The assessment of the fetus with a skeletal dysplasia

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The assessment of the fetus with a skeletal dysplasia

Philippe Jeanty, MD, PhD, Gloria Valero, MD*

Women’s Health Alliance, Nashville, TN, USA and * Ultrasonido Diagnóstico, Magdalena, Son, México

Since skeletal dysplasias are uncommon, their prenatal diagnosis is difficult. Acquiring a large experience
takes time. This chapter will review the birth prevalence and classification of skeletal dysplasias and
provide a frame to approach the diagnoses of conditions identifiable at birth1.
Social and historical importance
Skeletal anomalies are unique among birth defects. Although many dysplasias are lethal some affected
individual survive and lead productive life without the intervention of therapeutics. Therefore, the
identification of patients with abnormal skeleton existed since the beginning of history. This is in contrast
with many other birth defects. Four thousand years ago, for instance, a child born in Egypt with multicystic
kidney disease, posterior urethral valve, transposition of the great vessels or many other conditions would
have died and not appeared much different to observers than any other still birth due to a complicated
delivery. In contrast, a child with achondroplasia or a conjoined twin could have survived and caused
various interest.
This has resulted in a rich documentation in the Arts of individuals with skeletal anomalies, the most
common being probably clubfeet and achondroplasia.
The following painting is one of the most famous representations of skeletal dysplasia. It is called “Las
Meninas” from Velázquez (1656, Prado museum, Madrid). It represents Velázquez painting the court of
king Philip IV and the Queen (Mariana of Austria). The composition is interesting because it is the view the
King and Queen, not the view of the painter. The king and Queen are actually visible in the mirror on the
back wall. The center person is the infant Margarita and her play maid (meninas). Of course our interest is
in Mari-Bárbola. The facial appearance, the square forehead, the short arms and legs and the hands are very
typical of achondroplasia. Velázquez had a kind eye for her and for many other people with anomalies
(look at his painting of “Prince Baltasar Carlos and Dwarf” Prince Baltasar in the riding school, Sebastián
de Morra, El niño de Vallecas, Diego de Acedo “El Primo” )

Fig. 1: Las Meninas, Velázquez (1656, Prado museum, Madrid, Spain).

The term “dwarf” is often used in a pejorative connotation, and it is best reserved to cartoons by Walt
Disney then to describe fellow human. A more appropriate terminology is to talk about “short-limb
dysplasias”. The names of the painting should not be changed though.

Achondroplasts have led important careers in the Arts as movie goers surely know, in specific trades (a
team of achondroplasts worked in the maintenance of the wings of the Enola Gay bomber during World
War II), and in more conventional functions in the society.

The second figure is a painting from Henry de Toulouse-Lautrec a French painter famous for his painting
of the life around Montmartre in Paris. The parents of Henry belonged to an old family who could trace
their lineage all the way to Charlemagne. As many french noble families in the last century, their fortune
was no longer considerable, and in order to preserve as much as possible it was common to intermarry

within the family. As such the father of Henry (Count Alphonse de Toulouse-Lautrec) was first cousin with
his mother (Countess Alèle Tapié de Ceyleran). Henry de Toulouse-Lautrec is considered to have suffered
from a disorder called pycknodysostosis2,3,4,5,6. Pycknodysostosis is an autosomal recessive skeletal
disorder characterized by short stature, increased bone density, delayed closure of cranial sutures, loss of
the mandibular angle, dysplastic clavicles, dissolution of the terminal phalanges of the hands and feet,
dental abnormalities and increased bone fragility. The defect links to a narrow region on band 21 of the
long arm of chromosome 1.

When Henry was a child (13 and then 14 years old), he broke a femur after a horse fall during a training
session with his father (an avid equestrian) and later broke the second femur. Because of the bone disorder
it took almost a year for the fracture to heal. Understandably, little Henry was not eager to repeat the
experience, and preferred to spend time improving his drawing and painting skills which he developed
during his long convalescence. This led to paternal rejection and a sensation that he did not belong to his
original aristocratic environment. Like many in this situation, he gravitated towards others rejected by the
society and found a more tolerant environment in the artistic and entertainment population around

The painting entitled: “Dance au Moulin Rouge” (a famous establishment at the time) is centered around
the visual axis created by the upper middle class woman in pink and the two dancers. Note the
contemptuous attitude of the lady in pink towards the dancers and in particular “La Goulue” (the female
dancer that raises her left leg). “La Goulue” (the Glutton) was so nicknamed for her habit to go to the tables
of the customers, sit on the lap of the gentleman and drink their drinks (thus increasing the consumption in
the establishment!). Actually the important personage in the painting, his her dancer partner: “Valentin le
Désossé” (the Snakeman in English). Vincent, which appears in other paintings of Toulouse-Lautrec, was a
famous contortionist, a skill made easy because of his condition of Ehler-Danlos a connective tissue
dysplasia with some similarities with osteogenesis imperfecta.

Fig. 2: “Dance au Moulin Rouge”, Henry de Toulouse-Lautrec 1890 Philadelphia Museum of Art,

Clearly the artistic patrimony of the world has been enlarged by the contribution of Henry de Toulouse-
Lautrec, and his art was significantly influenced by his disorder.

Patients with skeletal dysplasia have existed in all societies and we should make effort to allow them to
function as normally as possible in the society (fig. 3). One of my friends with achondroplasia was relating
her anxiety when taking an elevator once in a big city. When the door closed behind her, there was no
button she could reach and she was trapped in the elevator until someone else came in. Fortunately, the
passage in the United States of the American with Disability Act has contributed to the adaptation of these
special people in our society. We can only hope that this will be more widespread around the globe.

Fig. 3: Our society has to adapt to the needs of patients with short-limb dysplasia (© 1972 Quino “Ia a mi
no me grite” Ediciones de la Flor)

Many organizations assist patients with skeletal dysplasia. A vibrant example is the Little People of
America ( that assist patients with achondroplasia and similar disorders. Physicians
have to be aware of these resources and help their patients take advantage of the support they provide.

Birth prevalence and contribution to perinatal mortality
The birth prevalence of skeletal dysplasias, excluding the limb amputations, recognizable in the neonatal
period has been estimated to be 2.4/10,000 births7. In a large series, 23% of affected infants were stillbirths,
and 32% died during the first week of life. The overall frequency of skeletal dysplasias among perinatal
deaths was 9.1/1,000. The relative frequencies of the different skeletal dysplasias are shown in figure 4.

Thoracic dysplasia

The four most common skeletal dysplasias found were thanatophoric dysplasia, achondroplasia,
osteogenesis imperfecta and achondrogenesis. Thanatophoric dysplasia and achondrogenesis accounted for
62% of all lethal skeletal dysplasias8. The most common non-lethal skeletal dysplasia is achondroplasia.
In another large series, reporting the prevalence and classification of lethal neonatal skeletal dysplasias in
West Scotland, the prevalence was 1.1/10,000 births, and the most frequently diagnosed conditions were
thanatophoric dysplasia (0.24:10,000), osteogenesis imperfecta (0.18:10,000), rhizomelic chondrodysplasia
punctata (0.12:10,000), campomelic syndrome (0.1/10,000) and achondrogenesis (0.1/10,000)9.

The following chart is the prevalence of selected skeletal dysplasias in the studies of Anderson and Camera.

Campomelic dysplasia
Multiple epiphyseal dysplasia tarda
Multiple cartilaginous exostoses
Spondylo-thoracic dysplasia
Chondrodysplasia punctacta
Asphixiating thoracic dysplasia
Osteogenesis imperfecta type III
Osteogenesis imperfecta type II
Thanatophoric dysplasia
Prevalence per 10,000 births
Andersen P, Hauge M. Congenital generalised bone dysplasia: a clinical, radiological, and epidemiological survey. J Med Genet 1989;26:37-44.
Camera G, Mastroiacovo P. Birth prevalence of skeletal dysplasias in the Italian multicentric study. In: Papadatos C, Bartsocas C. Skeletal
dysplasias, eds. Proceedings of the Third International Clinical Genetics Seminar. New York: Liss, 1982, 441-9.

Classification of skeletal dysplasias
Until recently the classification of skeletal dysplasia has been hampered by the rarity of the condition and
the lack of understanding of the etiologies. Thus disorders that look the same were assimilated, and then
separated under new entities. This lack of understanding resulted in classifications that were mainly
descriptive and the technique most likely to identify the findings was predominantly used to categorize the
anomalies. Therefore many definitions are based on radiological criteria with a fewer based on histological
or clinical criterias. This in turn, further complicated matters because the nomenclature of disorder was then
either a description of the clinical outcome (thanatophoric dysplasia = that carries (result in) death), clinical
description (diastrophic dysplasia = referred to the twisted joints, cleidocranial dysplasia…), or possible
pathogenesis (osteogenesis imperfecta, achondrogenesis). Those disorders too uncertain or with too many
features were given eponyms (Ellis-van Creveld syndrome).

In an attempt to bring some order, an International Nomenclature for Skeletal Dysplasias was proposed by
a group of experts Paris in 1977. This classification was revised in Germany in 1992 and more recently in
Los Angeles in 1998. The current version has been renamed “International Nomenclature of
Constitutional Disorders of Bone”
and it is available on line at

The original 5 categories have been enlarged into 32 groups.

The reason for the rapid revision has been the explosion of knowledge brought in by the discoveries of the
genetic defect underlying many of the conditions. In 1994, two groups (Le Merrer10 at the INSERM, Paris,
France and Velinov11 in Farmington CT, USA) independently concluded that the gene responsible for
achondroplasia was located in the telomeric region of the 16.3 band of the short arm of the chromosome 4.
The next year Bellus12, at John Hopkins, demonstrated that a Glycine to Arginine at codon 380 of the
Fibroblast Growth Factor Receptor 3 was responsible for achondroplasia. Fibroblast growth factors regulate
cell proliferation, differentiation and migration by a transmembrane tyrosine-kinase receptor called
“fibroblast-growth-factor-receptor” (FGFR). These molecules contain transmembrane domains components
and an extracellular component composed of 3 immunoglobulin-like domains (fig. 5).
S - S
S - S
S - S

Fig.5: Schematic representation of the Fibroblast Growth Factor Receptor (FGFR). On the left, the
molecule starts with a signal peptide. The extracellular component is composed of 3 immunoglobulin-like
domains (the 3 arches). On the right side of the molecule are the transmembrane domains.

Over the next few months and years a literal explosion of knowledge occurred with the locus for Pfeiffer,
Aperts, Crouzon, Jackson-Weiss, thanatophoric dysplasia, achondroplasia, hypochondroplasia and many
other being identified. Several other deficient proteins were subsequently discovered.

Although more than 271 skeletal dysplasias have been described, and more will probably be identified as
distinct entities, the number that can be recognized with the use of sonography in the antepartum period is
considerably smaller.
Definitions and “what to look for ?” when doing a prenatal examination
Skeletal dysplasias are disorders of bones. They may result from abnormal:
1. Growth: resulting in abnormal shape and size of the skeleton.
2. Number: either decreased or increased
3. Texture: either decreased or increased activity of the remodeling process and mineral deposition.

Shortening of the extremities can involve the entire limb (micromelia), the proximal segment (rhizomelia),
the intermediate segment (mesomelia) or the distal segment (acromelia) (fig. 6).


Fig. 6: Shortening of the extremities can involve the entire limb (micromelia), the proximal segment
(rhizomelia), the intermediate segment (mesomelia) or the distal segment (acromelia). Extra digits on the
ulnar or fibular side are “post-axial” and “pre-axial” if they are located on the radial or tibial side.

The diagnosis of rhizomelia or mesomelia requires the comparison of the dimensions of the bones of the
legs and forearm with those of the thigh and arm.

Acromelia may be due to several anomalies of the hands and feet. Polydactyly refers to the presence of
more than five digits. It is classified as post-axial if the extra digits are on the ulnar or fibular side and pre-
axial if they are located on the radial or tibial side (fig. 6). Most commonly the extra digit is a simple skin
tag, difficult to see by ultrasound, but occasionally bones may be present too.

Fig. 7: Polydactyly refers to the presence of extra digits. Most commonly the extra digit is a simple skin
tag, difficult to see by ultrasound, but occasionally bones or a completely duplicated but non functional
digit may be present too. In this illustration post-axial polydactylies have been represented.

Syndactyly refers to soft tissue or bony fusion of adjacent digits and is difficult to recognize in the less
severe forms (fig. 7).

Fig. 7: Bony syndactyly.

Clinodactyly consists of deviation of a finger(s). It may result from an abnormal middle 5th phalanx such as
in brachymesophalangia (fig. 8)

Fig. 8: Left: an abnormal middle 5th phalanx can be responsible for clinodactyly.

Clubbing of the hand is very suggestive of “radial-ray” anomalies. These anomalies range from abnormal
thumbs (sometimes triphalangeal as in Holt-Oram syndrome) to hypoplasia or absence of the thumb and
sometimes absence of the radius or even the radius and the hand. The three most likely diagnoses include
Holt-Oram syndrome, the thrombocytopenia-absent radius (TAR) syndrome and trisomy 18.

Fig. : “Radial-ray” anomalies range from abnormal thumbs to hypoplasia or absence of the thumb and
sometimes absence of the radius or even the radius and the hand.

The foot length is very close to the femoral length and can be used to compare the two13,14. At the level of
the feet, a rocker-bottom foot (abnormal vertical position of the talus and calcaneus) or a clubfoot should
also be sought.


Fig. : An abnormal vertical position of the talus and calcaneus causes a rockerbottom foot.

At the level of the head, deviations from the normal shape of the head should be observed. These include
brachycephaly, scaphocephaly and the craniosynostoses.

Fig. : Normal appearance of the skull in cross-section (middle image) should be compared to
scaphocephaly (the lateral flattening, first image) and brachycephaly (the antero-posterior shortening,
right image)

Brachycephaly occurs in many acrocephalopolysyndactilies. Scaphocephaly is more common and is
associated with premature rupture of the membranes, growth restriction, in-utero crowding and
acromesomelic dysplasia.

Craniosynostoses result from premature fusions of the suture. The expanding brain deforms the adjacent
bones resulting in specific anomalies. One of the common one being the clover-leaf shape (or
kleeblattschadel) that occurs in the Type II Thanatophoric dysplasia. Other conditions with
craniosynostosis are Carpenter's syndrome, hypophosphatasia, acrocephalosyndactyly, Crouzon – Aperts,
acrodysostosis, trimethadone sequence and many others.

Fig. : Craniosynostosis results from premature fusions of the suture.

Frontal bossing is a deformity of the forehead that may be associated with achondroplasia and the
craniosynostosis but also due to increased intracranial size with large hydrocephalus. The diagnosis is often