Skeletogenesis (Genetics and Embryology)

Skeletogenesis involves four steps: patterning, organogenesis, growth, and homeostasis. Patterning is the process by which the final size, shape, number, and arrangement of bones are determined. 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. 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. The ectoderm covering the sides of the bud regulates dorsoventral patterning. 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. Besides FGFs, 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), Wn7-a, engrailed (en), and LIM homeobox transcription factor 1 beta (Lmx1b).

Bone and cartilage are formed during the organogenesis period, which consists of three phases: condensation, cell differentiation, and histogenesis. Condensation is of great importance in skeletal development, because the templates for future bones are defined at this stage. 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 neural cell adhesion molecule [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 beta [TGF-β]). Osteogenesis initiates during the 7th week of embryonic development (9th menstrual week), with bones developing by either endochondral or membranous ossification.

Endochondral Ossification

The axial and appendicular skeletons are formed by endochondral ossification ( Fig. 11-2 ). The axial skeleton (e.g., vertebrae and the dorsal part of the ribs) originates from the somites. 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 weeks of development (9th to 14th menstrual weeks). SOX9 plays an important role in chondrogenesis. 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 insufficiency. Another gene involved in chondrogenesis is procollagen type II alpha 1 ( COL2A1 ), which encodes collagen type II.

Endochondral bone formation. A, Mesenchymal cells condense. B, Cells of condensations become chondrocytes (c). C, Chondrocytes at the center of condensation stop proliferating and become hypertrophic (h). D, Perichondrial cells adjacent to hypertrophic chondrocytes become osteoblasts forming bone collar (bc). Hypertrophic chondrocytes direct the formation of mineralized matrix, attract blood vessels, and undergo apoptosis. E, Osteoblasts of primary spongiosa accompany vascular invasion forming the primary spongiosa (ps). F, Chondrocytes continue to proliferate, lengthening the bone. Osteoblasts of primary spongiosa are precursors of eventual trabecular bone; osteoblasts of bone collar become cortical bone. G, At the edge of the bone, the secondary ossification center (soc) forms through cycles of chondrocyte hypertrophy, vascular invasion, and osteoblast activity. The growth plate below the secondary center of ossification forms orderly columns of proliferating chondrocytes (col). Hematopoietic marrow (hm) expands in marrow space along with stromal cells.

(From Kronenberg HM: Developmental regulation of the growth plate. Nature 423:332-336, 2003.)

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. Simultaneously, osteoblasts in the perichondrium begin to deposit a collar of compact bone matrix along the diaphysis. Osteoblast differentiation is controlled by RUNX2 and Osterix, whereas proliferation is controlled by the low-density lipoprotein receptor–related protein 5 (LPR5) signaling pathway. Eventually, cartilage in the center of the anlagen degrades, mineralizes, and is removed by osteoclasts. 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. Some of these invading cells differentiate into hematopoietic stem cells, whereas others differentiate into osteoclasts or osteoblasts.

Secondary ossification centers begin to appear at the extremities of bones (epiphyses) later in pregnancy. The portion of cartilage trapped between the expanding primary and secondary ossification centers is known as the growth plate or physis. This structure is formed by a cartilaginous component (epiphyseal plate), a bony component (metaphysis), and fibrous tissue surrounding the periphery of the plate. The growth plate is responsible for the longitudinal growth of long bones until definitive fusion of epiphyses and diaphyses occurs at the end of puberty. Longitudinal growth is coordinated by Indian hedgehog (Ihh), a stimulator of chondrocyte proliferation at the growth plate. 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.

It is noteworthy that when a long bone is imaged by ultrasound, only the diaphyses are measured, because the epiphyses are hypoechoic and are not always clearly visualized. Under favorable conditions, good sonographic images of the epiphysis can be obtained, especially when high-frequency transducers are used ( Fig. 11-3 ). 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. 11-4 ). When all three centers are identified, it is likely that the fetus is at least 37 weeks’ gestational age. These ossification centers may be seen slightly earlier in female fetuses than in male fetuses. The timeline for radiographic and histologic appearance of primary and secondary ossification centers is illustrated in Figure 11-5 .

A, Proximal humeral epiphysis imaged with a high-frequency linear transducer (10 MHz) in a fetus at 29 weeks’ gestation. B, Measurement of the femur in a third trimester. The femur should be measured along the ossified bone (between the electronic calipers).

A, Sonogram of the knee in a fetus at 35 weeks’ gestation. Increased echogenicity from the secondary ossification centers of distal femoral (DFE) and proximal tibial (PTE) epiphyses are seen. B, Sonogram of the proximal humerus in a fetus at 38 weeks’ gestation. Ossification of the proximal humeral epiphyseal ossification center (PHE) is noted.

Diagram of the skeleton of a full-term newborn. The times that the ossification centers appear are designated in embryologic weeks (add 2 weeks for menstrual age). These times are somewhat different from those using ultrasound because ultrasound is more sensitive for detection of ossification than radiographic methods. All refer to the primary ossification centers unless otherwise designated. Only at birth do the lower extremities have the same length as the upper extremities; subsequently, the lower extremities become longer than the upper extremties.

(Illustration by Netter FH; from Crelin ES: Development of the musculoskeletal system. CIBA Clin Symp 33:13, 1981. Used with permission from CIBA-GEIGY Corporation, Summit, NJ.)

Formation and detachment of new somites in the axial skeleton from the paraxial mesoderm occur in craniocaudal direction following a molecular clock produced by oscillations of cycling genes (e.g., c-hairy-1, lunatic fringe [l-fng], and naked cuticle 1 [nkd1]) that stimulate Notch receptor signaling waves that sweep through the paraxial mesoderm. Spatial coordination is provided by a decreasing gradient of FGF8 from the posterior to the anterior pole of the embryo. Differential expression of delta-like (Dll) proteins determines the size and polarity of the somites, which mature as they move rostrally and differentiate into dermatomyotomes and sclerotomes. 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 the Sonic hedgehog gene ( SHH ).

Intramembranous Ossification

The craniofacial skeleton and clavicles develop by intramembranous ossification. 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. Bone remodeling is accomplished by continuous and concerted action of osteoblasts (cells that produce bone matrix) and osteoclasts (cells that remove bone).

Birth Prevalence and Contribution to Perinatal Mortality

In a large multicenter study conducted by Camera and Mastroiacovo the birth prevalence of skeletal dysplasias (excluding limb amputations) was estimated as 2.4/10,000 births. 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 9.1/1000. This study also reported on the birth prevalence of the different skeletal dysplasias and their relative frequency among perinatal deaths. 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. In another large series from western Scotland, the prevalence of skeletal dysplasias at birth was 1.1/10,000 births. The most frequent conditions were thanatophoric dysplasia (1/42,000), OI (1/56,000), chondrodysplasia punctata (1/84,000), campomelic syndrome (1/112,000), and achondrogenesis (1/112,000). Rasmussen and associates reported a prevalence of 2.1/10,000 deliveries in a longitudinal study, which included elective pregnancy termination, stillborn infants at more than 20 weeks of gestation, and liveborn infants diagnosed by the 5th day of life. The rate of lethal cases in this study was 0.95/10,000 deliveries. 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. An overview of the prevalence of skeletal dysplasias in different populations is presented in Table 11-1 .

Classification of Skeletal Dysplasias

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. 11-6 ). The diagnosis of rhizomelia or mesomelia requires comparing the bony dimensions of the lower legs and forearms with those of the thighs and arms. Figures 11-7 and 11-8 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 11-5 presents a list of skeletal dysplasias characterized by rhizomelia, mesomelia, and micromelia.

Varieties of short limb dysplasia according to the involved segment.

Relationship between the lengths of the ulna (mm) and the humerus (mm).

Relationship between the lengths of the tibia (mm) and femur (mm).

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 flattening of the vertebrae ( Fig. 11-9 ). Xyphosis, scoliosis ( Figs. 11-10 and 11-11 ), hemivertebra ( Fig. 11-12 ), and coronal clefting of vertebral bodies have been also reported.

A, Longitudinal scan of the spine in a fetus with thanatophoric dysplasia and platyspondyly. The intervetebral disks ( white arrows ) are greater in height than the vertebrae ( black arrows ), which are flat. B, Lateral spine radiograph from a fetus with platyspondyly and thanatophoric dysplasia. Note the markedly flattened vertebrae.

Coronal scan of the fetal spine by two-dimensional sonography showing scoliosis.

Three-dimensional ultrasound image of the fetal spine showing scoliosis.

Coronal scan of the fetal spine showing lateral hemivertebra ( arrow ) in the thoracic segment.

Long bone biometry has been used extensively for the prediction of gestational age. Nomograms for this purpose display the distribution of bone lengths in relation to gestational weeks. 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 11-6 and 11-7 present nomograms of the measurement of limb biometry for the upper and lower extremities, respectively. Comparisons between the limb dimensions and head circumference can be used for patients presenting with uncertain gestational age ( Figs. 11-13 and 11-14 ).

Relationship between the head circumference (mm) and the length of the humerus (mm).

Relationship between the head circumference (mm) and the length of the femur (mm).

The nomograms and figures in this chapter provide the mean, 3rd, and the 97th percentiles of limb biometric parameters. The reader should be aware that approximately 6% of the general population will 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 has been based on a sufficient number of patients to provide an accurate discrimination between the 3rd 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 (i.e., 1st or 3rd percentile) is not critical. An exception to this is achondroplasia, in which limb biometry is only mildly affected until the third trimester, when abnormal growth can be detected by examining the slope of growth of the femur length. In a study including 127 cases of 17 skeletal dysplasias, Gonçalves and Jeanty concluded, with the use of discriminant analysis, that the degree of femur length shortening 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 and coworkers reported the early diagnosis of skeletal dysplasias in eight women with previous pregnancies affected with skeletal dysplasias. Five recurrent cases were identified during the first trimester by the femur length/crown rump length ratio and the femur length/biparietal diameter ratio. The results of this study suggest that early evaluation of fetal structures might be helpful in the diagnosis of severe skeletal dysplasias. 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 published, but still their role in the early assessment of pregnancies at risk for skeletal dysplasias remains to be determined.

Clinical Presentation

In general, the challenges of the prenatal diagnosis of skeletal dysplasias presents in one of two ways: (1) a patient who has delivered an infant with a skeletal dysplasia and desires antenatal assessment in a subsequent pregnancy or (2) the incidental finding of a shortened, bowed, or anomalous extremity during a routine sonographic examination. In patients at risk, the examination is easier when the particular phenotype of the skeletal dysplasia is known. The inability to obtain reliable information about skeletal mineralization and the effect of depth on sonography is a limiting factor in establishing an accurate diagnosis after identification of an incidental finding. Another limitation is the paucity of information about the in utero natural history of these disorders. Yet, despite these difficulties and limitations, good medical reasons justify attempting an accurate prenatal diagnosis of skeletal dysplasias. A number of these disorders are uniformly lethal, whereas others are associated with severe physical handicap and neurodevelopmental disabilities. In addition, there is a group of disorders associated with thrombocytopenia for which vaginal delivery may expose the infant to an increased risk of intracranial hemorrhage. Therefore, accurate diagnosis of skeletal dysplasias is important for prenatal counseling.

Diagnostic Imaging and Prenatal Diagnosis of Skeletal Dysplasias

Despite increasing availability of molecular testing, in about one third of skeletal dysplasias their molecular basis has not been defined. The role of diagnostic imaging in the prenatal investigation of skeletal dysplasias is (1) to narrow the differential diagnosis of skeletal dysplasias, so that appropriate confirmatory molecular tests can be done; (2) to predict lethality; and (3) to identify the fetus with a skeletal dysplasia early enough in gestation so that the diagnostic workup can be completed before the limit of fetal viability.

Sonography is the primary imaging modality used for detection of an affected fetus. The prevalence of skeletal dysplasias identified by ultrasound examination during the second and third trimesters of pregnancy is about 7.5/10,000 pregnancies. In early pregnancy (11-14 weeks) the most frequently diagnosed skeletal dysplasias are thanatophoric dysplasia and achondrogenesis. However, despite ultrasound findings highly suggestive of skeletal dysplasia, the definitive diagnosis should only be determined by molecular testing and confirmation of the ultrasound findings later in pregnancy. Table 11-8 summarizes the sensitivity of 2D sonography for the prenatal diagnosis of skeletal dysplasias. Schramm and associates reported a 67.9% (110/162) correct diagnosis and a 30.9% (50/162) partially correct diagnosis of skeletal dysplasia by evaluating the following sonographic parameters: (1) measurements of all segments of the long bones; (2) examination of the hands, spine, and head; (3) assessment of mineralization and shape of the bones; and (4) a full anatomic survey. For lethal skeletal dysplasias, the accuracy of sonographic findings was 99% (113/114). The authors reported that an accurate diagnosis of skeletal dysplasias before 24 weeks of gestation was possible in 62% of cases, although achondroplasia was the only skeletal dysplasia that could not be diagnosed before 24 weeks of gestation. When there is a family history of skeletal dysplasias, the following should be carefully evaluated on ultrasound imaging: complete biometry including the biparietal diameter, head and abdominal circumferences, lengths of all long bones, femur-foot ratio, and measurements of the mandible, clavicle, scapula, skull, chest, and spine. Other ultrasound parameters that might also be helpful in differentiating skeletal dysplasias include the fetal facial profile (e.g., flattened nasal bridge), presence and shape of vertebral bodies, appearance of the hands and feet (e.g., extra, missing, or malformed digits), and fetal thorax to assess the risk for lethality. More recently, Nelson and colleagues reported an overall prevalence of skeletal dysplasias of 2/10,000 pregnancies. In their series, 60% of skeletal dysplasias survived to hospital discharge, although 20% died in the neonatal period, 4% were stillbirths, and 16% were terminated. The authors reported that a femur/abdominal circumference ratio less than 0.16 was the main discriminator among fetuses with lethal skeletal dysplasias, and that this measurement had better performance than femur shortening, thoracic circumference, and thoracic circumference/abdominal circumference ratio.

Several investigators have also proposed that 3D ultrasonography may improve the prenatal diagnostic accuracy for skeletal dysplasias and arthrogryposis. It allows observation of phenotypic features that can be difficult to detect by 2D sonography such as detailed evaluation of the face, scapular anomalies, and abnormal calcification patterns. As an example, Moeglin and Benoit applied the multiplanar view to demonstrate the pointed appearance of the upper femoral diaphysis in achondroplasia. 3D reconstruction of the fetal bones is best performed using the maximum intensity projection or skeletal mode, a rendering algorithm that prioritizes the display of the brightest voxels contained within a region of interest selected by the operator ( Fig. 11-15 ). It is noteworthy that if a fetus is examined early enough in pregnancy, the entire skeleton can be included within the region of interest, and therefore, panoramic imaging can be obtained. However, in some skeletal dysplasias the abnormal features may not be detectable until later in fetal development. Case reports and small series of skeletal dysplasias have described phenotypic characteristics or skeletal features for which 3D sonography may provide additional information ( Table 11-9 ).

Comparison between the surface rendering mode ( A ) and the maximum intensity projection mode ( B ) for visualization of the fetal arm in a fetus with mesomelic shortening of the long bones. Using the maximum intensity projection mode, only voxels with the highest intensity are displayed, thus allowing a clear representation of the mesomelic shortening of the radius and ulna.

3D-HCT has been proposed as an adjunctive imaging modality for improving the prenatal diagnosis and clinical management of skeletal dysplasias ( Fig. 11-16 ). 3D-HCT overcomes the main limitation of 2D and 3D ultrasonography for assessment of bones (i.e., acoustic shadowing), allowing easy and exquisite 3D rendering of mineralized bones at the expense of a mild radiation exposure to the fetus. Long bone measurements in fetuses with suspected skeletal dysplasias obtained using ultrasound show a good correlation with measurements obtained by postmortem 3D-HCT within 24 hours of delivery. Measurements obtained from 3D-HCT are not distance dependent and therefore are more accurate. Excellent panoramic images of the fetal skeleton can be obtained without superimposition of the maternal skeleton (which occurs with radiography). Yet, because of the low radiation dose currently used in pregnancy, 3D-HCT provides limited visualization of bone density, of fetal metaphyseal deformities, and of the feet and hands at early gestational ages.

Comparison of phenotypic features of osteogenesis imperfecta by three-dimensional helical computed tomography (3HCT), three-dimensional ultrasound (3DUS) images, two-dimensional ultrasound (2DUS) images, and postmortem radiographs. A, 2DUS: transverse section of fetal head with a skull fracture (f) deformed by the transducer pressure. B, 2DUS: coronal section of fetal thorax showing irregular ribs ( arrow ). C, 2DUS: sagittal section of the right superior limb showing a short and bowed arm. D, 2DUS: sagittal section of fetal femur with a fracture (f). E, 3DUS 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 abnormal shape depending on the transducer pressure; this was confirmed by 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 bowed radius and ulna. H, 3DUS-rendered bone mode image showing a fractured femur (f). I, 3HCT: posterior view of entire fetus confirming fractures (f) of ribs and femur 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.)

The contribution of 3D-HCT, 3D sonography, and 2D sonography in the evaluation of skeletal dysplasias was analyzed by Ruano and coworkers, who compared the phenotypic characteristics of fetuses with skeletal dysplasias (achondroplasia [ n = 3], OI [ n = 2], and chondrodysplasia punctata [ n = 1]) using these three imaging modalities. Deformation of the fetal pelvis and an increase in the intervertebral space of the lumbar vertebrae were diagnosed more often using 3D-HCT. In contrast, some phenotypic characteristics of fetuses with skeletal dysplasias were demonstrated only by ultrasound such as phalangeal hypoplasia, point-calcified epiphysis (by both 2D and 3D sonography), and facial dysmorphism (by 3D sonography only). Although the overall count of correct phenotypic characteristics detected prenatally favored 3D-HCT over 3D sonography (94.3% [33/35] vs. 77.1% [27/35]; P = 0.03), the diagnostic performance of 3D-HCT was not superior to that of 3D sonography, as the correct prenatal diagnosis was established by both modalities in all cases. However, 3D sonography has two important advantages over 3D-HCT, namely the lack of radiation exposure and wider availability in the clinical setting. It is also noteworthy that the overall experience with 3D sonography for the diagnosis of skeletal dysplasias is still limited. Nevertheless, even in the study of Ruano and coworkers 3D sonography performed better than 2D sonography in the identification of phenotypic characteristics (77.1% [27/35] vs. 51.4% [18/35]; P = 0.004) and in establishing an accurate diagnosis.

Fetal magnetic resonance imaging (MRI) is useful when the ultrasound examination is inconclusive because of oligohydramnios, maternal obesity, late gestational age, or fetal position. Both skeleton and muscle can be assessed by MRI using echoplanar imaging, with thick slab T2-weighted and dynamic sequences. Echoplanar imaging can demonstrate epimetaphyseal characteristics used in measurement of fetal long bones, increasing the accuracy of diagnosing short long bones. MRI can also be useful in differentiating between normal bone development and bone dysplasia caused by a disruption of endochondral ossification. Moreover, MRI can be applied to measure fetal thoracic and lung volumes, which are used to predict lethality in skeletal dysplasias.

Approach to the Diagnosis of Skeletal Dysplasias

A proposed systematic approach to the prenatal diagnosis of skeletal dysplasias is summarized in Table 11-10 and described in greater detail in the following section.

Evaluation of the Long Bones

Measurements.

All long bones must be measured in all extremities. Comparisons with other segments should be performed to establish whether the limb shortening is predominantly rhizomelic, mesomelic, or acromelic, or whether it involves all segments (see Figs. 11-6 to 11-8 ). A detailed examination of each bone is necessary to exclude absence or hypoplasia of individual bones (fibula, tibia, ulna, radius, clavicles, and scapulae). From a group of fetuses less than 24 weeks of gestation with a short femur length, Papageorghiou and associates reported that 35% presented with skeletal dysplasias; all affected fetuses had associated anomalies. The authors suggested that in the presence of a short femur, a complete fetal anatomic evaluation is necessary. The most frequently associated skeletal dysplasias were asphyxiating thoracic dystrophy, osteogenesis imperfecta, thanatophoric dysplasia, and campomelic dysplasia.

Degree of Mineralization.

An attempt should be made to characterize the degree of mineralization, which can be assessed by examining the acoustic shadow behind the bone as well as the echogenicity of the bone itself. Signs of demineralization include visualization of an unusually prominent falx in the fetal brain and the absence of or decreased echogenicity of the spine. It should be emphasized that there are limitations to the sonographic evaluation of long bone mineralization and that other structures, such as the fetal skull, may be better suited for such assessment ( Fig. 11-17 ).

Demineralization of the skull in a case of osteogenesis imperfecta. The lateral ventricle and choroid plexus in the near field are well visualized because of lack of normal mineralization of the calvarium. In normal fetuses, reverberation artifact from the calvarium would obscure the ultrasound image of these structures.

Degree of Long Bone Curvature.

At present, there is no objective means to assess long bone curvature, and experience is necessary to assist the operator in discerning the boundary between normality and abnormality. Bowed or angulated femora (campomelia) ( Fig. 11-18 ) is characteristic of campomelic dysplasia, thanatophoric dysplasia, osteogenesis imperfecta, short rib dysplasia, and hypophosphatasia.

Bowing of long bones of the limbs ( arrows ) in fetuses with campomelic dysplasia ( A ) and with thanatophoric dysplasia ( B ).

Metaphyseal Flaring.

Metaphyseal flaring denotes widening at the level of the metaphyseal growth plate. It can be observed in many conditions, including achondroplasia, hypochondroplasia, hypochondrogenesis, asphyxiating thoracic dysplasia, chondrodysplasia punctata, diastrophic dysplasia, hypophosphatasia, Kniest dysplasia, kyphomelic dysplasia, metatropic dysplasia, and OI.

Femoral Angle.

Khalil and colleagues reported an increased diaphysis-metaphysis femoral angle measured at 20 weeks to 23 weeks and 6 days of gestation in fetuses later diagnosed with achondroplasia. The femoral angle in affected fetuses was 125 degrees as compared to 95 degrees in normal fetuses. The authors conclude that estimation of the femoral angle might improve the early detection of fetuses with achondroplasia.

Fractures.

Fractures can be found in certain skeletal dysplasias such as OI and hypophosphatasia ( Fig. 11-19 ). The fractures may be extremely subtle or may lead to angulation and separation of segments of the affected bone ( Fig. 11-20 ).

A, Three-dimensional sonogram in a fetus with osteogenesis imperfecta type II. The volume dataset was rendered using the maximum intensity mode. Multiple fractures in the ribs are present. Note the severe bowing and shortening of the femur (F) and humerus (H). B, Sonogram of a fetus with osteogenesis imperfecta type II. The femur is markedly shortened ( arrow ) with multiple fractures.

In utero fracture ( A ) and bowing ( B ) of the long bones in a fetus with osteogenesis imperfecta. The arrow indicates the hypoechogenic fracture line. Hypomineralization of the spine is shown in the longitudinal view ( C ).

Prediction of Pulmonary Hypoplasia

Skeletal dysplasias associated with a hypoplastic thorax frequently have lung hypoplasia, which is the most frequent cause of death for these conditions. 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, even though the specific type of skeletal dysplasia may be unknown. A number of sonographic parameters have been investigated for the prediction of pulmonary hypoplasia. They 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 sonography or MRI.

A detailed evaluation of the thorax in order to answer the following questions can assist in the diagnosis of the particular skeletal dysplasia :

• •
  

  Is the thorax extremely small? (thanatophoric dysplasia)

  
  
• •
  

  Is the thorax long and narrow? (Jeune syndrome)

  
  
• •
  

  Are the ribs extremely short? (short rib–polydactyly syndromes)

  
  
• •
  

  Are there rib fractures? (osteogenesis imperfecta type II)

  
  
• •
  

  Are there gaps within the ribs? (cerebra-costo-mandibular syndrome)

  
  
• •
  

  Are there fused ribs? (spondylocostal dysplasia)

  
  
• •
  

  Is there clavicular aplasia, hypoplasia, or pseudoarthrosis? (cleidocranial dysplasia)

  
  
• •
  

  Are the scapulae abnormal? (hypoplasia or absence in campomelic dysplasia)

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

Thoracic and lung biometry has been extensively studied to identify fetuses at high risk for pulmonary hypoplasia. Table 11-11 lists the skeletal dysplasias associated with altered thoracic dimensions, and Figures 11-21 and 11-22 illustrate features associated with a hypoplastic thorax. Methods used to measure the thorax, lungs, and heart by 2D sonography are illustrated in Figure 11-23 . Thoracic areas and volumes in fetuses with a known gestational age can be evaluated using the nomograms reproduced in Tables 11-12 and 11-13 . When gestational age is uncertain, age-independent ratios, such as the thoracic/abdominal circumference ratio (normal value: 0.77 to 1.01) and the thoracic/head circumference ratio (normal value: 0.56 to 1.04) can be used.

TABLE 11-11

Skeletal Dysplasias Associated With Altered Thoracic Dimensions

Long, Narrow Thorax

Asphyxiating thoracic dysplasia (Jeune)

Chondroectodermal dysplasia (Ellis–van Creveld)

Metatropic dysplasia

Fibrochondrogenesis

Atelosteogenesis

Camptomelic dysplasia

Jarcho-Levin syndrome

Achondrogenesis

Osteogenesis imperfecta type II

Hypophosphatasia

Dyssegmental dysplasia

Cleidocranial dysplasia

Short Thorax

Osteogenesis imperfecta (type II)

Kniest dysplasia (metatropic dysplasia type II)

Pena-Shokeir syndrome

Hypoplastic Thorax

Short rib–polydactyly syndrome (type I, type II)

Thanatophoric dysplasia

Cerebrocostomandibular syndrome

Cleidocranial dysplasia syndrome

Homozygous achondroplasia

Melnick-Needles syndrome (osteodysplasty)

Fibrochondrogenesis

Otopalatodigital syndrome type II

 

Longitudinal section of a fetus with thanatophoric dysplasia. Note the significant disproportion between the chest and abdomen.

Extremely short ribs in a fetus with short rib–polydactyly syndrome.

Illustration of the various methods to measure thoracic, lung, and heart dimensions. A, Thoracic circumference. B, Cardiac circumference. C, Lung diameter/thoracic area ratio. D, Cardiac area/lung area ratio.

TABLE 11-12

Lung Area (Manual Tracing [2.5th, 50th, 97.5th Percentiles]) and Lung Volume From 12 to 32 Gestational Weeks

Weeks	LEFT LUNG AREA			RIGHT LUNG AREA			LEFT LUNG VOLUME			RIGHT LUNG VOLUME			TOTAL LUNG VOLUME
	2.5th	50th	97.5th	2.5th	50th	97.5th	2.5th	50th	97.5th	2.5th	50th	97.5th	2.5th	50th	97.5th
12	20	36	51	44	58	71	0.63	0.64	0.65	0.59	0.6	0.62	1.37	1.56	1.75
13	26	47	68	42	69	96	0.37	0.57	0.77	0.5	0.75	1	0.85	1.4	1.94
14	36	62	89	48	88	129	0.26	0.69	1.11	0.54	1.06	1.58	0.7	1.65	2.61
15	49	82	114	61	115	169	0.31	0.97	1.64	0.7	1.53	2.36	0.9	2.32	3.74
16	65	104	144	80	148	215	0.49	1.42	2.35	1	2.16	3.33	1.42	3.36	5.31
17	83	130	177	105	186	267	0.79	2.02	3.24	1.42	2.96	4.51	2.25	4.77	7.29
18	103	158	213	134	229	323	1.22	2.76	4.3	1.97	3.92	5.87	3.36	6.52	9.67
19	125	188	252	168	275	383	1.75	3.63	5.51	2.64	5.04	7.44	4.72	8.57	12.4
20	148	220	293	204	325	447	2.38	4.62	6.85	3.43	6.31	9.19	6.31	10.9	15.5
21	172	254	335	243	378	512	3.09	5.71	8.33	4.33	7.73	11.1	8.1	13.5	18.9
22	196	288	380	283	432	580	3.87	6.9	9.92	5.34	9.28	13.2	10.1	16.3	22.6
23	220	323	425	325	486	648	4.71	8.16	11.6	6.45	11	15.5	12.2	19.3	26.5
24	244	358	471	366	541	716	5.58	9.49	13.4	7.64	12.8	17.9	14.4	22.5	30.7
25	268	392	517	406	595	783	6.49	10.9	15.3	8.9	14.7	20.5	16.6	25.8	35
26	290	426	563	445	647	849	7.4	12.3	17.2	10.2	16.7	23.2	18.9	29.2	39.5
27	310	459	609	482	697	913	8.31	13.7	19.1	11.6	18.8	26	21.2	32.7	44.1
28	328	491	653	515	744	973	9.19	15.1	21.1	13	21	29	23.5	36.1	48.7
29	344	521	697	545	787	1029	10	16.6	23.1	14.4	23.2	32	25.7	39.6	53.4
30	358	548	738	569	825	1081	10.8	17.9	25	15.9	25.5	35.1	27.7	42.9	58.1
31	368	573	777	589	858	1127	11.5	19.3	27	17.2	27.7	38.2	29.6	46.2	62.7
32	374	594	814	602	885	1167	12.1	20.5	28.9	18.6	30	41.3	31.3	49.3	67.3

 

From Peralta CF, Cavoretto P, Csapo B, et al: Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 26:718-724, 2005; Peralta CF, Cavoretto P, Csapo B, et al: Lung and heart volumes by three-dimensional ultrasound in normal fetuses at 12-32 weeks’ gestation. Ultrasound Obstet Gynecol 27:128-133, 2006.

TABLE 11-13

Thoracic Diameters (10th, 50th, 90th Percentiles) From 12 to 41 Weeks of Gestation

	THORACIC ANTEROPOSTERIOR DIAMETER			THORACIC TRANSVERSE DIAMETER			THORACIC CIRCUMFERENCE
Weeks	10th	50th	90th	10th	50th	90th	10th	50th	90th
12	11.7	14.2	16.5	11.7	14.2	16.5	11.7	14.2	16.5
13	14.3	17.2	19.8	14.3	17.2	19.8	14.3	17.2	19.8
14	17.1	20.3	23.3	17.1	20.3	23.3	17.1	20.3	23.3
15	19.9	23.4	26.7	19.9	23.4	26.7	19.9	23.4	26.7
16	22.8	26.5	30.2	22.8	26.5	30.2	22.8	26.5	30.2
17	25.8	29.6	33.6	25.8	29.6	33.6	25.8	29.6	33.6
18	28.7	32.6	37.0	28.7	32.6	37.0	28.7	32.6	37.0
19	31.6	35.6	40.5	31.6	35.6	40.5	31.6	35.6	40.5
20	34.2	38.5	43.9	34.2	38.5	43.9	34.2	38.5	43.9
21	36.8	41.4	47.2	36.8	41.4	47.2	36.8	41.4	47.2
22	39.2	44.3	50.4	39.2	44.3	50.4	39.2	44.3	50.4
23	41.5	47.2	53.6	41.5	47.2	53.6	41.5	47.2	53.6
24	43.9	50.0	56.6	43.9	50.0	56.6	43.9	50.0	56.6
25	46.5	52.8	59.5	46.5	52.8	59.5	46.5	52.8	59.5
26	49.1	55.5	62.3	49.1	55.5	62.3	49.1	55.5	62.3
27	51.7	58.2	64.9	51.7	58.2	64.9	51.7	58.2	64.9
28	54.2	60.8	67.4	54.2	60.8	67.4	54.2	60.8	67.4
29	56.6	63.4	69.8	56.6	63.4	69.8	56.6	63.4	69.8
30	58.9	65.9	72.3	58.9	65.9	72.3	58.9	65.9	72.3
31	61.1	68.4	74.9	61.1	68.4	74.9	61.1	68.4	74.9
32	63.2	70.9	77.7	63.2	70.9	77.7	63.2	70.9	77.7
33	65.1	73.2	80.6	65.1	73.2	80.6	65.1	73.2	80.6
34	67.0	75.4	83.4	67.0	75.4	83.4	67.0	75.4	83.4
35	68.8	77.3	85.8	68.8	77.3	85.8	68.8	77.3	85.8
36	70.6	79.0	88.0	70.6	79.0	88.0	70.6	79.0	88.0
37	72.5	80.5	90.0	72.5	80.5	90.0	72.5	80.5	90.0
38	74.3	81.9	91.8	74.3	81.9	91.8	74.3	81.9	91.8
39	75.9	83.1	93.5	75.9	83.1	93.5	75.9	83.1	93.5
40	77.5	84.1	94.9	77.5	84.1	94.9	77.5	84.1	94.9
41	78.8	84.9	95.8	78.8	84.9	95.8	78.8	84.9	95.8

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