American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:145–153 (1999)

Neuroanatomic and Neuropsychological Outcome

in School-Age Children With Achondroplasia
Nora M. Thompson,1* Jacqueline T. Hecht,2 Timothy P. Bohan,3 Larry A. Kramer,4 Kevin Davidson,6
Michael E. Brandt,5 and Jack M. Fletcher2
1
Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas
2
Department of Pediatrics, University of Texas Medical School, Houston, Texas
3
Department of Neurology Pediatrics, University of Texas Medical School, Houston, Texas
4
Department of Radiology, University of Texas Medical School, Houston, Texas
5
Department of Psychiatry and Behavioral Sciences, University of Texas Medical School, Houston, Texas
6
FSD Data Services, Inc.

We previously reported on cognitive and re-
spiratory factors in a series of infants with
achondroplasia (ACH). We now present the
results of neuropsychological evaluation
and magnetic resonance imaging in 16
school-age children with ACH, 7 of whom
had been included as infants in our previous
report. We examined the neuroanatomic
and cognitive status of this sample, as well
as the predictive stability of the prior infant
assessment. Seventeen normally developing
children of average stature and 21 preterm
children with arrested (compensated, un-
shunted) hydrocephalus constituted the
comparison groups. Brain volumes of chil-
dren with ACH were significantly larger
than those of the comparison groups. In ad-
dition, children with ACH exhibited kinking
of the medulla and neuroanatomic abnor-
malities consistent with arrested hydro-
cephalus, including enlarged ventricles and
hypoplasia of the corpus callosum. Cogni-
tive abilities at school age were average, al-
though mild deficits were seen on visual-
spatial tasks, similar to those obtained by
the hydrocephalic comparison group. Only
gross motor coordination deficits distin-
guished the ACH group from the hydroce-
phalic controls. Infant assessment overesti-
mated later school-age IQ scores in those in-
fants with ACH who scored above average.
These findings point to generally preserved
cognitive skills in selected children with
ACH at early school age, although children
Contract grant sponsor: NINDS; Contract grant number:
NS29368.
*Correspondence to: Nora M. Thompson, Ph.D., Disabled Stu-
dent Services, University of Washington, Box 355839, Seattle,
WA 98195.
Received 1 November 1996; Accepted 10 February 1998
© 1999 Wiley-Liss, Inc.
with ACH should be evaluated individually
as they are at risk for cognitive, academic,
and motor deficits. Am. J. Med. Genet. (Neu-
ropsychiatr. Genet.) 88:145–153 1999.
© 1999 Wiley-Liss, Inc.
KEY WORDS: achondroplasia; intelligence;
cognition; MRI; dwarfism;
hydrocephalus
INTRODUCTION
Achondroplasia (ACH) is a common dwarfing condi-
tion which has been associated with average intelli-
gence in spite of the presence of central nervous system
(CNS) anomalies [Priestly and Lorber, 1981]. ACH has
been shown to be caused by a mutation in fibroblast
growth factor receptor 3 (FGFR3) [Francomano et al.,
1994; Shiang et al., 1994]. FGFR3 plays an important
role in both bone and neuronal development. Yet the
consequences of a mutation in FGFR3 for brain devel-
opment are unclear, since the precise role of FGFR3 in
the central nervous system is largely unknown.
CNS anomalies associated with ACH include hydro-
cephalus, as well as compression and upward displace-
ment of the brainstem [Kao et al., 1989; Steinbok et al.,
1989]. Respiratory dysfunction, a frequent complica-
tion in ACH, has been linked to compression of the
brain stem in some patients [Mador and Tobin, 1990;
Nelson et al., 1988; Waters et al., 1993]. In a previous
study of 13 infants with ACH, we showed that respira-
tory dysfunction, as measured by polysomnogram, was
associated with decreased mental abilities on the Bay-
ley Scales of Infant Development [Hecht et al., 1991].
The hydrocephalus associated with ACH has been
characterized as resulting from transient increases in
intracranial pressure during infancy and early child-
hood [Hecht and Butler, 1990], attributed to deficient
flow of cerebral spinal fluid and reduced venous uptake
secondary to the small vascular channels and small
foramen magnum [DiMario et al., 1995; Steinbok et al.,
146 Thompson et al.
1989]. DiMario et al. [1995] used magnetic resonance
imaging (MRI) to study brain and skull base variables
in very young (newborn to 6-year-old) children with
ACH. They found significant differences relative to
age-matched controls on over half of the dimensions
studied, including larger bifrontal and bicaudate
widths, larger frontal horn diagonal length, and larger
biatrial widths, as well as smaller frontal lobe depths,
optic angles, foramen magnum diameters, and sino-
jugular transition zones. The authors concluded that
rostral displacement of the brain stem and gradual
compression of the frontal lobes occur in ACH due to
the effects of venous sinus distension, causing enlarge-
ment of the supratentorial ventricular spaces. Yet, the
influence of hydrocephalus on cognitive development in
ACH is not clear. Although intelligence has been de-
scribed as normal in ACH, cognitive deficits have been
reported [Brinkman et al., 1993].
Brinkman et al. [1993] studied a group of 30 children
with ACH in comparison to children with other forms
of dwarfism, sibling controls, and normal controls.
They found that children with ACH had more frequent
histories of early motor and speech development delay
and lower school grades. Although cognitive scores
were within normal range, they were lower than those
of siblings and normal controls, particularly in lan-
guage comprehension. The authors felt that this cogni-
tive disparity was related to frequent middle-ear infec-
tions and subsequent hearing loss in ACH.
In order to more clearly delineate outcome in ACH,
we sought to evaluate those aspects of cognitive and
behavioral outcome specific to ACH (etiology-specific)
in relation to secondary neurologic factors, i.e., hydro-
cephalus and hypoxia, which can be associated with
ACH. To this end, we selected a comparison group con-
sisting of children with transient hydrocephalus sec-
ondary to prematurity. These children are similar to
the children with ACH in the presence of unshunted
hydrocephalus as well as an early history of respiratory
distress. Although hydrocephalus of prematurity dif-
fers in onset and pathological process from hydroceph-
alus associated with ACH, increased intracranial pres-
sure is transient in both groups. Thus, children with
hydrocephalus secondary to prematurity share certain
secondary features in common with children with ACH
(transient hydrocephalus and respiratory problems)
that may help to disentangle the effects of ACH from
those of secondary associated features.
Because few group studies of cognitive skill in child-
hood ACH have been published, we chose to measure a
broad range of cognitive skills with a comprehensive
battery of tests selected for their utility with early
school-age children. These included measures known to
be sensitive to the manifestations of hydrocephalus in
children. Previous studies of children with early hydro-
cephalus demonstrated significant reductions in cogni-
tive and motor skills, with nonverbal cognitive devel-
opment more vulnerable to delay than language skill
[Dennis et al., 1981; Fletcher et al., 1992a; Fletcher and
Levin, 1988]. Sensitive language tests were also in-
cluded, since earlier studies suggested deficits in this
area in ACH [Brinkman et al., 1993]. Hence, we stud-
ied neuroanatomic, cognitive, and behavioral outcomes
at school age of a sample of children with ACH.
Neuropsychological assessment and magnetic reso-
nance imaging of the brain were performed on a group
of school-age ACH children and compared to those of
normal controls and syndrome controls (i.e., children
with arrested hydrocephalus and hypoxia secondary to
premature birth). In addition, comparison of school-age
results with scores obtained in infancy was made for
the 7 children from a previous study in order to assess
the stability of infant assessment in ACH.
MATERIALS AND METHODS
Subjects
The subjects for this study were 54 children ranging
in age from 5.5–14 years, including 16 children with
ACH, 21 children born prematurely, and 17 normally
developing children of average stature. All children
had either a Verbal or Performance IQ above 69 on
either the Wechsler Intelligence Scales for Children-
Revised (WISC-R) [Wechsler, 1974] or the McCarthy
Scales of Children’s Abilities [McCarthy, 1972]. The
children were recruited as part of a larger study of
children with hydrocephalus [Fletcher et al., 1992a,b].
Children were excluded from the larger study if they
had a history of severe psychiatric disorder (autism or
psychosis), uncontrolled seizure disorder, other neuro-
logic disorder (e.g., head trauma, tumor), child abuse,
or sensory deficit (hearing impairment or uncorrected
visual impairment), or were unable to speak English.
The 16 children with ACH were diagnosed by clinical
and radiographic criteria at the University of Texas–
Houston Medical School Medical Genetics Clinic. All
children were recruited for participation in this study
through this clinic either in conjunction with a regu-
larly scheduled clinic visit, or by telephone for five
families who had moved out of state. Three children
with ACH were excluded from the study. One child was
excluded due to an acquired neurologic disorder, one
child was excluded due to hemiparesis, and one child
was not able to speak English. Three of the five fami-
lies who had relocated agreed to undergo neuropsycho-
logical evaluation while attending an annual meeting
on dwarfism (Little People of America), but were un-
able to perform the neuroimaging study.
Seven of the children with ACH had been followed at
the clinic since infancy, and information pertaining to
respiratory function was available. Five had a normal
history, but one child had cessation of respiratory func-
tion while awake (daytime apnea) in conjunction with a
normal polysomnogram, and one child had a history of
obstructive apnea confirmed by an abnormal polysom-
nogram (i.e., more frequent than 5 per hour).
In the premature group, all children had a history of
very low birth weight (<1,600 g) and were born at no
more than 34 weeks of gestation. All premature chil-
dren had previous imaging studies which supported
group placement. Most of the children had a history of
either grade III (n ⳱ 12) or grade IV (n ⳱ 5) intraven-
tricular hemorrhage, which resulted in progressive
ventricular dilation. Four children had enlargement of
ventricular dilation with periventricular leukomalacia
 Outcome in Children With Achondroplasia 147

(hydrocephaluas ex vacuo). Hydrocephalus was severe normally developing groups, but were significantly
enough to warrant medication treatment (e.g., diuret- lower in the premature group than in the normally
ics) for hydrocephalus shortly after birth, but resolved developing group (F(1,37) ⳱ 142.7, P < .0001) and the
in all cases. No premature child was included who had ACH group (F(1,33) ⳱ 127.1, P < .0001). Likewise,
a history of severe bronchopulmonary dysplasia, sig- mean gestational age in weeks was significantly
nificant pulmonary immaturity, or severe retrolental shorter in the premature group than in the normally
fibroplasia. developing group (F(1,37) ⳱ 286.2, P < .0001) and the
The normally developing children were sibs or rela- ACH group (F(1,33) ⳱ 206.6, P < .0001). The prema-
tives of the children with ACH or the premature chil- ture children spent the longest time in the hospital
dren, or were recruited from families whose child with immediately after birth than either the normally de-
ACH or hydrocephalus fell outside of the age param- veloping children (F(1,37) ⳱ 49.8, P < .0001) or the
eters for inclusion in the larger study. This group was children with ACH (F(1,33) ⳱ 38.6, P < .0001). Differ-
well-matched for family demographic and environmen- ences in birth weight, gestational age, and time spent
tal factors, and demonstrated complete absence of ac- in hospital after birth are consistent with prematurity,
quired neurological disorder. very low birth weight, and early medical complications
Table I shows that the three groups did not differ in that are associated with premature birth.
gender (␹2(2,N ⳱ 54) ⳱ 1.03, P < .60) or race ␹2(6,N ⳱
54) ⳱ 3.73, P < .71). Although the age differences were Procedures
not significant (F(2,53) ⳱ 3.11, P < .06) the children
with ACH tended to be younger than those in the other Each child underwent a neuropsychological evalua-
two groups. Consequently, all psychometric tests were tion and magnetic resonance imaging of the brain as
age-adjusted, and MRI quantitative measures were re- part of a comprehensive assessment of the child’s de-
ported as ratios to brain size, or included age as a co- velopment [Fletcher et al., 1992a,b]. Some children did
variate to control age-related variability. There were not complete all of the tests because of fatigue or time
no significant group differences in socioeconomic status constraints, leading to slight variation in sample size
(␹2(4,N ⳱ 54) ⳱ 2.34, P < .67), or family material re- across analyses. Parental consent and child assent
sources (F(2,48) < 1, P < .89), as measured by the Fam- were approved by the University of Texas–Houston
ily Resource Scale [Dunst and Leet, 1987; Hollingshead Health Science Center Committee for the Protection of
and Redlich, 1958]. All children were independently Human Subjects.
ambulatory. One child with ACH and three premature The neuropsychological evaluation included the fol-
children had a history of seizures, but all were seizure- lowing areas: intelligence (Wechsler Intelligence Scale
free at the time of evaluation. Table I also shows birth for Children-Revised, Verbal IQ and Performance IQ
weights, which did not differ between the ACH and [Wechsler, 1974]); academic achievement, including
measures of reading decoding, reading comprehension,
and arithmetic from the Woodcock-Johnson Tests of
TABLE I. Demographic and Birth Characteristics of the
Sample (N ⳱ 54) by Group* Academic Achievement-Revised [Woodcock and
Johnson, 1989], spelling and arithmetic from the Wide
Group Range Achievement Test-Revised (WRAT-R) [Jastak
Premature and Wilkinson, 1984], and sentence writing [Gaddes
Achondro- with Hydro Normal and Crockett, 1975]; language, including measures of
plasia and Hypoxia control phonological awareness (Auditory Analysis Test [Ros-
Variable (N) (16) (21) (17) ner and Simon, 1971]), receptive vocabulary (Peabody
Age (months) Picture Vocabulary Test-Revised [Dunn and Dunn,
Mean 88.8 106.5 111.1 1980], verbal fluency [Gaddes and Crockett, 1975], and
SD 16.4 27.8 34.3
rapid automatized naming [Denkla and Rudel, 1974];
Gender (%)
Male 62 48 47 fine motor coordination (speed of finger tapping and
Female 38 52 53 peg placement on grooved pegboard and Purdue peg-
Race (%) board [Knights and Moule, 1986]); gross motor coordi-
White 75 71 76 nation (leg and arm coordination [McCarthy, 1972]);
African American 6 9 0 visual-spatial skills, including a motor-based design
Hispanic 19 9 18
copying task (Beery Test of Visual Motor Integration
Other 0 9 6
Socioeconomic status (%)** [Beery, 1982]) and a motor-free spatial matching task
Low (4–5) 19 33 41 (judgment of line orientation [Benton et al., 1994]); and
Middle (3) 25 14 18 memory, including serial learning for verbal and non-
High (1–2) 56 52 41 verbal material, using a selective reminding procedure
Birth weight (g) [Fletcher, 1985] and visual recognition memory [Han-
Mean 3,365 1,369 3,325
nay and Levin, 1988]. Adaptive behavior was measured
SD 593 205 663
Gestational age (weeks) using the Vineland Adaptive Behavior Scales-Revised
Mean 39.0 30.0 39.8 Survey Edition [Sparrow et al., 1984], while the Child
SD 1.6 2.1 1.4 Behavior Checklist was used to obtain parent ratings
of behavioral adjustment [Achenbach, 1991].
*Hydro, hydrocephalus.
**Socioeconomic status was measured with the two-factor scale of Holling- Magnetic resonance imaging was performed either
shead and Redlich [1958]. on the same day as the neuropsychological testing or as
148 Thompson et al.

soon as possible afterward if equipment or scheduling related variability. Corpus callosum and ventricular
problems occurred. The scans were read by a radiolo- volumes were analyzed, using ANOVA, as ratios to
gist (L.A.K.) and a pediatric neurologist experienced in whole-brain volume in order to control for variations in
imaging studies (T.P.B.). The imaging was conducted brain size. Alpha was set at P < .05, since there were
using a 1.5-T superconducting magnet (General Elec- only five comparisons made.
tric, Milwaukee, WI). One sequence of sagittal images The methods used for quantitation of MRI have been
and two sequences of axial images were obtained for previously described [Fletcher et al., 1992b]. The MRI
each child. The T1-weighted sagittal images were ob- films were reviewed to identify the most midline sag-
tained by means of a spin-echo two-dimensional se- ittal slice depicting the corpus callosum. From this
quence with an echo time of 20 msec and a pulse rep- point, each sagittal slice depicting the lateral ventricles
etition time of 700 msec. Conventional spin-echo proton in the right and left hemisphere was identified. A re-
density and T2-weighted axial images were obtained gion-filling algorithm was used to count the total num-
using 30- and 80-msec echo times, respectively, and a ber of pixels enclosed within its irregularly shaped
repetition time of 2,000–3,000 msec. For the T1 sagit- boundaries. For the corpus callosum, the cross-
tal, proton density, and T2 axial sequences, the slices sectional area in square millimeters was computed. For
were 5 mm thick and had a 2.5-mm interslice spacing. the lateral ventricles, the volume in cubic millimeters
The T1 axial slices were 3 mm thick and had a 1.0-mm was computed as the product of the cross-sectional
interslice spacing. area, slice thickness, and interslice spaces. A small
amount of freehand drawing was necessary to separate
Design and Analysis sinuses and cerebellum from brain or hemisphere. The
reliability coefficients ranged from 0.76 (corpus callo-
This study used a between-group, repeated measures sum/whole brain) to 0.97 (lateral ventricle/hemisphere),
multivariate design [O’Brien and Kaiser, 1985]. First, all above acceptable levels.
the neuropsychological data were age-adjusted based Finally, the WISC-R IQ and Bayley Scales of Infant
on national or local norms and converted to standard Development scores of the 7 ACH children who had
scores (M ⳱ 100 ± 15). Two types of data were analyzed been evaluated as infants were compared to determine
for this study. Performance of the three groups of chil- the predictive validity of infant testing in ACH.
dren were compared across tasks within the nine
neuropsychological domains, using repeated measures RESULTS
multivariate analysis of variance (MANOVA). The be- Neuroimaging Results
tween-subjects factor was Group (three levels), and the
within-subject factor was Task. Significance of the in- MRI data were obtained for 11 of the 16 children
teraction terms or, in the absence of a significant in- with ACH. Three children lived at too great a distance
teraction, significance of the main effect of Group was from the scanner, one had parents who declined the
determined by examining the F value associated with
Pillai’s Trace. Since Task effects were not central to the TABLE II. Frequencies of Abnormalities on Magnetic
hypotheses under investigation, they will not be re- Resonance Imaging in Achondroplasia and Premature
ported. School-Age Children With Arrested Hydrocephalus
Three planned contrasts were established: 1) ACH Group
vs. the normally developing group; 2) ACH vs. the nor-
mally developing and premature groups; and 3) ACH Achondroplasia Premature
Abnormality (N) (11) (19)
and premature vs. the normally developing group.
These contrasts enable a depiction of ACH relative to Lateral ventricle
normative development as well as determining those Normal 2 6
Enlarged 9 13
aspects of outcome in ACH that are etiology-specific Occipital horn
and those that are common to the presence of hydro- Normal 7 8
cephalus-hypoxia syndrome. When significant main ef- Enlarged 4 11
fects occurred, post hoc analyses were conducted using Fourth ventricle
univariate and multivariate analysis of variance. To Normal 10 3
maintain alpha at the .05 level and to control for mul- Enlarged 1 16
Third ventricle
tiple comparisons, alpha was adjusted to P < .05/3 ⳱ Normal 8 3
.0167. Enlarged 3 16
The groups were then compared with regard to neu- Periventricular leukomalacia
roimaging data. Each child’s MRI was tabulated for None 11 10
percentages of abnormalities. Next, the area of the cor- Mild 0 4
pus callosum was measured, along with the volumes of Moderate 0 3
Severe 0 2
the cerebral hemispheres containing the lateral ven- Corpus callosum
tricles. Absolute measures of the cerebral hemisphere Hypoplastic 7 11
volumes were compared because of evidence suggesting Parital agenesis 0 0
that children with ACH have larger brains. This com- Medulla
parison of cerebral hemisphere volumes across groups Kinking 7 0
was performed using analysis of covariance (ANCOVA), Cerebellum
Abnormal 2 2
with age as a covariate in order to control for age-

scan, and one was not scanned due to scheduling con-
flicts. Visual examination of these 11 MRI scans re-
vealed that nine scans exhibited findings consistent
with noncommunicating hydrocephalus with enlarged
lateral ventricles. Similar findings were also obtained
for the premature group. Seven children with ACH
showed hypoplasia of the posterior aspects of the cor-
pus callosum. Kinking of the medulla was noted in
seven children with ACH. Findings for the premature
cohort were as expected, with ventricular dilation, hy-
poplasia of the corpus callosum, and periventricular
leukomalacia (Table II).
Analysis of the quantitative MRI measures revealed
no effect of Group on the corpus callosum/whole brain
ratio (F(2,23) ⳱ 1.82, P < .19). However, the NOVA was
significant for ratios involving the right hemisphere
(F(2,22) ⳱ 6.51, P < .006), and tended towards signifi-
cance for the left hemisphere (F(2,22) ⳱ 2.36, P < .10).
Follow-up tests using the Tukey Honestly Significant
Difference (HSD) procedure showed that both the ACH
and premature groups had larger right ventrical/brain
ratios than controls, with no differences for the left
ventrical/brain ratio (Table III).
When the volumes of cerebral hemispheres were
analyzed (Table III) brain volumes were larger in
the ACH group relative to the other two groups. The
ANCOVA was significant for both the right hemisphere
(F(2,21) ⳱ 3.74, P < .05) and the left hemisphere
(F(2,21) ⳱ 4.43, P < .03). Follow-up tests showed sig-
nificantly larger brain volumes in the ACH group rela-
tive to the normally developing group, with no other
post hoc tests achieving statistical significance.
Neuropsychological Results
Results revealed that as a group, intelligence in chil-
dren with ACH at school-age was in the average range
(mean WISC-R Verbal IQ ⳱ 93.6, SD ⳱ 18.3; Perfor-
mance IQ ⳱ 100.8, SD ⳱ 14.6). There was no interac-
tion of Group by type of IQ score, nor was there a sig-
nificant main effect of Group on IQ score. Similarly,
there were no significant interactions or main effects of
Group on any of the academic achievement measures.
Thus, the three groups were similar in IQ level and
academic achievement (Table IV).
The Group × Task × Hand MANOVA for fine motor
tasks yielded no significant interactions or main ef-
fects. Nonetheless, Table IV shows the lower scores and
TABLE III. Means and Standard Deviations for the Quantitative Magnetic Resonance Imaging Measures
Variable Achondroplasia
Corpus callosum/whole brain ratio (mm2)
Mean ± SD 0.0522 ± 0.0096
N 9
Lateral ventricle/whole brain ratio (mm3)
Right, mean ± SD 0.0424 ± 0.00246
Left, mean ± SD 0.0398 ± 0.0258
N 8
Whole brain (mm3)
Right, mean ± SD 202,768.5 ± 60,666.7
Left, mean ± SD 212,962.5 ± 59,789.0
N 8
Outcome in Children With Achondroplasia 149
elevated standard deviations for the ACH and prema-
ture groups, particularly on the Grooved Pegboard and
Purdue Pegboard tasks.
Sample size was reduced for the gross motor tasks
because some children were unable to complete the
testing due to fatigue or time constraints. Nonetheless,
the ANOVA for upper-extremity coordination was sig-
nificant (F(2,35) ⳱ 5.3, P < .0167). The children with
ACH as a group scored significantly lower than the
normally developing group, but did not differ from the
premature group. Lower-extremity coordination also
differed significantly between groups (F(2,35) ⳱ 11.8,
P < .001). A similar pattern of post hoc differences
emerged, with the ACH group obtaining lower scores
than the normally developing group. Again, the prema-
ture group obtained an intermediate score which did
not differ from those of the other two groups. Overall,
the ACH group obtained significantly lower scores on
measures of gross motor coordination of both upper and
lower extremities (Table V). The lower scores of the
ACH group most likely reflect difficulties that arise
because of physical differences in limb structure.
The Group × Task MANOVA for visual-spatial skills
(Beery Visual Motor Integration and Judgment of Line
Orientation) yielded only a significant main effect of
Group (F(4,96) ⳱ 3.2, P < .0167). Group contrasts re-
vealed that the normally developing group obtained
higher scores than both the ACH group (F(2,27) ⳱ 6.4,
P < .01) and the premature group (F(2,35) ⳱ 4.9, P <
.01), who did not differ from each other. These results
suggest that visual-spatial skills may be influenced by
the presence of arrested hydrocephalus and/or hypoxia
common to both groups.
Table VI depicts the means and standard deviations
on the language and memory tests. The Group × Task
MANOVAs for the language tasks, selective reminding
tests, and continuous recognition memory test yielded
no significant interactions or main effects of group.
The ANOVA for the composite score from the Vine-
land Adaptive Behavior Scales was significant for
Group (F(2,48) ⳱ 3.47, P < .04). The ACH vs. normally
developing group contrast was significant (F(1,28) ⳱
5.90, P < .01), while the contrast between the normally
developing and premature groups only approached sig-
nificance (F(1,36) ⳱ 4.3, P < .05). The deficits in adap-
tive behavior in ACH are expected and are most likely
attributable to physical differences in limb structure
Group
Prematures Normal
0.0425 ± 0.0144 0.0500 ± 0.0084
7 10
0.0400 ± 0.0214 0.0145 ± 0.0063
0.0514 ± 0.0566 0.0171 ± 0.0067
7 10
148,059.5 ± 72,828.8 138,549.1 ± 47,733.1
132,435.2 ± 26,502.0 175,342.9 ± 97,618.7
7 10
150 Thompson et al.

TABLE IV. Means and Standard Deviations for Academic Achievement Measures*
Group
Premature
Achondroplasia arrested hydrocephalus Normally developing
N M SD N M SD N M SD
Woodcock-Johnson
Reading decoding 12 97.1 15.7 19 98.0 15.5 17 103.3 14.0
Reading comprehension 12 96.1 16.5 19 103.8 16.0 17 108.1 16.1
Calculations 15 100.3 9.9 19 96.6 19.6 17 107.7 12.6
WRAT-R
Spelling 14 88.4 18.2 19 88.0 16.9 17 97.4 16.0
Arithmetic 15 88.9 7.7 19 85.7 14.9 17 96.1 13.3
Sentence writing 12 80.1 31.8 19 87.6 26.4 17 94.6 22.8
*WRAT-R, Wide Range Achievement Test-Revised [Jastak and Wilkinson, 1984].

TABLE V. Means and Standard Deviations for Motor and Visual-Spatial-Motor Tests by Group
Group
Premature
Achondroplasia arrested hydrocephalus Normally developing
N M SD N M SD N M SD
Fine Motor 12 20 17
Finger tapping
Dominant 108.9 30.8 97.8 26.2 105.1 29.8
Nondominant 104.5 21.6 93.9 26.0 110.9 37.8
Grooved pegboard
Dominant 89.3 19.8 88.7 27.5 111.3 9.7
Nondominant 88.3 24.5 86.7 25.1 104.9 16.8
Purdue pegboard
Dominant 79.8 19.2 80.6 25.3 94.2 9.2
Nondominant 90.7 16.2 83.0 23.2 95.6 10.1
Gross motor* 13 12 13
Arm coordination 72.6 18.2 84.8 16.9 92.7 11.8
Leg coordination 78.7 27.4 94.6 16.7 104.3 5.9
Visual-spatial-motor* 13 21 12
Beery VMI 81.5 11.8 81.0 15.0 92.1 9.4
JLO 84.6 16.2 90.2 15.1 100.0 15.0
*Achondroplasia vs. normally developing, P < .0167. VMI, visual motor integration; JLO, judgment of line orientation.

TABLE VI. Means and Standard Deviations for Language and Memory Tests*
Group
Premature arrested Normally developing
Achondroplasia (N ⳱ 14) hydrocephalus (N ⳱ 21) (N ⳱ 17)
M SD M SD M SD
Language
Auditory analysis 92.4 21.3 91.2 19.3 102.7 15.8
Rapid naming 97.1 18.9 98.7 15.6 105.7 11.8
Verbal fluency 92.3 13.3 99.4 16.5 99.4 16.5
PPVT-R 85.9 16.4 93.6 16.4 99.5 12.2
Memory
Selective reminding
Verbal 89.2 10.5 87.5 18.4 97.9 16.6
Nonverbal 94.8 26.8 82.5 21.6 102.3 20.8
Continuous recognition memory
Hits 87.0 23.8 90.0 17.1 97.5 22.3
False alarms 81.5 27.5 76.4 26.3 81.7 23.1
*PPVT-R, Peabody Picture Vocabulary Test-Revised [Dunn and Dunn, 1981].
 Outcome in Children With Achondroplasia 151

TABLE VII. Means and Standard Deviations for Adaptive Behavior and Behavior Problems
Group
Premature arrested
Achondroplasia hydrocephalus Normally developing
N M SD N M SD N M SD
Vineland Adaptive Behavior Scalesa 13 21 17
Communication 95.2 20.0 95.7 16.6 102.1 17.8
Daily living skills 87.8 12.8 92.0 13.2 103.0 12.5
Socialization 92.8 15.5 92.7 11.8 99.1 15.5
Composite* 87.8 15.2 91.2 13.7 101.9 18.5
Child Behavior Checklistb 15 21 16
Internalizing 54.5 8.2 53.4 9.2 52.5 10.0
Externalizing 52.3 9.2 51.1 10.2 53.1 9.8
a
M ⳱ 100 ± 15.
b
M ⳱ 50 ± 10.
*Normally developing vs. Achondroplasia, P < .0167.

and motor incoordination that can undermine perfor-
mance on activities of daily living (see Table VII).
Behavioral adjustment did not differ across groups.
The Group × Scale MANOVA for the Child Behavior
Checklist yielded no significant interactions (F < 1) or
main effect of Group (F < 1). Thus, parental concerns
regarding behavioral adjustment did not reach signifi-
cant levels in any of the three groups.
Prediction of IQ From Infant Scores
The 7 children with ACH who had been evaluated as
infants had obtained scores falling in the low average
(1), average (3), high average (2), and superior (1)
ranges on the Mental Development Scale of the Bayley
Scales of Infant Development (BSID). The median
BSID score was 104, with a range from 80–123. Six
children who had been evaluated as infants did not
return for follow-up assessment because three had
relocated out of state, two were lost to follow-up, and
one had acquired a neurologic disorder. These six chil-
dren had obtained BSID scores as infants falling in the
mentally retarded (1), low average (2), average (1), and
high average (2) ranges. Their median BSID was 89,
with a range of <50–110. Although their BSID scores
were not significantly different from the returning chil-
dren (␹2(1,N ⳱ 13) ⳱ 12.5, P < .75), the nonreturning
children with ACH had slightly lower infancy scores as
a group, including one child scoring <50.
At school age, all seven of the returning children ob-
tained Wechsler Full-Scale IQs within the average
range (90–110), with a median score of 99 and a much
narrower range of 92–105. This convergence of scores
into the average range for children with ACH at school-
age is depicted in Figure 1 and is consistent with stud-
ies of normally developing children [Bayley, 1933]. In
contrast, infants who score in the mentally retarded

Fig. 1. Range of IQ scores at school-age relative to infant scores shows convergence of scores into the average range.
152 Thompson et al.
range on the Bayley are rarely described as intellectu-
ally normal at school-age. Since the single infant scor-
ing <50 was lost to follow-up, we were not able to ad-
dress the predictive value of a low infant score for later
intelligence in ACH.
DISCUSSION
The results of this study revealed generally average
cognitive abilities in children with achondroplasia, de-
spite several CNS abnormalities. These abnormalities
included larger overall brain volume, the enlarged ven-
tricles and distortion of the corpus callosum consistent
with arrested hydrocephalus, and kinking of the me-
dulla. Like the premature children with arrested hy-
drocephalus, children with ACH exhibited mild deficits
in visual-spatial skills. In addition, children with ACH
demonstrated marked problems with upper- and lower-
extremity coordination apparent only in the ACH
group. Whether the motor incoordination in ACH is
related to underlying abnormalities of bone develop-
ment as opposed to central nervous system dysfunction
requires further study.
Unlike Brinkman et al. [1993], we did not find defi-
cits in language skill, in spite of our use of sensitive
measures of linguistic processing. This disparity be-
tween studies is probably due to differences in the au-
ditory capacities of the children studied. Over half of
the children with achondroplasia studied by Brinkman
et al. [1993] had some unspecified hearing deficit by
parental report, and two children wore hearing aids at
the time of the evaluation. In the present study, none of
the children had hearing impairment or wore hearing
aids; group means in language, reading, and verbal
memory were generally in the average range. Because
of the elevated frequency of hearing loss in children
with ACH, early detection and intervention for hearing
impairment is needed and may prevent later verbal
deficit [Shohat et al., 1993].
Fine motor skills showed increased variability in the
ACH and premature groups. Although the statistical
tests did not reach significance, examination of the
means and standard deviations for the fine motor tasks
indicates that some children in both the ACH and pre-
mature groups performed well below average. Fine mo-
tor skill deficits have been documented in prior studies
in various etiologies of hydrocephalus, including chil-
dren born prematurely [Fletcher and Levin, 1988].
With a larger sample size, this comparison may have
reached statistical significance in our sample for the
two pegboard tasks. Children with ACH exhibit differ-
ences in limb and hand structure that can influence
motor performance on peg placement, copying, and
gross motor tasks.
Although the cognitive abilities of children with ACH
were generally average as a group, some children with
ACH obtained scores well below normal, as evidenced
by the large standard deviations on several tasks. Fur-
thermore, group average scores in spelling, writing,
arithmetic, and visual-spatial perception fell below the
25th percentile for children with ACH and prematu-
rity. In light of the higher socioeconomic status (SES)
levels of the ACH group, higher-than-average cognitive
scores would have been expected. With a larger sample
size, more statistically significant group differences
may have emerged on cognitive tests, showing children
with ACH, like other neurologically at-risk groups, to
exhibit reduced skills in particular cognitive domains.
Although enlarged head circumference apparent at
birth is one of the hallmarks of ACH, it has not been
clear whether this enlargement is due to a large cere-
brum (e.g., megalencephaly), dilated ventricles, or
other factors. In the present study, we found that chil-
dren with ACH exhibited significantly increased brain
volume in both hemispheres compared to the normally
developing group. The brain volume measure included
cerebral tissue but not ventriclar size. The increased
cerebral volume represents an important neurodevel-
opmental aspect of ACH. Whether the increased cere-
bral volume results from an excessive number or size of
cells, or an accumulation of metabolic products, re-
mains to be determined. Although some individuals
with isolated megalencephaly have normal to superior
intelligence, an unknown percentage suffer from men-
tal retardation [DeMyre, 1981]. The nature of the in-
creased cerebral volume and its relationship to other
brain area measurements and cognitive ability in ACH
are important topics for further study.
The remaining neuroanatomic findings are consis-
tent with prior studies of ACH [DiMario et al., 1995;
Kao et al., 1989]. Although visualization of the corpus
callosum showed hypoplasia, quantitative analysis re-
vealed that the callosum to whole brain ratio was simi-
lar to those of the normally developing children and the
hydrocephalic comparison group. Thus, although
stretching of the corpus callosum may have occurred
due to increased intracranial pressure, the area mea-
surement of the commissure showed no differences
among the groups. In contrast, quantitative analysis of
the ventricular system in children with ACH and the
premature children with arrested hydrocephalus re-
vealed noteworthy differences relative to the neurologi-
cally normal comparison group. Both the ACH and pre-
mature groups showed larger ventricular volumes.
However, quantitative analysis showed that the pre-
mature group exhibited enlarged lateral, fourth, and,
to a lesser degree, third ventricles. Similar to the find-
ings of DiMario et al. [1995], the children with ACH in
the present study predominantly exhibited enlarge-
ment of the lateral ventricles. The different patterns of
ventricular size may reflect a less severe ventricular
dilation in ACH than in the premature group, relative
to the more gradual onset of increased intracranial
pressure in ACH. Alternatively, these differences may
reflect differences in the underlying neuropathology of
ACH that influence compensation of increased intra-
cranial pressure [DiMario et al., 1995].
Future studies of ACH should include measures of
attention and executive function. Given the findings of
DiMario et al. [1995], whose results suggest gradual
compression of the frontal lobes during infancy, elec-
trophysiologic indices may be well-suited to monitor
changes in neuronal function. Future studies of chil-
dren and adults with ACH should include specific mea-
sures of attention and executive function in order to
examine the neurobehavioral consequences of hydro-

cephalus and smaller frontal lobe depths. Comparison
of such results to quantitative brain measures, ad-
justed for differences in brain volume, would lend in-
sight into the cognitive impact of hydrocephalus in
ACH.
The present study was limited by the small sample
size. A larger sample size may be necessary to obtain
significant findings for the fine motor skill tasks and to
increase confidence in the results of the quantitative
analysis. Further imaging studies linking brain vol-
ume with cognitive status may shed important light on
the role of FGF3 in the CNS. Nonetheless, the motor
and cognitive deficits are clearly related to everyday
adaptive functions, particularly involving school-
related abilities. Visual-spatial deficits may undermine
certain aspects of academic achievement such as early
handwriting, conceptual mathematics, and map usage.
Fine motor deficits can interfere with handwriting per-
formance as well as other aspects of daily living skills
(e.g., fastening buttons and zippers). In addition, the
gross motor coordination problems associated with
ACH necessitate adaptations in the school environ-
ment, in physical education, and in athletic activities.
Educational professionals aware of these vulnerabili-
ties can arrange for remediation or compensation in
the classroom.
ACKNOWLEDGMENTS
We are grateful to the children and families whose
participation made this research possible.
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