Fetal Musculoskeletal System. ASWIN.pptx

Evaluasi dan diagnostik kelainan muskuloskeletal fetus

1. Development of the Fetal Skeleton The skeleton is formed by 206 skeletal elements constituted by two tissues (bone and cartilage) and three cell types (osteoblasts, osteoclasts, and chondrocytes) . S keletal tissues derive from three embryonic cell lineages: (1) cranial neural crest cells, from which the craniofacial skeleton originates; (2) paraxial mesoderm cells or somites , which are the embryologic precursors of the axial skeleton; and (3) the lateral plate mesoderm, which is responsible for limb formation. Limb buds begin to develop during the 4th week of embryonic life (6th menstrual week) as clusters of mesenchymal cells covered by a layer of ectoderm.

2. Mesenchymal models of bone (anlagen: templates for future bones) form around the 5th week of embryonic life (7th menstrual week) (Fig. 11-1). Development of the upper limbs precedes the lower limbs in bud appearance, differentiation, and nal relative limb size. Limbs develop in a proximodistal sequence, with the anlagen of the humerus and femur forming first, followed by the radius and ulna, the tibia and bula , the metacarpal and metatarsal bones, and phalanges. Skeletogenesis (Genetics and Embryology) Skeletogenesis involves four steps: patterning, organogenesis, growth, and homeostasis. Patterning is the process by which the final size, shape, number, and arrangement of bones are determined.

3. Endochondral Ossification, The axial and appendicular skeletons are formed by endochondral ossi fi cation (Fig. 11-2). The axial skeleton (e.g., vertebrae and the dorsal part of the ribs) originates from the somites . Cartilaginous models of the future bones differentiate within mesenchymal condensations during the 6th week of development (8th menstrual week), with primary ossi fi cation centers developing in the middle of the anlagen between the 7th and 12th weeks of development (9th to 14th menstrual weeks). SOX9 plays an important role in chondrogenesis .

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

5. Skeletal Dysplasias Abnormal development, growth, or maintenance of cartilage and bone tissues results in skeletal dysplasias . Skeletal dysplasias are a heterogeneous group of disorders affecting the development of chondro -osseous tissues leading to abnormalities in the size, mineralization, and shape of various segments of the skeleton. Birth Prevalence and Contribution to Perinatal Mortality B irth prevalence of skeletal dysplasias (excluding limb amputations) was estimated as 2.4/10,000 births. Twenty-three percent of the affected infants were stillborn, whereas 32% died during the fi rst week of life. The overall frequency of skeletal dysplasias among perinatal deaths was 9.1/1000. The four most common skeletal dysplasias were thanatophoric dysplasia, achondroplasia , osteogenesis imperfecta (OI), and achondrogenesis .

6. Classification of Skeletal Dysplasias Molecular- Pathogenetic Classi cation of Skeletal Dysplasias Most skeletal anomalies are a phenotypic manifestation of a mutation in a gene and altered protein expression; therefore, they can be grouped according to the affected genes as they share similar clinical characteristics. The classi fi cation provides (1) the group/name of the skeletal disorder; (2) type of inheritance; (3) MIM (Mendelian Inheritance in Man) number; (4) locus of the mutation in the gene; (5) affected protein; and (6) associations/difference with other skeletal anomalies.

7. Skeletal Dysplasias Seen at Birth The molecular pathogenic classi fi cation of genetic disorders of the skeleton is very extensive and includes many conditions that may not be apparent at birth and therefore are not amenable to prenatal diagnosis by imaging methods. A more clinically relevant list of skeletal dysplasias that may be recognizable during pregnancy along with their mode of inheritance and causative genes has been published by Krakow (Table 11-3). Clinically Oriented Classi fi cation A skeletal anomaly is suspected prenatally either by family history or by ultrasound fi ndings , while after birth, the diagnosis is suspected based on family history and on clinical and radiographic fi nding .

8. Terminology Frequently Used to Describe Bone Dysplasias Shortening of the extremities can involve the entire limb ( micromelia ), the proximal segment ( rhizomelia ), the intermediate segment ( mesomelia ), or the distal segment ( acromelia ) (Fig. 11-6)

9. Clinical Presentation In general, the challenges of the prenatal diagnosis of skeletal dysplasias presents in one of two ways: (1) a patient who has delivered an infant with a skeletal dysplasia and desires antenatal assessment in a subsequent pregnancy or (2) the incidental fi nding of a shortened, bowed or anomalous extremity during a routine sonographic examination. Diagnostic Imaging and Prenatal Diagnosis of Skeletal Dysplasias The role of diagnostic imaging in the prenatal investigation of skeletal dysplasias is (1) to narrow the differential diagnosis of skeletal dysplasias , so that appropriate con fi rmatory molecular tests can be done; (2) to predict lethality; and (3) to identify the fetus with a skeletal dysplasia early enough in gestation so that the diagnostic workup can be completed before the limit of fetal viability diagnosis of skeletal dysplasia by evaluating the following sonographic parameters: (1) measurements of all segments of the long bones; (2) examination of the hands, spine, and head; (3) assessment of mineralization and shape of the bones; and (4) a full anatomic survey.

10. Approach to the Diagnosis of Skeletal Dysplasias , Evaluation of the Long Bones Measurements. All long bones must be measured in all extremities. Comparisons with other segments should be performed to establish whether the limb shortening is predominantly rhizomelic , mesomelic , or acromelic , or whether it involves all segments Degree of Mineralization. An attempt should be made to characterize the degree of mineralization, which can be assessed by examining the acoustic shadow behind the bone as well as the echogenicity of the bone itself. Degree of Long Bone Curvature. At present, there is no objective means to assess long bone curvature, and experience is necessary to assist the operator in discerning the boundary between normality and abnormality. Bowed or angulated femora ( campomelia ) Metaphyseal Flaring. Metaphyseal fl aring denotes widening at the level of the metaphyseal growth plate. It can be observed in many conditions, including achondroplasia , hypochondroplasia , hypochondrogenesis , asphyxiating thoracic dysplasia

11. Femoral Angle. Khalil and colleagues reported an increased diaphysis-metaphysis femoral angle measured at 20 weeks to 23 weeks and 6 days of gestation in fetuses later diagnosed with achondroplasia . Fractures. Fractures can be found in certain skeletal dysplasias such as OI and hypophosphatasia (Fig. 11-19). The fractures may be extremely subtle or may lead to angulation and separation of segments of the affected bone Prediction of Pulmonary Hypoplasia Skeletal dysplasias associated with a hypoplastic thorax frequently have lung hypoplasia, which is the most frequent cause of death for these conditions.

12. A detailed evaluation of the thorax in order to answer the following questions can assist in the diagnosis of the particular skeletal dysplasia: •  Is the thorax extremely small? ( thanatophoric dysplasia) •  Is the thorax long and narrow? ( Jeune syndrome) •  Are the ribs extremely short? (short rib– polydactyly syndromes) •  Are there rib fractures? ( osteogenesis imperfecta type II) •  Are there gaps within the ribs? (cerebra- costo -mandibular syndrome) •  Are there fused ribs? ( spondylocostal dysplasia) •  Is there clavicular aplasia, hypoplasia, or pseudoarthrosis ? ( cleidocranial dysplasia) •  Are the scapulae abnormal? (hypoplasia or absence in campomelic dysplasia)

13. Evaluation of Thoracic and Lung Dimensions by Two-Dimensional Ultrasound. Thoracic and lung biometry has been extensively studied to identify fetuses at high risk for pulmonary hypoplasia Short Femur Length and Prediction of Lethality in Skeletal Dysplasias . Rahemtullah and coworkers studied 18 fetuses with skeletal dysplasias in which all lethal cases were associated with a femur length/ abdominal circumference ratio of 0.16. Lung Volumetry by Three-Dimensional Sonography. Fetal lung volumetry by 3D sonography has been performed using two techniques: multiplanar Estimation of Pulmonary Hypoplasia by Magnetic Resonance Imaging. Parameters proposed to evaluate lung volume by MRI include the relative lung volume (observed/expected lung volume ratio), lung volume/estimated fetal weight (LV/EFW) ratio, and the lung/spinal fl uid signal intensity (L/SF) ratio

14. DopplerAssessmentofTrachealFluidFlow . Kalache and coworkers proposed that the volume of lung uid displaced in the trachea could be useful for the analysis of fetal lung function Doppler Velocimetry of the Pulmonary Arteries. Underdevelopment and structural changes of the pulmonary vascular bed in cases of pulmonary hypoplasia may result in increased pulmonary vascular resistance and reduced pulmonary arterial compliance Evaluation of Hands and Feet The fetal hands and feet should be examined to exclude polydactyly (Fig. 11-26), brachydactyly , and extreme postural deformities, such as those seen in diastrophic dysplasia Evaluation of the Fetal Cranium Several skeletal dysplasias are associated with defects of membranous ossication , and, therefore, skull bones are affected. Examination of the skull bones may reveal poor ossification Evaluation of the Fetal Face Sonographic examination of the fetal face is of major importance in the assessment and diagnosis of skeletal dysplasias , because many of these disorders are associated with characteristic abnormalitie

15. Increased Nuchal Translucency and Skeletal Dysplasias

16. Osteochondrodysplasias , Achondroplasia , Thanatophoric Dysplasia, and Hypochondroplasia T hese disorders are caused by different mutations in the broblast growth factor receptor-3 gene ( FGFR3 ). Mutations in FGFR3 are gain-of-function mutations that produce a constitutively active protein capable of initiating intracellular signal pathways in the absence of ligand binding. This activation leads to premature maturation of the bone. The critical clinical difference between thanatophoric dysplasia and achondroplasia / hypochondroplasia is severe shortening of the ribs in thanatophoric dysplasia, resulting in restricted lung volumes, respiratory insuf ciency , and death within hours or days after birth

17. Achondroplasia It is clinically characterized by rhizomelic shortening of the limbs and mild limb bowing, exaggerated lumbar lordosis, and an enlarged head. The bones of the hands and feet are short ( brachydactyly ). The head is large (macrocephaly), with frontal bossing, midface hypoplasia, a attened nasal bridge, and a broad mandible Thanatophoric Dysplasia it is characterized by severe rhizomelia , normal trunk length with a narrow thorax, and a large head with prominent forehead A reduced femur length and a normal growth of the skull have been suggested as a potential sonographic marker for the prenatal diagnosis of hypochondroplasia

18. Fibrochondrogenesis and Atelosteogenesis Fibrochondrogenesis characterized by micromelia with signi cant metaphyseal aring , normal head size, at face, attened nasal bridge with anteverted nostrils, prominent eyes, undermineralized skull, platyspondyly , clefting of the vertebral bodies, and a narrow and bell-shaped thorax Type IA achondrogenesis (Houston-Harris) is characterized by micromelia , lack of ossication of vertebral bodies (but ossication of the pedicles in the cervical and upper thoracic region), and short ribs with multiple fractures, The calvarium is demineralized. Type IB ( Fraccaro ), which is a recessively inherited chondrodysplasia, is caused by a mutation in the DTDS gene4

19. Osteogenesis Imperfecta and Hypophosphatasia

20. Diastrophic Dysplasia C haracterized by micromelia , clubfoot, hand deformities, multiple joint exion contractures, and scoliosis

21. Clubhand Deformities, Clubhand deformities are classi ed into two main categories: radial and ulnar. Radial clubhand includes a wide spectrum of disorders that encompass absent thumb, thumb hypoplasia, thin first metacarpal, and absent radius Whenever a clubhand is identi fi ed , it is important to conduct a thorough examination of the fetus and newborn to delineate associated anomalies that may suggest a syndrome. Fetal blood sampling can be helpful, and fetal echocardiography is recommended. A complete blood cell count, including platelets, is important for the diagnosis of Fanconi pancytopenia, TAR syndrome, and Diamond- Blackfan anemia. A fetal karyotype is indicated because several chromosomal abnormalities (e.g., trisomy 18 and trisomy 21) have been reported in association with clubhand deformities

22. Radial Clubhand and Hematologic Disorders An isolated radial clubhand is usually a sporadic nonsyndromic disorder however, other structural anomalies may be present (e.g., scoliosis and congenital heart disease) Radial clubhand may be part of the three syndromes characterized by hematologic abnormalities: Fanconi pancytopenia, TAR syndrome, and Diamond- Blackfan anemia. Radial Clubhand and Scoliosis Radial clubhand may also be associated with congenital scoliosis. Three conditions should be considered in the differential diagnosis: VATER/ VACTER association, some cases of the Goldenhar syndrome, and Klippel-Feil syndrom

23. Polydactyly , Polydactyly is the presence of an additional digit, and it is the most common hereditary limb deformation. The extra digit may range from a eshy nubbin to a complete digit with controlled exion and extension

24. Clubfoot Clubfoot ( talipes equinovarus ) is a congenital malformation of the bones of the ankle and foot, resulting in adduction of the forefoot, inversion of the heel, and plantar exion of the forefoot and ankle. There is subluxation of the talocalcaneonavicular joint. As a result of this malformation, the dorsal aspect of the foot is often rotated medially, which assumes a clublike appearance. The sonographic diagnosis is made when the metatarsals and phalanges of the foot are seen in the same plane as the tibia and fibula The severity of the clubfoot deformity varies from (1) a postural deformity often requiring no treatment; (2) an isolated clubfoot deformity needing casting and possible surgery, often with a favorable outcome; or (3) a complex clubfoot abnormality associated with other chromosomal, neuromuscular, or structural abnormalities. Clubfoot may also result from restriction of movement in utero, as in severe oligohydramnios