to quadraTraumatic
paresis.
Syringobulbia-myelia Syringomyelia as a consequence of apparent progression of the cystic myelomalacia has been observed.32,33 This also appears to be on the basis of local compression of the spinal cord by the constricted foramen Single, double (double-barreled
magnum.33
and elongated central calcified found in three individuals. These cystic were observed as an incidental finding on computed tomography and sagittal reconstruction to evaluate the size of the foramen magnum33 (Figure 7). The cystic changes appear to be secondary to traumatic cystic necrosis of the spinal cord, since similar findings have been observed in a child with achondroplasia who died suddenly.2’ A glioma29 and subependymal glioma associated with a syrinx3~ were identified in the brain stems of two children with achondroplasia at postmortem examination. The association of cystic myelomalacia from chronic foramen magnum stenosis and tumor formation suggests
shotgun appearance), lesions lesions
an
were
etiologic relationship.
Hydrocephalus See the section
,
on
macrocephaly.
Developmental Delay Psychomotor delays in infants with achondroplasia have been frequently observed. 1,15 Delay has been attributed to a relatively large head for body size contributing to head lag, skeletal abnormalities, and ligamentous laxity at various joints. Although these explanations are generally accepted to explain failure to walk until age 2 years, neurologic factors may be operative and hypotonia may be on a basis of myelopathy rather than solely due to ligamentous laxity. Children with achondroplasia usually have normal intelligence &dquo;-3 (J. T. H., unpublished data) unless there are neurologic complications related to hydrocephalus, head injury, or impaired respiratory function such as sleep apnea with hypoxemia (J. T. H., unpublished data). Six studies using formal psychometric testing found intelligence quotients of less than 80 in 10% to 16% of individuals with achondroplasia. 18,20,34-37 One study suggested that individuals with severe ventricular dilation had decreased intelligence . 38 However, this impression was not confirmed with formal psychometric testing. A recent study using Bayley scales on achondroplastic children less than 40 months of age found a mean mental developmental index of 96 and mean motor developmental index of 65 (J. T. H., unpublished data). The latter quotient reflects the severe motor delay characteristic of achondroplasia. Three children in this group with mental developmental indices of ~ 85 (50, 64, 85), had severe, chronic respiratory problems by history and polysomnography. The decreased mental devel-
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opmental index was significantly correlated with respiratory dysfunction (P < .05) (J. T. H., unpublished data). Frontal horn size did not correlate with decreased mental developmental index, suggesting that increased ventricular size was not the cause of mental retardation in this group. However, hydrocephalus resulting from aqueductal stenosis, although occurring rarely in achondroplasia, was the probable cause of mental retardation (IQs, 50 and 68) in two teenagers (J. T. H., unpublished data). Developmental charts for achondroplasia are available and should be used to monitor motor development. Hearing impairment may result from repeated otitis media and may only be recognized when speech development is delayed. Articulation problems are related to midface hypoplasia causing small maxilla and dental crowding. Tongue thrusting is common, often requiring speech therapy.
Vertebral Canal Stenosis Vertebrae of the spinal canal are also involved because they are derived from endochondral bone ossification. Although there are defects of the vertebral bodies, including wedged vertebrae and a posterior central bony spurring, most of the neurologic problems are secondary to the short pedicles and narrowing of the interpediculate distances. Spinal canal stenosis occurs at all levels of the vertebral column. Bony narrowing of the lumbar vertebrae can potentially compress the spinal cord and nerve roots of the cauda equina. This is particularly exaggerated in individuals with excessive lordosis. Lumbar stenosis appears most commonly in early adulthood and is aggravated by excessive
weight.
FIGURE 7
Computed tomographic scan showing &dquo;double-barrel&dquo; calcified syrinx (A), single calcified cavity (B), and single cavity on sagittal reconstruction (arrowhead) (C). Both patients had marked, chronic brain stem compression relieved by surgical suboccipital decompression.
Clinical symptoms and signs will depend on the level of involvement and range from quadriparesis or quadriplegia from cervical cord stenosis to paraparesis or paraplegia from thoracolumbar region stenosis. Gradual impairment of gait and excessive falling from ataxia and spasticity are often the first symptoms. Temporary deterioration in spinal cord function is often closely related to minor closed trauma such as a blow to the spine, falls, or suddenly sitting down on the buttocks. Any deterioration in bladder or bowel function in achondroplasia should be interpreted as an indication of spinal compression. Evaluation of bladder and bowel dysfunction in young children can be problematic but clinically important. Symptoms of intermittent claudication of the conus medullaris and cauda equina 39 are frequently associated with lower spinal compression. Commonly, there are complaints
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of
pain radiating from the buttocks down one or both legs and associated with back pain. Pain, paresthesias, or dysesthesias frequently become apparent after exercise such as walking a short distance. Persistent pain with weakness of the legs and falling occurs unless the individual with achondroplasia sits down and rests or assumes a squatting position with the back to
a
vertical support such
as a
wall. These
improve impaired blood supply to the conus medullaris and cauda equina by reducing the lumbar lordosis and decompressing the spinal cord and roots. This clinical picture is often dramatic and an indication of potentially progressive
postures
are
thought
to
permanent loss of motor and sensory function of the lower spinal cord. Clinical examination may assist in defining the extent and level of myelopathy. Dorsal column compression may affect vibration and proprioception sensations; however, in young children, demonstration of posterior cord compression may require laboratory evaluation using somatosensory evoked responses with stimulation both of upper and of lower limbs. 40 Pain and electrical sensations up and down the cervical spinal cord (Lhermitte’s sign) can occur with neck flexion when cervical cord stenosis is or inverted deep-tendon reflexes particularly in the upper arms, are indicative of cervical or lumbar radiculopathy. Evaluation for suspected myelopathy in achondroplasia depends on the combination of computed tomography to determine the level of bone compression and magnetic resonance imaging to observe the level of cord compression as demonstrated by spinal cord narrowing, gliosis, or cystic changes. Previously, myelography was performed; however, this is usually technically difficult because of the generalized spinal canal stenosis. Severe and persistent back pain was frequently observed postmyelography.
present. Absent, depressed,
marked angulation and compression of the spinal cord (Figure 8A). Claudication of the cauda equina is most pronounced while standing or walking upright with maximum tendency to lumbosacral lordosis. Symptoms of intermittent claudication of the cauda equina are relieved by squatting and resting against a firm wall. These measures reduce the degree of lordosis at the lumbosacral junction. A gibbus deformity of the thoracolumbar vertebrae is common in achondroplastic infants and should be investigated by lateral radiographs of the involved vertebrae (Figure 8B). Anterior wedging of one or more vertebral bodies is important, since angulation at this level can compress the conus medullaris and cauda equina. In the younger children, wedging of the vertebrae should be carefully followed radiologically because angulation may be progressive. Usually, the gibbus deformity resolves with ambulation and onset of exaggerated lordosis. Occasionally in the older patient, angulation becomes established and neurologic symptoms of paraparesis or intermittent claudication of the cauda equina occurs. A combined orthopedic approach of laminectomy and angle reduction may be necessary. Nerve Root Compression Compression of the nerve roots as they exit the spinal cord is common in achondroplasia. Both the abnor-
mal shortening of the pedicles of the vertebrae and small neural foramina appear to contribute to this problem. Narrowing of neural foramina can occur at multiple levels but is clinically significant in the cervical and lumbar regions. The patients complain of distal dysesthesias and paresthesias in the upper and lower limbs. This may subsequently cause loss of tendon reflexes and focal muscle wasting. Depressed triceps reflex unilaterally or bilaterally with an inverted reflex (flexion at the elbow) is an early sign of
Vertebral Column Malalignment Scoliosis and kyphosis are infrequent in achondroplasia and usually do not contribute to the neurologic problems. However, lumbar lordosis and thoracolumbar gibbus formation cause neurologic morbidity. Marked angulation of the sacrum is a common malformation of the spine in achondroplasia.9 The degree of lordosis increases with age. The causes of the sacral angulation to almost a right angle to the lumbar vertebrae are not well established but contribute to compression of nerve roots of the cauda equina. Occasionally lumbosacral lordosis is complicated by vertebral subluxation, which causes
root
compression. Occipital neuralgia is not uncommon in achondroplasia and is caused by compression of the occipital nerve or nerves exiting through the posterior atlanto-occipital membrane. Presumably, the nerve is entrapped by the fibrous membrane or by proximity to the posterior lip of the foramen magnum and posterior arch of the atlas (which may be fused in achondroplasia). Complaints of paresthesias or headache in the occipital region of the scalp or an area of anesthesia in the distribution of the occipital nerve is suggestive of occipital neuralgia. These symptoms may be difficult to distinguish clinically from those due to narrowing of the foramen magnum and compression of the cervicomedullary junction. nerve
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FIGURE 8 Lateral radiograph
’
showing gibbus deformity and wedging of L1 vertebrae (A). Magnetic
imaging of the lumbar spine showing subluxation of L1 angulation deformity of spinal cord (B). resonance
Electromyographic examination of specific muscle help to localize particular nerve roots that are functionally compressed. Often, following enlargement of the neural foramina surgically either at the time of laminectomy or, occasionally, as an isolated procedure at one or more foramina, there is improved function. Occipital neuralgia can be treated by occipital neurectomy provided that significant craniocervical junction compression has been exgroups will
cluded.
Homozygous Achondroplasia Homozygous achondroplasia can occur theoretically in a quarter of offspring of a union between two individuals with heterozygous achondroplasia.4 Most die at birth or in the early months of life of respiratory complications. Initially, the respiratory complications, including cor pulmonale, were attributed to the extremely small chest size and restrictive pulmonary disease.41 However, the severe bone dysplasia affects not only the long bones but the bones of the vertebral column and the foramen magnum, which is extremely small.4 As a result of the stenosis at the craniocervical junction, there may be marked compression of the medullary respiratory centers and outflow pathways
vertebrae and marked
and The
subsequent apnea and respiratory insufficiency. recognition that some of the respiratory complications could be related to medullary and cervical spinal cord compression has led to a more aggressive approach to treatment, with prolonged survival.4,2~,42 However, long-term survival has not been demonstrated, and the requirement for prolonged respiratory support brings into question the efficacy of surgical intervention. Motor delay and hypotonic quadriparesis or quadriplegia are complications of the homozygous achondroplasia. Hydrocephalus may be evident on computed tomography and require shunting procedures. The physical characteristics of these infants with homozygous achondroplasia are qualitatively similar to but quantitatively much more severe than those in heterozygous achondroplasia.41 Management of Achondroplasia Management of achondroplasia depends on age, but a multidisciplinary approach to follow patients is recommended11,12 (Figure 9). Diagnosis should be established by a geneticist, using clinical and radiographic findings. I ’13 Following diagnosis, complete neurologic assessment with special attention to attainment of developmental milestones, degree of ,
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FIGURE 9
Algorithm
for
management of achondroplasia.
and ligamentous laxity is suggested. Head size should be carefully monitored on a monthly basis during the first year of life and thereafter annually. Any deviation from normal head growth for achondroplasia should be an indication for further study. The hypotonia and delayed motor development should not be dismissed as related only to ligamentous laxity, since this may well be an early manifestation of spinal cord paralysis. After 3 months of age, we have found that somatosensory evoked responses in both upper and lower limbs may be helpful in evaluating the dorsal columns because neurologic assessment of this aspect of spinal cord function can be difficult.4° Furthermore, somatosensory evoked responses can be assessed serially and also before, during, and after surgical decompression. Abnormalities of somatosensory evoked responses may also have some localizing value in assessing the level of cord dysfunction (Figure 10), since the neurologic examination and routine radiographs may not be informative. Computed tomography with particular attention to the posterior fossa has been utilized in achondroplasia. Computed tomography permits evaluation of the brain and ventricles in addition to the foramen magnum size and growth centers. General population and achondroplastic foramen magnum values are available. 24,25 Sagittal reconstruction of the posterior fossa and upper cervical canal permits more detailed assessment of the relationship of the bones of the craniocervical junction, and soft-tissue structures can
hypotonia,
also be evaluated. These sagittal views enable visualization of the odontoid process as well as the posterior neural arches of the atlas and axis and may indicate multiple levels of cord compression, in addition to the small foramen magnum. Similar studies can be performed at the cervical and lumbar levels to demonstrate canal stenosis at these potentially significant sites. More recently, magnetic resonance imaging of the brain and spinal cord has been used to define the anatomic level of hydrocephalus and degree of ventricular compensation (eg, presence or absence of subependymal cerebrospinal fluid extravasation) or compression of the spinal cord (Figure 11). Gliosis, edema, and narrowing are readily apparent on magnetic resonance imaging of the cord, and an area of cystic necrosis or syringomyelia can be visualized at the level of compression. Magnetic resonance imaging appears helpful in the assessment of children requiring surgical decom-
pression ; however, computed tomographic scanning remains the basis of our assessments. Children with clinical respiratory problems must be assessed in order to define the relative contribution of peripheral (small chest cage, enlarged tonsils) and central (neurologic) mechanisms producing
stridor, apnea, snoring, repeated pneumonia,
or res-
piratory distress. In addition to chest radiographs and direct visualization of the upper airways, polysomnography has been used to investigate the nature of the respiratory disorder and, particularly, whether sleep apnea is present.11,12 Achondroplastic individ-
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FIGURE 10 Placement of
somatosensory evoked potential electrodes
directly spinal cord during surgical decompression of the brain stem (A); absence of the thalamocortical response on
prior to surgery (B); return of thalamocortical response (arrowheads) (C,D) after decompression.
FIGURE 111
Magnetic (B)
views
imaging scan of the upper cervical spine flexion (A) and showing compression at the level of the foramen magnum.
resonance
extension
cord
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’
uals with abnormal further evaluation for
polysomnograms may need cor pulmonale, including an and electrocardiogram echocardiogram. Intensive study of achondroplasia in the last decade has led to a greater understanding of the neurologic morbidity associated with the bony abnor-
11. Reid CS,
malities of the condition. Studies suggest that the associated complications such as myelopathy, apnea, respiratory drive abnormalities, and sudden death are not uncommon. Careful attention should be paid to children with achondroplasia in order to identify those at high risk for these complications. Identification and correction of these problems in childhood may help avert long-term and possibly irreversible neurologic complications and may increase longevity and the quality of life.
13.
,
Acknowledgments We are indebted to Dr Charles I. Scott, Jr, who suggested to us that there were serious neurologic complications in achondroplasia. We wish to thank Dr William A. Horton for encouraging and supporting these studies. We are indebted to Drs W. Goldie, W. Nelson, M. Miner, and L. Patchell for their involvement and help in all of the studies cited in the text. Dr J. Cabrera provided the excellent drawing of the cervical spine and somatosensory evoked potential tracings. Lynn Grace provided excellent typing and editorial skills.
References 1. Scott CI: Achondroplastic and hypochondroplastic dwarfism. Clin Orthop 1976;114:18-30. 2. Oberklaid F, Dands DM, Jensen F, et al: Achondroplasia and
hypochondroplasia. J Med Genet 1979;16:140-146. 3. Murdoch JL, Walker BA, Hall JG, et al: Achondroplasia—a genetic and statistical survey. Ann Hum Genet 1970;33:227-244. 4. Hecht JT, Horton WA, Butler IJ, et al: Foramen magnum stenosis in homozygous achondroplasia. EurJ Pediatr 1986;145: 545-547. 5. Ogilvie D, Wordsworth P, Thompson E, Sykes B: Evidence against the structural gene encoding type II collagen (COL2A1) as the mutant locus in achondroplasia. J Med Genet 1988;23: 19-22. 6. Francomano CA, Pyeritz RE: Achondroplasia is not caused by a mutation in the gene for type II collagen. Am J Med Genet
Pyeritz RE, Kopits SE, et al: Cervicomedullary compression in young patients with achondroplasia: Value of comprehensive neurologic and respiratory evaluation.J Pediatr 1987;110:522-530. FW, Hecht JT, Horton WA,
et al: Neurologic basis of respiratory complications in achondroplasia. Ann Neurol 1988;
12. Nelson
24:89-93.
Pediatr 1968;7:474-485. 14. Hecht JT, Francomano CA, Horton WA, Annegers JF: Mortality in achondroplasia. AmJ Hum Genet 1987;41:454-464. 15. Todorov AB, Scott CI, Warren AE, Leeper JD: Developmental screening tests in achondroplastic children. AmJ Med Genet
1981;9:19-23. JP, Rosenberg HS, Alvord EC: Megancephaly, internal
16. Dennis
hydrocephalus and other neurological aspects plasia. Brain 1961;84:427-445.
junction. Radiology 1987;164:515-519. 27. Pauli
death in infants with
et al:
Apnea and sudden achondroplasia. J Pediatr
1984;104:342-348. DC, Phillips JA, Leonard CO,
28. Stokes
29.
et al: Respiratory complications of achondroplasia. J Pediatr 1983;102:534-541. Fremion AS, Garg BP, Kalsbeck J: Apnea as the sole manifestation of cord compression in achondroplasia. J Pediatr 1984;
104:398-401.
Spillane JD: Three cases of achondroplasia with neurological complications. J Neurol Neurosurg Psychiatry 1952;15:246-252. Vogl A: The fate of the achondroplastic dwarf (neurologic complications of achondroplasia). Exp Med Surg 1962;20: 108-117.
RM, Scott CI, Wassman ER,
unexplained
30. 31. 32. 33.
61:644-662.
10.
of achondro-
17. Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978;93:435-438. 18. Pierre-Kahn A, Hirsch J-F, Renier D, et al: Hydrocephalus and achondroplasia. Childs Brain 1980;7:205-219. 19. Cohen ME, Rosenthal AD, Matson DD: Neurological abnormalities in achondroplastic children. J Pediatr 1967;71:367-376. 20. Mueller SM, Bell W, Cornell S, et al: Achondroplasia and hydrocephalus. Neurol 1977;27:430-434. 21. Yamada H, Nakamura S, Tajima M, Kageyama N: Neurological manifestations of pediatric achondroplasia. J Neurosurg 1981; 54:49-57. 22. Mueller SM, Reinertson JE: Reversal of emissary vein blood flow in achondroplastic dwarfs. Neurol 1980;30:769-772. 23. Sainte-Rose C, LaCombe J, Pierre-Kahn A, et al: Intracranial venous sinus hypertension: Cause or consequence of hydrocephalus in infants? J Neurosurg 1984;60:727-736. 24. Hecht JT, Nelson FW, Butler IJ, et al: Computerized tomography of the foramen magnum: Achondroplastic values compared to normal standards. AmJ Med Genet 1985;20:355-360. 25. Hecht JT, Horton WA, Reid CS, et al: Growth of the foramen magnum in achondroplasia. Am J Med Genet 1989;32:528-535. 26. Wang H, Rosenbaum AE, Reid CS, et al: Pediatric patients with achondroplasia: CT evaluation of the craniocervical
1988;29:955-961. 7. Strom CM: Molecular studies in achondroplasia using CO12A1 probes in human achondroplasia: A multidisciplinary approach, in Nicoletti B, Kopits SE, Ascani E, McKusick VA (eds): Human Achondroplasia. New York, Plenum Press, 1988, pp 59-60. 8. Vogl A, Osborne RL: Lesions of the spinal cord (transverse myelopathy) in achondroplasia. Arch Neurol Psychiatry 1949; 9.
Baumann PA, Gorlin RJ: Achondroplasia: Clinical radiologic features with comment on genetic implications. Clin
Langer LO,
34. 35.
Haponik EF, Givens D, Angelo J: Syringobulbia-myelia with obstructive sleep apnea. Neurology 1983;33:1046-1049. Reid CS, Metz SJ, Phillips JA, et al: Respiratory abnormalities in achondroplasia, abstract. Am J Hum Genet 1984;36:705. Yang SS, Corbett DP, Brough AJ, et al: Cervical myelopathy in J Pathol achondroplasia. Am1977;68:68-72. Hecht JT, Butler IJ, Scott CI: Long term neurological sequelae in achondroplasia. Eur J Pediatr 1984;143:58-60. Morris JV, MacGilvray RC: The mental capacity in achondroplasia.J Ment Sci 1953;99:547-556. Cohn S, Weinberg A: Identical hydrocephalic achondroplastic twins; subsequent delivery of single sibling with the same abnormalities. Am J Obstet Gynecol 1956;72:1346-1348.
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36.
Rogers JG, Perry MA, Rosenberg
LA:
IQ
measurements in
children with skeletal dysplasia. Pediatrics 1979;63:894-897. 37. Priestley BL, Lorber J: Ventricular size and intelligence in achondroplasia. Z Kinderchir 1981;34:320-326. 38. Wassman ER, Mehringer M, Hieshima G, et al: Computerized tomography of the head in healthy achondroplasts, abstract. AmJ Hum Genet 1982;38:114A, abstract 314. 39. Blau JN, Logue V: Intermittent claudication of the cauda equina. Lancet 1961;1:1081-1086.
40. Nelson FW, Goldie WD, Hecht JT, et al: Short-latency somatosensory evoked potentials in the management of patients with
achondroplasia. Neurology 1984;34:1053-1058. JG, Dorst JP, Toybi H, et al: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects 1969;
41. Hall
5:24-34. 42. Moskowitz
N, Carson B, Kopits S, et al: Foramen magnum decompression in an infant with homozygous achondroplasia.
Neurosurgery 1989;70:126-128.
Vignette Romberg’s Description of Stroke in Infancy The course of the medullary fibres from the spinal cord to the corona radiata and the hemisphere has hitherto only been shown in the roughest outlines, as followed with the naked eye in recent or hardened brains. The demonstration of different elements, and of their motor or sensory attributes, yet lacks much to render it at all satisfactory. We may expect some advancement in our knowledge of this subject by the dissection of the brains of subjects who have been paralysed for many years, and in whom the function of motion alone was impaired. An opportunity of this kind presented itself to me in the person of a girl, aged 19, who, according to her father’s statement, had been born healthy, but was attacked with violent convulsions at the age of 3 months, followed by paralysis of the right extremities. She was small for her age, and imperfectly developed; the arm and leg of the right side were much emaciated and were only half the size of their fellows. The fingers of the right hand felt as if they consisted only of soft tissues; at the same time they were generally contracted and turned in to the hollow of the hand, but could be easily extended. The movements of the foot and arm were very much limited; the foot was dragged in walking, and the patient was unable to squeeze with her right hand, or to raise the arm at all. At the same time there was no trace of paralysis in the face or the tongue. The patient’s speech, though monosyllabic, was unimpeded. The sensibility of the limbs was normal as well as the functions of the senses; but the intellect was almost reduced to a par with idiocy. The girl could only find expressions indicative of hunger and pain; she was unable to fix her attention or to form any idea. Menstruation occurred at the age of sixteen. In my lectures I stated my diagnosis to be atrophy of the left hemisphere of the cerebrum, and that as there was no external depression of the cranium, I assumed the vacant space to be filled up by serum. Death ensued from phthisis pulmonalis, and the post-mortem examination was made by Professor Henle on the 4th of March, 1838. In removing the calvarium the saw accidentally pene-
trated too deep, and caused a quantity of sero-sanguineous fluid to escape. The left half of the cranium was half an inch narrower than the right, and the left os frontis was thickened. The middle of the upper part of the left cerebral hemisphere was absent, and in its place was a serous cyst, which had been torn in opening the cranium, and had discharged its contents. This cyst was only separated from the lateral ventricle by its investing membrane. On dividing the latter, the ventricle was found dilated and containing a large quantity of clear serum. The foramen Monroi was much distended; the walls of the ventricle were half wanting, nothing but rudiments of the thalamus opticus and corpus striatum remaining, and they were bounded by a margin of the hardness of cartilage. No morbid appearances presented themselves in the corpus callosum, the fornix, the septum lucidum, and the anterior commissore. At the base of the brain, the optic tract, the eminentia mammillaris, the crus cerebri, the pons, and the pyramid of the left side were atrophied; the latter was converted into a thin strip, only a quarter the size of the right pyramid; at the same time the restiform bodies of both sides presented a normal volume, and the olivary body of the left side was even more arched and much fuller than that of the right. The dimensions of both hemispheres of the cerebellum were the same; the brachial plexus of the right side was normal. We were not permitted to open the spinal canal. In this case the commissural structures were sound; but a tract that extended through various cerebral structures was atrophic owing to its not having been able to execute its functions.
Excerpted
from
Romberg’s
Manual
of the
Nervous Diseases
of
Man, Volume 2, translated by E.H. Sieveking. The Sydenham Society, London, 1853, pp 417-419. This patient’s brain was the Anatomical Museum of Berlin and was described Edward Henoch in his 1842 dissertation De Atrophica Cerebri.
preserved in
by
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Ian J. Butler, MD
Abstract
Neurologic morbidity has long been appreciated in adults with achondroplasia and has recently been recognized to be common in children. Neurologic complications result from bony stenosis involving the entire vertebral column and the base of the skull. These complications are reviewed with special attention to the findings in children. ( JChild Neurol 1990;5:84-97).
is the best known and most form of the congenital shortlimbed dwarfing conditions. The disorder has been recognized for more than 5000 years and is represented in Egyptian statues, in paintings by Valasquez, and in the literature of Charles Dickens. Individuals with achondroplasia were gladiators in Roman times, court jesters in medieval history, and wrestlers or circus clowns in modern times.’1 Achondroplasia is apparent at birth and has a birth incidence of 1 in 26,000 live-born infants.2 The disorder is inherited as an autosomal dominant condition, although 80% of cases occur sporadically as new mutations. ~ Dwarfs frequently marry other dwarfs and should both have achondroplasia, there would be a 25% risk of having an offspring with a severe and lethal form of homozygous achondro-
Achondroplasia common
4
plasia.
The defect in achondroplasia is thought to reside in endochondral ossification; however, the basic defect has been elusive. A defect in type 2 collagen
considered, but three linkage studies have excluded type 2 collagen as a candidate gene.5-’ The neurologic complications of achondroplasia have been recognized in adults for more than half a century8-10 and can usually be attributed to the defect in bone formation, connective tissue structures, or was
Received August 1, 1989. Received revised Sept 28, 1989. Accepted for publication Oct 5, 1989. From the Departments of Pediatrics and Neurology, University of Texas Medical School at Houston, Houston, Texas. Address correspondence to Dr Jacqueline T. Hecht, Univer-
sity
of Texas Medical School, TX 77225.
20708, Houston,
Department
of Pediatrics, P.O. Box -
both tissues. Recently, similar neurologic complications have been recognized in infants, young 2 children, and teenagers with achondroplasia. 11, 12 Defective endochondral ossification leads to a small, abnormally shaped foramen magnum, short vertebral pedicles, and narrow spinal carnal. 13 The narrowing of the spinal canal may be a particular problem in the cervical and lumbar regions. Various foramina may be narrowed and compress structures passing through the bone.’ A small jugular foramen at the base of the skull may compress the internal jugular veins and exiting cranial nerves. Occasionally, defective vertebral column alignment leads to scoliosis, kyphoscoliosis, lumbar gibbus deformity, and severe lordosis that can compress the spinal cord and cauda equina. Defective connective tissue elements in achondroplasia frequently lead to ligamentous laxity, which can aggravate the complications associated with bony stenosis. The bony abnormalities have been shown to be a cause of neurologic morbidity 11 , 12 and lead to a shortened life span. &dquo; Associated problems are shown in Table 1 and will be discussed in this format. This paper will review the newly described neurologic complications associated with achondroplasia in childhood and provide recommendations for evaluating these children.
Macrocephaly Macrocephaly or an enlarged head is an easily recognizable and common phenotypic feature of achondroplasia. The etiology of the head enlargement is of concern, particularly in young children under 2 years of age with delayed motor developmeant. 15 Earlier studies suggested that hydrocephalus
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TABLE 1
Neurologic Complications of Achondroplasia
the cause of that head enlargement.9 Other studies have suggested that the enlarged head was due to a large brain (megalencephaly) and that the ventricles were normal or only mildly dilated.l6 Subsequently, standard growth curves for achondroplasia were developed, including those for head circumference, height, and weight. 17 These growth curves indicated that head size in achondroplasia is larger than in the normal population, although there is some overlap. These charts should be used routinely to assess growth and particularly any variation in head circumference over a period of time that could suggest progressive hydrocephalus. Although hydrocephalus with dilated ventricles has been recognized for many decades in achondroplasia, the exact mechanism in any individual is not always certain and remains controversial.ls Ventricles in achondroplasia may be mildly dilated but may also show marked dilation (Figure 1). Noncommunicating hydrocephalus has been attributed to stenosis of the aqueduct of Sylvius. 19 Kinking of the aqueduct and compressive obliteration of the basal cisterns related to the small cranial base (basis cranii)
was
has been identified.
Communicating hydrocephalus frequently in achondroplasia and is often diagnosed as hydrocephalus ex vacuo, without clinical evidence of brain atrophy. Mild communicating hydrocephalus may be difficult to distinguish from mild ventricular dilation frequently observed in achondroplasia by computed tomography.2° Communicating hydrocephalus, including prominent subarachnoid spaces over the cortex (Figure 1), has been attributed to impaired absorption of cerebrospinal fluid via the arachnoid villi of the superior sagittal sinus. Pressure in the venous drainage of the brain, including the sagittal sinus, can be elevated by constriction of the jugular veins in the at the deformed base of the achonjugular foramina 16,21 A recent study showed reversal droplastic skull. of blood flow in the emissary veins connecting the is
seen
more
intracranial and extracranial venous systems, suggesting that this was due to raised venous pressure in the jugular veins.22 Clinically, this increased venous pressure may appear as prominent scalp veins. Hydrocephalus in achondroplasia may not be obvious clinically and frequently is discovered during routine
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FIGURE 1
Computed tomography scans showing mild (A),
moderate (B), and severe (C) ventricular dilation. Prominent subarachnoid space and sulci occur frequently in achondroplasia.
evaluation of macrocephaly or neurologic manifestations such as gait impairment or weakness of the limbs. Often during the first year of life, hydrocephalus may be suspected because of a bulging anterior fontanel. Although computed tomography will often demonstrate the degree of ventricular dilation, 20 magnetic resonance imaging will show more detailed anatomy (eg, aqueductal stenosis) and also the presence of subependymal fluid, indicating decompensation of the hydrocephalus and possible need for surgical shunting. It is usually possible with computed tomography to serially monitor for mild to moderate communicating type of ventricular dilation. In these cases, surgery can often be avoided. Neuropsychological testing and evaluation by a neurosurgeon are indicated before deciding to perform a shunting procedure for clinically significant ventricular dilation. 18 A few cases of ventricular dilation have been attributed to severe jugular venous outflow obstruction. In these cases, venous angiography with venous pressure gradient evaluations were necessary prior to venous graft anastomosis of an internal venous sinus to an external vein in order to improve collateral circulation and decrease venous backflow pressure.23 Raised jugular venous pressure may produce dilated ventricles in young children due to communicating hydrocephalus, whereas in older subjects, pseudotumor cerebri occurs, with small ventricles.’-3 The ability of the skull to expand in the young child prior to fusion of the sutures may account for the difference in outcome. Subdural hematomas have been observed in several children with achondroplasia without a his-
tory of sufficient head trauma (Figure 2). Spontaneous onset of subdural hematoma could be
a result of large subarachnoid spaces commonly observed in achondroplasia. Excessive movement of the brain within the relatively large skull could lead to rupture of veins bridging the subdural space. Other causes appear to be postoperative ventriculoperitoneal shunting or leakage from the posterior fossa decompression site, with decreased intracranial pressure and dynamic shifts of brain structures leading to rupture of bridging veins. Because of the relatively large volume
FIGURE 2 resonance imaging scan showing large subdural hematoma in the region of the occipital lobe in a 2-monthold boy with achondroplasia. Prominent subarachnoid space is evident.
Magnetic
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of the skull, the subdural collections may have minimal neurologic effects. However, these collections can be a prelude to further bleeding and increase in head circumference, necessitating neuro-
surgical decompression. Craniocervical Junction Anomalies The bones of the cranial base and neural arches enlarge by endochondral ossification. Anomalies of the craniocervical junction are frequent in achondroplasia and result from the defect in endochondral ossification. 11,24,25 The various components of the craniocervical junction in achondroplasia that can lead to neurologic complications include foramen magnum stenosis, upper cervical vertebral canal stenosis (Cl, C2), abnormal odontoid shape or posi-
tion, ligamentous laxity, and jugular foramen stenosis. The reduced growth of the occipital bones pro-
achondroplasia.2‘~
duces a small foramen magnum in This reduction in growth leads to an abnormally shaped foramen magnum (Figure 3) and a reduction in the transverse and sagittal dimensions of the foramen magnum as determined by computed tomography.24-26 At birth, the foramen magnum in achondroplasia is smaller than that in the nonachondroplastic population, particularly in the transverse diameter.25 Growth in this area is greatly diminished in both dimensions, especially during the first 18 months of life, when maximum growth is (Figure 4). Although symptomatic and asymptomatic individuals with achondroplasia had similar foramen magnum dimensions at birth, the symptomatic individuals showed a decreased mean rate of growth
expected25
FIGURE 3 Foramen magnum shapes in achondroplasia are shown in A through D. The normal foramen magnum shape (E) should be oval and four synchondroses can be seen. In contrast, the foramen magnum in achondroplasia has a keyhold appearance and synchondroses are often displaced medially into one growth center. (Reprinted from Hecht et al2s with permission.)
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(Figure 5). This hypertrophied margin has been implicated in the severe angulation and pressure necrosis of the brain stem at this level. Neurologic complications such as myelopathy, apnea, and sudden death, resulting from compression at the medullary level, were not appreciated until recently. The two vertebrae making up the atlantoaxial complex also contribute to the narrowing of the vertebral canal in the upper cervical region. Furtherstem
the posterior neural arch of the atlas may fuse with the posterior margin of the foramen magnum. Defects in the odontoid process can also contribute to the neurologic morbidity. The odontoid process tends to project posteriorly and superiorly into the small foramen magnum, and the medulla oblongata is anatomically draped over this protuberance (Figure 5). In particular, projection of the odontoid process into the anterior aspects of the medulla can lead to compression necrosis affecting the corticospinal tracts 12 and may damage the arterial supply (anterior spinal artery) to the medulla and cervical cord, leading to more widespread neurologic damage. A posteriorly dislocated bulbous odontoid process has been noted in a case presenting with more,
FIGURE 4 Foramen magnum growth curves for the transverse (A) and sagittal dimensions (B) for the normal and achondroplastic populations. The general population curves are above the achondroplastic growth curves. The growth curves include the mean ± 2 SEM (standard error of the mean). The foramen magnum in achondroplasia, particularly in the transverse dimensions, does not show the dramatic growth seen in the general population foramen magnum. (Reprinted from Hecht et a125 with permission.)
dimensions, although this decrease was not statistically significant.25 The average adult foramen magnum in achondroplasia was the size of that in average-stature newborns and 2-year-olds in the transverse and sagittal dimensions, respectively.25 The failure of foramen magnum growth has been attributed not only to the defect in bone developin both
ment, but also to premature fusion and aberrant development of the posterior synchondroses .2’ The posterior fusion defect may also contribute to the hypertrophied margin of the posterior aspect of the foramen magnum that appears as a shelf radiologically and surgically (M. E. Miner, personal communication, 1987) and projects into the posterior brain
FIGURE 5 Sagittal reconstruction of the foramen magnum (bone window, A; and soft-tissue window, B) in a 1-year-old showing the hypertrophied occipital shelf projecting into the posterior fossa and brain stem.
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intermittent quadriparesis. 12 Presumably, both odontoid process size and ligamentous laxity in this patient accounted for the problem. Bony stenosis and instability at the craniocervical junction can compress the cervicomedullary cord and upper spinal nerve roots. Serious complications associated with damage of the spinal cord at this high level include sudden infant death, sleep apnea syndrome, disorders of respiration, myelopathy, syringobulbia-myelia, and hydrocephalus.
Sudden Infant Death Sudden unexpected death has been described in infants with achondroplasia. Thirteen such cases were found and described by retrospective case ascertainment sturdy. 27 A cohort study of 781 individuals with achondroplasia confirmed that sudden death was significantly increased.14 The risk of dying suddenly for those less that 1 year of age was 7.5% (Figure 6). Surprisingly, there was a 2.5% risk of sudden death from 1 to 4 years of age. This finding suggested that sudden death in achondroplasia was different from sudden death in the general population. Indeed, it has been shown that compression at the level of the foramen magnum can interfere with the respiratory control centers, causing cessation of respiration that may result in death of the infant with achondroplasia. 12, 27, 28 This often occurs during
respiratory control centers during this particularly sensitive either to postural effects at the craniocervical junction (neck flexion) or changes in carbon dioxide and oxygen levels in blood have had during sleep. A few younger children recurrent diurnal apneic episodes, 12’29 some of which may be alarmingly prolonged and misdiagnosed as a seizure disorder. Gliosis, edema, and cystic myelo-
sleep,
time
since the
are
malacia at the level of the medulla noted at postmortem examination appear to be causes of disordered respiratory control centers.2’ Both acute and chronic compression of the spinal cord by constriction at the foramen magnum stenosis can cause these changes.
Sleep Apnea Syndrome Various sleep apnea syndromes have been recognized in achondroplasia.11,12 Commonly, children with achondroplasia will have a history of excessive snoring at night and this symptom may be a valuable clue to the need for further studies. Recurrent apneic episodes during sleep can cause multiple arousals, sleep walking, and enuresis. Lack of nocturnal sleep in these children can present with excessive daytime somnolence, excessive weight gain, poor linear growth, fluid retention, headache, and dyspnea. The latter problems are due to cor pulmonale with carbon dioxide retention during the apneic episodes, which causes reactive constriction of pulmonary vasculature. Sleep apnea syndromes in achondroplasia had previously been considered secondary to obstruction of the airway due to enlarged tonsils, glossoptosis, and pharyngolaryngeal wall laxity. Recent studies have shown that there is
a
neural basis for
some
cases.11,12 Polysomnography has demonstrated the presence of obstructive, central, and mixed (obstructive and central) forms of apnea during sleep.11,12
Improvement
in apnea, both obstructive and central
types, has been observed following decompression of the medulla oblongata by enlargement of the foramen magnum. Similar findings have been observed in other neurologic conditions having clinically significant obstructive apnea, including syringomyelia, poliomyelitis, and lateral medullary syndrome. 30 Presumably, foramen magnum stenosis causes damage to the medulla oblongata, impairing the respiratory control mechanisms and leading to apnea during either wakefulness or In addition, apnea can result from injury to the motor nuclei of the brain stem that control the reflex movements of the larynx and pharynx during respiration, and discoordinated movements of the upper airway muscle wall during inspiration can cause severe airway obstruction. This
sleep.12, 29
FIGURE 6 Survival curve for achondroplasia showing excessive mortality between birth and 4 years. Mean survival is 61 years for achondroplasia compared to 72 years in the general population. (Reprinted from Hecht et al 14 with permission of Arn J Hurn Gelled.)
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clinical picture presents as obstructive apnea but has a central brain stem etiology.
Disorders
of Respiration Respiratory dysfunction is estimated to occur in 10% to 85% of achondroplastic children. 11, 12,2&dquo; A number of factors have been implicated as having an etiologic role in impaired respiration and dyspnea in achondroplasia. A small chest circumference could restrict respirations; however, this does not12appear to be a factor in the sleep apnea syndrome. Chest circumference is small in achondroplasia, but catch-up growth in the first 2 years of life usually leads to a normal chest circumference.31 Chest size was not found to correlate with respiratory dysfunction in children less than 2 years of ague. 12 Following progressive cervical myelopathy or as a complication after surgical decompression of the cervical cord, there may be impairment of phrenic nerve control of the diaphragm or spinal tracts to the intercostal nerves. The effect on respiration would depend on the degree of involvement and, in particular, whether there was unilateral or bilateral spinal cord injury. Two children presenting with central respiratory abnormalities and marked foramen magnum compression initially had relief of respiratory problems after a suboccipital decompression. Later, they presented with a mixed obstructive and central apnea on polysomnography and cor pulmonale. Treatment with continuous positive airway pressure at night with resolution of all symptoms suggested that central respiratory drive abnormalities were presenting as obstructive apnea (J. T. H., unpublished
data).
Myelopathy
myelopathy of the medulla due to foramen magnum stenosis is well recognized in achondroplasia at all ages, although in our experience it is more frequently recognized in the young. There may be extreme hypotonia in the infant, progressing to hypertonia with increased reflexes and extensor plantar responses. Older children may have impaired dorsal column sensation with a positive Romberg sign and gait disturbances progressing to quadraTraumatic
paresis.
Syringobulbia-myelia Syringomyelia as a consequence of apparent progression of the cystic myelomalacia has been observed.32,33 This also appears to be on the basis of local compression of the spinal cord by the constricted foramen Single, double (double-barreled
magnum.33
and elongated central calcified found in three individuals. These cystic were observed as an incidental finding on computed tomography and sagittal reconstruction to evaluate the size of the foramen magnum33 (Figure 7). The cystic changes appear to be secondary to traumatic cystic necrosis of the spinal cord, since similar findings have been observed in a child with achondroplasia who died suddenly.2’ A glioma29 and subependymal glioma associated with a syrinx3~ were identified in the brain stems of two children with achondroplasia at postmortem examination. The association of cystic myelomalacia from chronic foramen magnum stenosis and tumor formation suggests
shotgun appearance), lesions lesions
an
were
etiologic relationship.
Hydrocephalus See the section
,
on
macrocephaly.
Developmental Delay Psychomotor delays in infants with achondroplasia have been frequently observed. 1,15 Delay has been attributed to a relatively large head for body size contributing to head lag, skeletal abnormalities, and ligamentous laxity at various joints. Although these explanations are generally accepted to explain failure to walk until age 2 years, neurologic factors may be operative and hypotonia may be on a basis of myelopathy rather than solely due to ligamentous laxity. Children with achondroplasia usually have normal intelligence &dquo;-3 (J. T. H., unpublished data) unless there are neurologic complications related to hydrocephalus, head injury, or impaired respiratory function such as sleep apnea with hypoxemia (J. T. H., unpublished data). Six studies using formal psychometric testing found intelligence quotients of less than 80 in 10% to 16% of individuals with achondroplasia. 18,20,34-37 One study suggested that individuals with severe ventricular dilation had decreased intelligence . 38 However, this impression was not confirmed with formal psychometric testing. A recent study using Bayley scales on achondroplastic children less than 40 months of age found a mean mental developmental index of 96 and mean motor developmental index of 65 (J. T. H., unpublished data). The latter quotient reflects the severe motor delay characteristic of achondroplasia. Three children in this group with mental developmental indices of ~ 85 (50, 64, 85), had severe, chronic respiratory problems by history and polysomnography. The decreased mental devel-
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opmental index was significantly correlated with respiratory dysfunction (P < .05) (J. T. H., unpublished data). Frontal horn size did not correlate with decreased mental developmental index, suggesting that increased ventricular size was not the cause of mental retardation in this group. However, hydrocephalus resulting from aqueductal stenosis, although occurring rarely in achondroplasia, was the probable cause of mental retardation (IQs, 50 and 68) in two teenagers (J. T. H., unpublished data). Developmental charts for achondroplasia are available and should be used to monitor motor development. Hearing impairment may result from repeated otitis media and may only be recognized when speech development is delayed. Articulation problems are related to midface hypoplasia causing small maxilla and dental crowding. Tongue thrusting is common, often requiring speech therapy.
Vertebral Canal Stenosis Vertebrae of the spinal canal are also involved because they are derived from endochondral bone ossification. Although there are defects of the vertebral bodies, including wedged vertebrae and a posterior central bony spurring, most of the neurologic problems are secondary to the short pedicles and narrowing of the interpediculate distances. Spinal canal stenosis occurs at all levels of the vertebral column. Bony narrowing of the lumbar vertebrae can potentially compress the spinal cord and nerve roots of the cauda equina. This is particularly exaggerated in individuals with excessive lordosis. Lumbar stenosis appears most commonly in early adulthood and is aggravated by excessive
weight.
FIGURE 7
Computed tomographic scan showing &dquo;double-barrel&dquo; calcified syrinx (A), single calcified cavity (B), and single cavity on sagittal reconstruction (arrowhead) (C). Both patients had marked, chronic brain stem compression relieved by surgical suboccipital decompression.
Clinical symptoms and signs will depend on the level of involvement and range from quadriparesis or quadriplegia from cervical cord stenosis to paraparesis or paraplegia from thoracolumbar region stenosis. Gradual impairment of gait and excessive falling from ataxia and spasticity are often the first symptoms. Temporary deterioration in spinal cord function is often closely related to minor closed trauma such as a blow to the spine, falls, or suddenly sitting down on the buttocks. Any deterioration in bladder or bowel function in achondroplasia should be interpreted as an indication of spinal compression. Evaluation of bladder and bowel dysfunction in young children can be problematic but clinically important. Symptoms of intermittent claudication of the conus medullaris and cauda equina 39 are frequently associated with lower spinal compression. Commonly, there are complaints
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of
pain radiating from the buttocks down one or both legs and associated with back pain. Pain, paresthesias, or dysesthesias frequently become apparent after exercise such as walking a short distance. Persistent pain with weakness of the legs and falling occurs unless the individual with achondroplasia sits down and rests or assumes a squatting position with the back to
a
vertical support such
as a
wall. These
improve impaired blood supply to the conus medullaris and cauda equina by reducing the lumbar lordosis and decompressing the spinal cord and roots. This clinical picture is often dramatic and an indication of potentially progressive
postures
are
thought
to
permanent loss of motor and sensory function of the lower spinal cord. Clinical examination may assist in defining the extent and level of myelopathy. Dorsal column compression may affect vibration and proprioception sensations; however, in young children, demonstration of posterior cord compression may require laboratory evaluation using somatosensory evoked responses with stimulation both of upper and of lower limbs. 40 Pain and electrical sensations up and down the cervical spinal cord (Lhermitte’s sign) can occur with neck flexion when cervical cord stenosis is or inverted deep-tendon reflexes particularly in the upper arms, are indicative of cervical or lumbar radiculopathy. Evaluation for suspected myelopathy in achondroplasia depends on the combination of computed tomography to determine the level of bone compression and magnetic resonance imaging to observe the level of cord compression as demonstrated by spinal cord narrowing, gliosis, or cystic changes. Previously, myelography was performed; however, this is usually technically difficult because of the generalized spinal canal stenosis. Severe and persistent back pain was frequently observed postmyelography.
present. Absent, depressed,
marked angulation and compression of the spinal cord (Figure 8A). Claudication of the cauda equina is most pronounced while standing or walking upright with maximum tendency to lumbosacral lordosis. Symptoms of intermittent claudication of the cauda equina are relieved by squatting and resting against a firm wall. These measures reduce the degree of lordosis at the lumbosacral junction. A gibbus deformity of the thoracolumbar vertebrae is common in achondroplastic infants and should be investigated by lateral radiographs of the involved vertebrae (Figure 8B). Anterior wedging of one or more vertebral bodies is important, since angulation at this level can compress the conus medullaris and cauda equina. In the younger children, wedging of the vertebrae should be carefully followed radiologically because angulation may be progressive. Usually, the gibbus deformity resolves with ambulation and onset of exaggerated lordosis. Occasionally in the older patient, angulation becomes established and neurologic symptoms of paraparesis or intermittent claudication of the cauda equina occurs. A combined orthopedic approach of laminectomy and angle reduction may be necessary. Nerve Root Compression Compression of the nerve roots as they exit the spinal cord is common in achondroplasia. Both the abnor-
mal shortening of the pedicles of the vertebrae and small neural foramina appear to contribute to this problem. Narrowing of neural foramina can occur at multiple levels but is clinically significant in the cervical and lumbar regions. The patients complain of distal dysesthesias and paresthesias in the upper and lower limbs. This may subsequently cause loss of tendon reflexes and focal muscle wasting. Depressed triceps reflex unilaterally or bilaterally with an inverted reflex (flexion at the elbow) is an early sign of
Vertebral Column Malalignment Scoliosis and kyphosis are infrequent in achondroplasia and usually do not contribute to the neurologic problems. However, lumbar lordosis and thoracolumbar gibbus formation cause neurologic morbidity. Marked angulation of the sacrum is a common malformation of the spine in achondroplasia.9 The degree of lordosis increases with age. The causes of the sacral angulation to almost a right angle to the lumbar vertebrae are not well established but contribute to compression of nerve roots of the cauda equina. Occasionally lumbosacral lordosis is complicated by vertebral subluxation, which causes
root
compression. Occipital neuralgia is not uncommon in achondroplasia and is caused by compression of the occipital nerve or nerves exiting through the posterior atlanto-occipital membrane. Presumably, the nerve is entrapped by the fibrous membrane or by proximity to the posterior lip of the foramen magnum and posterior arch of the atlas (which may be fused in achondroplasia). Complaints of paresthesias or headache in the occipital region of the scalp or an area of anesthesia in the distribution of the occipital nerve is suggestive of occipital neuralgia. These symptoms may be difficult to distinguish clinically from those due to narrowing of the foramen magnum and compression of the cervicomedullary junction. nerve
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FIGURE 8 Lateral radiograph
’
showing gibbus deformity and wedging of L1 vertebrae (A). Magnetic
imaging of the lumbar spine showing subluxation of L1 angulation deformity of spinal cord (B). resonance
Electromyographic examination of specific muscle help to localize particular nerve roots that are functionally compressed. Often, following enlargement of the neural foramina surgically either at the time of laminectomy or, occasionally, as an isolated procedure at one or more foramina, there is improved function. Occipital neuralgia can be treated by occipital neurectomy provided that significant craniocervical junction compression has been exgroups will
cluded.
Homozygous Achondroplasia Homozygous achondroplasia can occur theoretically in a quarter of offspring of a union between two individuals with heterozygous achondroplasia.4 Most die at birth or in the early months of life of respiratory complications. Initially, the respiratory complications, including cor pulmonale, were attributed to the extremely small chest size and restrictive pulmonary disease.41 However, the severe bone dysplasia affects not only the long bones but the bones of the vertebral column and the foramen magnum, which is extremely small.4 As a result of the stenosis at the craniocervical junction, there may be marked compression of the medullary respiratory centers and outflow pathways
vertebrae and marked
and The
subsequent apnea and respiratory insufficiency. recognition that some of the respiratory complications could be related to medullary and cervical spinal cord compression has led to a more aggressive approach to treatment, with prolonged survival.4,2~,42 However, long-term survival has not been demonstrated, and the requirement for prolonged respiratory support brings into question the efficacy of surgical intervention. Motor delay and hypotonic quadriparesis or quadriplegia are complications of the homozygous achondroplasia. Hydrocephalus may be evident on computed tomography and require shunting procedures. The physical characteristics of these infants with homozygous achondroplasia are qualitatively similar to but quantitatively much more severe than those in heterozygous achondroplasia.41 Management of Achondroplasia Management of achondroplasia depends on age, but a multidisciplinary approach to follow patients is recommended11,12 (Figure 9). Diagnosis should be established by a geneticist, using clinical and radiographic findings. I ’13 Following diagnosis, complete neurologic assessment with special attention to attainment of developmental milestones, degree of ,
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FIGURE 9
Algorithm
for
management of achondroplasia.
and ligamentous laxity is suggested. Head size should be carefully monitored on a monthly basis during the first year of life and thereafter annually. Any deviation from normal head growth for achondroplasia should be an indication for further study. The hypotonia and delayed motor development should not be dismissed as related only to ligamentous laxity, since this may well be an early manifestation of spinal cord paralysis. After 3 months of age, we have found that somatosensory evoked responses in both upper and lower limbs may be helpful in evaluating the dorsal columns because neurologic assessment of this aspect of spinal cord function can be difficult.4° Furthermore, somatosensory evoked responses can be assessed serially and also before, during, and after surgical decompression. Abnormalities of somatosensory evoked responses may also have some localizing value in assessing the level of cord dysfunction (Figure 10), since the neurologic examination and routine radiographs may not be informative. Computed tomography with particular attention to the posterior fossa has been utilized in achondroplasia. Computed tomography permits evaluation of the brain and ventricles in addition to the foramen magnum size and growth centers. General population and achondroplastic foramen magnum values are available. 24,25 Sagittal reconstruction of the posterior fossa and upper cervical canal permits more detailed assessment of the relationship of the bones of the craniocervical junction, and soft-tissue structures can
hypotonia,
also be evaluated. These sagittal views enable visualization of the odontoid process as well as the posterior neural arches of the atlas and axis and may indicate multiple levels of cord compression, in addition to the small foramen magnum. Similar studies can be performed at the cervical and lumbar levels to demonstrate canal stenosis at these potentially significant sites. More recently, magnetic resonance imaging of the brain and spinal cord has been used to define the anatomic level of hydrocephalus and degree of ventricular compensation (eg, presence or absence of subependymal cerebrospinal fluid extravasation) or compression of the spinal cord (Figure 11). Gliosis, edema, and narrowing are readily apparent on magnetic resonance imaging of the cord, and an area of cystic necrosis or syringomyelia can be visualized at the level of compression. Magnetic resonance imaging appears helpful in the assessment of children requiring surgical decom-
pression ; however, computed tomographic scanning remains the basis of our assessments. Children with clinical respiratory problems must be assessed in order to define the relative contribution of peripheral (small chest cage, enlarged tonsils) and central (neurologic) mechanisms producing
stridor, apnea, snoring, repeated pneumonia,
or res-
piratory distress. In addition to chest radiographs and direct visualization of the upper airways, polysomnography has been used to investigate the nature of the respiratory disorder and, particularly, whether sleep apnea is present.11,12 Achondroplastic individ-
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FIGURE 10 Placement of
somatosensory evoked potential electrodes
directly spinal cord during surgical decompression of the brain stem (A); absence of the thalamocortical response on
prior to surgery (B); return of thalamocortical response (arrowheads) (C,D) after decompression.
FIGURE 111
Magnetic (B)
views
imaging scan of the upper cervical spine flexion (A) and showing compression at the level of the foramen magnum.
resonance
extension
cord
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’
uals with abnormal further evaluation for
polysomnograms may need cor pulmonale, including an and electrocardiogram echocardiogram. Intensive study of achondroplasia in the last decade has led to a greater understanding of the neurologic morbidity associated with the bony abnor-
11. Reid CS,
malities of the condition. Studies suggest that the associated complications such as myelopathy, apnea, respiratory drive abnormalities, and sudden death are not uncommon. Careful attention should be paid to children with achondroplasia in order to identify those at high risk for these complications. Identification and correction of these problems in childhood may help avert long-term and possibly irreversible neurologic complications and may increase longevity and the quality of life.
13.
,
Acknowledgments We are indebted to Dr Charles I. Scott, Jr, who suggested to us that there were serious neurologic complications in achondroplasia. We wish to thank Dr William A. Horton for encouraging and supporting these studies. We are indebted to Drs W. Goldie, W. Nelson, M. Miner, and L. Patchell for their involvement and help in all of the studies cited in the text. Dr J. Cabrera provided the excellent drawing of the cervical spine and somatosensory evoked potential tracings. Lynn Grace provided excellent typing and editorial skills.
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hypochondroplasia. J Med Genet 1979;16:140-146. 3. Murdoch JL, Walker BA, Hall JG, et al: Achondroplasia—a genetic and statistical survey. Ann Hum Genet 1970;33:227-244. 4. Hecht JT, Horton WA, Butler IJ, et al: Foramen magnum stenosis in homozygous achondroplasia. EurJ Pediatr 1986;145: 545-547. 5. Ogilvie D, Wordsworth P, Thompson E, Sykes B: Evidence against the structural gene encoding type II collagen (COL2A1) as the mutant locus in achondroplasia. J Med Genet 1988;23: 19-22. 6. Francomano CA, Pyeritz RE: Achondroplasia is not caused by a mutation in the gene for type II collagen. Am J Med Genet
Pyeritz RE, Kopits SE, et al: Cervicomedullary compression in young patients with achondroplasia: Value of comprehensive neurologic and respiratory evaluation.J Pediatr 1987;110:522-530. FW, Hecht JT, Horton WA,
et al: Neurologic basis of respiratory complications in achondroplasia. Ann Neurol 1988;
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Pediatr 1968;7:474-485. 14. Hecht JT, Francomano CA, Horton WA, Annegers JF: Mortality in achondroplasia. AmJ Hum Genet 1987;41:454-464. 15. Todorov AB, Scott CI, Warren AE, Leeper JD: Developmental screening tests in achondroplastic children. AmJ Med Genet
1981;9:19-23. JP, Rosenberg HS, Alvord EC: Megancephaly, internal
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Spillane JD: Three cases of achondroplasia with neurological complications. J Neurol Neurosurg Psychiatry 1952;15:246-252. Vogl A: The fate of the achondroplastic dwarf (neurologic complications of achondroplasia). Exp Med Surg 1962;20: 108-117.
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17. Horton WA, Rotter JI, Rimoin DL, et al: Standard growth curves for achondroplasia. J Pediatr 1978;93:435-438. 18. Pierre-Kahn A, Hirsch J-F, Renier D, et al: Hydrocephalus and achondroplasia. Childs Brain 1980;7:205-219. 19. Cohen ME, Rosenthal AD, Matson DD: Neurological abnormalities in achondroplastic children. J Pediatr 1967;71:367-376. 20. Mueller SM, Bell W, Cornell S, et al: Achondroplasia and hydrocephalus. Neurol 1977;27:430-434. 21. Yamada H, Nakamura S, Tajima M, Kageyama N: Neurological manifestations of pediatric achondroplasia. J Neurosurg 1981; 54:49-57. 22. Mueller SM, Reinertson JE: Reversal of emissary vein blood flow in achondroplastic dwarfs. Neurol 1980;30:769-772. 23. Sainte-Rose C, LaCombe J, Pierre-Kahn A, et al: Intracranial venous sinus hypertension: Cause or consequence of hydrocephalus in infants? J Neurosurg 1984;60:727-736. 24. Hecht JT, Nelson FW, Butler IJ, et al: Computerized tomography of the foramen magnum: Achondroplastic values compared to normal standards. AmJ Med Genet 1985;20:355-360. 25. Hecht JT, Horton WA, Reid CS, et al: Growth of the foramen magnum in achondroplasia. Am J Med Genet 1989;32:528-535. 26. Wang H, Rosenbaum AE, Reid CS, et al: Pediatric patients with achondroplasia: CT evaluation of the craniocervical
1988;29:955-961. 7. Strom CM: Molecular studies in achondroplasia using CO12A1 probes in human achondroplasia: A multidisciplinary approach, in Nicoletti B, Kopits SE, Ascani E, McKusick VA (eds): Human Achondroplasia. New York, Plenum Press, 1988, pp 59-60. 8. Vogl A, Osborne RL: Lesions of the spinal cord (transverse myelopathy) in achondroplasia. Arch Neurol Psychiatry 1949; 9.
Baumann PA, Gorlin RJ: Achondroplasia: Clinical radiologic features with comment on genetic implications. Clin
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Rogers JG, Perry MA, Rosenberg
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Vignette Romberg’s Description of Stroke in Infancy The course of the medullary fibres from the spinal cord to the corona radiata and the hemisphere has hitherto only been shown in the roughest outlines, as followed with the naked eye in recent or hardened brains. The demonstration of different elements, and of their motor or sensory attributes, yet lacks much to render it at all satisfactory. We may expect some advancement in our knowledge of this subject by the dissection of the brains of subjects who have been paralysed for many years, and in whom the function of motion alone was impaired. An opportunity of this kind presented itself to me in the person of a girl, aged 19, who, according to her father’s statement, had been born healthy, but was attacked with violent convulsions at the age of 3 months, followed by paralysis of the right extremities. She was small for her age, and imperfectly developed; the arm and leg of the right side were much emaciated and were only half the size of their fellows. The fingers of the right hand felt as if they consisted only of soft tissues; at the same time they were generally contracted and turned in to the hollow of the hand, but could be easily extended. The movements of the foot and arm were very much limited; the foot was dragged in walking, and the patient was unable to squeeze with her right hand, or to raise the arm at all. At the same time there was no trace of paralysis in the face or the tongue. The patient’s speech, though monosyllabic, was unimpeded. The sensibility of the limbs was normal as well as the functions of the senses; but the intellect was almost reduced to a par with idiocy. The girl could only find expressions indicative of hunger and pain; she was unable to fix her attention or to form any idea. Menstruation occurred at the age of sixteen. In my lectures I stated my diagnosis to be atrophy of the left hemisphere of the cerebrum, and that as there was no external depression of the cranium, I assumed the vacant space to be filled up by serum. Death ensued from phthisis pulmonalis, and the post-mortem examination was made by Professor Henle on the 4th of March, 1838. In removing the calvarium the saw accidentally pene-
trated too deep, and caused a quantity of sero-sanguineous fluid to escape. The left half of the cranium was half an inch narrower than the right, and the left os frontis was thickened. The middle of the upper part of the left cerebral hemisphere was absent, and in its place was a serous cyst, which had been torn in opening the cranium, and had discharged its contents. This cyst was only separated from the lateral ventricle by its investing membrane. On dividing the latter, the ventricle was found dilated and containing a large quantity of clear serum. The foramen Monroi was much distended; the walls of the ventricle were half wanting, nothing but rudiments of the thalamus opticus and corpus striatum remaining, and they were bounded by a margin of the hardness of cartilage. No morbid appearances presented themselves in the corpus callosum, the fornix, the septum lucidum, and the anterior commissore. At the base of the brain, the optic tract, the eminentia mammillaris, the crus cerebri, the pons, and the pyramid of the left side were atrophied; the latter was converted into a thin strip, only a quarter the size of the right pyramid; at the same time the restiform bodies of both sides presented a normal volume, and the olivary body of the left side was even more arched and much fuller than that of the right. The dimensions of both hemispheres of the cerebellum were the same; the brachial plexus of the right side was normal. We were not permitted to open the spinal canal. In this case the commissural structures were sound; but a tract that extended through various cerebral structures was atrophic owing to its not having been able to execute its functions.
Excerpted
from
Romberg’s
Manual
of the
Nervous Diseases
of
Man, Volume 2, translated by E.H. Sieveking. The Sydenham Society, London, 1853, pp 417-419. This patient’s brain was the Anatomical Museum of Berlin and was described Edward Henoch in his 1842 dissertation De Atrophica Cerebri.
preserved in
by
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