Fetal Skeletal Dysplasias
Author:
Craig V. Towers M.D.
Objectives: Upon the completion of this CME article, the reader will be able to:
1.
Describe the evaluation of the fetal skeletal system.
2.
Explain why prenatal diagnosis is important when dealing with skeletal dysplasia
3.
Describe the ultrasound findings seen with some of the more common disorders,
such as Thanatophoric Dysplasia, Achondroplastic Dysplasia, and Achondrogenesis.
Introduction / Embryology
Following conception, the embryo continually divides and eventually three types of
tissue develop. These tissues are called the endoderm, mesoderm and ectoderm. The
endoderm primarily makes up the internal organs, the ectoderm involves the skin and neural
tissue and the mesoderm makes up the bones and muscles. One of the cells that develops in
the mesoderm is the osteoblast, which starts the production of bone. The long bones begin
as cartilage that is eventually converted into bone, whereas the flat bones develop directly
into bone. The long bones have two ossification centers. The primary center develops first
and is called the diaphysis or shaft. At each end of the diaphysis, there is a zone of growth
called the metaphysis. The secondary centers of ossification (which form later, starting in
the third trimester and continuing after birth) are the epiphyseal discs that are found on
either end of the long bone. In the adult, these epiphyseal discs have joined the metaphysis
portion of the diaphysis to form one continuous bone.
Evaluation of the Fetal Skeletal System
When evaluating the skeletal system, terminology is important, but is also very
confusing. The following lists contain some of the more commonly used words and they are
somewhat organized into groups.
Achiria
Apodia
Amelia
Adactyly
= absent hand
= absent foot
= absent limb
= absent digit
Acromelia
Mesomelia
Rhizomelia
= short hands or feet
= short middle portion of the limb (lower arm or leg, ie. radius/tibia)
= short proximal portion of a limb (upper arm or leg, ie. humerus)
Micromelia
Phocomelia
= entire limb is short
= absent middle portion of the limb
Clinodactyly
Polydactyly
Preaxial
Postaxial
Syndactyly
= deviation of the digits (medial or lateral)
= extra digits
= located on the radial or thumb side or the tibial side
= located on the ulnar or little finger side or the fibular side
= digits stuck together or fused (webbed)
Varus
Valgus
= bent inward (ie. a foot bending inward)
= bent outward (ie. a foot bending outward)
For the vertebral bodies:
Scoliosis
= curved or bent spine laterally (to the side)
Kyphosis
= an abnormal posterior curvature of the thoracic spine (hunchback)
Lordosis
= an abnormal anterior curvature of the lumbar spine (more than the
normal curvature – sometimes called swayback or saddle back)
Hemivertebrae = partially formed vertebral body
Platyspondylia = or platyspondylisis which is a flattening of the vertebral body
The ultrasound evaluation of the long bones involves their presence or absence,
shape (curvature) and whether any fractures are noted. The long bones are fairly easy to
identify and many tables are in existence for normal lengths. The most common long bone
measured is the femur followed by the humerus; however, normograms also exist for the
radius, ulna, tibia, and fibula. The three-epiphyseal centers that may be seen prenatally are
the distal femur, proximal tibia, and proximal humerus. Their visualization at a certain size
may suggest fetal maturity.
It is important to recognize that the length of the arms and legs of the normal
population can vary greatly. When scanning a patient, a femur length or humerus length that
is off by a few weeks is probably normal in most cases. Therefore, a repeat scan in a few
weeks can re-evaluate this finding to see if the variation in size is stable or increasing. The
majority of skeletal dysplasias will eventually demonstrate a large difference in measurement
when compared to the abdomen or head measurement (figure 1).
The ultrasound evaluation of the feet and hands can be performed to look for their
presence or absence, to assess the number of digits, and to look for polydactyly or
syndactyly. One can also look for a clenched fist with overlapping fingers, clubbed feet or
rocker bottom feet. The fetal skull can be examined for overall shape and for the presence
of frontal bossing (prominent forehead) or cloverleaf deformity (signaling craniosynostosis –
a premature fusing of the sutures).
The fetal spine can be examined for overall symmetry, any signs of disorganization,
or any curvature. The thorax on the other hand is usually examined for its overall size in
comparison to the head or abdomen. The size of the thorax is an important evaluation
when dealing with a possible fetal skeletal anomaly because many of the lethal defects result
in thoracic constriction.
A final note in regard to the evaluation of the fetal skeletal system is when an
ultrasound scan identifies polyhydramnios. Besides looking for central nervous system
anomalies such as neural tube defects or gastrointestinal defects, the ultrasonographer
should also rule out dwarfism.
Skeletal Anomalies
Well over 100 different skeletal dysplasias can occur and to keep them all organized
in your head is very difficult if next to impossible. This is due to the fact that there are
similarities in their appearance and most of them are extremely rare (a single ultrasound
department may only see one or two cases in an entire year). However, many of these
skeletal disorders are lethal and if not, can result in significant emotional trauma to the
pregnant couple in dealing with the possibility of having a dwarf or a child that is disfigured
due to bony abnormalities.
The goal of this next section is to describe some of the more common dysplasias and
to create some lists that can be kept, which may help you in classifying an anomaly if one is
found in an ultrasound evaluation. As you will see, many of these are genetic in origin –
usually autosomal recessive, meaning that both parents are normal but are carrying a
recessive gene (similar to how cystic fibrosis is carried). Occasionally you will see that some
are autosomal dominant, which would suggest that one of the parents should also display the
bone abnormality. However, in the majority of these cases, the abnormal autosomal
dominant gene is a “new mutation” and again the parents would be normal. It is important
to remember that if a skeletal anomaly is suspected, all of the long bones should be
measured and compared to normogram tables as well as a full evaluation of the size of the
thorax, shape of the spine and skull and examination of the hands and feet.
Prevalence of Skeletal Dysplasias:
Thanatophoric Dysplasia
(numbers are approximations)
1 in 15,000
Achondroplastic
Achondrogenesis
Osteogenesis Imperfecta type II
Osteogenesis Imperfecta types I, III, IV
Asphyxiating Thoracic Dystrophy
Chondrodysplasia Punctata
Camptomelic Dysplasia
Chondroectodermal Dysplasia
Mesomelic Dysplasia
Others
Total Overall
1 in 25,000
1 in 40,000
1 in 50,000
1 in 50,000
1 in 70,000
1 in 100,000
1 in 200,000
1 in 200,000
1 in 200,000
1 in 100,000
1 in 4,500 pregnancies
Skeletal Dysplasias that are Lethal:
Thanatophoric Dysplasia
Achondrogenesis
Osteogenesis Imperfecta type II
Asphyxiating Thoracic Dystrophy (70% to 80% of cases are lethal)
Camptomelic Dysplasia (90% of cases are lethal)
Chondroectodermal Dysplasia (50% of cases are lethal)
Chondrodysplasia Punctata (rhizomelic type)
Short-Rib Polydactyly Syndrome types I, II, and III
Homozygous Achondroplasia (two autosomal dominant genes instead of one)
Hypophosphatasia (neonatal or congenital form)
Fibrochondrogenesis
Atelosteogenesis
(Diastrophic Dysplasia – only about 10% to 20% of cases are lethal)
Thanatophoric Dysplasia
The word thanatophoric means “death-seeking” dwarfism. It is the most common
skeletal dysplasia and it is lethal. The ultrasound findings reveal severe rhizomelic limbs with
a large head and a narrow thorax. Two types have been suggested – type I has bowed
femurs and no cloverleaf skull and type II has straight femurs with a cloverleaf skull. The
vertebral bodies are flattened and significant polyhydramnios is seen in 70% of cases. The
inheritance is not completely understood. Most cases are just sporadic, others cases seem to
be autosomal recessive or new mutations (figure 2).
Achondroplastic Dysplasia
This is the second most common disorder but is the most common non-lethal
dwarfism. Its inheritance is usually autosomal dominant as a new mutation. The
homozygous form (where the child receives a dominant gene from both parents) is lethal.
The ultrasound findings are rhizomelic limbs that are bowed with a large head. The chest
size, however, is normal in size when compared to the abdomen. Hydrocephalus can be
seen in some cases. The difficulty with this disorder is that the majority of decreased limb
growth occurs after 20 to 24 weeks gestation. Therefore, early prenatal diagnosis is difficult.
The majority of diagnoses occur in the third trimester.
Achondrogenesis
This is a lethal dysplasia that is inherited as an autosomal recessive disorder. The
ultrasound findings reveal very severe micromelia (figure 3), a short trunk with a large head
and there is poor ossification. There are two types compared below.
Bone
Type I (Parenti-Fraccaro)
Limbs
micromelia
Ribs
thin with fractures
Vertebra
not ossified
Skull
poorly ossified
Iliac
poorly ossified
Sacrum/Pubic
absent
Type II (Langer-Saldino)
micromelia
short/stubby no fractures
lumbar not ossified
usually well ossified
usually well ossified
poorly ossified
Associated anomalies that have been reported include hydrocephalus, cystic
hygroma, cleft lip and palate, heart anomalies and renal anomalies. Severe pulmonary
hypoplasia usually occurs.
Osteogenesis Imperfecta
This is a group of collagen disorders with fragile bones and blue sclera. There are
four types with Type II being lethal. Type I is autosomal dominant and has the triad of blue
sclera, fragile bones (but usually no fracture inutero) and deafness. Type II is autosomal
recessive and unfortunately is the most common. On ultrasound, the long bones are
shortened and fractured with a “crumpled” appearance. The skull is poorly ossified, rib
fractures are common, and the thorax can be short (figures 4 & 5). Type III seems to be
inherited as both autosomal recessive and dominant. Again, the bones are fragile but
fractures occur late in pregnancy, near birth, or after delivery. The sclera is blue but may
turn white later in life. Type IV is the most mild and is autosomal dominant. The long
bones may bow but no fractures occur. The sclera is blue but turns white later in life.
Asphyxiating Thoracic Dystrophy
This disorder is autosomal recessive and is also called Jeune Syndrome. It is usually
lethal but not uniformly and survivors have been reported. The ultrasound findings reveal a
narrow bell-shaped thorax with horizontal ribs but the limbs are less affected. The longs
bones are either mildly short or are normal. Polydactyly, cleft lip and palate, and renal
anomalies have also been reported (figure 6).
Chondrodysplasia Punctata
There are two types reported – the rhizomelic type, which is lethal, and the nonrhizomelic type. The rhizomelic type is autosomal recessive, rare, with severe shortening of
the proximal long bones (rhizomelia). The non-rhizomelic form is more common and the
ultrasound findings are non-specific.
Camptomelic Dysplasia
This disorder is usually autosomal recessive or sporadic in inheritance. The majority
of cases are lethal but a few survivors have been reported. Camptomelic means “bentlimbed”. Therefore, the characteristic finding is bowing of the long bones, especially the
femur and the tibia. The length of the long bones may be normal. Frequently, there are
other associated anomalies including cleft palate, microcephaly, micrognathia,
hydrocephalus, congenital heart defects and hydronephrosis.
Chondroectodermal Dysplasia
This disorder is also autosomal recessive and has been called Ellis-Van Creveld
Syndrome. The limbs are usually mesomelic in appearance and there is postaxial polydactyly
(ulnar side). The chest can be small and 50% or more have congenital heart defects. The
ectodermal dysplasia means absent teeth and nails. About half of the cases are lethal.
Atelosteogenesis
The genetics of this disorder are either sporadic or autosomal recessive. The limbs
have severe micromelia – often thick at the proximal end and thin at the distal end making
them look club-shaped. This dysplasia is also lethal. The chest is often narrow and there
may be poor ossification of the thoracic spine, humerus, and femur.
Short-Rib Polydactyly Syndrome
This is a group of autosomal recessive disorders that are lethal and all consist of
short limbs, a constricted thorax, and postaxial polydactyly. The types mainly vary in their
associated anomalies. Type I (Saldino-Noonan Syndrome) has thin long bones, femurs with
pointed ends, and may have renal, gastrointestinal, and cardiac anomalies. Type II
(Majewski Syndrome) has very short tibias, and may have cleft lip and palate, cardiac
anomalies and polycystic kidneys. Type III (Naumoff Syndrome) has wide metaphyses and
renal anomalies are common. Type IV (Beemer-Langer Syndrome) may have cleft lip and
palate, umbilical hernia with a protuberant abdomen, gastrointestinal anomalies, and renal
anomalies.
Hypophosphatasia
This is an autosomal recessive disorder that can present as four types based on
presentation. The neonatal type or congenital form is lethal. The other forms are juvenile,
adult and latent. The problem is characterized by bone demineralization of the skull and
long bones. Therefore, the long bones may bow and even fracture. The blood also shows a
low level of the enzyme alkaline phosphatase.
Diastrophic Dysplasia
This disorder is autosomal recessive and the abnormal gene has been located on
chromosome number 5. Diastrophic means “twisted”. The limbs usually display micromelia
along with multiple joint contractures, micrognathia, and cleft palate. Hand deformities are
also common with an extended thumb giving it a “hitchhiker thumb” appearance. Severe
clubfoot and kyphoscoliosis can also be seen. A few cases have been lethal, however, the
majority of individuals survive and intellect is not usually affected.
Fibrochondrogenesis
This disorder is autosomal recessive and is lethal. The limbs have severe rhizomelia
but often the metaphyses are flared giving a dumb-bell shaped appearance.
Summary
As you can see from the following discussion regarding some of the more common
skeletal dysplasias, many similarities exist and prenatal diagnosis can be difficult. With
difficult cases, a combination of radiography modalities might be employed along with
general sonography, such as three-dimensional sonography and helical computer
tomography. Recently, there have been several case reports of increased fetal nuchal
translucency thickness identified on first trimester scans associated with some skeletal
dysplasias; however, this finding is not specific for any certain type of skeletal dysplasia.
Remember, when scanning a patient, if a skeletal dysplasia is considered, the sonographer
should try to evaluate all of the long bones, the hands and feet, the spine, the ribs and the
cranium, if possible. In addition, a thorough evaluation for associated anomalies can often
be helpful.
Figures
1
This shows the measurement values from a patient with achondroplasia at 32 weeks
gestation by dates. Note the femur length, which is behind by 6 weeks and the head
measurements, which are ahead by 4 weeks.
2
A thanatophoric skeletal dysplasia showing the narrow chest in comparison to the
head and abdomen.
3
Severe micromelia seen with Achondrogenesis.
4 & 5 Poor mineralization and an unusual appearance of the fetal cranium and upper
extremity from osteogenesis imperfecta Type II.
6
A fetal thorax from a case of asphyxiating thoracic dystrophy showing that the
majority of area consists of the heart – consistent with probable pulmonary
hypoplasia.
References or Suggested Reading:
1.
Ruano R, Molho M, Roume J, Ville Y. Prenatal diagnosis of fetal skeletal dysplasias
by combining two-dimensional and three-dimensional ultrasound and intrauterine
three-dimensional helical computer tomography. Ultrasound Obstet Gynecol
2004;24:134-40.
2.
Tonni G, Ventura A, De Felice C. First trimester increased nuchal translucency
associated with fetal achondroplasia. Am J Perinatol 2005;22:145-148.
3.
Venkat-Raman N, Sebire NJ, Murphy KW, et al. Increased first-trimester fetal
nuchal translucency thickness in association with Chondroectodermal dysplasia
(Ellis-Van Creveld syndrome). Ultrasound Obstet Gynecol 2005;25:412-414.
4.
Ramus RM, Martin LB, Twickler DM. Ultrasonographic prediction of fetal outcome
in suspected skeletal dysplasias with use of the femur length to abdominal
circumference ratio. Am J Obstet Gynecol 1998;179:1348.
5.
Rahemtullah A, McGillivray B, Wilson RD. Suspected skeletal dysplasias: Femur
length to abdominal circumference ratio can be used in Ultrasonographic prediction
of fetal outcome. Am J Obstet Gynecol 1997;177:864.
6.
Tongsong T, Chanprapaph P, Thongpadungroj T. Prenatal sonographic findings
associated with asphyxiating thoracic dystrophy – Jeune Syndrome J Ultrasound Med
1999;18:573.
7.
Stoll C, Dott B, Roth MP, et al. Birth prevalence rates of skeletal dysplasias. Clin
Genet 1989;35:88.
8.
Rouse GA, Filly RA, Toomey F, et al. Short-limb skeletal dysplasias: Evaluation of
the fetal spine with sonography and radiography. Radiology 1990;174:177.
9.
Exacoustos C, Rosati P, Rizzo G, et al. Ultrasound measurements of the fetal long
bones. Ultrasound Obstet Gynecol 1991;1:325.
10.
Sharony R, Browne C, Lachman RS, et al. Prenatal diagnosis of the skeletal dysplasia.
Am L Obstet Gynecol 1993;169:668.
11.
Kurtz AB, Wapner RJ. Ultrasonographic diagnosis of second trimester skeletal
dysplasia: A prospective analysis in high-risk population. J Ultrasound Med
1983;2:99.
12.
Fink IJ, Filly RA, Callen PW, et al. Sonographic diagnosis of thanatophoric dwarfism
in utero. J Ultrasound Med 1982;1:337.
13.
Cordone M, Lituania M, Bocchino G, et al. Ultrasonographic features in a case of
heterozygous achondroplasia at 25 weeks gestation. Prenat Diagn 1993;13:395.
14.
Mertz E, Goldhofer W. Sonographic diagnosis of lethal osteogenesis imperfecta in
the second trimester: case report and review. J Clin Ultrasound 1986;14:380.
15.
Zorzoli A, Kustermann A, Caravelli E, et al. Measurements of fetal limb bones in
early pregnancy. Ultrasound Obstet Gynecol 1994;4:29.
16.
Winter R, Rosenkranz W, Hofmann H, et al. Prenatal diagnosis of camptomelic
dysplasia by ultrasonography. Prenat Diagn 1995;5:1.
17.
Soothill PW, Vuthiwong C, Rees H. Achondrogenesis type II diagnosed by
transvaginal ultrasound at 12 weeks gestation. Prenat Diagn 1993;13:523.
18.
Benacerraf B, Osathanondh R, Bieber FR. Achondrogenesis type I: Ultrasound
diagnosis in utero. J Clin Ultrasound 1984;12:356.
19.
Orioli M, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for skeletal
dysplasias. J Med Genet 1986;23:328.
About the Author
Dr. Towers is currently on a sabbatical writing a series of books that deal with the
safety of over-the-counter drugs, herbal medications, and natural remedies used during
pregnancy. The first is in print entitled “I’m Pregnant & I Have a Cold – Are Over-theCounter Drugs Safe to Use?” published by RBC Press, Inc.
Before his sabbatical, Dr. Towers was an Associate Professor in the Department of
Obstetrics and Gynecology at the University of California, Irvine. He also was the Director
of Perinatal Medicine at Long Beach Memorial Women’s Hospital in Long Beach California.
He has practiced clinically in the states of Kansas, California, and Wisconsin. Dr. Towers has
multiple publications in peer review medical journals and he has given lectures on a wide
variety of obstetrical topics nationwide.
Examination:
1.
Following conception, the embryo continually divides and eventually three types of
tissue develop. The bones and muscles come from
A.
endoderm
B.
ectoderm
C.
mesoderm
D.
periosteum
E.
endosteum
2.
The cell that develops in the mesoderm that starts the production of bone is the
A.
osteocyte
B.
osteoclast
C.
osteoblast
D.
osteum
E.
endosteocyte
3.
An example of rhizomelia would be
A.
short fingers
B.
short femur
C.
short radius
D.
short tibia
E.
absent tibia
4.
Extra digits that are found on the little finger side of the hand are called
A.
Adactyly digits
B.
Syndactyly digits
C.
Clinodactyly digits
D.
Postaxial digits
E.
Preaxial digits
5.
An abnormal anterior curvature of the lumbar spine (more than the normal
curvature – sometimes called swayback or saddle back) is
A.
Scoliosis
B.
Lordosis
C.
Kyphosis
D.
Hemivertebrae
E.
Platyspondylia
6.
An epiphyseal center that may be seen prenatally is the
A.
proximal femur
B.
distal tibia
C.
distal humerus
D.
proximal radius
E.
proximal humerus
7.
When an ultrasound scan identifies polyhydramnios, possible causes include
everything listed EXCEPT
A.
renal agenesis
B.
neural tube defects
C.
gastrointestinal defects
D.
central nervous system anomalies
E.
dwarfism.
8.
Which of the following statements is true?
A.
If a skeletal dysplasia is autosomal recessive, that means that one of the
parents should also display the bone abnormality.
B.
If a skeletal dysplasia is autosomal dominant, that means that both parents
are normal but are carrying the abnormal gene.
C.
If a skeletal anomaly is suspected, besides measuring the long bones, the rest
of the evaluation only needs to include the abdomen and head measurements
and fluid volume.
D.
It is important to remember that if a skeletal anomaly is suspected, only the
femur and humerus need to be measured and compared to normogram
tables.
E.
If the cause of a skeletal dysplasia is an abnormal autosomal dominant gene
that is a “new mutation”, the parents would be normal.
9.
In looking at the prevalence rates of skeletal dysplasias, the total risk overall is
approximately 1 in ______ pregnancies.
A.
4500
B.
9500
C.
D.
E.
15,000
25,000
45,000
10.
Thanatophoric Dysplasia
A.
on ultrasound evaluation, has a normal appearing thorax.
B.
is lethal 50% of the time.
C.
on ultrasound evaluation, reveals severe mesomelic limbs.
D.
is the most common skeletal dysplasia
E.
is associated with polyhydramnios in about 20% of cases.
11.
Achondroplastic Dysplasia
A.
is the third most common disorder and is usually lethal.
B.
by inheritance is usually autosomal recessive.
C.
as a homozygous form (where the child receives a dominant gene from both
parents) is rarely lethal.
D.
by ultrasound reveals acromelic limbs that are straight with a large head.
E.
can be difficult to diagnose early in pregnancy because the majority of
decreased limb growth occurs after 20 to 24 weeks gestation.
12.
Achondrogenesis is a lethal dysplasia that has all of the following characteristics
EXCEPT
A.
on ultrasound evaluation reveals a short trunk with a large head.
B.
on ultrasound evaluation reveals severe micromelia.
C.
on ultrasound evaluation reveals poorly ossified bones.
D.
is inherited as an autosomal dominant disorder that is a new mutation.
E.
based on findings can be divided into two types.
13.
Osteogenesis Imperfecta Type II
A.
on ultrasound evaluation reveals shortened fractured long bones.
B.
is the least common.
C.
is the least severe.
D.
is autosomal dominant.
E.
on ultrasound evaluation reveals a well ossified skull.
14.
Osteogenesis Imperfecta Type IV
A.
is autosomal recessive.
B.
is the most mild.
C.
is the most common.
D.
on ultrasound evaluation reveals shortened fractured long bones.
E.
has the triad of blue sclera, deafness, and fragile bones.
15.
Asphyxiating Thoracic Dystrophy
A.
on ultrasound evaluation reveals a narrow bell-shaped thorax.
B.
is uniformly lethal.
C.
on ultrasound evaluation reveals very micromelic limbs.
D.
is autosomal dominant and is also called Jeune Syndrome.
E.
is isolated and not associated with other anomalies.
16.
The word camptomelic means
A.
“twisted”
B.
“hitchhiker thumb”
C.
“bent-limbed”
D.
“death-seeking”
E.
“blue sclera”
17.
Chondroectodermal Dysplasia
A.
is autosomal recessive and has been called Jeune Syndrome.
B.
on ultrasound evaluation reveals preaxial polydactyly.
C.
on ultrasound evaluation reveals limbs that are usually rhizomelic in
appearance.
D.
is uniformly lethal
E.
can be associated with a small chest and 50% or more have congenital heart
defects.
18.
Short-Rib Polydactyly Syndrome Type III displays short limbs, a constricted thorax,
postaxial polydactyly, and may have
A.
thin long bones and femurs with pointed ends.
B.
wide metaphyses and renal anomalies.
C.
very short tibias and polycystic kidneys.
D.
an umbilical hernia and a protuberant abdomen.
E.
cleft lip and palate.
19.
For Hypophosphatasia, which of the following statements is FALSE?
A.
It can present as four types.
B.
It is characterized by bone demineralization of the skull and long bones.
C.
The blood shows high levels of the enzyme alkaline phosphatase.
D.
It is an autosomal recessive disorder.
E.
The neonatal type or congenital form is lethal.
20.
For Diastrophic Dysplasia, which of the following statements is FALSE?
A.
Hand deformities are common with an extended thumb giving it a
“hitchhiker thumb” appearance.
B.
The disorder is autosomal recessive and the abnormal gene has been located
on chromosome number 5.
C.
The limbs usually display micromelia along with multiple joint contractures,
micrognathia, and cleft palate.
D.
A few cases have been lethal, however, the majority of individuals survive
but with severe mental retardation.
E.
Diastrophic means “twisted”.