The skeleton is composed of two tissues (bone and cartilage), three cell types (osteoblasts, osteoclasts, and chondrocytes), and more than 200 skeletal elements spread throughout the body.1,2 Skeletal tissues derive from three embryonic cell lineages: (1) cranial neural crest cells, which originate the craniofacial skeleton, including the calvarium, midface, mandible and teeth; (2) paraxial mesoderm cells or somites, which are the embryologic precursors of the axial skeleton; and (3) the lateral plate mesoderm, which is responsible for limb formation.1,36 Embryologically, limb buds begin to develop during the 4th week of embryonic life (6th menstrual week) as clusters of mesenchymal cells covered by a layer of ectoderm.13 Mesenchymal models of bone (anlagen) form around the 5th week of embryonic life (7th menstrual week) (Fig. 12-1).3 Development of the upper limbs antecedes that of the lower limbs in bud appearance, differentiation, and establishment of final relative limb size. Limbs develop in a proximodistal sequence, with the anlagen of the humerus and femur forming first, followed by the radius and the ulna, the tibia and the fibula, the metacarpal and the metatarsal bones, and, finally, the phalanges.1,2,7

Skeletogenesis (Genetics and Embryology)

Skeletogenesis involves four steps: patterning, organogenesis, growth, and homeostasis.6 Patterning is the process by which the final size, shape, number and arrangement of bones are determined.2,6 This process takes place long before skeletogenesis, and three signaling regions have been identified: (1) an apical ectodermal ridge; (2) an area consisting of ectoderm covering the sides of the bud; and (3) a zone of polarizing activity.5 The apical ectodermal ridge consists of densely packed ectodermal cells located at the tip of the limb bud, which express several fibroblast growth factors (FGFs) that initiate and control limb outgrowth.5,8,9 The ectoderm covering the sides of the bud regulates dorsoventral patterning.5 The zone of polarizing activity is located on the posterior limb bud margin. It is responsible for anteroposterior patterning and, thus, the formation of digits.9,10 Besides FGFs, several other genes are involved in the control of limb patterning, including Sonic hedgehog (Shh), GLI-Kruppel family member GLI3 (Gli3), sal-like 1 (Sall1), Hoxd13, Hoxa13, bone morphogenetic/cartilage-derived morphogenetic protein (CDMP), growth differentiation factors (GDFs), noggin (Nog), t-box family 4 and 5 (Tbx-4 and Tbx-5), Wn7-a, radical fringe (Rfng), engrailed (en), and LIM homeobox transcription factor 1 beta (Lmx1b).1

Bone and cartilage are formed during the organogenesis period, which consists of three phases: condensation, cell differentiation, and histogenesis. Condensation is pivotal in skeletal development, because the templates for the future bones (anlagen) are defined at this stage.4 Condensation initiation, boundary set, proliferation, adhesion, and growth are regulated by complex interactions between extracellular matrix molecules, cell surface receptors, cell adhesion molecules (e.g., fibronectin, tenascin, Noggin, syndecan, and N-CAM), homeobox genes (e.g., Hoxa-2, Hoxa-13, Hoxd-11, and Hoxd-11-13), transcription factors (e.g. runt related transcription factor 2 [RUNX2], winged-helix transcription factor [CFKH-1], mesenchyme forkhead 1 [MFH-1], paired box transcription factors 1 and 9 [PAX-1, PAX-9], periaxin 1 and 2 [PRX-1 and PRX-2], scleraxis, and mammalian SRY box 9 [SOX-9]), and growth factors (e.g. bone morphogenetic proteins, fibroblast growth factor-2 [FGF-2], transforming growth factor β).11

Cell differentiation and histogenesis (osteogenesis) initiate during the 7th week of embryonic development (9th menstrual week), with bones developing by either endochondral or membranous ossification.6

Endochondral Ossification

The axial and appendicular skeletons are formed by endochondral ossification (Fig. 12-2). Cartilaginous models of the future bones differentiate within mesenchymal condensations during the 6th week of development (8th menstrual week), with primary ossification centers developing in the middle of the anlagen between the 7th and 12th week of development (9th to 14th menstrual weeks).3 SOX9 plays an important role in chondrogenesis and, indeed, mutations in this gene cause campomelic dysplasia, a severe skeletal disorder characterized by congenital bowing and angulation of the long bones (especially of the tibia), hypoplastic scapulae, sex reversal in male fetuses, and a high lethality rate due to respiratory distress.1 Another gene involved in chondrogenesis is procollagen type II alpha 1 (COL2A1), which encodes collagen type II.1,12

Within primary ossification centers, hypertrophic cartilage matrix is degraded, chondrocytes undergo apoptosis, osteoblasts replace the disappearing cartilage with trabecular bone, and bone marrow is formed.1 Simultaneously, osteoblasts in the perichondrium begin to deposit a collar of compact bone matrix along the diaphysis.1,12 Osteoblast differentiation is controlled by RUNX213 and Osterix,14 whereas proliferation is controlled by the low-density lipoprotein receptor–related protein 5 (LPR5) signaling pathway.2 Eventually, cartilage in the center of the anlagen degrades, mineralizes, and is removed by osteoclasts.3,4 Vascular ingrowth is stimulated by vascular endothelial growth factor, with the influx of osteoprogenitor cells occurring at the same time that the bone matrix is deposited along the periosteum of the midshaft.3,4,15 Some of these invading cells differentiate into hematopoietic stem cells, whereas others differentiate into osteoclasts or osteoblasts.6

Secondary ossification centers begin to appear at the extremities of bones (epiphysis) later in pregnancy.3 The portion of cartilage trapped between the expanding primary and secondary ossification centers is known as the growth plate or physis.3 This structure is responsible for the longitudinal growth of long bones until definitive fusion between epiphyses and diaphyses occurs at the end of puberty.3,4,12 Longitudinal growth is coordinated by Indian hedgehog (Ihh), a stimulator of chondrocyte proliferation at the growth plate.1 Bone mass, shape, and strength are maintained throughout development and adult life by balancing bone destruction and formation. Homeostasis is the process that controls the continuing remodeling of bones.6

It is important to realize that when a long bone is imaged by ultrasound, only the diaphyses are measured, because the epiphyses usually are not clearly visualized. With favorable conditions, good images of the epiphysis can be obtained, especially when high frequency transducers are used (Fig. 12-3). Secondary ossification centers may often be visualized by ultrasound in the third trimester. The distal femoral ossification center may be seen at approximately 32 to 33 weeks of gestation, the proximal tibial epiphyseal center at 34 to 35 weeks, and the proximal humeral epiphyseal ossification center at 37 to 38 weeks of gestation (Fig. 12-4A and B). When all three centers are identified, it is likely that the fetus is at least 37 weeks. These ossification centers may be seen slightly earlier in female fetuses than in male fetuses. The timeline for the radiographic and histologic appearance of primary and secondary ossification centers is illustrated in Figure 12-4C.

The axial skeleton (e.g., vertebrae and the dorsal part of the ribs) originates from the somites. Formation of new somites and detachment of these structures from the paraxial mesoderm occur in the craniocaudal direction in a highly organized fashion.5 A molecular clock produced by oscillations of cycling genes (e.g. c-hairy-1, lunatic fringe [l-fng], and naked cuticle 1 [nkd1]) stimulates Notch receptor signaling waves that sweep through the paraxial mesoderm.1619 Spatial coordination is provided by a decreasing gradient of FGF8 from the posterior to the anterior pole of the embryo.5,18,20 Differential expression of delta-like (Dll) proteins determines the size and polarity of the somites,5 which mature as they move rostrally and differentiate into dermatomyotomes and sclerotomes.5,18 Dermatomyotomes give rise to the appendicular and axial musculatures, as well as the dorsal epithelium. The sclerotome is the precursor of the axial skeleton, and its formation is initiated and controlled by Sonic hedgehog.5,21,22

Intramembranous Ossification

The craniofacial skeleton and clavicles develop by intramembranous ossification.1 This process differs from endochondral ossification by the direct differentiation of mesenchymal cells into osteoblasts, which produce a bone matrix rich in type I collagen.13,12,15 Bone remodeling is accomplished by the continuous and concerted action of osteoblasts (cells that produce bone matrix) and osteoclasts (cells that remove bone).


Abnormal development, growth, or maintenance of cartilage and bone tissues result in skeletal dysplasias. Skeletal dysplasias are a heterogeneous group of disorders affecting the development of chondro-osseous tissues and resulting in abnormalities in the size and shape of various segments of the skeleton. Despite recent advances in imaging and molecular genetics,2325 accurate prenatal diagnosis of skeletal dysplasias remains a clinical challenge.26 Although 253 osteochondrodysplasias and 45 genetically determined dysostoses have been included in the most recent revision of the International Nosology and Classification of Constitutional Disorders of Bone27 (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. In subsequent sections of this chapter, we review the birth prevalence, classification, and molecular genetics of skeletal dysplasias that are identifiable at birth.

Birth Prevalence and Contribution to Perinatal Mortality

In a large multicenter study conducted in Italy, the birth prevalence of skeletal dysplasias recognizable in the neonatal period, excluding limb amputations, was estimated as 2.4/10,000 births.28 Twenty-three percent of the affected infants were stillborn, whereas 32% died during the first week of life. The overall frequency of skeletal dysplasias among perinatal deaths was 9.1 per 1000. This study also reported on the birth prevalence of the different skeletal dysplasias and their relative frequency among perinatal deaths (Table 12-1). The four most common skeletal dysplasias were thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta (OI), and achondrogenesis. Thanatophoric dysplasia and achondrogenesis accounted for 62% of all lethal skeletal dysplasias, and the most common nonlethal skeletal dysplasia was achondroplasia.28 In another large series performed in western Scotland, the prevalence of skeletal dysplasias at birth was 1.1 per 10,000 births. The most frequent conditions were thanatophoric dysplasia (1/42,000), OI (1/56,000), chondrodysplasia puntacta (1/84,000), campomelic syndrome (1/112,000), and achondrogenesis (1/112,000).29 Rasmussen et al30 reported a prevalence of 2.14/10,000 deliveries in a longitudinal study, which included elective pregnancy termination, stillborn infants at more than 20 weeks of gestation, and live-born infants diagnosed by the 5th day of life. The rate of lethal cases in this latter study was 0.95/10,000 deliveries.30 Other studies reporting on the prevalence of skeletal dysplasias are summarized in Table 12-2.2839 Of interest, the study reporting the highest prevalence of skeletal dysplasias at birth (9.5/10,000 births) was conducted in a population with a high rate of consanguineous unions.39

Table 12-1 Birth Prevalence of Skeletal Dysplasias (per 10,000 total births)

  Birth Prevalence (per 10,000) Frequency Among Perinatal Deaths
Thanatophoric dysplasia 0.69 1:246
Achondroplasia 0.37
Achondrogenesis 0.23 1:639
Osteogenesis imperfecta type II 0.18 1:799
Osteogenesis imperfecta (other types) 0.18
Asphyxiating thoracic dysplasia 0.14 1:3,196
Chodrodysplasia puntacta 0.09
Campomelic dysplasia 0.05 1:3,196
Chondroectodermal dysplasia 0.05 1:3,196
Larsen’s syndrome 0.05
Mesomelic dysplasia (Larger’s type) 0.05
Others 0.46 1:800

From Camera G, Mastroiacovo P: Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects. In Papadatos CJ, Bartsocas CS (eds): Skeletal Dysplasias. New York, Alan R. Liss, 1982, p 441.

Table 12-2 Overall Birth Prevalence of Osteochondrodysplasias – Summary of 12 Studies

Reference Rate per 10,000 Comment
Gustavson and Jorulf31 4.7 In newborns
Camera and Mastroiacovo28 2.4 In neonates
Connor et al.29 1.1 Lethal skeletal dysplasias in neonates
Weldner et al.32 7.5  
Orioli et al.33 2.3 First 3 days of life
Stoll et al.34 3.2 First 8 days of life
Andersen and Hauge35 7.6 Diagnosed in all ages
Andersen36 1.5 Lethal chondrodysplasias only
Kallen et al.37 1.6 No details about age
Rasmussen et al.30    
All cases 2.1 In first 5 days of life
Lethal chondrodysplasias 0.95  
Gordienko et al.38 3.1  
Al Gazali et al.39 9.5

Classification of Skeletal Dysplasias

International Nosology and Classification of Constitutional Disorders of Bone

Over the past 30 years, the classification of skeletal dysplasias has evolved from one based on clinical/radiologic/pathologic descriptions to one that also includes the underlying molecular abnormality for those conditions for which the defect is known.40

The first uniform classification, proposed in 1977, was called International Nomenclature for Skeletal Dysplasias. The classification was based purely on descriptive findings of either clinical or radiologic nature.41 Since its initial publication, the classification has undergone three revisions. In 1992,4244 it was reoriented based on radiologic diagnosis and morphologic criteria, and similar conditions were grouped into families, depending on the presumed pathogenetic similarities. Five years later, the classification was reorganized to take into account information regarding genes or protein defects underlying the families of disorders.45,46 Thus, those disorders for which a genetic defect was well documented were regrouped into distinct families based on specific mutations. These included, for example, the “achondroplasia group” of disorders with mutations in the fibroblast growth factor receptor 3 gene, the “diastrophic dysplasia group” of disorders with mutations in the diastrophic dysplasia sulfate transporter gene, the type II collagenopathies with mutations in the type II collagen gene, and the type XI collagenopathies with mutations in the cartilage oligomeric protein gene. Several new groups were added, including the lethal skeletal dysplasias group, the fragmented bones group, and the miscellaneous neonatal severe dysplasia group. The classification was last revised during the 5th Meeting of the International Skeletal Dysplasia Society, which took place in Oxford, England in 2001; it is now called the International Nosology and Classification of Constitutional Disorders of Bones (2001).27 Although this classification remains a combination of morphologic and molecular groupings of disorders, genetically determined dysostoses were added to skeletal dysplasias (or osteochondrodysplasias), because these two groups overlap in clinical practice. Dysostoses are skeletal malformations that occur during the first 8 weeks of embryonic life and for which the phenotype is static, that is, the phenotype does not evolve throughout life.27 In contrast, skeletal dysplasias, which often present after the embryonic period, are characterized by a more general involvement of the skeleton, and the phenotype continues to evolve throughout life.27 Genetically determined dysostoses have been divided into three groups: those with predominant cranial and facial involvement (e.g., Crouzon syndrome), those with predominant axial involvement (e.g., spondylocostal disostoses), and those with predominant involvement of the extremities (e.g., Fanconi syndrome). The full version of the International Nosology and Classification of Constitutional Disorders of Bones27 can be downloaded from the International Skeletal Dysplasia Society website (

Molecular-Pathogenetic Classification of Skeletal Dysplasias

As acknowledged earlier, at least in part, by the above-metioned nosology classification, evolving knowledge regarding the molecular basis of skeletal dysplasias indicates that a spectrum of phenotypes share a similar genetic basis.24,25,4751 For example, disorders that originate during patterning are generally caused by Hox or Pax genes.6 In contrast, growth defects are frequently caused by mutations in genes that encode for extracellular matrix products or for regulatory signal peptides.6 Therefore, a parallel molecular classification based on the structure and function of implicated genes and proteins has been developed to help further understand the pathogenesis of individual disorders. The Molecular-Pathogenetic Classification of Genetic Disorders of the Skeleton is presented in Table 12-3,24 and complements the International Nosology and Classification of Constitutional Disorders of Bone.27 Skeletal disorders with a well-documented genetic and biochemical basis have been assigned to one of seven groups: (1) defects in extracellular structural proteins; (2) defects in metabolic pathways (including enzymes, ion channels and transporters); (3) defects in folding and degradation of macromolecules; (4) defects in hormones and signal transduction mechanisms; (5) defects in nuclear proteins and transcription factors; (6) defects in oncogenes and tumor suppressor genes; and (7) defects in RNA and DNA processing and metabolism.

The reader is reminded that only approximately one third of bone dysplasias have had their molecular basis elucidated, and that new genes involved in skeletal dysplasias are continually being discovered.25 We review the mutations associated with specific skeletal dysplasias in subsequent sections of this chapter.

Lethal Skeletal Dysplasias

Of special interest to perinatologists are the group of lethal osteochondrodysplasias, which were classified by Spranger and Maroteaux52 into 11 subgroups based on radioanatomic manifestations (Table 12-4). The purpose of this classification was to facilitate differential diagnosis, and the groups do not necessarily constitute pathogenetic families.

Table 12-4 Nosology of Lethal Osteochondrodysplasias

1. Hypophosphatasia and morphologically similar disorders
1.01 Hypophosphatasia
1.02 Probable hypophosphatasia
1.03 Lethal metaphyseal dysplasia
2. Chondrodysplasia punctata and similar disorders
2.01 Rhizomelic chondrodysplasia punctata
2.02 Lethal chondrodysplasia punctata, X-linked dominant
2.03 Greenberg dysplasia
2.04 Dappled diaphysis dysplasia
3. Achondrogenesis and similar disorders
3.01 Achondrogenesis I-A (Houston Harris)
3.02 Achondrogenesis I-B (Fraccaro)
3.03 New lethal osteochondrodysplasia
3.04 Achondrogenesis II (Langer-Saldino)
3.05 Hypochondrogenesis
4. Thanatophoric dysplasia and similar disorders
4.01 Thanatophoric dysplasia, type 1
4.02 Thanatophoric dysplasia, type 2
4.03 Homozygous achondroplasia
4.04 Lethal achondrodysplasia
4.05 Glasgow variant
5. Platyspondylic lethal chondrodysplasias
5.01 Platyspondylic chondrodysplasia, Torrance type
5.02 Platyspondylic chondrodysplasia, San Diego type
5.03 Platyspondylic chondrodysplasia, Luton type
5.04 Platyspondylic chondrodysplasia, Shiraz type
5.05 Opsismodysplasia
5.06 Sixth form of platyspondylic chondrodysplasia
5.07 Seventh form of platyspondylic chondrodysplasia
6. Short rib polydactyly syndromes
6.01 Short rib polydactyly syndrome, type I (Saldino-Noonan)
6.02 Short rib polydactyly syndrome, type II (Verma-Naumoff)
6.03 Short rib polydactyly syndrome, type III (Le Marec)
6.04 Short rib polydactyly syndrome, type IV (Yang)
6.05 Short rib polydactyly syndrome, type V
6.06 Short rib polydactyly syndrome, type VI (Majewski)
6.07 Short–rib–polydactyly syndrome, type VII (Beemer)
7. Lethal metatropic dysplasia and similar disorders
7.01 Lethal metatropic dysplasia (hyperchondrogenesis)
7.02 Isolated case
7.03 Isolated case
7.04 Fibrochondrogenesis
7.05 Schneckenbecken dysplasia
7.06 Isolated case
7.07 Isolated case
7.08 Isolated case
8. Kniest-like disorders
8.01 Dyssegmental dysplasia, Silverman type
8.02 Dyssegmental dysplasia, Rolland-Desbuquois
8.03 Lethal Kniest disease
8.04 Chondrodysplasia resembling Kniest dysplasia
8.05 Isolated case
8.06 Blomstrand chondrodysplasia
9. Lethal osteochondrodysplasias with pronounced diaphyseal abnormalities
9.01 Campomelic syndrome
9.02 Stuve-Wiedemann syndrome
9.03 Boomerang dysplasia
9.04 Atelosteogenesis
9.05 Disorder resembling atelosteogenesis
9.06 De la Chappele dysplasia
9.07 McAlister dysplasia
9.08 Pseudodystrophic dysplasia
10. Osteogenesis imperfecta and similar disorders
10.01 Osteogenesis imperfecta II-A
10.02 Osteogenesis imperfecta II-B
10.03 Osteogenesis imperfecta II-C
10.04 Isolated case
10.05 Astley-Kendall dysplasia
11. Lethal disorders with gracile bones
11.01 Fetal hypokinesia phenotype
11.02 Lethal osteochondrodysplasia with gracile bones
11.03 Lethal osteochondrodysplasia with intrauterine over-tibulation

From Spranger J, Maroteaux P: The lethal osteochondrodysplasias. Adv Hum Genet 19:1, 1990.

Terminology Frequently Used to Describe Bone Dysplasias

Shortening of the extremities can involve the entire limb (micromelia), the proximal segment (rhizomelia), the intermediate segment (mesomelia), or the distal segment (acromelia) (Fig. 12-5). The diagnosis of rhizomelia or mesomelia requires comparing the dimensions of the bones of the legs and forearm with those of the thighs and arms. Figures 12-6 and 12-7 display the relationships between the humerus and ulna, as well as the femur and tibia, which can be used for the objective assessment of rhizomelia and mesomelia. Table 12-5 presents a list of skeletal dysplasias characterized by rhizomelia, mesomelia, and micromelia.

Table 12-5 Skeletal Dysplasias Characterized by Rhizomelia, Mesomelia, and Micromelia

Several skeletal dysplasias feature alterations of the hands and feet. The term polydactyly refers to the presence of more than five digits. It is classified as postaxial if the extra digits are on the ulnar or fibular side, and preaxial if they are located on the radial or tibial side. Syndactyly refers to soft tissue or bony fusion of adjacent digits. Clinodactyly consists of deviation of a finger (or fingers).

The most common spinal abnormality seen in skeletal dysplasias is platyspondyly, which consists of the flattening of the vertebrae (Fig. 12-8).5359 Kyphosis and scoliosis can also be identified in utero (Figs. 12-9 and 12-10).6064 Prenatal diagnosis of hemivertebra (Fig. 12-11)60,65,66 and coronal clefting of vertebral bodies have been made.63,67

Biometry of the Fetal Skeleton in the Diagnosis of Bone Dysplasias

Long bone biometry has been used extensively for the prediction of gestational age. Nomograms for this purpose make use of the long bone as the independent variable and the estimated fetal age as the dependent variable. However, the type of nomogram required to assess the normality of bone dimensions uses gestational age as the independent variable and long bone length as the dependent variable. For the proper use of these nomograms, the clinician must know the accurate gestational age of the fetus. Therefore, patients at risk for skeletal dysplasias are advised to seek prenatal care at an early gestational age in order to assess all clinical estimators of gestational age. Tables 12-6 and 12-7 present nomograms for the measurement of limb biometry for the upper and lower extremities, respectively. Comparisons between limb dimensions and the head circumference can be used for patients presenting with uncertain gestational age (Figs. 12-12 and 12-13). Although some investigators have employed the biparietal diameter for this purpose, the head circumference has the advantage of being shape independent. A limitation of this approach is that it assumes that the cranium is not involved in the dysplastic process, and this may not be the case in some skeletal dysplasias.

The nomograms and figures in this chapter provide the mean, the 5th, and the 95th percentiles of limb biometric parameters. The reader should be aware that 5% of the general population would fall outside these boundaries. Ideally, a more stringent criterion, such as the 1st percentile of limb growth for gestational age, should be used for diagnosis. Unfortunately, none of the currently available nomograms have been based on a sufficient number of patients to provide an accurate discrimination between the 5th and the 1st percentiles. However, most skeletal dysplasias diagnosed in utero or at birth are associated with dramatic long bone shortening, and under these circumstances, the precise boundary used (1st or 5th percentile) is not critical. An exception to this is achondroplasia, in which limb biometry is mildly affected until the third trimester, when abnormal growth can be detected by examining the slope of growth of the femur length.68 In a study including 127 cases of 17 skeletal dysplasias, Gonçalves and Jeanty69 concluded, with the use of discriminant analysis, that the degree of shortening of the femur length can be used as the initial step in distinguishing among the five most common disorders: thanatophoric dysplasia, OI type II, achondrogenesis, achondroplasia, and hypochondroplasia. Gabrielli et al.70 evaluated the possibility of an early diagnosis of skeletal dysplasias in high-risk patients. A total of 149 consecutive, uncomplicated singleton pregnancies at 9 to 13 weeks after amenorrhea were scanned by transvaginal ultrasound. Eight additional patients with previous pregnancies affected with skeletal dysplasias were evaluated with serial examinations every 2 weeks from 10 to 11 weeks of gestation onward. Significant correlations between femur length and both crown rump length and biparietal diameter were found. Of the five cases with skeletal dysplasias, two (one with recurrent OI, the other with recurrent achondrogenesis) were diagnosed in the first trimester. The results of this study suggest that an early evaluation of the fetus and the correlation of femur length with crown rump length and of femur length with biparietal diameter might be helpful in the early diagnosis of severe skeletal dysplasias. In less severe cases, however, biometric evaluation appeared to be of limited value. Nomograms for long bone measurements according to crown rump length in a large population of normal fetuses examined between 11 and 14 weeks of gestation have been recently published and their role in the early assessment of pregnancies at risk for skeletal dysplasias remains to be determined.71

Diagnostic Imaging and the Prenatal Diagnosis of Skeletal Dysplasias

Despite the increasing availability of molecular testing, a comprehensive molecular diagnostic search for all skeletal dysplasias is not possible at this time. Indeed, as mentioned in a previous section of this chapter, only about one third of skeletal dysplasias have had their molecular basis defined.25 Therefore, the role of diagnostic imaging in the prenatal investigation of skeletal dysplasias are (1) to narrow the differential diagnosis of skeletal dysplasias so that appropriate confirmatory molecular tests can be selected, (2) to predict lethality; and (3) to identify the fetus with a skeletal dysplasia early enough in pregnancy so that the diagnostic workup can be completed before the limit of fetal viability.7377

Ultrasound is the primary imaging modality used for the initial diagnostic evaluation of an affected fetus, and several studies have explored the role of ultrasound in the detection of skeletal dysplasias.53,68,7888 The first was a prospective analysis of a high-risk population (15 women, 16 cases) carrying a genetic risk for skeletal dysplasias conducted by Kurtz et al.68 Based on second trimester findings, five abnormal fetuses among 16 fetuses at risk were correctly diagnosed. Weldner et al32 screened 12,453 patients in the second and third trimesters, and estimated the prevalence of skeletal dysplasias detectable by prenatal ultrasound as 7.5/10,000. Sharony et al84 studied fetuses and stillbirths referred from other centers for suspected skeletal dysplasia. Most of the cases were sporadic, and the most common final diagnoses were OI (16%) and thanatophoric dysplasia (14%). Table 12-8 summarizes the diagnostic accuracy of two-dimensional ultrasound (2DUS) for prenatal diagnosis of skeletal dysplasias.26,38,8891

Several investigators have proposed that three-dimensional ultrasonography (3DUS) may improve the diagnostic accuracy for prenatal diagnosis of skeletal dysplasia.92104 The rationale for this expectation is that the availability of rendering algorithms to reconstruct the fetal skeleton may allow the observation of phenotypic features not detectable by 2DUS. For example, Garjian et al95 and Krakow et al102 reported on the diagnosis of additional facial95,102 and scapular anomalies,95 as well as abnormal calcification patterns102 in fetuses with skeletal dysplasias. Moeglin and Benoit,98 on the other hand, used the multiplanar visualization method to demonstrate the pointed appearance of the upper femoral diaphysis in achondroplasia. Three-dimensional reconstruction of the fetal bones is best performed using the maximum intensity projection mode, a rendering algorithm that prioritizes the display of voxels with the highest gray levels contained within a region of interest selected by the user95,98 (Fig. 12-14). If the fetus is examined early enough in the pregnancy, the entire skeleton can be included within the region of interest, and therefore, panoramic visualization can be achieved.95 However, the diagnosis may still be missed, because the phenotypic characteristics of some skeletal dysplasias do not manifest until later in pregnancy. Case reports and small series of skeletal dysplasias have been published describing phenotypic characteristics or skeletal features for which 3DUS may provide additional information (Table 12-9).93,9598,100103,105

Table 12-9 Additional Phenotypic Findings and Improved Visualization in Cases of Skeletal Dysplasias by Prenatal 3DUS as Compared to 2DUS in Published Reports

Skeletal Dysplasia Phenotypic Characteristics Identified Better by 3DUS than 2DUS
Platylospondylic lethal chondrodysplasia93

Campomelic dysplasia95,103,116

Thanatophoric dysplasia9597,102


Chondrodysplasia puntacta, rhizomelic form102

Achondrogenesis102 Panoramic demonstration of short neck and severe shortening of all segments of the limbs
Jarcho-Levin syndrome101 Vertebral defects with absence of ribs and transverse process
Spondylocostal dysostosis111 Fan-like rib cage with rib fusion
Larsen syndrome105 Genu recurvatum, midface hypoplasia, low set ears
Cleidocranial dysplasia115 Widened cranial sutures, poor mineralization of the occipital bones, pseudoarthrosis of the clavicle
Apert syndrome113,114 Coronal craniosynostosis

2DUS, two-dimensional ultrasound; 3DUS, three-dimensional ultrasound.

Phenotypic characteristics of osteogenesis imperfecta,95 short rib–polydactyly syndrome,100 and Apert’s syndrome102 have also been described using 3DUS, although no additional findings to 2DUS were observed.

Three-dimensional helical computerized tomography (3DHCT) has recently been proposed as an adjunctive imaging modality for the prenatal diagnosis of skeletal dysplasias (Fig. 12-15).106 Like 3DUS, postprocessing techniques such as maximum intensity projection, surface rendering, and volume rendering can be used for three-dimensional reconstruction.107109 Long bone measurements obtained by postmortem helical CT studies have been compared with those obtained within 24 hours of delivery by ultrasound, and a significant correlation between the two methods was observed.110 Excellent panoramic images of the fetal skeleton can be obtained by 3DHCT without superimposition of the maternal skeleton (which occurs with radiography). Ruano et al106 compared the phenotypic characteristics of three skeletal dysplasias [achondroplasia (n=3), OI (n=2), and chondrodysplasia puntacta (n=1)] visualized by prenatal 3DHCT, 3DUS, and 2DUS. Deformation of the fetal pelvis and an increase in the intervertebral space of the lumbar vertebrae were diagnosed more often using 3DHCT than 2DUS and 3DUS. In contrast, some phenotypic characteristics of fetuses with skeletal dysplasias were demonstrated only by ultrasound: phalangeal hypoplasia, point-calcified epiphysis (both by 2DUS and 3DUS), and facial dysmorphism (by 3DUS only). Although the overall count of correct phenotypic characteristics detected prenatally favored 3DHCT over 3DUS (94.3% [33/35] versus 77.1% [27/35], p=0.03, McNemar’s test for correlated samples), the diagnostic performance of 3DHCT was not superior to that of 3DUS, because the correct prenatal diagnosis was established by both modalities in all cases. Provided that the two diagnostic methods have comparable diagnostic accuracy, 3DUS has two important advantages over 3DHCT, namely the lack of radiation exposure and wider availability in the clinical setting. It is also noteworthy that the overall experience with 3DUS for the diagnosis of skeletal dysplasias is still limited.92105,111116 Nevertheless, even in this study, 3DUS performed better than 2DUS, both in the identification of phenotypic characteristics (77.1% [27/35] versus 51.4% [18/35], p=0.004, McNemar’s test for correlated samples) and in establishing an accurate diagnosis.


FIGURE 12-15 Comparison of phenotypic features of osteogenesis imperfecta by three-dimensional helical computer tomography (3DHCT), three-dimensional ultrasound (3DUS), two-dimensional ultrasound (2DUS), and postmortem radiographs. Prenatal diagnosis of osteogenesis imperfecta at 33 weeks of gestation by 2D-US, 3D-US, and 3-HCT. A. 2DUS: transverse section of fetal head with a skull fracture (f) deformed due to the transducer pressure. B. 2DUS: coronal section of fetal thorax showing irregular ribs (arrow). C. 2DUS: sagittal section of the right arm showing a short and bowed arm (f). D. 2DUS: sagittal section of fetal femur with a fracture (f). E. 3DUS: three-dimensional rendered bone mode image showing lateral view of fetal skull with a fracture (f) that could be differentiated from a normal coronal suture (CS) by the location and the deforming aspect depending on the transducer pressure; this was confirmed at postmortem examination. F. 3DUS: rendered bone mode demonstrating posterior view of fetal thorax showing fractured and irregular ribs (f). G. 3DUS: rendered bone mode image showing short and bowing radius and cubitus (f). H. 3DUS: rendered bone mode image showing a fractured femur (f). I. 3DHCT: posterior view of entire fetus confirming fractures of ribs and femur (f) as well as decreased mineralization of the skull. J. Postmortem radiologic examination, confirming shortening, bowing and fracture of long bones.

(From Ruano R, Molho M, Roume J, et al: Prenatal diagnosis of fetal skeletal dysplasias by combining two-dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography. Ultrasound Obstet Gynecol 24:134, 2004.)

Approach to the Diagnosis of Skeletal Dysplasias

A proposed systematic approach to the prenatal diagnosis of skeletal dysplasias is summarized in Table 12-10 and described in greater detail in the following section.

Table 12-10 Steps for Examination of the Fetus With a Suspected Skeletal Dysplasia by Two-Dimensional and Three-Dimensional Ultrasound

Evaluation of the Long Bones

Prediction of Pulmonary Hypoplasia

Several skeletal dysplasias are associated with a hypoplastic thorax. This is extremely important because chest restriction leads to pulmonary hypoplasia, a frequent cause of death in these conditions (see Table 12-4). When a severe skeletal dysplasia is diagnosed, the presence of marked thoracic involvement and pulmonary hypoplasia will allow the clinician to counsel the parents regarding prognosis despite the fact that the specific type of dysplasia may not be known. A number of ultrasonographic parameters have been investigated for the prediction of pulmonary hypoplasia. These include measurements of the thorax and lungs, ratios between thoracic measurements and other biometric parameters, Doppler velocimetry of the pulmonary arteries, Doppler evaluation of tracheal fluid flow, and more recently, three-dimensional volumetric measurements of the fetal lungs by either ultrasound or magnetic resonance imaging (MRI).

Evaluation of Thoracic and Lung Dimensions by Two-Dimensional Ultrasound.

Thoracic and lung biometry have been extensively studied to identify fetuses at high risk for pulmonary hypoplasia.122133 Table 12-11 lists skeletal dysplasias associated with altered thoracic dimensions, whereas Figures 12-20 and 12-21 illustrate features associated with a hypoplastic thorax.

Table 12-11 Skeletal Dysplasias Associated With Altered Thoracic Dimensions

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