Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative

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1 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at EDUCATION EXHIBIT Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases CME FEATURE See accompanying test at /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 4 After reading this article and taking the test, the reader will be able to: Describe US imaging technique in skeletal dysplasia. Discuss the use of a systematic algorithmic approach for developing a differential diagnosis for skeletal dysplasia at US. Correlate radiologic findings with pathologic findings in skeletal dysplasia. TEACHING POINTS See last page Manjiri Dighe, MD Corinne Fligner, MD Edith Cheng, MD Bill Warren, MD Theodore Dubinsky, MD Skeletal dysplasias are a heterogeneous group of conditions associated with various abnormalities of the skeleton. These conditions are caused by widespread disturbance of bone growth, beginning during the early stages of fetal development and evolving throughout life. Despite recent advances in imaging, fetal skeletal dysplasias are difficult to diagnose in utero due to a number of factors, including the large number of skeletal dysplasias and their phenotypic variability with overlapping features, lack of precise molecular diagnosis for many disorders, lack of a systematic approach, the inability of ultrasonography (US) to provide an integrated view, and variability in the time at which findings manifest in some skeletal dysplasias. US of suspected skeletal dysplasia involves systematic imaging of the long bones, thorax, hands and feet, skull, spine, and pelvis. Assessment of the fetus with three-dimensional US has been shown to improve diagnostic accuracy, since additional phenotypic features not detectable at twodimensional US may be identified. The radiologist plays a major role in making an accurate diagnosis; however, representatives of other disciplines, including clinicians, molecular biologists, and pathologists, can also provide important diagnostic information. RSNA, 2008 radiographics.rsnajnls.org Abbreviations: FGFR3 = fibroblast growth factor receptor 3, 3D = three-dimensional RadioGraphics 2008; 28: Published online /rg Content Codes: 1 From the Department of Radiology, University of Washington Medical Center, 1959 NE Pacific St, BB308, Box , Seattle, WA Recipient of a Certificate of Merit award for an education exhibit at the 2006 RSNA Annual Meeting. Received May 22, 2007; revision requested July 24; final revision received October 4; accepted October 5. All authors have no financial relationships to disclose. Address correspondence to M.D. ( dighe@u.washington.edu). RSNA, 2008

2 1062 July-August 2008 RG Volume 28 Number 4 Introduction Skeletal dysplasias are a heterogeneous group of conditions associated with abnormalities of the skeleton, including abnormalities of bone shape, size, and density, that manifest as abnormalities of the limbs, chest, or skull (1). Over the past 30 years, the classification of skeletal dysplasia has evolved from one based on clinical-radiologic-pathologic features to one that includes the underlying molecular abnormality for conditions in which the genetic defect is known (2). In 1977, the European Society of Pediatric Radiology adopted the international nomenclature of constitutional-intrinsic bone disease. This nomenclature was modified in 1983, 1997, and The major change in 2001 was the addition of genetic dysostoses-osteochondrodysplasias (3). Dysostoses occur singly or in combination. Skeletal dysplasias are caused by widespread disturbance of bone growth, beginning during the early stages of fetal development and evolving throughout life due to active gene involvement. The five original categories have been expanded to 32 groups and are described in an article by Hall (3) on the classification of constitutional disorders of bone, of which approximately 50 are apparent and identifiable at birth. Because they may be detected before birth, these conditions are of particular importance to maternal-fetal medicine specialists and radiologists. The prevalence of skeletal dysplasias (excluding limb amputations) is estimated at 2.4 per 10,000 births (4). In a large multicenter study, Camera and Mastroiacovo (5) found that 23% of patients with skeletal dysplasia were stillborn and 32% died within 1 week. The overall prevalence of skeletal dysplasias among perinatal deaths was 9.1 per 1000 cases (5). Despite recent advances in imaging, fetal skeletal dysplasias are difficult to diagnose in utero. Some of the factors that lead to difficulty in diagnosis are the large number of skeletal dysplasias and their phenotypic variability with overlapping features, lack of precise molecular diagnosis for many disorders, lack of a systematic approach, the inability of ultrasonography (US) to provide an integrated view such as an overt clinical inspection can offer, and variability in the time at which findings manifest in some skeletal dysplasias. Prenatal diagnosis is easier in the presence of a positive family history and a precise description of the phenotype, since many disorders are inherited as autosomal dominant or recessive disorders (6). It is also not unusual for skeletal dysplasia to first be suspected during routine US examination after a shortened long bone or abnormal skeletal finding has been observed (7). In addition to delineating the differential diagnosis, it is important to recognize possible lethality on the basis of US findings, including chest circumference, femur length abdominal circumference ratio, the presence of cloverleaf skull, and so on. US is the primary method for imaging a fetus. Therefore, in this article we outline the US technique for assessing fetal skeletal dysplasia; discuss and illustrate the US diagnosis of skeletal dysplasias such as limb deficiency, thanatophoric dysplasia, osteogenesis imperfecta, chondrodysplasia punctata, and diastrophic dysplasia; and briefly review postnatal evaluation in affected patients. US Technique for Assessing Fetal Skeletal Dysplasia An organized and comprehensive examination of the fetal skeleton is needed. The worksheet used at our institution while imaging a fetus with suspected skeletal dysplasia is shown in Figure 1. US of suspected skeletal dysplasia involves systematic imaging of the long bones, thorax, hands and feet, skull, spine, and pelvis. Long Bones The long bones in all of the extremities should be measured. If limb shortening is present, the segments involved should be defined. A detailed examination of the involved bones is necessary to exclude absence, hypoplasia, and malformation of the bones. The bones should be assessed for presence, curvature, degree of mineralization, and fractures. The femur length abdominal circumference ratio (<0.16 suggests lung hypoplasia) and femur length foot length ratio (normal = 1, <1 suggests skeletal dysplasia) should be calculated. Thorax The chest circumference and cardiothoracic ratio should be measured at the level of the fourchamber view of the heart. A chest circumference less than the 5th percentile for gestational age (8 10) has been proposed as an indicator of pulmonary hypoplasia. Other parameters used are a chest circumference abdominal circumference ratio less than the 5th percentile (11 14), chest area, a heart area chest area ratio less than the 5th percentile (12,14), a chest trunk length ratio less than 0.32 (15), and a femur length abdominal circumference ratio less than 0.16 (14,15). Hypoplastic thorax occurs in many skeletal dysplasias such as thanatophoric dysplasia, Teaching Point Teaching Point

3 RG Volume 28 Number 4 Dighe et al 1063 Figure 1. Worksheet used in the Department of Radiology and Obstetrics at the University of Washington Medical Center while imaging a fetus with suspected skeletal dysplasia.

4 1064 July-August 2008 RG Volume 28 Number 4 Figure 2. Diagram illustrates a diagnostic algorithm for use in fetuses with severe limb shortening and normal mineralization. OI = osteogenesis imperfecta. Figure 3. Diagram illustrates a diagnostic algorithm for use in fetuses with moderate limb shortening and normal mineralization. OI = osteogenesis imperfecta. Teaching Point Teaching Point achondrogenesis, hypophosphotasia, camptomelic dysplasia, chondroectodermal dysplasia, osteogenesis imperfecta, and short-rib polydactyly and may lead to pulmonary hypoplasia, which is the main cause of neonatal death in many lethal skeletal dysplasias (8). The shape and integrity of the thorax should be noted. Abnormal rib size and configuration are also seen in patients with lethal skeletal dysplasias. The clavicles should be measured, since absence or hypoplasia of the clavicles is seen in cleidocranial dysplasia (16). The presence of the scapula should also be noted, since its absence is a useful defining feature of camptomelic dysplasia (17). Hands and Feet The hands and feet should be evaluated to exclude the presence of (a) pre- or postaxial polydactyly (the presence of more than five digits; preaxial if the extra digits are located on the radial or tibial side and postaxial if they are located on the ulnar or fibular side); (b) syndactyly (soft-tissue or bone fusion of adjacent digits); (c) clinodactyly (deviation of a finger); and (d) other deformities. Foot length should be measured and any missing bones evaluated. Any postural deformities such as hitchhiker s thumb, rocker-bottom feet, and clubbed feet or hands should also be evaluated. Clubbing of the hand is suggestive of the spectrum of radial ray anomalies, which include an abnormal thumb (Holt-Oram syndrome), hypoplasia and absence of the thumb,

5 RG Volume 28 Number 4 Dighe et al 1065 Figure 4. Diagram illustrates a diagnostic algorithm for use in fetuses with mild limb shortening and normal mineralization and in fetuses with partial or complete limb agenesis. OI = osteogenesis imperfecta. evaluated for platyspondyly (flattened vertebral body shape with reduced distance between the endplates), which is typically seen in thanatophoric dysplasia. However, platyspondyly may be difficult to identify even for the experienced US operator. Figure 5. Diagram illustrates a diagnostic algorithm for use in fetuses with normal or shortened limbs and decreased mineralization. OI = osteogenesis imperfecta. and sometimes, absence of the radius or of both the radius and the hand. Skull Head circumference and biparietal diameter should be measured to exclude macrocephaly. The shape, mineralization, and degree of ossification of the skull should be evaluated. Interorbital distance should be measured by using the binocular diameter and interocular diameter to exclude hyper- or hypotelorism. Other features such as micrognathia, short upper lip, abnormally shaped ears, frontal bossing, and cloverleaf skull should be assessed. Deviations from the normal shape of the head, including brachycephaly (anteroposterior shortening of the head), scapocephaly (lateral flattening of the head), and craniosynostoses (premature fusion of the sutures), should be noted. Spine The spine should be carefully imaged to assess the relative total length and the presence of curvature to exclude scoliosis. Mineralization of vertebral bodies and neural arches should be evaluated. Vertebral height should be subjectively Pelvis The shape of the pelvis can be important in certain dysplasias and dysostoses, such as limb-pelvic hypoplasia; femoral hypoplasia unusual face syndrome (hypoplastic acetabulae, constricted iliac base with vertical ischial axis, and large obturator foramina); achondroplasia (flat, rounded iliac bones with lack of iliac flaring; broad, horizontal superior acetabular margins; and small sacrosciatic notches); and so on. Pelvic shape may be difficult to evaluate at routine US, and threedimensional (3D) US may be necessary. Assessment of the fetus with 3D US has been shown to improve diagnostic accuracy, since additional phenotypic features not detectable at two-dimensional US may be identified (18 20). For example, Garjian et al (20) and Krakow et al (21) reported the diagnosis of additional facial and scapular anomalies and abnormal calcification patterns in fetuses with skeletal dysplasia at 3D US. Diagnosis with US If the limbs are disproportional (Figs 2 5), the following questions should be addressed: 1. Does the abnormality affect the proximal (rhizomelic), middle (mesomelic), or distal (acromelic) segment? 2. Is polydactyly, ectrodactyly, clinodactyly, or syndactyly present? 3. Are there any fractures, curved bones, or joint deformities, or clubbing of the foot or hand?

6 1066 July-August 2008 RG Volume 28 Number 4 Figure 6. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia and thoracic abnormalities. OI = osteogenesis imperfecta. Figure 7. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia and facial abnormalities. OI = osteogenesis imperfecta. 4. Are metaphyseal changes present? 5. Is there a premature appearance of ossification centers? 6. Are there any hypoplastic or absent bones? If the spine is mainly affected, one should ask the following questions: 1. Is the spine short because of missing parts (eg, sacral agenesis)? 2. Is there abnormal curvature? 3. Is there shortening of vertebral bodies? 4. Are all parts of the spine equally affected (eg, achondrogenesis)?

7 RG Volume 28 Number 4 Dighe et al 1067 Figure 8. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia and skull abnormalities. OI = osteogenesis imperfecta. 5. Is platyspondyly present (thanatophoric dysplasia)? 6. Is the spinal canal of normal width? 7. Are any meningomyeloceles present? If the thorax is mainly affected (Fig 6), the following questions should be addressed: 1. Is the thorax extremely small (thanatophoric dysplasia)? 2. Is the thorax long and narrow (Jeune syndrome)? 3. Are the ribs extremely short (short-rib polydactyly)? 4. Are fractures present (osteogenesis imperfecta type II)? 5. Is there clavicular aplasia, hypoplasia, or partitioning (cleidocranial dysostosis)? 6. Is the scapula normal or abnormal (camptomelic dysplasia)? 7. Are there any gaps between ribs (Jarcho- Levine syndrome)? Additional findings include external anomalies (abnormally shaped ears, caudal appendage), facial deformities (cleft palate, micrognathia, short nasal bridge [Fig 7]), internal anomalies (eg, cardiac anomalies [Ellis van Creveld syndrome]), urinary tract abnormalities (short-rib polydactyly type 2), genital abnormalities (Robert syndrome, camptomelic dysplasia [ambiguous genitalia]); gastrointestinal tract abnormalities (achondrogenesis type 1), and skull abnormalities (asymmetry, basilar invagination, cloverleaf skull, craniosynostosis, defective ossification, macro- or microcephaly [Fig 8]). Examples of Fetal Skeletal Dysplasia Limb Deficiency The overall prevalence of limb deficiency (Fig 9) is approximately 0.49 per 10,000 births. Most are simple transverse reduction deficiencies of one forearm or hand without associated anomalies. The remainder consist of multiple reduction deficiencies, with additional anomalies of internal organs or craniofacial structures. Isolated extremity amputation can be due to amniotic band syndrome, exposure to a teratogen, or vascular accident (22). In most cases, the anomaly is sporadic, and risk of recurrence is negligible. Nearly

8 1068 July-August 2008 RG Volume 28 Number 4 Figure 9. Isolated limb deficiency. (a, b) Two-dimensional (a) and 3D (b) US images show a shortened forearm with an abnormal hand (arrow) (note the lack of a normal hand and the abnormal soft tissue at the distal end of the forearm), normal limb bone echogenicity, and otherwise normal anatomy. According to the diagram in Figure 4, the patient appeared to have distal limb agenesis as an isolated finding. (c) Radiograph shows abnormal bone tissue (arrow) at the end of the normally formed and mineralized forearm bone. (d) Autopsy photograph shows an abnormal left hand with five tiny fingers and apparent fingernails (arrow). all limb deficiencies occur in patterns and can be grouped and classified according to the system of Swinyard and Marquardt, which is a modification of the classification system of Frantz and O Rahilly (22,23). In this system, only two basic terms are used: amelia, indicating complete absence of a limb; and meromelia, indicating partial absence of a limb. All deficiencies are classified as either terminal (absence of all skeletal elements along a longitudinal ray beyond a given point) or intercalary (absence of the proximal or middle segment of a limb with all or part of the distal segment present). Further subgrouping is based on the axis of deficiency (transverse or longitudinal) and the individual bones involved. Thanatophoric Dysplasia The term thanatophoric dysplasia is derived from the Greek word thanatophoros, which means bearing death. Thanatophoric dysplasia is the most common lethal skeletal dysplasia. Langer et al (24) separated this condition into two types: type 1 (Fig 10) and type 2 (Fig 11). Both types are caused by mutations of the gene-encoding fibroblast growth factor receptor 3 (FGFR3) (25). Inheritance is generally autosomal dominant (26). Thanatophoric dysplasia is characterized by disproportionate dwarfism with very short extremities, which are bowed in type 1 and may be straight in type 2. The trunk length is normal, but the thorax is narrow. There is distinct flattening of vertebral ossification centers (platyspondyly) (less severe in type 2 than in type 1), as well as a disproportionately large head, depressed nasal bridge, prominent forehead, and protruding eyes (27,28). Secondary skull deformity is often present due to the premature closure of cranial sutures. Cloverleaf skull deformity is generally seen in type 2 (29). Polyhydramnios is present in almost 50% of cases. Death occurs in early infancy in the majority of cases due to respiratory insufficiency from pulmonary hypoplasia (30,31).

9 RG Volume 28 Number 4 Dighe et al 1069 Figure 10. Thanatophoric dysplasia type 1. (a) Transverse US image shows a normal-shaped but enlarged head. (b) Sagittal US image shows a depressed nasal bridge (arrowhead), a prominent forehead (double arrows), and an undersized thorax (single arrow) compared with the abdomen. (c) US image shows a telephone receiver shaped femur (arrows). Normal limb echogenicity with severe shortening and bowing of the limbs, a narrow chest, and macrocephaly suggest thanatophoric dysplasia type 1 according to the diagrams in Figures 2, 6, and 8, respectively. (d) Postmortem radiograph shows bowed long bones (white arrows), a narrow chest, and platyspondyly (black arrow). (e, f) Autopsy photographs show shortened limbs, the depressed nasal bridge (arrowhead in f), a short trunk, an enlarged abdomen, and the prominent forehead (arrows in f).

10 1070 July-August 2008 RG Volume 28 Number 4 Figure 11. Thanatophoric dysplasia type 2. (a) Axial US image shows an oversized head with a cloverleaf shape (arrows). (b) Sagittal US image shows a temporal bulge (arrow). (c) US image shows a trident hand. Normal limb echogenicity with severe shortening, a narrow chest, and an irregular shape of the head suggest thanatophoric dysplasia type 2 according to the diagrams in Figures 2, 6, and 8, respectively. (d) US image shows a short but relatively straight long bone. (e) Coronal US image through the abdomen-chest shows a hypoplastic thorax (arrow). (f) Radiograph shows the cloverleaf skull shape created by the temporal bulge in the skull (arrow). (g, h) Postmortem photographs show the prominent forehead; the typical temporal bulge, resulting in the cloverleaf skull shape (double arrows); and the trident hand (single arrow in h). Note the bulge in the occipital region, a finding that represents an occipital encephalocele (an unusual finding in thanatophoric dysplasia).

11 RG Volume 28 Number 4 Dighe et al 1071 Figure 12. Osteogenesis imperfecta. (a c) US images show bone fractures and deformities. Note the femoral irregularity and angulation (arrow in a), a finding that is consistent with fractures; the decreased skull ossification, which allows easy visualization of the intracranial structures (b); and the irregular shape of the ribs (arrow in c), a finding that also suggests fractures. Decreased echogenicity of the limbs with shortening, decreased echogenicity of the ribs with fractures, and hypoechogenicity of the head suggest osteogenesis imperfecta according to the diagrams in Figures 5, 6, and 8, respectively. (d) Postmortem photograph shows irregular ribs (arrow) due to healing fractures. (e) Postmortem photograph shows deformed extremities, findings that are consistent with fractures. (f) Postmortem radiograph shows wavy ribs (black arrow) and irregular deformed long bones (white arrows) due to multiple fractures. Osteogenesis Imperfecta The term osteogenesis imperfecta (Fig 12) refers to a clinically, radiologically, and genetically heterogeneous group of disorders caused by mutations in genes that encode type I collagen, leading to increased bone fragility (32). The overall prevalence of osteogenesis imperfecta is one in 28,500 live births (33). The classification of osteogenesis imperfecta was first proposed by Sillence, whose system was subsequently modified by Byers et al (34). The mutations that cause

12 1072 July-August 2008 RG Volume 28 Number 4 Table 1 Features of Various Types of Osteogenesis Imperfecta I Type II* III IV/V *Perinatal lethal. Description Generalized demineralization; increased bone fragility, sometimes with secondary deformities; retarded ossification of the cranial vault Generalized demineralization with multiple fractures; thick, short crumpled shafts of the long bones; rectangular femora with a wavy appearance; severe retardation of calvarial bone formation; short, thick ribs with continuous beading Generalized osteopenia; short, deformed long tubular bones with broad metaphyses and thinner diaphyses; retarded calvarial ossification; thin ribs with discontinuous fractures Generalized demineralization; increased bone fragility, sometimes with secondary deformities; bowed long bones; retarded ossification of the cranial vault osteogenesis imperfecta are generally new mutations and are inherited in an autosomal dominant pattern, except for rare instances of type III disease that are inherited in an autosomal recessive pattern (35). Variations in the number of fractures, time of presentation of patients with fractures (prenatal or postnatal), secondary deformities, and softtissue changes result in a wide variety of clinical and radiologic phenotypes, which are presently grouped according to the Sillence classification system. The major radiologic features of osteogenesis imperfecta are generalized osteoporosis, retarded calvarial bone formation, wormian bones, collapsed vertebral bodies, rib fractures, thin cortex in tubular bones, and, in more severe cases, thin shafts with fractures and bowing deformities (Table 1). The fetal movements may be reduced (36,37). The skull may be thinner than usual, and the weight of the US probe may deform the head quite easily. In severe cases, the cranial vault has a wavy outline and is easily compressed (38). Chondrodysplasia Punctata Chondrodysplasia punctata (Fig 13) includes a varied group of disorders in which there is calcific stippling of epiphyses, generally identified on conventional radiographs. Rhizomelic chondrodysplasia punctata and a nonrhizomelic type (Conradi-Hunermann syndrome) were originally described, with recessive and X-linked dominant inheritance, respectively, but an X-linked recessive type exists as well. Rhizomelic chon- drodysplasia punctata with autosomal recessive inheritance is due to alterations in perioxisomal metabolism, whereas the X-linked dominant type is a result of mutations in the delta 8 sterol isomerase enzyme, resulting in abnormal cholesterol biosynthesis. Other forms with different inheritance have also been described (39,40). Findings can include craniofacial dysmorphism, ocular abnormalities, cutaneous abnormalities, asymmetric shortening of the limbs, and joint contractures (39 41). Prognosis is extremely poor, with severe mental retardation, spastic tetraplegia, and thermoregulatory instability (42). Radiologic features include very short humeri and relatively short femora with some metaphyseal splaying. Punctate calcification of epiphyses at the ends of long bones is present and may be seen prenatally (43 45). Facial features include a flat face with a small saddle nose. There are multiple contractures. Ascites and polyhydramnios have been reported (46). The radiologic finding of diffuse epiphyseal calcific stippling can be seen in a number of inherited and acquired disorders, such as exposure to drugs (warfarin, hydantoin); lysosomal, peroxisomal, and metabolic disorders; and trisomies 18 and 21. The definitive diagnosis of the case illustrated in Figure 13 was difficult. Cultured fibroblasts were sent for testing, the results of which excluded peroxisomal disorders, specifically PEX7-rhizomelic chondrodysplasia punctata (type 1) and disorders of peroxisomal fatty acid oxidation. However, sterol quantification demonstrated an elevated 8[9] cholesterol/cholesterol ratio, consistent with the diagnosis of sterol delta 8 isomerase deficiency, or chondrodysplasia punctata type 2 (CDPX2) (Conradi-Hunermann syndrome).

13 RG Volume 28 Number 4 Dighe et al 1073 Figure 13. Chondrodysplasia punctata. (a) US image shows flattening of the nose (arrow). (b) US image shows a small head (microcephaly) and punctate irregular epiphyses in the long bones (arrows). The differential diagnosis could include spondyloepiphyseal dysplasia, hypochondroplasia, and chondrodysplasia punctata according to the diagrams in Figures 4, 7, and 8, respectively. In this case, clinical correlation and laboratory studies were needed to arrive at the diagnosis of chondrodysplasia punctata. (c, d) Radiographs show a small head with a flat face (arrow in c) and stippled epiphyses in the long bones (arrows in d). Diastrophic Dysplasia The term diastrophic implies twisting and describes the twisted habitus in diastrophic dysplasia (Fig 14). The mode of inheritance is autosomal recessive due to mutations in the diastrophic dysplasia sulfate transporter gene located at chromosome 5q32-q33.1, resulting in undersul- fated proteoglycans in the cartilage matrix (47,48). Micromelic dwarfism with clubfeet, hand deformities (abducted or hitchhiker s thumb), multiple flexion contractures, and scoliosis are present.

14 1074 July-August 2008 RG Volume 28 Number 4 Figure 14. Diastrophic dysplasia. (a d) US images show short broad long bones (calipers in a), hitchhiker s thumb (arrows in b), bilateral clubfeet (arrowheads in c), a sloping forehead (arrow in d), and marked micrognathia (arrowhead in d). According to the diagrams in Figures 2 and 7, the pathognomonic finding of hitchhiker s thumb characterized by flexion at the metacarpophalangeal joint and hyperextension at the interphalangeal joint suggests diastrophic dysplasia. (e) Postmortem photograph shows the bilateral clubfeet with limb shortening (arrowheads) and bilateral hitchhiker s thumb (arrow). Scale is in centimeters. (f) Postmortem photograph shows the micrognathia (arrowhead) and sloping forehead (arrow). (g) Radiograph shows the metaphyseal widening of long bones (double arrows) and irregularity of the metacarpal and metatarsal bones (single arrow).

15 RG Volume 28 Number 4 Dighe et al 1075 Table 2 Genes That Can Be Screened or Diagnosed In Utero Disease Entities Genes Multiple epiphyseal dysplasia, pseudoachondroplasia COMP, COL9A1, COL9A2, COL9A3, MATN3 Ellis van Creveld syndrome EVC Osteogenesis imperfecta types I IV, Ehlers-Danlos syndrome COL1A1, COL1A2 Achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia, spondyloepimetaphy- COL2A1 seal dysplasia, Stickler dysplasia Thanatophoric dysplasia types 1 and 2, achondroplasia, FGFR3 hypochondroplasia, other FGFR3 disorders, SADDAN dysplasia Diastrophic dysplasia, achondrogenesis type 1B, atelosteogenesis type II, multiple epiphyseal dysplasia (recessive), DTDST (SLC26A2) other diastrophic dysplasia variant disorders Cleidocranial dysplasia RUNX2 Note. For a more detailed list of biochemical and molecular tests available for the diagnosis of skeletal dysplasia, see the University of Washington sponsored World Wide Web page GeneTests ( COL1A1 = collagen, type I, alpha 1; COL1A2 = collagen, type I, alpha 2; COL2A1 = collagen, type II, alpha 1; COL9A1 = collagen, type IX, alpha 1; COL9A2 = collagen, type IX, alpha 2; COL9A3 = collagen, type IX, alpha 3; COMP = cartilage oligomeric matrix protein gene; EVC = Ellis van Creveld; DTDST (SLC26A2) = diastrophic dysplasia sulfate transporter (solute carrier family 26 [sulfate transporter] member 2); MATN3 = matrilin 3; RUNX2 = runt-related transcription factor 2; SADDAN = severe achondroplasia with developmental delay and acanthosis nigricans. Teaching Point The bones are characterized by crescent-shaped flattened epiphyses, a short and broad femoral neck, and shortening and metaphyseal widening of the tubular bones. There is irregular deformity and shortening of the metacarpal bones, metatarsal bones, and phalanges, along with abduction of the great toes and clubfeet. Progressive thoracolumbar kyphoscoliosis, cervical kyphosis, and irregular deformities of vertebral bodies are seen (48 50). In addition, micrognathia and cleft palate are frequently observed (51). Postnatal Evaluation A substantial percentage of fetuses with a skeletal dysplasia die in utero, are stillborn, die as neonates, or are delivered after elective termination of pregnancy. Establishment of the correct diagnosis of the skeletal dysplasia will likely require pathologic diagnostic work-up. Minimal postmortem (autopsy) work-up should include (a) external examination with photographs; (b) postmortem whole-body radiographs; and (c) skin or other tissue biopsy specimens for chromosome analysis and preservation of fibroblasts for possible later biochemical, enzymatic, or genetic studies, to be sent to specialty laboratories as indicated. If possible, complete autopsy should be performed by a pathologist experienced in perinatal- fetal pathologic analysis, although the internal examination is not as critical as the three items listed in the preceding paragraph. The postnatal work-up should provide essential diagnostic information for (a) counseling parents for future pregnancies, including formulating recurrence risk; and (b) designing strategies for prenatal monitoring and diagnosis in future pregnancies. For example, more than 99% of patients with achondroplasia have either a GLY380Arg substitution resulting from point mutation in the FGFR3 gene or a mutation at nucleotide 1138; hence, a definite diagnosis is possible in the majority of cases (52). Osteogenesis imperfecta is caused by mutations in either the COL1A1 or COL1A2 gene, resulting in abnormal molecular constitution of procollagen type I (53 55). The diagnosis can be confirmed with biochemical analysis of collagen or DNA sequencing of COL1A1 and COL1A2 (56). Some of the genes that can be screened are listed in Table 2. A more detailed list of biochemical and molecular tests for the diagnosis of skeletal dysplasia is available at the University of Washington sponsored Web page GeneTests (

16 1076 July-August 2008 RG Volume 28 Number 4 Conclusions Because skeletal dysplasias represent a very heterogeneous group of relatively rare disorders, making an accurate diagnosis is often challenging in practice. Although the radiologist plays a major role in this process, representatives of other disciplines, including clinicians, molecular biologists, and pathologists, can provide important information necessary for establishing the correct diagnosis. References 1. Rimon DL, Lachman RS. The chondrodysplasias. In: Emery AEH, Rimon DL, eds. Emery and Rimoin s principles and practice of medical genetics. New York, NY: Churchill Livingstone, 1983; Savarirayan R, Rimoin DL. The skeletal dysplasias. Best Pract Res Clin Endocrinol Metab 2002;16: Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002;113: Rasmussen SA, Bieber FR, Benecerraf BR, Lachman RS, Rimoin DL, Holmes LB. Epidemiology of osteochondrodysplasias: changing trends due to advances in prenatal diagnosis. Am J Med Genet 1996;61: Camera G, Mastroiacovo P. Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects. Prog Clin Biol Res 1982;104: Maymon E, Romero R, Ghezzi F, Pacora P, Pilu G, Jeanty P. Fetal skeletal anomalies. In: Fleischer A, Manning F, Jeanty P, Romero R, eds. Sonography in obstetrics and gynecology: principles and practice. New York, NY: McGraw-Hill, 2001; Parilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003;22: Nimrod C, Davies D, Iwanicki S, Harder J, Persaud D, Nicholson S. Ultrasound prediction of pulmonary hypoplasia. Obstet Gynecol 1986;68: Chitkara U, Rosenberg J, Chrvenak FA, et al. Prenatal sonographic assessment of the fetal thorax: normal values. Am J Obstet Gynecol 1987;156: Songster GS, Gray Dl, Crane JP. Prenatal prediction of lethal pulmonary hypoplasia using ultrasonic fetal chest circumference. Obstet Gynecol 1989;73: Johnson A, Callan NA, Bhutani VK, Colmorgen GH, Weiner S, Bolognese RJ. Ultrasonic ratio of fetal thoracic to abdominal circumference: an association with fetal pulmonary hypoplasia. Am J Obstet Gynecol 1987;157: Vintzileos AM, Campbell WA, Rodis JF, Nochimson DJ, Pinette MG, Petrikovsky BM. Comparison of six different ultrasonographic methods for predicting lethal fetal pulmonary hypoplasia. Am J Obstet Gynecol 1989;161: Yoshimura S, Masuzaki H, Gotoh H, Fukuda H, Ishimaru T. Ultrasonographic prediction of lethal pulmonary hypoplasia: comparison of eight different ultrasonographic parameters. Am J Obstet Gynecol 1996;175: Ramus RM, Martin LB, Twickler DM. Ultrasonographic prediction of fetal outcome in suspected skeletal dysplasias with use of the femur length-toabdominal circumference ratio. Am J Obstet Gynecol 1998;179: Ishikawa S, Kamata S, Usui N, Sawai T, Nose K, Okada A. Ultrasonographic prediction of clinical pulmonary hypoplasia: measurement of the chest/ trunk-length ratio in fetuses. Pediatr Surg Int 2003; 19: Jones KL. Cleidocranial dysostosis. In: Smith s recognizable patterns of human malformation. 6th ed. Philadelphia, Pa: Saunders, 2006; Mortier GR, Rimoin DL, Lachman RS. The scapula as a window to diagnosis of skeletal dysplasia. Pediatr Radiol 1997;27: Merz E, Bahlmann F, Weber G, Macchiella D. Three-dimensional ultrasonography in prenatal diagnosis. J Perinat Med 1995;23: Steiner H, Spitzer D, Weiss-Wichert PH, Graf AH, Staudach A. Three-dimensional ultrasound in prenatal diagnosis of skeletal dysplasia. Prenat Diagn 1995;15: Garjian KV, Pretorius DH, Budorick NE, Cantrell CJ, Johnson DD, Nelson TR. Fetal skeletal dysplasia: three-dimensional US initial experience. Radiology 2000;214: Krakow D, Williams J 3rd, Poehl M, Rimoin DL, Platt LD. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol 2003;21: O Rahilly R. Morphological patterns in limb deficiencies and duplications. Am J Anat 1951;89: Stevenson RE, Meyer LC. The limbs. In: Stevenson RE, Hall JE, Goodman RM, eds. Human malformations and related anomalies. Oxford Monographs on Medical Genetics Vol 2 No 27. New York, NY: Oxford University Press, 1993; Langer LO, Yang SS, Hall JG, et al. Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 1987;3: Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types 1 and 2) caused by distinct mutation in fibroblast growth factor receptor 3. Nat Genet 1995;9:

17 RG Volume 28 Number 4 Dighe et al Martínez-Frías ML, Ramos-Arroyo MA, Salvador J. Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet 1988;31: Sahinoglu Z, Uludogan M, Gurbuz A, Karateke A. Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet 2003; 269: Machado LE, Bonilla-Musoles F, Raga F, Bonilla F Jr, Machado F, Osborne NG. Thanatophoric dysplasia: ultrasound diagnosis. Ultrasound Q 2001;17: van der Harten HJ, Brons JT, Dijkstra PF, et al. Some variants of lethal neonatal short-limbed platyspondylic dysplasia: a radiological, ultrasonographic, neuropathological and histopathological study of 22 cases. Clin Dysmorphol 1993;2: Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 1997;70: Jones KL. Thanatophoric dysplasia. In: Smith s recognizable patterns of human malformation. 6th ed. Philadelphia, Pa: Saunders, 2006; Byers PH. Osteogenesis imperfecta. In: Royce PM, Steinman B, eds. Connective tissue and its heritable disorders. New York, NY: Wiley-Liss, 2002; Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16: Byers PH, Krakow D, Nunes M, Pepin M. Genetic evaluation of suspected osteogenesis imperfecta (OI). Genet Med 2006;8: Steiner RD, Pepin MG, Byers PH. Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta. J Pediatr 1996;128: Elejalde BR, de Elejalde MM. Prenatal diagnosis of perinatally lethal osteogenesis imperfecta. Am J Med Genet 1983;14: Ghosh A, Woo JS, Wan CW, Wong VC. Simple ultrasonic diagnosis of osteogenesis imperfecta type II in early second trimester. Prenat Diagn 1984; 4: Romero R, Pilu GL, Jeanty P. Prenatal diagnosis of congenital anomalies. Norwalk, Conn: Appleton & Lange, Jones KL. Chondrodysplasia punctata, x-linked dominant type. In: Smith s recognizable patterns of human malformation. 6th ed. Philadelphia, Pa: Saunders, 2006; Yang SS, Gilbert-Barness E. Skeletal system. In: Gilbert-Barness E, ed. Potter s pathology of the fetus and infant. St Louis, Mo: Mosby, 1997; Spranger JW, Brill PW, Poznanski A. Bone dysplasias. 2nd ed. New York, NY: Oxford University Press, Heselson NG, Cremin BJ, Beighton P. Lethal chondrodysplasia punctata. Clin Radiol 1978;29: Duff P, Harlass FE, Milligan DA. Prenatal diagnosis of chondrodysplasia punctata by sonography. Obstet Gynecol 1990;76: Gendall PW, Baird CE, Becroft DM. Rhizomelic chondrodysplasia punctata: early recognition with antenatal ultrasonography. J Clin Ultrasound 1994; 22: Hertzberg BS, Kliewer MA, Decker M, Miller CR, Bowie JM. Antenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata. J Ultrasound Med 1999;18: Straub W, Zarabi M, Mazer J. Fetal ascites associated with Conradi s disease (chondrodysplasia punctata): report of a case. J Clin Ultrasound 1983;11: Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 mutations, mutation review, associated skeletal phenotypes and diagnostic relevance. Hum Mutat 2001;17: Jones KL. Diastrophic dysplasia. In: Smith s recognizable patterns of human malformation. 6th ed. Philadelphia, Pa: Saunders, 2006; Bianchi DW, Crombleholme TM, D Alton ME. Diastrophic dysplasia. In: Fetology: diagnosis and management of the fetal patient. New York, NY: McGraw-Hill, 2000; Mantagos S, Weiss RR, Mahoney M, Hobbins JC. Prenatal diagnosis of diastrophic dwarfism. Am J Obstet Gynecol 1981;139: Wax JR, Carpenter M, Smith W, et al. Secondtrimester sonographic diagnosis of diastrophic dysplasia: report of 2 index cases. J Ultrasound Med 2003;22(8): Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic forms of dwarfism, achondroplasia. Cell 1994;78: Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor 3 receptor disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis and Crouzon syndrome with acanthosis nigricans. Endocr Rev 2000;21: Barsh GS, Roush CL, Bonadio J, Byers PH, Gelinsa RE. Intron-mediated recombination may cause a deletion in an alpha 1 type collagen chain in a lethal form of osteogenesis imperfecta. Proc Natl Acad Sci U S A 1985;82: Chu ML, Gargiulo V, Williams CJ, Ramirez F. Multiexon deletion in an osteogenesis imperfecta variant with increased type III collagen mrna. J Biol Chem 1985;260: Barsh GS, Byers PH. Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta. Proc Natl Acad Sci U S A 1981;78: This article meets the criteria for 1.0 credit hour in category 1 of the AMA Physician s Recognition Award. To obtain credit, see accompanying test at

18 RG Volume 28 Volume 4 July-August 2008 Dighe et al Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases Manjiri Dighe, MD, et al RadioGraphics 2008; 28: Published online /rg Content Codes: Page 1062 The bones should be assessed for presence, curvature, degree of mineralization, and fractures. Page 1062 A chest circumference less than the 5th percentile for gestational age has been proposed as an indicator of pulmonary hypoplasia. Page 1064 [A]bsence or hypoplasia of the clavicles is seen in cleidocranial dysplasia. Page 1064 The presence of the scapula should also be noted, since its absence is a useful defining feature of camptomelic dysplasia. Page 1075 Minimal postmortem (autopsy) work-up should include (a) external examination with photographs; (b) postmortem whole-body radiographs; and (c) skin or other tissue biopsy specimens for chromosome analysis and preservation of fibroblasts for possible later biochemical, enzymatic, or genetic studies, to be sent to specialty laboratories as indicated.