imaging in intrauterine skeletal dysplasia


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imaging in intrauterine skeletal dysplasia

  1. 1. 1
  2. 2. Definitions  Osteochondrodysplasias: - Abnormalities of bone and/or cartilage growth - Because of abnormal gene expression, phenotypes continue to evolve throughout lifespan  Dysostoses : - Altered blastogenesis in first 6 weeks of IU life - Phenotype fixed 2
  3. 3. •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.
  4. 4. •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
  5. 5. Lack of a systematic approach the inability of ultrasonography (US) to provide an integrated view, variability in the time at which findings manifest in some skeletal dysplasias.
  6. 6. •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 identified. at two dimensional US may be
  7. 7. •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. •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.
  8. 8. • 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. • In 1977, the European Society of Pediatric Radiology adopted the international nomenclature of constitutional-intrinsic bone disease.
  9. 9. •This nomenclature was modified in 1983, 1997, and 2001. The major change in 2001 was the addition of genetic dysostoses-osteochon-drodysplasias. • 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
  10. 10.  International Classification of Osteochondrodysplasias, published in 2002  Classified1. Osteochondrodysplasias - 33 groups (Groups 1–33) 2. Dysostoses – 3 (Groups A–C) - A - predominantly craniofacial involvement - B - predominant axial involvement - C - predominant involvement of hands & feet 10
  11. 11. •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.
  12. 12. • The overall prevalence of skeletal dysplasias among perinatal deaths was 9.1 per 1000 cases. • Despite recent advances in imaging, fetal skeletal dysplasias are difficult to diagnose in utero.
  13. 13. • 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.
  14. 14. •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. •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.
  15. 15. •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.
  16. 16. •US is the primary method for imaging a fetus.
  17. 17. •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.
  18. 18. Imaging Approach : Antenatal US  Long Bones: - Long bones lengths - Absence and malformation - Hypoplasia : Rhizomelia, Mesomelia, Rhizo- mesomelia, Acromelia - Curvature, degree of mineralization, and fractures - The femur length–abdominal circumference ratio (<0.16 - lethal outcome) - Femur length–foot length ratio (normal = 1, <1 suggests skeletal dysplasia/Trisomy 21) 18
  19. 19. 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.
  20. 20. •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.
  21. 21. 21
  22. 22. Femur Length  22
  23. 23. Thorax •The chest circumference and cardiothoracic ratio should be measured at the level of the four-chamber view of the heart. • ~ 11 weeks : 0.38 • ~ 17 - 20 weeks : 0.45 • term : 0.5 • A chest circumference less than the 5th percentile for gestational age has been proposed as an indicator of pulmonary hypoplasia.
  24. 24. •Other parameters used are a chest circumference-abdominal circumference ratio less than the 5th percentile , chest area, a heart area-chest area ratio less than the 5th percentile, a chest-trunk length ratio less than 0.32 , and a femur length-abdominal circumference ratio less than 0.16 .
  25. 25. •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 .
  26. 26. •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. The presence of the scapula should also be noted, since its absence is a useful defining feature of camptomelic dysplasia.
  27. 27. Chest  Chest–trunk length ratio less than 0.32  Femur length–abdominal circumference ratio less than 0.16  Hypoplastic thorax occurs in – lethal dysplasia, e.g. thanatophoric dysplasia, achondrogenesis, osteogenesis imperfecta. 27
  28. 28. 28
  29. 29. 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.
  30. 30. Ultrasound Clinodactyly, right hand Hypoplastic middle phalanx in the right 5th finger indicated by the arrow.
  31. 31. Syndactyly “mitten hand” Apert syndrome: acrocephalosyndactyly
  32. 32. • 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.
  33. 33. Hitchhiker thumb Second-Trimester Sonographic Diagnosis of Diastrophic Dysplasia.
  34. 34. Hands and Feet  Pre- or postaxial polydactyly  Syndactyly  Clinodactyly 34
  35. 35. The Hitchhiker's Thumb consists of : •Oval and hypoplastic first metacarpal. •Abducted proximally positioned thumb. •Low set first digit. •Etiology: 1.Skeletal dysplasia • Diastrophic dysplasia. •Campomelic dysplasia. 2.Isolated and familial (15%). 3.Trisomy 18 (30%) and trisomy 13. 4.Fetal akinesia and arthrogryposis. 5.Prolonged oligohydramnios. 6.Limb-body wall complex (32%). 7.Spina-bifida.
  36. 36. rocker-bottom foot It is characterized by a prominent calcaneus (heel) and a convex rounded sole. The presence of a rocker bottom foot in an antenatal ultrasound scan is sometimes classified as a soft sign for aneuploidic anomalies 3
  37. 37. 37
  38. 38. 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
  39. 39. •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.
  40. 40.  The inter-ocular distance (IOD) is a measurement between the two medial canthi of each eye 40
  41. 41. 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
  42. 42. Spine and Pelvis  Platyspondyly 42
  43. 43. 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.
  44. 44. •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 .
  45. 45. RG ■ Volume 28 • Number 4 Long bones - Dighe et al 1063 All long bones to be measured Measurement Bones Mineralization Curvature Fractures (mm) Standard measurement for wks Femur Right Left Tibia Right Left Fibula Right Left Humerus Right Left Ulna Right Left Radius Right Left Bones Absent Hypoplastic Any malformation Thorax Chest circumference to be obtained Measurement of the four chamber view of the heart at the level Normal measurement for wks Any bones missing? Feet - Yes / No Hands -Yes / No Polydactyly Chest Cir/ Abdominal Cir Clavicle Measurement Normal measurement of clavicles at wks Clavicles Right Left Hands and feet Foot measurement Shape of thorax Bell Shaped - Yes / No Chest circumference Measurement Normal Preaxial Postaxial Syndactyly Yes /No Postural deformities Clubfeet Yes / No Clubhand Yes / / No Micrognathia: YesNo Short upper lips: Yes / measurement of foot at wks No Abnormally shaped ears: Yes / No Normal = 1 Fetal Motion - Normal / Decreased AFI - Normal / Decreased / Increased Foot Femur/foot ratio Spine Skull and Face: Macrocrania: Yes / No Mineralization of skull bones: Normal / Decreased Relative length - Normal / Decreased Mineralization of vertebral bodies - Normal / Frontal bossing: Yes / No Decreased Vertebral Height - Normal / Decreased Biorbital diameter - Distance between the inner margins of the orbits Measurement Normal measurement of biorbital diameter at_ wks Biorbital diameter Any other organ abnormality: 3D dataset of the following to be acquired: 1. Face (profile view to look at the facial features) 2. Chest (transverse and sagittal 3D dataset from anterior aspect preferably to calculate lung volumes for pulmonary hypoplasia) 3. Hand (one only) 4. Foot (one only) 5. Pelvis (transverse 3D dataset from anterior aspect for iliac flaring) 6. Spine (sagittal 3D dataset to look at the vertebral height) 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.
  46. 46. 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?
  47. 47. 4. Are metaphyseal changes present? 5. Is there a premature appearance of ossification centers? 6. Are there any hypoplastic or absent bones?
  48. 48. Figure 3. Diagram illustrates a diagnostic algorithm for use in fetuses with moderate limb shortening and normal mineralization. OI = osteogenesis imperfecta.
  49. 49. 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.
  50. 50. Figure 5. Diagram illustrates a diagnostic algorithm for use in fetuses with normal or shortened limbs and decreased mineralization. OI = osteogenesis imperfecta.
  51. 51. 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?
  52. 52. 4. Are all parts of the spine equally affected (eg, achondrogenesis)? 5. Is platyspondyly present (thanatophoric dysplasia)? 6. Is the spinal canal of normal width? 7. Are any meningomyeloceles present?
  53. 53. 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)?
  54. 54. 5. Is there clavicular aplasia, hypoplasia, or partitioning (cleidocranial dysostosis)? 6. Is the scapula normal or abnormal (camp-tomelic dysplasia)? 7. Are there any gaps between ribs (Jarcho-Levine syndrome)?
  55. 55. Figure 6. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia abnormalities. OI = osteogenesis imperfecta. and thoracic
  56. 56. 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 poly dactyly 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
  57. 57. Figure 7. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia abnormalities. OI = osteogenesis imperfecta. and facial
  58. 58. Figure 8. Diagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia and skull abnormalities. OI = osteogenesis imperfecta.
  59. 59. 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.
  60. 60. •Isolated extremity amputation can be due to amniotic band syndrome, exposure to a teratogen, or vascular accident . •In most cases, the anomaly is sporadic, and risk of recurrence is negligible.
  61. 61. Figure 9. Isolated limb deficiency. (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.. (c) Radiograph shows abnormal bone tissue (arrow) at the end of the normally formed and mineralized forearm bone.
  62. 62. •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. • In this system, only two basic terms are used: amelia, indicating complete absence of a limb; and meromelia, indicating partial absence of a
  63. 63. •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 sub grouping is based on the axis of deficiency (transverse or longitudinal) and the individual bones involved.
  64. 64. Thanatophoric Dysplasia •The term “thanatophoric dysplasia” is derived from the Greek word thanatophoros, which means “bearing death.” •Thanatophoric dysplasia is themost common lethal skeletal dysplasia. Langer et al separated this condition into two types: type 1 (Fig 10) and type 2 (Fig 11).
  65. 65. •Both types are caused by mutations of the geneencoding fibroblast growth factor receptor 3 (FGFR3). • Inheritance is generally autosomal dominant . •Thanatophoric dysplasia is characterized by disproportionate dwarfism with very short extremities, which are bowed in type 1 and may be
  66. 66. •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 .
  67. 67. •Secondary skull deformity is often present due to the premature closure of cranial sutures. •Cloverleaf skull deformity is generally seen in type 2 . • Polyhydramnios is present in almost 50% of cases. •Death occurs in early infancy in the majority of cases due to respiratory insufficiency from
  68. 68. d. e. f. 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).
  69. 69. 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).
  70. 70. 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 •The overall prevalence of osteogenesis imperfecta is
  71. 71. •The classification of osteogenesis imperfecta was first proposed by Sillence, whose system was subsequently modified by Byers et al . •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 .
  72. 72. •The fetal movements may be reduced . •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.
  73. 73. • 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.
  74. 74. •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).
  75. 75. 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.
  76. 76. Table 1 Features of Various Types of Osteogenesis Imperfecta Type I Description Generalized demineralization; increased bone fragility, sometimes with secondary deformities; retarded ossification of the cranial vault II* 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 III Generalized osteopenia; short, deformed long tubular bones with broad metaphyses and thinner di-aphyses; retarded calvarial ossification; thin ribs with discontinuous fractures IV/V Generalized demineralization; increased bone fragility, sometimes with secondary deformities; bowed long bones; retarded ossification of the cranial vault *Perinatal lethal.
  77. 77. 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 Xlinked dominant inheritance, respectively, but an Xlinked recessive type exists as well.
  78. 78. •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.
  79. 79. •Other forms with different inheritance have also been described. Findings can include craniofacial dysmorphism, ocular abnormalities, cutaneous abnormalities, asymmetric shortening of the limbs, and joint contractures
  80. 80. •Prognosis is extremely poor, with severe mental retardation, spastic tetraplegia, and thermoregulatory instability. •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
  81. 81. •Facial features include a flat face with a small “saddle” nose. There are multiple contractures. •Ascites and polyhydramnios have been reported. 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.
  82. 82. •However, sterol quantification demonstrated an elevated cholesterol/cholesterol ratio, consistent with the diagnosis of sterol delta 8 isomerase deficiency, or chondrodysplasia punctata type 2 (CDPX2) (Conradi-Hunermann syndrome).
  83. 83. 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).
  84. 84. 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 dia-strophic dysplasia sulfate transporter gene located at chromosome 5q32-q33.1, resulting in under sulfated proteoglycans in the cartilage matrix .
  85. 85. •Micromelic dwarfism with clubfeet, hand deformities (abducted or hitchhiker‟s thumb), multiple flexion contractures, and scoliosis are present.
  86. 86. 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). (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).
  87. 87. •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.
  88. 88. •Progressive thoracolumbar kyphoscoliosis, cervical kyphosis, and irregular deformities of vertebral bodies are seen. •In addition, micrognathia and cleft palate are frequently observed .
  89. 89. Table 2 Genes That Can Be Screened or Diagnosed In Utero Disease Entities Multiple epiphyseal dysplasia, pseudoachondroplasia Ellis-van Creveld syndrome Osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome Achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia, Stickler dysplasia Thanatophoric dysplasia types 1 and 2, achondroplasia, hypochondroplasia, other FGFR3 disorders, SADDAN dysplasia Diastrophic dysplasia, achondrogenesis type 1B, atelosteogenesis type II, multiple epiphyseal dysplasia (recessive), other diastrophic dysplasia variant disorders Cleidocranial dysplasia Genes COMP, COL9A1, COL9A2, COL9A3, MATN3 EVC COL1A1, COL1A2 COL2A1 FGFR3 DTDST (SLC26A2) RUNX2 Note.—For a more detailed list of biochemical and molecular tests available for the diagnosis of skeletal dysplasia, see the University ofWashington-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.
  90. 90. 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.
  91. 91. • 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.
  92. 92. Imaging Approach : Post-natal Skeletal Survey  AP and lateral skull to include the atlas and axis  AP chest  AP pelvis  AP lumbar spine  Lateral thoracolumbar spine  AP one lower limb  AP one upper limb  Postero-anterior (PA) one hand (usually left for bone age assessment) 93
  93. 93. Modifications  In preterm fetuses and stillbirths, babygram i.e. two anteroposterior (AP) and lateral films from head to foot  Cone down views also required  Imaging of other family members suspected of having same condition 94
  94. 94. What to look for?  A – Anatomical localisation  B – Bones  C – Complications  D – Dead/alive 95
  95. 95. A- Anatomical site  Cleidocranial dysplasia, ischiopubicpatella syndrome  Spondyloepimetaphyseal dysplasia (tarda or congenita)  Metaphyseal chondrodysplasia 96
  96. 96. B – Bones  Structure  Shape  Size  Sum  Soft tissues 97
  97. 97. Structure  Bone density  Exostoses and enchondromas  Metaphyseal striations- osteopathia striata  Bone islands e.g. osteopoikilosis 98
  98. 98. 99
  99. 99. Shape         Metaphyses – flared Epiphyses- stippled or cone-shaped Platyspondyly Hooked vertebral bodies as in mucopolysaccharidoses Posterior scalloping of vertebral bodies as in neurofibromatosis and achondroplasia Sloping acetabular roofs as in mucopolysaccharidoses Horizontal trident acetabular roofs seen as in achondroplasia Trident of the hands in achondroplasia 100
  100. 100. Flared Metaphyses Stippled Epiphyses Hooked vertebral bodies 101
  101. 101. Size  Short, long, large, broad or hypoplastic Sum  Too many, too few, or fused Complications  Fractures e.g. osteogenesis imperfecta  Atlantoaxial subluxation as in mucopolysaccharidosis  Progressive scoliosis  Limb length discrepancies as in Epiphyseal stippling, dysplasia epiphysealis  Malignancy e.g in Multiple cartilaginous exostoses and Maffucci‟ s syndrome 102
  102. 102. Fractures Atlantoaxial instability 103
  103. 103. •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.
  104. 104. • 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.
  105. 105. • Osteogenesis imperfecta is caused by mutations in either the COL1A1 or COL1A2 gene, resulting in abnormal molecular constitution of procollagen type I. •The diagnosis can be confirmed with biochemical analysis of collagen or DNA sequencing of COL1A1 and COL1A2 . Some of the genes that can be screened are listed in Table 2.
  106. 106. Group 1 (Achondroplasia group) Achondroplasia : - Bullet-shaped‟ vertebral bodies - Decrease in interpedicular distance in lumbar spine caudally - Flat acetabular roofs - Short wide tubular bones - Large skull vault, relatively short base & Small foramen magnum - Relative overgrowth of fibula 107
  107. 107. 108
  108. 108. Group 1  Thanatophoric dysplasia - Most common lethal neonatal skeletal dysplasia - Short ribs with wide costochondral junctions - Severe platyspondyly - „telephone receiver femora‟ - „clover leaf skull‟ - Short broad tubular bones in - the hands feet 109
  109. 109. Group 3 (Metatropic Dysplasia Group)  Short tubular bones with marked metaphyseal widening (dumb-bell)  Platyspondyly, Progressive kyphoscoliosis  Large intervertebral discs  Flat acetabular roofs 110
  110. 110. Group 4/Asphyxiating thoracic dysplasia •Small thorax with short ribs, horizontally orientated •Horizontal acetabula with medial and lateral „spurs‟ (trident) Asphyxiating thoracic dysplasia 111
  111. 111. Group 8 (Type II Collagenopathies)  Spondyloepiphyseal dysplasia congenita & Tarda Characteristic mound of bone in central and posterior part of the vertebral end plates 112
  112. 112. Group 11 (Multiple Epiphyseal Dysplasias And Pseudoachondroplasia  Short limbs with normal head and face  Platyspondyly with tongue-like anterior protrusion of the vertebral bodies  Biconvex configuration of vertebral end plates  Irregular metaphyses 113
  113. 113. Group 12 (Chondrodysplasia Punctata/Stippled Epiphyses)  Stippled calcification in cartilage, particularly around the joints and in laryngeal and tracheal cartilages 114
  114. 114. Group 13 (Metaphyseal Dysplasias)  Metaphyseal chondrodysplasia (Schmid) - Metaphyseal flaring - Increased density and unevenness of metaphyses, particularly of upper femora and around knees 115
  115. 115. Group 19 (Dysplasias With Predominant Membranous Bone Involvement)  Cleidocranial dysplasia 116
  116. 116. Group 22 (Dysostosis Multiplex)  Mucopolysacchari - - doses Macrocephaly Thick vault with „ground-glass capacity‟ „J‟-shaped sella Ovoid, hookshaped vertebral bodies with thoracolumbar gibbus 117
  117. 117. Morquio's Syndrome (MPS-IV)  Normal intelligence  Absent odontoid peg  Platyspondyly  Progressive disappearance of femoral capital epiphyses 118
  118. 118. Group 24 (Dysplasias With Decreased Bone Density)  Osteogenesis imperfecta - a group of conditions sec. to abnormality of Type 1 collagen - Type I-IV - Most severe Type II & III - Mildest Type I 119
  119. 119.  Wormian bones  Basilar     invagination Hyperplastic callus Severe protrusio acetabuli „Codfish‟ vertebral bodies „Tam O'Shanter‟ appearance 120
  120. 120. Group 26 (Increased Bone Density Without Modification Of Bone Shape)  Osteopetrosis - Generalized increase in skeletal density - Alternating bands of radiolucency and sclerosis 121
  121. 121.  Osteopoikilosis - Sclerotic foci (islands), around pelvis and metaphyses of long bones 122
  122. 122. Group 31 (Disorganized Development Of Cartilaginous And Fibrous Components Of The Skeleton)  Multiple cartilaginous exostoses - Multiple flat or protuberant exostoses - Short ulna distally (reverse Madelung deformity) 123
  123. 123. Diaphysial Aclasis 124
  124. 124.  Enchondrom atoses (Ollier's disease/ Maffuci syndrome) - Expansion of the bone with cortical thinning - Areas of calcification within the lesions 125
  125. 125.  Fibrous dysplasia - Skull - asymmetrical thickening of the - vault with sclerosis at base: multiple rounded areas of radiolucency Obliteration of the paranasal air sinuses Obliteration of the paranasal air sinuses „Ground-glass‟ areas in alteration with patchy sclerosis and expansion Cortical thinning and endosteal scalloping 126
  126. 126. 127
  127. 127. Prenatal CT as a tool for dx of severe skeletal abnormalities 128
  128. 128. How to CONSENT  Mark with US the top and bottom of the uterus  Image ONLY what is strictly necessary  Topogram  kVp: 80-100  Actual scan-few seconds.  No contrast. 129
  129. 129. 130
  130. 130. Radiation load to fetus Low-dose fetal CT, NEVER first trimester  Radiation dose: varies according to maternal size  Mean radiation dose: 4.8 mSv  Up to 50 mSv is “negligible”  100 mSv, threshold for fetal damage 131
  131. 131. Thanatophoric dysplasia 132
  132. 132. Oseogenesis imperfecta 133
  133. 133. THANK YOU. 134