Osteogenesis imperfecta in childhood:

Prognosis for walking

Raoul H. H. Engelbert, PCS, PhD, Cuno S. P. M. Uiterwaal, MD, PhD, Vincent A. M. Gulmans, PCS, PhD,
Hans Pruijs, MD, PhD, and Paul J. M. Helders, PSC, MSc, PhD

Osteogenesis imperfecta is a skeletal

Objectives: We studied the predicted value of disease-related characteris- disorder of remarkable clinical vari-
tics for the ability of children with osteogenesis imperfecta (OI) to walk. ability. In most cases in European pop-
Study design: The severity of OI was classified according to Sillence. The ulations, OI results from quantitative
parents were asked to report the age at which the child achieved motor and qualitative defects in the synthesis
of collagen I.1 Major clinical character-
milestones, the fracture incidence, and the age and localization of the first
istics of OI are bone fragility, osteope-
surgical intervention. The present main means of mobility was classified
nia, variable degrees of short stature,
according to Bleck.
and progressive skeletal deformities.
Results: There were 76 replies to the 98 questionnaires, of which 70 were Additional clinical manifestations in-
included (type I, 41; type III, 11; type IV, 18). The type of OI was strongly cluding blue sclerae, dentinogenesis
associated with current walking ability, as was the presence of dentinogene- imperfecta, joint laxity, and maturity
sis imperfecta. Patients with type III and IV had a lower chance of ultimate- onset deafness are observed.2 OI oc-
ly walking compared with those with type I. Children with more than 2 curs in approximately 1:20,000 births3;
intramedullary rods in the lower extremities had a reduced chance of walk- because it is not diagnosed in a signifi-
ing than patients without rods. Rolling over before 8 months, unsupported cant number of children as a result of
sitting before 9 months, the ability to get in sitting position without support mild expression, the real incidence is
before 12 months, and the ability to get in a standing position without sup- probably higher. Byers and Steiner4
report a prevalence of approximately
port before 12 months showed positive odds ratios. In Bleck 4, multivari-
1:5,000 to 1:10,000 individuals of all
ate analysis revealed that only the presence of rodding (yes/no) in the lower
racial and ethnic origins.
extremities had additional predictive value to the type of OI. The presence
of dentinogenesis imperfecta and rodding (yes/no) had additional value in OI Osteogenesis imperfecta
Bleck 5.
Conclusion: The type of OI is the single most important clinical indicator The severity of the disease influences
of the ultimate ability to walk. Information about motor development adds the ability to walk. Therefore it is im-
little. The early achievement of motor milestones contributes to the ability portant for physicians, patients, and
of independent walking when the type of OI is uncertain. Intramedullary the patients parents to gain insight
rodding of the lower extremities is primarily related to the severity of the into the severity and classification of
disease and in this way provides consequences for the ability to walk. the disease and the influence of dis-
(J Pediatr 2000;137:397-402) ease-related characteristics on the
prognosis for walking. Sillence et al5
state that rehabilitation strategies
should focus on the achievement of
From the Department of Pediatric Physical Therapy, the Department of Epidemiology, and the Department of Pedi-
community walking in the mildest type
atric Orthopaedics, University Medical Center; Wilhelmina Childrens Hospital, Utrecht, The Netherlands.
Submitted for publication Aug 26, 1999; revision received Jan 19, 2000; accepted Apr 4, 2000.
of OI (type I), whereas in type II B ex-
Reprint requests: R. H. H. Engelbert, PCS, PhD, Department of Pediatric Physical Therapy,
ercise walking, in type III exercise or
University Medical Center; Wilhelmina Childrens Hospital, PO Box 85090, 3508 AB Utrecht, household walking, and in type IV
The Netherlands. household or community walking
Copyright 2000 by Mosby, Inc. should be possible.
0022-3476/2000/$12.00 + 0 9/21/107892 Daly et al6 studied the relation be-
doi:10.1067/mpd.2000.107892 tween the age of achieving motor mile-

397
 ENGELBERT ET AL
Table I. Patient characteristics
Type of OI
Number of patients
Mean age (SD)
Male/female
Dentinogenesis imperfecta present
Dentinogenesis imperfecta not present
Dentinogenesis imperfecta not known
Rodding: none
Rodding: lower extremity in 1 bone
Rodding: lower extremity in 2 bones
Rodding: lower extremity in 3 bones
Rodding: lower extremity in 4 bones
Fracture incidence: P50 (P25-P75)
Fracture incidence: 1: 10 fractures; 2: 11 to 20 fractures; 3: 21 to 30 fractures; 4: 31 to 40
fractures; 5: >40 fractures.
stones and the prognosis for walking.
They found that independent sitting at
the age of 10 months was a predictor of
walking as the main means of mobility
in 76% of the patients. In those who
did not achieve sitting by the age of 10
months, walking became the main
means of mobility in only 18%.
In this study in children with estab-
lished OI, we studied the prognostic
value of disease-related characteristics
(severity of the disease, fracture inci-
dence, presence of dentinogenesis im-
perfecta, presence of intramedullary
rodding in lower extremities) and
the age of achieving motor milestones
on the ability of walking with or with-
out the use of crutches in a household
situation.
METHODS
Our hospital is a national referral
center for diagnosis and treatment of
children with OI. Most children visit
our hospital from birth or early child-
hood, and data regarding the time of
achieving motor milestones are record-
ed. Children with the mildest type of
OI are examined physically once a
year and children with the severest
types at lease twice a year. We studied
70 children with established OI. Base-
398
I III IV
41 11 18 70
10.8 (5.8) 9.4 (2.9) 13.0 (4.6) 11.2 (5.2)
17:24 7:4 8:10 32:38
6 10 11 27
33 1 7 41
2 2
32 6 38
4 2 6 for that child.
3 1 4 8
1 1 2 4
1 9 4 14
2 (1-3) 2.5 (1-4) 3 (3-4)
line characteristics are presented in
Table I. The severity of the disease was
classified according to Sillence et al7
based on clinical, genetic, and radi-
ographic data.
The presence of dentinogenesis im-
perfecta was recorded.
Motor Development
The families of 98 patients with a
definite diagnosis of OI were sent a
questionnaire regarding the age of
achievement of the following motor
milestones: lifting the head to 45 de-
grees in prone position, rolling,
supported sitting, unsupported sit-
ting, sitting down independently,
bottom-shuffling, crawling, sup-
ported standing, unsupported stand-
ing, pulling to standing, walking
with assistance, unsupported walk-
ing, cycling on a tricycle, and cy-
cling on a bicycle. We urged the par-
ents to be as precise as possible in the
age of achievement of the developmen-
tal milestones and advised them to
check the age of achievement of motor
milestones with available data from
primary health care. All data were
checked with data, if present, from
physical examination in our hospital in
early childhood.
If parents were uncertain, we ad-
vised them not to fill in the age of a cer-
THE JOURNAL OF PEDIATRICS
SEPTEMBER 2000
tain motor milestone. If parents did not
know the age of achieving a certain
Total
motor milestone, but the age of this
milestone was recorded in health care
records, it was used for analysis. If
comparison of the age of achieving cer-
tain milestones of the parental ques-
tionnaire and (peri-) medical data
revealed a discrepancy of >3 months,
this item was excluded from the study
Fracture Incidence and Insertion
of First Rodding
Parents were asked to provide infor-
mation regarding the fracture inci-
dence during life, classified in 5 groups
(1: 0 to 10 fractures, 2: 11 to 20 frac-
tures, 3: 21 to 30 fractures, 4: 31 to 40
fractures, 5: >40 fractures).
Parents also reported the age and local-
ization of insertion of the first intramed-
ullary rod in the lower extremities.
Outcome Measurement: Present
Main Means of Mobility
The parents were also asked to state
the present level of mobility, classified
according to Bleck.8 Bleck classifies the
level of ambulation as nonwalker, ther-
apy or exercise walker, household
walker, neighborhood walker, and com-
munity walker. Children younger than
2 years of age could not be classified ac-
cording to Bleck. This classification has
been extended into a 9-point scale (1,
nonwalker older than 2 years of age; 2,
therapy walker with the use of crutches
or canes; 3, therapy walker without the
use of crutches or canes; 4, household
walker with the use of crutches or
canes; 5, household walker without the
use of crutches or canes; 6, neighbor-
hood walker with the use of crutches or
canes; 7, neighborhood walker without
the use of crutches or canes; 8, commu-
nity walker with the use of crutches or
canes; 9, community walker without the
use of crutches or canes).
All data from health care records
were verified by the first author.
The ability to dependently walk in a
household situation (score according
THE JOURNAL OF PEDIATRICS
VOLUME 137, NUMBER 3
Table II. Main means of present mobility in 70 children with osteogenesis imperfecta, classified according to Bleck2
Main means of present mobility
1: Nonwalker (electrical wheelchair)
2: Therapy walker with crutches or canes
3: Therapy walker without crutches or canes
4: Household walker with crutches or canes
5: Household walker without crutches or canes
6: Neighborhood walker with crutches or canes
7: Neighborhood walker without crutches or canes
8: Community walker with crutches or canes
9: Community walker without crutches or canes
Children <2 years of age
to Bleck, 4) establishes a certain level
of functional independence. Walking
in a household situation without the
use of aiding devices (score according
to Bleck, 5) should, in our opinion, be
considered a precondition for eventu-
ally walking in the neighborhood or
community with or without crutches.
The classification of the children that
met the inclusion criteria for depen-
dent and independent walking in a
household situation with and without
the use of aiding devices posed no
problems. The classification of the chil-
dren who were not able to walk depen-
dently and independently in a house-
hold situation required some additional
criteria. The total group of patients
with OI included children in a wide
age range (mean age 11.2 years; range
1.2 to 27.9 years). Valid outcome as-
sessment was obviously dependent on
age. Therefore 5 children who were
not yet old enough to expect walking
(cutoff point: 4.5 years) were excluded
from the study. A 7-year-old boy was
excluded. Although conditions includ-
ing muscle strength and range of joint
motion permitted walking in a house-
hold situation, unrelated psychologic
reasons prevented him from walking.
Statistics
The association of categoric vari-
ables were analyzed with the use of
odds ratios and 95% CI. The prognos-
tic value of disease-related characteris-
Type I (n = 41)
3 2
3 3
5
4
2 2
24
tics and developmental milestones with
respect to current walking ability was
analyzed with logistic regression. Cur-
rent walking ability (Bleck 4 and
Bleck 5, respectively) was used as the
dependent variable, and disease-relat-
ed characteristics and developmental
milestones were studied as predictors.
All relevant variables were first ana-
lyzed univariately. Because of the lim-
ited number of subjects and end points,
we restrictively used multivariate lo-
gistic regression to evaluate the joint
prognostic value of sets of at most 2
variables.
RESULTS
Patient Characteristics
There were 76 replies (44 girls, 32
boys) to the 98 questionnaires (type I,
46; type III, 11; type IV, 19). The mean
age at answering of the questionnaire
was 10.5 years of age (SD 5.5; range
1.2 to 27.9) in patients with type I, 9.4
years (SD 2.9; range 5.5 to 15.3) in pa-
tients with type III, and 12.7 years
(SD 4.6; range 4.5 to 20) in patients
with type IV. After the children men-
tioned in the Methods section were ex-
cluded, 70 children participated in this
study (type I, 41; type III, 11; type IV,
18). Baseline characteristics are pre-
sented in Table I. The age of outcome
assessment was comparable between
those classified as walkers (median
10.1 years; range 4.6 to 25.1 years) and
ENGELBERT ET AL
Type III (n = 11) Type IV (n = 18)
5 4
4
2
1 1
5
as nonwalkers (median 11.7; range 4.5
to 18.9 years).
Main Means of Mobility
The present main means of mobility,
classified according to Bleck, is pre-
sented in Table II.
In type I, 11 (27%) of 41 children
could not achieve more than the level
household walking without the use of
crutches, whereas 24 (58%) of 41
were community walkers without the
use of crutches. In type III, 5 (45%)
of 11 children were limited to electric
wheelchair function, whereas 3 (27%)
of 11 were household walkers with
the use of crutches, and 1 (9%) of 11
walked in the neighborhood with
crutches.
In type IV, 10 (52%) of 19 children
could not achieve more than the level
household walking without the use of
crutches, whereas 5 (26%) of 19 were
community walkers without the use of
crutches.
Seven of 70 children regressed in
level of ambulation. In the past they
had had a higher level of ambulation
than at the time of this study. Two of 41
children with OI type I were therapy
walkers with crutches (Bleck, 2) at the
time of the study and used to walk in a
household situation with crutches
(Bleck, 4) in the past. One child with
type I walked with crutches in a house-
hold situation (Bleck, 4), whereas in
the past he was able to walk in the
399
 ENGELBERT ET AL THE JOURNAL OF PEDIATRICS
SEPTEMBER 2000

Table III. Associations in patients with osteogenesis imperfecta between predictors and subsequent ability to walk with crutches
(Bleck: 4) and without crutches (Bleck: 5)
Bleck: 4 Bleck: 5
Odds ratio 95% CI Odds ratio 95% CI
Sex 1.62 0.61-4.35 1.44 0.54-3.83
Dentinogenesis imperfecta 0.14 0.05-0.43 0.12 0.04-0.37
Type osteogenesis imperfecta*
Type 3 and 4 0.04 0.01-0.15 0.08 0.02-0.25
Type 4 0.09 0.02-0.37 0.14 0.04-0.49
Rolling over (prone to supine) before 8 months 5.04 1.40-18.13 0.27 0.82-8.94
Sitting without support before 9 months 16.99 2.07-139.37 4.54 1.14-18.06
Ability to get in sitting position without support before 12 months 4.40 1.32-14.70 3.06 0.96-9.74
Standing without support before 12 months 5.19 0.59-45.47 5.18 0.59-45.47
Ability to get in standing position without support before 12 months 5.03 1.02-24.93 5.03 1.02-24.92
Number of intramedullary rods
1 0.17 0.02-1.35 0.23 0.32-1.71
2 0.09 0.01-0.53 0.11 0.2-0.67
3 0.03 0.002-0.37 0.04 0.003-0.47
4 0.01 0.001-0.07 0.009 0.009-0.08
*Reference category type I.
Reference category: no rods, 95% CI.

neighborhood with crutches (Bleck, 6).
One of 11 with OI type III regressed
from exercise walking with crutches
(Bleck, 2) to nonwalking (Bleck, 1). In
patients with OI type IV, 3 children
who were household walkers (Bleck,
4) in the past became nonwalkers
(Bleck, 1) at the time of the study.
Univariate Analysis
The results of the univariate analysis
are shown in Table III. The type of OI
was strongly associated with current
walking ability, as was the presence of
dentinogenesis imperfecta. Children
with type III and IV had a reduced
chance of ultimately walking com-
pared with those with type I. Children
in whom dentinogenesis imperfecta
was present had a reduced chance of
ultimately walking compared with
those in whom dentinogenesis imper-
fecta was not present. In a similar
fashion, the children with >2 in-
tramedullary rods in the lower extrem-
ities had a reduced chance of walking
compared with patients without rods.
Motor milestones positively associated
with current walking ability included
rolling over before 8 months, unsup-
ported sitting before 9 months, the
ability to get in sitting position without
support before 12 months, and the
ability to get in a standing position
without support before 12 months.
Multivariate Analysis
The univariate analysis showed that
particularly the type of OI was the most
important predictor of walking. Because
the type of OI is determined as part of
the diagnosis, multivariate analysis was
used to evaluate whether later clinical
characteristics had prognostic value in
addition to knowledge of the type of OI.
Therefore each of the variables shown in
Table I was separately added to a model
with current walking ability as the de-
pendent variable and type of OI as the
independent variable. With the use of
Bleck 4 for definition of current walk-
ing, only the presence of rodding
(yes/no) in the lower extremities had ad-
ditional prognostic value to the type of
OI (odds ratio 0.09, 95% CI 0.02 to
0.40). With the use of Bleck 5, the pres-
ence of dentinogenesis imperfecta had
additional value (odds ratio 0.29, 95% CI
0.08 to 1.09) and rodding (yes/no) (odds
ratio 1.10, 95% CI 0.02 to 0.42).
Furthermore, the prognosis of a child
with a particular type of OI is of clini-
cal interest. We therefore restricted the
analyses to type I and to the combina-
tion of type III and IV. Within type I (n
= 41) we found that rodding (yes/no)
(odds ratio 0.07, 95% CI 0.006 to 0.78)
and number of fractures (odds ratio
0.20, 95% CI 0.06 to 0.71) were indica-
tors of worse outcome with respect to
Bleck 4. Similar results were found
within the combination of type III and
IV (n = 29) for the presence of in-
tramedullary rodding (yes/no) with
Bleck 4 (odds ratio 0.11, 95% CI 0.01
to 0.79) and with Bleck 5 (odds ratio
0.13, 95% CI 0.01 to 0.99). The ability
to come to a sitting position without
support before 12 months was related
to better outcome (Bleck 4) (odds
ratio 11.3, 95% CI 1.11 to 114.4).
DISCUSSION
The single most important clinical in-
dicator of the ultimate ability to walk

400
THE JOURNAL OF PEDIATRICS
VOLUME 137, NUMBER 3
in a household situation is the type of
OI. Sillences9 classification regarding
the severity and inheritance of OI is a
significant improvement compared
with previous classifications, although
a significant number of patients with
OI cannot be classified satisfactorily
into any of these 4 groups.10
We found that the type of OI mainly
predicts the ability of dependent and
independent walking in a household
situation. The addition of developmen-
tal motor milestones does not signifi-
cantly contribute to this prediction.
Because timing of achievement of
motor milestones is strongly deter-
mined by the type of OI, we believe
the observations of Daly et al6 to be in
line with our study. Daly et al studied
the relation between the age of achiev-
ing motor milestones and the progno-
sis for walking and concluded that in-
dependent sitting at the age of 10
months was a predictor of walking as
the main means of mobility in 76%. Of
the patients who did not achieve sitting
by the age of 10 months, walking be-
came the main means of mobility in
only 18%. The age of achieving this
motor milestone is comparable to the
age of 9 months we found in our study.
Daly et al used univariate analysis for
predicting the ability to walk and
therefore did not correct for the type
or severity of the disease.
The severity of the collagen defect in
turn predicts walking ability. The
severity of the collagen defect also pre-
dicts consequences on other levels
such as growth, joint function, and
functional ability. Disease- and severi-
ty-related profiles have been studied
regarding growth, range of joint mo-
tion, muscle strength, functional abili-
ty, and motor development.11-14 Be-
cause several profiles do not change
over time (range of joint motion and
muscle strength), they might be clini-
cal characteristics of the disease and
therefore related to the genetic disor-
der.13 Increased fracture incidence and
severely decreased range of joint mo-
tion and muscle strength, as frequently
observed in type III and IV, might pre-
vent the child from weight bearing on
his or her feet, standing, and eventual-
ly walking.
Sillence et al5 mention that the major
goal of rehabilitation in patients with
OI type I should be community walk-
ing, whereas in patients with type II B
exercise walking, type III exercise or
household walking, and type IV house-
hold or community walking should be
possible. We believe their goals for re-
habilitation are too optimistic. Our
children with type I achieved commu-
nity ambulation without the use of
crutches in only 52% of the cases; 45%
of our children with type III were re-
stricted to an electrical wheelchair,
with only 27% achieving household
ambulation with crutches. In children
with type IV, 57% could not achieve
more than the level household walking
without the use of crutches, whereas
26% were community walkers without
the use of crutches. Our observations
regarding the type-related ability to
walk with or without the use of crutch-
es in a household situation should
guide rehabilitation strategies. Chil-
dren with OI type III with dentinogen-
esis imperfecta have severe restriction
in their efforts to achieve dependent,
and especially independent, walking
in a household situation. Therefore
treatment strategies should focus on
improvement of self-care and compen-
satory strategies, which significantly
improve at follow-up, without primari-
ly focusing on ambulation.13 On the
other hand, the ability to walk may not
reflect the functional status of the pa-
tient. For example, a child may not be
able to walk but may be fully indepen-
dent with respect to ambulating and
the activities of daily living.
From our study it seems that regres-
sion in level of ambulation might occur.
Children who were not able to walk at
the time of the study might have been
able to walk in the past. On the other
hand, children who were able to walk
at the time of the study might lose the
walking capability in the future. Bren-
ENGELBERT ET AL
ner et al15 reported that in type III and
IV, even when ambulation is achieved,
walking is frequently lost in the second
decade of life because of progressive
spinal deformity, decreased motivation
in physical therapy, and the increasing
use of a wheelchair. Knowledge of de-
velopmental and functional profiles and
the relation between those and walking
capacity in the different types of OI
seems to be essential for developing
treatment strategies. Only in this way
can individual customized care be de-
signed without overloading the child
and parents physiologically and psy-
chologically.
From our study it seems that the
presence of dentinogenesis imperfecta
also has prognostic capacity regarding
the ability to walk. Lund et al16 studied
the dental manifestations of OI and ab-
normalities of collagen I metabolism
and concluded that patients with type
I with dentinogenesis imperfecta were
more severely affected with decreased
mobility than patients without the
presence of dentinogenesis imperfecta.
In patients with OI type III and IV,
they found no differences regarding
mobility and the presence or absence
of dentinogenesis imperfecta. On the
other hand, they found a striking dis-
crepancy between the overall severity
of the disease and tooth changes. In 3
severely affected patients with substi-
tutions in the a 1(I) chain, normal teeth
were observed.
The presence of intramedullary rods
in the lower extremities indicates a
worse prognosis with respect to ulti-
mate walking. Rodding is thereby an
indicator of disease severity. This ob-
servation should be interpreted with
caution. In general, intramedullary
rodding in the lower extremities is pri-
marily indicated in the most severe
types to stabilize bone and to correct
deformities. Because no randomized
clinical trials have been performed for
ethical reasons, the improvement of
possibilities for ambulation after in-
tramedullary rodding of the lower ex-
tremities remains questionable. Sever-
401
 ENGELBERT ET AL
al authors state that intramedullary
rodding of the legs improved the possi-
bility for ambulation,17-21 whereas oth-
ers found no differences in patients
who did and did not receive in-
tramedullary rodding in the age of first
achieving motor milestones and the
ability for walking in later life.6 Engel-
bert et al22 mentioned that after in-
tramedullary rodding of the legs was
performed, functional ability, especial-
ly in the prestanding milestones, im-
proved in patients with type III and IV,
whereas in patients with type I, walk-
ing ability improved.
This study has intrinsic limitations.
First of all, the sample size of our study
was very small (n = 70) and thereby in-
fluenced statistical analysis. Confi-
dence intervals of the odds ratios were
very wide, probably because of small
numbers. Therefore statements must
be made with caution. Second, the
ability of the children to walk was
scored by the parents and was verified
by studying health care records. Based
on follow-up of these patients, we as-
sumed no changes in level of ambula-
tion, but we do not know whether all
children will be able to walk in the
same way as they did at the time of
study, especially when they reach ado-
lescence. On the other hand, we hy-
pothesized that, based on stable clini-
cal characteristics over time regarding
range of joint motion, muscle strength,
and increasing weight, walking ability
in the severely handicapped children
will never be possible. Third, we must
also discuss the possibility that nonre-
sponse to the questionnaire differen-
tially influenced our results. Twenty-
two (22%) parents did not respond to
the questionnaire (type I, 17; type III,
5; type IV, 0). Of these children, de-
tailed information regarding the age of
achieving motor milestones, dentino-
genesis imperfecta, fracture incidence,
and intramedullary rodding was pres-
ent in health care records in 14 of 22
children (type I, 10; type III, 4). These
observations were excluded from the
402
study and interpretation of the results,
because parents did not respond to the
questionnaire. However, these observa-
tions revealed the same outcome in age
and sequence of motor development as
was observed in the study group.
Therefore we conclude that differences
in response rate by type of OI have not
materially affected our results.
We thank P. van der Torre, PT, BSc, and J.
Witkam, PT, BSc, for their collaboration in
this study.
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