DOI: 10.1148/rg.284075122
RadioGraphics 2008;28:1061-1077
© RSNA, 2008
Fetal Skeletal Dysplasia: An Approach to Diagnosis with Illustrative Cases1
Manjiri Dighe, MD,
Corinne Fligner, MD,
Edith Cheng, MD,
Bill Warren, MD, and
Theodore Dubinsky, MD
1 From the Department of Radiology, University of Washington Medical Center, 1959 NE Pacific St, BB308, Box 357115, Seattle, WA 98195. 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. (e-mail: dighe{at}u.washington.edu).
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Abstract
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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 two-dimensional 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
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LEARNING OBJECTIVES FOR TEST 4
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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.
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Introduction
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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 2001. 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.
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US Technique for Assessing Fetal Skeletal Dysplasia
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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 four-chamber 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, 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, 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 (antero-posterior 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 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.
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 three-dimensional (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.
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Diagnosis with US
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If the limbs are disproportional (Figs 2–5), the following questions should be addressed:
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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.
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- Does the abnormality affect the proximal (rhizomelic), middle (mesomelic), or distal (acromelic) segment?
- Is polydactyly, ectrodactyly, clinodactyly, or syndactyly present?
- Are there any fractures, curved bones, or joint deformities, or clubbing of the foot or hand?
- Are metaphyseal changes present?
- Is there a premature appearance of ossification centers?
- Are there any hypoplastic or absent bones?
If the spine is mainly affected, one should ask the following questions:
- Is the spine short because of missing parts (eg, sacral agenesis)?
- Is there abnormal curvature?
- Is there shortening of vertebral bodies?
- Are all parts of the spine equally affected (eg, achondrogenesis)?
- Is platyspondyly present (thanatophoric dysplasia)?
- Is the spinal canal of normal width?
- Are any meningomyeloceles present?
If the thorax is mainly affected (Fig 6), the following questions should be addressed:
- Is the thorax extremely small (thanatophoric dysplasia)?
- Is the thorax long and narrow (Jeune syndrome)?
- Are the ribs extremely short (short-rib polydactyly)?
- Are fractures present (osteogenesis imperfecta type II)?
- Is there clavicular aplasia, hypoplasia, or partitioning (cleidocranial dysostosis)?
- Is the scapula normal or abnormal (camptomelic dysplasia)?
- 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]).
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Examples of Fetal Skeletal Dysplasia
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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 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.
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Figure 9a. 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).
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Figure 9b. 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).
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Figure 9c. 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).
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Figure 9d. 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).
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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).
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Figure 10a. 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).
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Figure 10b. 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).
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Figure 10c. 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).
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Figure 10d. 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).
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Figure 10e. 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).
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Figure 10f. 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).
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Figure 11a. 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).
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Figure 11b. 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).
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Figure 11c. 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).
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Figure 11d. 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).
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Figure 11e. 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).
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Figure 11f. 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).
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Figure 11g. 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).
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Figure 11h. 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).
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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 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).
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Figure 12a. 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.
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Figure 12b. 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.
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Figure 12c. 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.
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Figure 12d. 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.
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Figure 12e. 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.
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Figure 12f. 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.
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Variations in the number of fractures, time of presentation of patients with fractures (prenatal or postnatal), secondary deformities, and soft-tissue 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 chondrodysplasia 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).
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Figure 13a. 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).
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Figure 13b. 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).
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Figure 13c. 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).
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Figure 13d. 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).
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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 undersulfated 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. 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).
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Figure 14a. 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).
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Figure 14b. 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).
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Figure 14c. 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).
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Figure 14d. 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).
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Figure 14e. 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).
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Figure 14f. 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).
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Figure 14g. 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).
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Postnatal Evaluation
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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 (http://www.genetests.org).
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Conclusions
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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.
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Footnotes
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Abbreviations: FGFR3 = fibroblast growth factor receptor 3, 3D = three-dimensional
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D. S. Bae, C. E. Barnewolt, and R. W. Jennings
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J. Bone Joint Surg. Am.,
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[Full Text]
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Abstract
LEARNING OBJECTIVES FOR TEST...
