Clinical Genetics 1989: 35: 88-92

Birth prevalence rates of skeletaI

dysplasias
CLAUDE STOLL, BEATRICEDon, MARIE-PAULE ROTH AND YVES ALEMBIK
Institut de Puericulture, Strasbourg, France

This study establishes the prevalence rates at birth of the skeletal dysplasias which can be
diagnosed in the perinatal period or during pregnincy. Using a population-based register of
congenital anomalies, a prevalence rate of 3.22 O/OOO was observed. The most frequent types
of skeletal dysplasia were achondroplasia and osteogenesis imperfecta (0.64 O/OOO, 1/15 OOO
births), thanatophoric dysplasia and achondrogenesis (0.28 O/OOO). The mutation rate for
achondroplasia was higher in our material than in the other studies: 3.3 x per gamete per
generation. Our study demonstrates that prenatal diagnosis by ultrasound is possible in some
skeletal dysplasias.

Received 17 June. accepted for publication 3 September I988

Key wordr: achondrogenesis; achondroplasia; mutation rate; osteogenesis imperfecta; prenatal

diagnosis; skeletal dysplasia; thanatophoric dysplasia.

Few studies have been undertaken to evalu-
ate the birth prevalence rate of skeletal dys-
plasias: Gustavson & Jorulf (1975) found
the birth prevalence rate of skeletal dys-
plasias to be 4.7 O/OOO; a lower figure was
reported by Camera & Mastroiacovo
(1982), 2.4 O/OOO. The results of Camera &
Mastroiacovo (1982) were obtained
through a multicenter, hospital-based Ital-
ian programme (IMMSBD) with a larger
size of birth sample than that of Gustav-
son & Jorulf. Another multi-hospital birth
defects register, the Latin-American Colla-
borative Study of Congenital Malfor-
mations (ECLAMC), concluded that the
birth prevalence rate of skeletal dysplasias
was 2.3 O/OOO (Orioli et al. 1986). However,
in this collaborative study under-ascertain-
ment was high, according to the authors
themselves, and the given rate was an esti-
mate.
In these earlier studies there were various
omissions or defects, i.e. absence of specific
lesion diagnosis, experience limited to hos-
pitals or data restricted to a small series of
newborn. The study presented kere aimed
to analyse the birth prevalence rates for the
skeletal dysplasias in a population-based
register of congenital anomalies, the “Regi-
stre des malformations conghitales du Bas-
Rhin” .
Material and Methods
The newborn of 11 maternity hospitals were
examined for the period January 1, 1979, to
December 3 1,1986. The region of investiga-
tion was the city of Strasbourg (an urban
area) and the area defined by the “Dkparte-
ment du Bas-Rhin” in which Strasbourg is
situated (a rural area). All newborn children
were registered within the first 8 days post-
partum, as well as all fetuses with a mini-
mum age of 20 weeks. No delivery took
 B I R T H PREVALENCE RATES 89

place at home in the area under study. Each on the children dying soon after delivery.
malformed newborn was notified to the Echography was available for the interrup-
registry on a notification form. ted pregnancies. In each case information
At regular intervals (each month) all the about the family (history: ages, height and
maternity hospitals (n = 11) situated in the health of the parents and the sibs, consan-
study area were visited by a doctor. The guinity of the parents), on the pregnancy,
consultant neonatologist and paediatrician on the previous pregnancies and on the en-
were interviewed concerning the skeletal vironmental factors during pregnancy were
dysplasia cases detected among births in the available.
maternity units or in infants admitted to the Each skeletal dysplasia was diagnosed
neonatal units. This constituted the main and classified according to the International
source of information. Nomenclature of Constitutional Diseases of
Similarly, visiting doctors were also inter- Bone (1984) after discussion with paedi-
viewed in order to identify cases not requir- atricians, geneticists, radiologists and path-
ing treatment or transfer to a neonatal unit. ologists.
All autopsy reports of fetuses and dead
infants in the study area were investigated
for skeletal dysplasias. Results
Admissions to the university paediatric Skeletal dysplasias were diagnosed in 34
units were also checked for eligible cases. newborn out of 105374 births, a crude
Finally, all the hospital and private paedi- prevalence rate of 3.22 O/OOO, including four
atricians and well-baby clinic staff members pregnancies which were interrupted after
in the study area were informed about the prenatal diagnosis of skeletal dysplasias and
study and asked to notify all cases of skel- four stillborn.
etal dysplasias. The observed prevalence rate for each
When a suspected or a confirmed case specific diagnostic group compared with
was notified, the requested information was those from the Italian (Camera & Mastroia-
checked by the doctor in available records: COVO 1982), the South-American (Orioli et
prenatal consultation records, maternity al. 1986) and the Swedish (Gustavson &
files, neonatal unit files, autopsy reports, Jorulf 1975) studies are shown in Table 1.
out-patient clinic files, and paediatric and The highest prevalence rates were obtained
surgery files. for achondroplasia and osteogenesis imper-
For each malformed case a control was fecta.
studied. The control was the normal child All infants with achondroplasia were
of the same sex born after the case in the sporadic cases. The mean paternal age for
same maternity hospital. achondroplasia was 34.5 years, mean pa-
A total of 105374 births (including 752 ternal age of controls was 29.5 years. Mean
stillbirths) were examined prospectively maternal age in the same group was 29.2
from 1979 to 1986. The study included four (controls 26.7). The difference is significant
pregnancies interrupted after prenatal diag- for paternal age (p < 0.01) but not for ma-
nosis. ternal age using the Wilcoxon test.
For each newborn with suspected skeletal The calculated mutation rate for
dysplasias, a detailed clinical examination achondroplasia was 3.3 x lo-$ per gamete
and a roentgenological survey of the whole per generation.
skeleton were performed. Autopsy was car- Parental mean ages were not increased
ried out on the stillborn, on the fetus and for osteogenesis irnperfecta.
90 STOLL ET A L .

Table 1
Birth prevalence rates (per 10000) for the skeletal dysplasias as reported in the present study
and in three previous studies
Gustavson LL Camera a Orioli et al. This study
Jorulf Mastroiacovo (ECLAMC)
Type of SD n Rate n Rate n Rate n Rate

- Achondroplasia 1 0.67 8 0.37 16 0.48 7 0.64

- Ouestlonable achondroplasia 17 0.48
- Thanatophoric dysplasia 2 13 0.60 3 0.08 3 0.28
- Achondrogenesis 5 0.23 1 0.03 3 0.28
- Achondrogenesis or thanatophoric
dysplasia 4 0.11
-- Osteogenesis imperfecta
Campomelic dysplasia 1 .
8
1
0.36
0.05
15
3
0.43
0.09
7
1
0.64
0.09
-- Chondroectodermal dysplasia
Chondrodysplrsia punctata:
1 1 0.05 2 0.06 1 0.09

Conradi-HGnermann 1 2 0.09 1 0.03 2 0.18

Rhizometic type 1 0 1 0.03 1 0.09
- Diastrophic dysplasia 0 1 0.03 1 0.09
- Fibrous dysplasia 0 1 0.03 1 0.09
- Osteopetrosis 2 0.18
- Jeune thoracic dystrophy 3 0.14 1 0.09
- Spondylo-sctodermal dysplasia
congenita 3 0.14 1 0.09
- Multiple exostosea 2 0.18
- Enaelman disease 1 0.09

Total 8 4.7 53 2.44 80 2.28 34 3.22

There were 18 females and 16 males
among the skeletal dysplasia cases, which
did not differ siyuficantly from the sex ratio
of controls, 1.06. This analysis cannot be
performed for each diagnostic category
owing to small sample sizes.
Only one set of parents was consanguin-
eous.
The family history was unremarkable ex-
cept in the case of osteopetrosis which in-
volved two children of the same family, a
brother and a sister, the only children of
parents who were the consanguineous cou-
ple. One child with osteopetrosis died at 4
months of age; the other child had a bone
marrow transplantation. Unfortunately, af-
ter the transplantation, surinfection ap-
peared and the child died. No positive fam-
ily history was recorded in osteogenesis im-
perfecta.
Prenatal diagnosis was performed in
three fetuses with osteogenesis imperfecta
and in one fetus with thanatophoric dwar-
fism. Interruption of pregnancy was per-
formed.
In the other case with thanatophoric
dwarfism the child was stillborn, as were
one child with osteogenesis imperfecta and
two of the three children with achondro-
genesis.
The child with Jeune thoracic dystrophy
died a couple of hours after delivery. The
other liveborn children survived the peri-
natal period.
Dlrcusrlon
The prevalence of osteochondrodysplasia at
birth has often been masked by a high neo-
natal mortality and incomplete radiological
investigation of the cases. Our study dem-
onstrates, however, that the prevalence at
birth is high: 3.22 per 10000. This preva-
lence is higher than those of the Italian
 BIRTH PREVALENCE RATES
study (Camera & Mastroisacovo 1982) 2.44
O/OOO and the South American series (Orioli
et al. 1986) 2.29 O/OOO. The prevalence rate
at birth was higher in the study of Gustav-
son and Jorulf (1975) in Sweden: 4.7 O/OOO,
and similar to ours in the series of Centa &
Camera (1975). These four studies were
hospital-based; our study is a population-
based study. The collaborative Italian and
South American studies used a large size of
birth sample which was obtained through a
multicenter, hospital-based programme. A
total of 349470 births were examined in the
South American study and a total of
217061 births were analysed in the Italian
programme.. In these studies the diagnosis
was done retrospectively. Several indi-
cations of under-registration were obtained
in the ECLAMC (Orioli et al. 1986) study
and are probable in the IMMSBD study
(Camera & Mastroiacovo 1982). The stud-
ies of Gustavson & Jorulf (1975) and of
Centa & Camera (1975) were performed in
a single hospital with limited sample sizes:
14918 births for the former and 43060
births for the latter.
Our study was not hospital-based but was
a population-based study. We registered
105374 births over 7 years. Our study was
prospective. Therefore it seems that our
prevalence rate at birth is closer to reality,
at least for the more common skeletal dys-
plasias. For example, considering
achondroplasia, the rate was 0.46 in the
ECLAMC study and 0.37 in the IMMSBD.
In our study this rate was 0.64 O/OOO. The
same rates were obtained for osteogenesis
imperfecta in these three studies. The rate
for achondrogenesis was similar in the
IMMSBD study and in our series (0.23 and
0.28 O/OOO), but very low in the ECLAMC
study 0.03. This may be the consequence of
under-ascertainment as the group of ques-
tionable achondroplasia with death in the
perinatal period was likely to include cases
with thanatophoric dysplasia and achon-
91
drogenesis in the ECLAMC study. The rate
of thanatophoric dysplasia in the IMMSBD
study (0.60) was high, twice the rate of our
series. This high rate was not due t o familial
concentration of cases as all cases were
sporadic, suggesting a new dominant mu-
tation (Camera & Mastroiacovo 1982). It
was not possible to analyse the prevalence
rate at birth of the other conditions which
were studied, as only one or two cases of
these skeletal dysplasias were registered in
each study.
In the ECLAMC study (Orioli et al. 1986)
the mutation rate for achondroplasia was
1.49~ in five hospitals with 105721
births, but this rate was 0 in the remaining
21 hospitals. It is difficult to draw con-
clusions from these conflicting results, un-
less again these results are due to under-
registration in these 21 hospitals. In the five
other hospitals the mutation rate vaned
from 0.62 to 1.90 O/OOO births. In the
IMMSBD study (Camera & Mastroiacovo
1982) the mutation rate was 1 . 8 lo-’. ~ In
another study (Oberklaid et al. 1979) where
the patients were discovered in the course
of a very intensive program seeking to ascer-
tain all dwarf patients in the state of Victo-
ria, Australia, the mutation rate for
achondroplasia was 1.93 x The mu-
tation rate in our material was quite twice
that of the IMMSBD and the ECLAMC
five hospitals-limited studies. This, again,
demonstrates the limits of a hospital-based
retrospective study compared to a popula-
tion-based prospective study. The figures
published many years ago by March (1941)
for the mutation rate of achondroplasia
were the consequence of over-registration
of achondroplasia, which was common be-
cause most of the differential diagnoses
were still unknown. In achondroplasias the
excess of the observed paternal mean age
over control mean found in the present
study fell within the range of the other stud-
ies (in Stoll et al. 1982).
92 STOLL ET AL.

Our study demonstrates that prenatal di- diagnosis by measurement of fetal femoral
length.
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