Fetal Musculoskeletal System






  • Outline



  • Development of the Fetal Skeleton, 273




    • Skeletogenesis (Genetics and Embryology), 273



    • Endochondral Ossification, 273



    • Intramembranous Ossification, 275




  • Skeletal Dysplasias, 275




    • Birth Prevalence and Contribution to Perinatal Mortality, 275



    • Classification of Skeletal Dysplasias, 275



    • Terminology Frequently Used to Describe Bone Dysplasias, 277



    • Clinical Presentation, 288



    • Diagnostic Imaging and Prenatal Diagnosis of Skeletal Dysplasias, 288



    • Approach to the Diagnosis of Skeletal Dysplasias, 291



    • Increased Nuchal Translucency and Skeletal Dysplasias, 303




  • Osteochondrodysplasias, 303




    • Achondroplasia, Thanatophoric Dysplasia, and Hypochondroplasia, 303



    • Fibrochondrogenesis and Atelosteogenesis, 306



    • Achondrogenesis, 307



    • Osteogenesis Imperfecta and Hypophosphatasia, 309



    • Diastrophic Dysplasia, 310



    • Kniest-like Disorders, 311



    • Dyssegmental Dysplasia, 312



    • Campomelic Dysplasia, 312



    • Skeletal Dysplasias Characterized by a Hypoplastic Thorax, 313



    • Skeletal Dysplasias With Predominant Membranous Bone Involvement, 316



    • Limb Deficiency or Congenital Amputations, 317



    • Syndromes With Absent Limbs and Facial Anomalies, 318



    • Limb Reduction Defects Associated With Other Anomalies, 319




  • Split Hand and Foot Deformities, 320



  • Ectrodactyly Ectodermal Dysplasia–Cleft Lip/Palate Syndrome, 320



  • Clubhand Deformities, 321




    • Radial Clubhand, 321



    • Radial Clubhand and Hematologic Disorders, 321



    • Radial Clubhand and Scoliosis, 322



    • Other Conditions Associated With Radial Clubhand, 323



    • Polydactyly, 323



    • Arthrogryposis, 323




  • Clubfoot, 325




Summary of Key Points





  • The prevalence of skeletal dysplasias is about 2.4/10,000 births, and 9.1/1000 among perinatal deaths; the most common anomalies are thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta, and achondrogenesis.



  • The new edition of Nosology and Classification of Genetic Skeletal Disorders includes 436 clinical conditions classified into 42 groups involving 364 affected genes; therefore, molecular diagnosis is possible in about 75% of skeletal disorders.



  • Molecular diagnosis can be offered to couples with a family history of skeletal dysplasia to estimate the risk in a future pregnancy, or to pregnant women with ultrasound signs suggestive of fetal skeletal dysplasia.



  • Two-dimensional (2D) and three-dimensional (3D) sonography and 3D helical computed tomography (3D-HCT) are the main imaging modalities used to evaluate a fetus with suspected skeletal dysplasia.



  • Thanatophoric dysplasia and achondrogenesis account for 60% of all lethal skeletal dysplasias and are characterized by extremely reduced thoracic dimensions and very short long bones.



  • A complete fetal ultrasound evaluation, including assessment of fetal movements, should be performed if a skeletal disorder is suspected.



  • Ultrasound signs suggestive of a skeletal dysplasia include bones with reduced length, abnormal shape, reduced mineralization, and fractures; abnormal fetal facial profile; polyhydramnios; and abnormal pattern of fetal movements.



  • The diagnosis of a possible skeletal dysplasia during pregnancy should be corroborated by molecular diagnosis and neonatal or pathologic evaluation.





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). Skeletal 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. 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 final 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 fibula, the metacarpal and metatarsal bones, and phalanges.




FIG 11-1


Diagram of the mesenchymal precartilage primordia of the axial and appendicular skeletons at 5 weeks’ embryologic age (7 weeks’ menstrual age). These primordia develop further and eventually ossify to form skeletal structures.

(Illustration by Netter FH; from Crelin ES: Development of the musculoskeletal system. CIBA Clin Symp 33:6, 1981. Used with permission from CIBA-GEIGY Corporation, Summit, NJ.)


Skeletogenesis (Genetics and Embryology)


Skeletogenesis involves four steps: patterning, organogenesis, growth, and homeostasis. Patterning is the process by which the final size, shape, number, and arrangement of bones are determined. This process takes place long before skeletogenesis, and three signaling regions have been identified: (1) an apical ectodermal ridge; (2) an area consisting of ectoderm covering the sides of the bud; and (3) a zone of polarizing activity. The apical ectodermal ridge consists of densely packed ectodermal cells located at the tip of the limb bud, which express several fibroblast growth factors (FGFs) that initiate and control limb outgrowth. The ectoderm covering the sides of the bud regulates dorsoventral patterning. The zone of polarizing activity is located on the posterior limb bud margin. It is responsible for anteroposterior patterning and, thus, the formation of digits. Besides FGFs, other genes are involved in the control of limb patterning, including Sonic hedgehog (Shh), GLI-Kruppel family member GLI3 (Gli3), sal-like 1 (Sall1), Hoxd13, Hoxa13, bone morphogenetic/cartilage-derived morphogenetic protein (CDMP), growth differentiation factors (GDFs), Noggin (Nog), Wn7-a, engrailed (en), and LIM homeobox transcription factor 1 beta (Lmx1b).


Bone and cartilage are formed during the organogenesis period, which consists of three phases: condensation, cell differentiation, and histogenesis. Condensation is of great importance in skeletal development, because the templates for future bones are defined at this stage. Condensation initiation, boundary set, proliferation, adhesion, and growth are regulated by complex interactions between extracellular matrix molecules, cell surface receptors, cell adhesion molecules (e.g., fibronectin, tenascin, Noggin, syndecan, and neural cell adhesion molecule [N-CAM]), homeobox genes (e.g., Hoxa-2, Hoxa-13, Hoxd-11, and Hoxd-11-13), transcription factors (e.g., runt-related transcription factor 2 [RUNX2], winged-helix transcription factor [CFKH-1], mesenchyme forkhead 1 [MFH-1], paired box transcription factors 1 and 9 [PAX-1, PAX-9], periaxin 1 and 2 [PRX-1 and PRX-2], scleraxis, and mammalian SRY box 9 [SOX-9]), and growth factors (e.g., bone morphogenetic proteins, fibroblast growth factor 2 [FGF-2], transforming growth factor beta [TGF-β]). Osteogenesis initiates during the 7th week of embryonic development (9th menstrual week), with bones developing by either endochondral or membranous ossification.


Endochondral Ossification


The axial and appendicular skeletons are formed by endochondral ossification ( Fig. 11-2 ). The axial skeleton (e.g., vertebrae and the dorsal part of the ribs) originates from the somites. Cartilaginous models of the future bones differentiate within mesenchymal condensations during the 6th week of development (8th menstrual week), with primary ossification centers developing in the middle of the anlagen between the 7th and 12th weeks of development (9th to 14th menstrual weeks). SOX9 plays an important role in chondrogenesis. Mutations in this gene cause campomelic dysplasia, a severe skeletal disorder characterized by congenital bowing and angulation of the long bones (especially of the tibia), hypoplastic scapulae, sex reversal in male fetuses, and a high lethality rate due to respiratory insufficiency. Another gene involved in chondrogenesis is procollagen type II alpha 1 ( COL2A1 ), which encodes collagen type II.




FIG 11-2


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

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


Within primary ossification centers, hypertrophic cartilage matrix is degraded, chondrocytes undergo apoptosis, osteoblasts replace the disappearing cartilage with trabecular bone, and bone marrow is formed. Simultaneously, osteoblasts in the perichondrium begin to deposit a collar of compact bone matrix along the diaphysis. Osteoblast differentiation is controlled by RUNX2 and Osterix, whereas proliferation is controlled by the low-density lipoprotein receptor–related protein 5 (LPR5) signaling pathway. Eventually, cartilage in the center of the anlagen degrades, mineralizes, and is removed by osteoclasts. Vascular ingrowth is stimulated by vascular endothelial growth factor, with the influx of osteoprogenitor cells occurring at the same time that the bone matrix is deposited along the periosteum of the midshaft. Some of these invading cells differentiate into hematopoietic stem cells, whereas others differentiate into osteoclasts or osteoblasts.


Secondary ossification centers begin to appear at the extremities of bones (epiphyses) later in pregnancy. The portion of cartilage trapped between the expanding primary and secondary ossification centers is known as the growth plate or physis. This structure is formed by a cartilaginous component (epiphyseal plate), a bony component (metaphysis), and fibrous tissue surrounding the periphery of the plate. The growth plate is responsible for the longitudinal growth of long bones until definitive fusion of epiphyses and diaphyses occurs at the end of puberty. Longitudinal growth is coordinated by Indian hedgehog (Ihh), a stimulator of chondrocyte proliferation at the growth plate. Bone mass, shape, and strength are maintained throughout development and adult life by balancing bone destruction and formation. Homeostasis is the process that controls the continuing remodeling of bones.


It is noteworthy that when a long bone is imaged by ultrasound, only the diaphyses are measured, because the epiphyses are hypoechoic and are not always clearly visualized. Under favorable conditions, good sonographic images of the epiphysis can be obtained, especially when high-frequency transducers are used ( Fig. 11-3 ). Secondary ossification centers may often be visualized by ultrasound in the third trimester. The distal femoral ossification center may be seen at approximately 32 to 33 weeks of gestation, the proximal tibial epiphyseal center at 34 to 35 weeks, and the proximal humeral epiphyseal ossification center at 37 to 38 weeks of gestation ( Fig. 11-4 ). When all three centers are identified, it is likely that the fetus is at least 37 weeks’ gestational age. These ossification centers may be seen slightly earlier in female fetuses than in male fetuses. The timeline for radiographic and histologic appearance of primary and secondary ossification centers is illustrated in Figure 11-5 .




FIG 11-3


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



FIG 11-4


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



FIG 11-5


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

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


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


Intramembranous Ossification


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




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. Despite recent advances in imaging and molecular genetics, accurate prenatal diagnosis of skeletal dysplasias remains a clinical challenge. In the most recent revision of the International Nosology and Classification of Constitutional Disorders of Bone it is mentioned that in approximately 25% of all bone disorders the mutated gene has not been yet identified. It is important to acknowledge the contribution of the International Skeletal Dysplasia Registry in the identification and study of skeletal anomalies, assisting providers and patients in the diagnosis and clinical management of skeletal disorders.


In subsequent sections of this chapter, we will review the birth prevalence, classification, and molecular genetics of skeletal dysplasias that are identifiable at birth.


Birth Prevalence and Contribution to Perinatal Mortality


In a large multicenter study conducted by Camera and Mastroiacovo the birth prevalence of skeletal dysplasias (excluding limb amputations) was estimated as 2.4/10,000 births. Twenty-three percent of the affected infants were stillborn, whereas 32% died during the first week of life. The overall frequency of skeletal dysplasias among perinatal deaths was 9.1/1000. This study also reported on the birth prevalence of the different skeletal dysplasias and their relative frequency among perinatal deaths. The four most common skeletal dysplasias were thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta (OI), and achondrogenesis. Thanatophoric dysplasia and achondrogenesis accounted for 62% of all lethal skeletal dysplasias, and the most common nonlethal skeletal dysplasia was achondroplasia. In another large series from western Scotland, the prevalence of skeletal dysplasias at birth was 1.1/10,000 births. The most frequent conditions were thanatophoric dysplasia (1/42,000), OI (1/56,000), chondrodysplasia punctata (1/84,000), campomelic syndrome (1/112,000), and achondrogenesis (1/112,000). Rasmussen and associates reported a prevalence of 2.1/10,000 deliveries in a longitudinal study, which included elective pregnancy termination, stillborn infants at more than 20 weeks of gestation, and liveborn infants diagnosed by the 5th day of life. The rate of lethal cases in this study was 0.95/10,000 deliveries. Of interest, the study reporting the highest prevalence of skeletal dysplasias at birth (9.5/10,000 births) was conducted in a population with a high rate of consanguineous unions. An overview of the prevalence of skeletal dysplasias in different populations is presented in Table 11-1 .



TABLE 11-1

Prevalence of Skeletal Dysplasias
























































Study * Prevalence Comment
Gustavson and Jorulf 1/2117 Newborns
Camera and Mastroiacovo 1/4600 Neonates
Connor et al 1/8900 Neonates
Weldner et al 1/1333 Achondroplasia
Orioli et al 1/4347 First 3 days of life
Stoll et al 1/3125 First 8 days of life
Andersen 1/6667 At birth
Kallen et al 1/6250 Multicenter study
Rasmussen et al 1/4166 First 5 days of life
Barbosa-Buck et al 1/21,276 Thanatophoric dysplasia
Donnelly et al 1/8000 Thanatophoric dysplasia
Stevenson et al 1/7900 Osteogenesis imperfecta

* Studies are listed in the references at the end of the chapter.



Classification of Skeletal Dysplasias


Molecular-Pathogenetic Classification of Skeletal Dysplasias


The first classification of skeletal anomalies was proposed more than 40 years ago and was mainly based on clinical and radiographic findings. Since that time, the classification has continuously evolved owing to the contribution of imaging and molecular biology techniques. This classification is currently known as Nosology and Classification of Genetic Skeletal Disorders. 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 International Skeletal Dysplasia Society (ISDS) periodically reviews this classification, and the last version corresponding to the 9th edition was published in 2015. In this document, the authors acknowledge the contribution of next-generation sequencing technologies and the increasing availability of whole exome sequencing, allowing the discovery of more gene-related skeletal anomalies. For this review, 436 clinical conditions were classified into 42 groups involving 364 affected genes ( Table 11-2 ). The classification 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. Skeletal dysplasias, metabolic bone disorders, dysostosis, skeletal malformations, and reduction syndromes are included in this classification. However, the authors also clarify that in approximately 25% of skeletal disorders, the mutated gene has not yet been identified. The genetic basis for classification of very rare diseases was done by family pedigree, or was based on homogeneity or phenotype in unrelated families. The classification aims to provide more complete information for prenatal counseling and clinical management. The full document can be consulted at the ISDS website.



TABLE 11-2

Nosology and Classification of Genetic Skeletal Disorders






































GROUPS/NAME OF DISORDER


  • 1.

    FGFR3 chondrodysplasia group



    • a.

      Thanatophoric dysplasia type 1 (TD1), type 2 (TD2)


    • b.

      Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)


    • c.

      Achondroplasia


    • d.

      Hypochondroplasia


    • e.

      Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)


    • f.

      Hypochondroplasia-like dysplasia(s)



  • 2.

    Type 2 collagen group



    • a.

      Achondrogenesis type 2 (ACG2; Langer-Saldino)


    • b.

      Platyspondylic dysplasia, Torrance type


    • c.

      Hypochondrogenesis


    • d.

      Spondyloepiphyseal dysplasia congenita (SEDC)


    • e.

      Spondyloepimetaphyseal dysplasia (SEMD), Strudwick type


    • f.

      Kniest dysplasia


    • g.

      Spondyloperipheral dysplasia


    • h.

      Mild SED with premature onset arthrosis


    • i.

      SED with metatarsal shortening (formerly Czech dysplasia)


    • j.

      Stickler syndrome type 1



  • 3.

    Type 11 collagen group



    • a.

      Stickler syndrome type 2


    • b.

      Marshall syndrome


    • c.

      Stickler syndrome type 3 (nonocular)


    • d.

      Fibrochondrogenesis


    • e.

      Oto-spondylo-mega-epiphyseal dysplasia (OSMED), recessive type


    • f.

      Oto-spondylo-mega-epiphyseal dysplasia (OSMED), dominant type (Weissenbacher-Zweymüller syndrome, Stickler syndrome type 3)



  • 4.

    Sulfation disorders group



    • a.

      Achondrogenesis type 1B (ACG1B)


    • b.

      Atelosteogenesis type 2 (AO2)


    • c.

      Diastrophic dysplasia (DTD)


    • d.

      MED, autosomal recessive type (rMED; EDM4)


    • e.

      SEMD, PAPSS2 type


    • f.

      Brachyolmia, recessive type


    • g.

      Chondrodysplasia gPAPP type (includes Catel-Manzke-like syndrome


    • h.

      Chondrodysplasia with congenital joint dislocations, CHST3 type (recessive Larsen syndrome)


    • i.

      Ehlers-Danlos syndrome, CHST14 type (“musculoskeletal variant”)



  • 5.

    Perlecan group



    • a.

      Dyssegmental dysplasia, Silverman-Handmaker type


    • b.

      Dyssegmental dysplasia, Rolland-Desbuquois type


    • c.

      Schwartz-Jampel syndrome (myotonic chondrodystrophy)



  • 6.

    Aggrecan group



    • a.

      SED, Kimberley type


    • b.

      SEMD, Aggrecan type


    • c.

      Familial osteochondritis dissecans




  • 7.

    Filamin group and related disorders



    • a.

      Frontometaphyseal dysplasia


    • b.

      Osteodysplasty Melnick-Needles


    • c.

      Otopalatodigital syndrome type 1 (OPD1)


    • d.

      Otopalatodigital syndrome type 2 (OPD2)


    • e.

      Terminal osseous dysplasia with pigmentary defects (TODPD)


    • f.

      Atelosteogenesis type 1 (AO1)


    • g.

      Atelosteogenesis type 3 (AO3)


    • h.

      Larsen syndrome (dominant)


    • i.

      Spondylo-carpal-tarsal dysplasia


    • j.

      Frank-ter Haar syndrome




  • 8.

    TRPV4 group



    • a.

      Metatropic dysplasia


    • b.

      Spondyloepimetaphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2)


    • c.

      Spondylometaphyseal dysplasia, Kozlowski type


    • d.

      Brachyolmia, autosomal dominant type


    • e.

      Familial digital arthropathy with brachydactyly



  • 9.

    Ciliopathies with major skeletal involvement



    • a.

      Chondroectodermal dysplasia (Ellis–van Creveld)


    • b.

      Short rib–polydactyly syndrome (SRPS) type 1/3 (Saldino-Noonan/Verma-Naumoff)


    • c.

      Asphyxiating thoracic dysplasia (ATD; Jeune)


    • d.

      SRPS type 2 (Majewski)


    • e.

      SRPS type 4 (Beemer)


    • f.

      SRPS type 5


    • g.

      Oral-facial-digital syndrome type 4 (Mohr-Majewski)


    • h.

      Cranioectodermal dysplasia (Levin-Sensenbrenner) types 1, 2


    • i.

      Thoracolaryngopelvic dysplasia (Barnes)



  • 10.

    Multiple epiphyseal dysplasia and pseudoachondroplasia group



    • a.

      Pseudoachondroplasia (PSACH)


    • b.

      Multiple epiphyseal dysplasia (MED) type 1 (EDM1)


    • c.

      Multiple epiphyseal dysplasia (MED) type 2 (EDM2)


    • d.

      Multiple epiphyseal dysplasia (MED) type 3 (EDM3)


    • e.

      Multiple epiphyseal dysplasia (MED) type 5 (EDM5)


    • f.

      Multiple epiphyseal dysplasia (MED) type 6 (EDM6)


    • g.

      Multiple epiphyseal dysplasia (MED), other types


    • h.

      Stickler syndrome, recessive type


    • i.

      Familial hip dysplasia (Beukes)


    • j.

      Multiple epiphyseal dysplasia with microcephaly and nystagmus (Lowry-Wood)



  • 11.

    Metaphyseal dysplasias



    • a.

      Metaphyseal dysplasia, Schmid type (MCS)


    • b.

      Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type)


    • c.

      Metaphyseal dysplasia, CHH-like, POP1 type


    • d.

      Metaphyseal dysplasia, Jansen type


    • e.

      Eiken dysplasia


    • f.

      Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman-Bodian-Diamond syndrome, SBDS)


    • g.

      Metaphyseal anadysplasia types 1, 2


    • h.

      Metaphyseal dysplasia, Spahr type


    • i.

      Metaphyseal dysplasia with maxillary hypoplasia



  • 12.

    Spondylometaphyseal dysplasias (SMD)



    • a.

      Spondyloenchondrodysplasia (SPENCD)


    • b.

      Odontochondrodysplasia (ODCD)


    • c.

      SMD, Sutcliffe type or corner fractures type


    • d.

      SMD with cone-rod dystrophy


    • e.

      SMD with retinal degeneration, axial type




  • 13.

    Spondylo-epi-(meta-)physeal dysplasias (SE(M)D)



    • a.

      Dyggve-Melchior-Clausen dysplasia (DMC)


    • b.

      Immuno-osseous dysplasia (Schimke)


    • c.

      SED, Wolcott–Rallison type


    • d.

      SEMD, Matrilin type


    • e.

      SEMD, short limb–abnormal calcification type


    • f.

      SED tarda, X-linked (SED-XL)


    • g.

      Spondylodysplastic Ehlers-Danlos syndrome


    • h.

      SPONASTRIME dysplasia


    • i.

      Platyspondyly (brachyolmia) with amelogenesis imperfecta


    • j.

      CODAS syndrome




  • 14.

    Severe spondylodysplastic dysplasias



    • a.

      Achondrogenesis type 1A (ACG1A)


    • b.

      Schneckenbecken dysplasia


    • c.

      Spondylometaphyseal dysplasia, Sedaghatian type


    • d.

      Severe spondylometaphyseal dysplasia (SMD Sedaghatian-like)


    • e.

      Opsismodysplasia


    • f.

      Mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene (MAGMAS) related skeletal dysplasia



  • 15.

    Acromelic dysplasias



    • a.

      Tricho-rhino-phalangeal dysplasia types 1/3


    • b.

      Tricho-rhino-phalangeal dysplasia type 2 (Langer-Giedion)


    • c.

      Acrocapitofemoral dysplasia


    • d.

      Geleophysic dysplasia


    • e.

      Acromicric dysplasia


    • f.

      Weill-Marchesani


    • g.

      Myhre dysplasia


    • h.

      Acrodysostosis


    • i.

      Angel-shaped phalango-epiphyseal dysplasia (ASPED)


    • j.

      Albright hereditary osteodystrophy



  • 16.

    Acromesomelic dysplasias



    • a.

      Acromesomelic dysplasia type Maroteaux (AMDM)


    • b.

      Grebe dysplasia


    • c.

      Fibular hypoplasia and complex brachydactyly (Du Pan)


    • d.

      Acromesomelic dysplasia with genital anomalies


    • e.

      Acromesomelic dysplasia, Osebold-Remondini type



  • 17.

    Mesomelic and rhizomesomelic dysplasias



    • a.

      Dyschondrosteosis (Leri-Weill)


    • b.

      Langer type (homozygous dyschondrosteosis)


    • c.

      Omodysplasia


    • d.

      Omodysplasia, dominant


    • e.

      Robinow syndrome, recessive type and dominant type


    • f.

      Mesomelic dysplasia, Kantaputra type


    • g.

      Mesomelic dysplasia, Nievergelt type


    • h.

      Mesomelic dysplasia, Kozlowski-Reardon type


    • i.

      Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer type)


    • j.

      Mesomelic dysplasia, Savarirayan type (triangular tibia–fibular aplasia)



  • 18.

    Campomelic dysplasia and related disorders



    • a.

      Campomelic dysplasia (CD)


    • b.

      Stuve-Wiedemann dysplasia


    • c.

      Kyphomelic dysplasia, several forms



  • 19.

    Slender bone dysplasia group



    • a.

      33-M syndrome


    • b.

      Kenny-Caffey dysplasia


    • c.

      Osteocraniostenosis


    • d.

      Microcephalic osteodysplastic primordial dwarfism types 1/3 (MOPD1)


    • e.

      Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2; Majewski type)


    • f.

      IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies)


    • g.

      Hallermann-Streiff syndrome




  • 20.

    Dysplasias with multiple joint dislocations



    • a.

      Desbuquois dysplasia (with accessory ossification center in digit 2)


    • b.

      Desbuquois dysplasia with short metacarpals and elongated phalanges (Kim type)


    • c.

      Desbuquois dysplasia type 2


    • d.

      Pseudodiastrophic dysplasia


    • e.

      SEMD with joint laxity (SEMD-JL) leptodactylic or Hall type


    • f.

      SEMD with joint laxity (SEMD-JL) Beighton type




  • 21.

    Chondrodysplasia punctata (CDP) group



    • a.

      CDP, X-linked dominant, Conradi-Hünermann type (CDPX2)


    • b.

      CDP, X-linked recessive, brachytelephalangic type (CDPX1)


    • c.

      CHILD (congenital hemidysplasia, ichthyosis, limb defects)


    • d.

      Keutel syndrome


    • e.

      Greenberg dysplasia


    • f.

      Rhizomelic CDP types 1, 2, 3


    • g.

      CDP tibial-metacarpal type


    • h.

      Astley-Kendall dysplasia



  • 22.

    Neonatal osteosclerotic dysplasias



    • a.

      Blomstrand dysplasia


    • b.

      Desmosterolosis


    • c.

      Caffey disease (including prenatal, infantile, and attenuated)


    • d.

      Caffey dysplasia (severe variants with prenatal onset)


    • e.

      Raine dysplasia (lethal and nonlethal forms)



  • 23.

    Osteopetrosis and related disorders



    • a.

      Osteopetrosis, severe neonatal or infantile forms (OPTB1)


    • b.

      Osteopetrosis, severe neonatal or infantile forms (OPTB4)


    • c.

      Osteopetrosis, severe neonatal or infantile forms (OPTB8)


    • d.

      Osteopetrosis, infantile form, with nervous system involvement (OPTB5)


    • e.

      Osteopetrosis, intermediate form, osteoclast-poor (OPTB2)


    • f.

      Osteopetrosis, infantile form, osteoclast-poor with immunoglobulin deficiency (OPTB7)


    • g.

      Osteopetrosis, intermediate form (OPTB6)


    • h.

      Osteopetrosis, intermediate form (OPTA2)


    • i.

      Osteopetrosis with renal tubular acidosis (OPTB3)


    • j.

      Osteopetrosis, late-onset form type 1 (OPTA1)


    • k.

      Osteopetrosis, late-onset form type 2 (OPTA2)


    • l.

      Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)


    • m.

      Osteopetrosis, moderate form with defective leukocyte adhesion (LAD3)


    • n.

      Osteopetrosis, moderate form with defective leukocyte adhesion


    • o.

      Pyknodysostosis


    • p.

      Osteopoikilosis


    • q.

      Melorheostosis with osteopoikilosis


    • r.

      Osteopathia striata with cranial sclerosis (OSCS)


    • s.

      Melorheostosis


    • t.

      Dysosteosclerosis




  • 24.

    Other sclerosing bone disorders



    • a.

      Craniometaphyseal dysplasia, autosomal dominant type


    • b.

      Diaphyseal dysplasia Camurati-Engelmann


    • c.

      Hematodiaphyseal dysplasia Ghosal


    • d.

      Hypertrophic osteoarthropathy


    • e.

      Pachydermoperiostosis (hypertrophic osteoarthropathy, primary, autosomal dominant)


    • f.

      Oculo-dento-osseous dysplasia (ODOD) mild type


    • g.

      Oculo-dento-osseous dysplasia (ODOD) severe type


    • h.

      Osteoectasia with hyperphosphatasia (juvenile Paget disease)


    • i.

      Sclerosteosis


    • j.

      Endosteal hyperostosis, van Buchem type


    • k.

      Trichodento-osseous dysplasia


    • l.

      Craniometaphyseal dysplasia,


    • m.

      Diaphyseal medullary stenosis with malignant fibrous histiocytoma


    • n.

      Craniodiaphyseal dysplasia


    • o.

      Craniometadiaphyseal dysplasia, Wormian bone type


    • p.

      Endosteal sclerosis with cerebellar hypoplasia


    • q.

      Lenz-Majewski hyperostotic dysplasia


    • r.

      Metaphyseal dysplasia, Braun-Tinschert type


    • s.

      Pyle disease



  • 25.

    Osteogenesis imperfecta and decreased bone density group



    • a.

      Osteogenesis imperfecta, nondeforming form (OI type 1)


    • b.

      Osteogenesis imperfecta, perinatal lethal form (OI type 2)


    • c.

      Osteogenesis imperfecta, progressively deforming type (OI type 3)


    • d.

      Osteogenesis imperfecta, moderate form (OI type 4)


    • e.

      Osteogenesis imperfecta with calcification of the interosseous membranes and/or hypertrophic callus (OI type 5)


    • f.

      X-linked osteoporosis


    • g.

      Bruck syndrome type 1 (BS1)


    • h.

      Bruck syndrome type 2 (BS2)


    • i.

      Osteoporosis-pseudoglioma syndrome


    • j.

      LRP5 primary osteoporosis


    • k.

      Calvarial doughnut lesions with bone fragility


    • l.

      Idiopathic juvenile osteoporosis


    • m.

      Cole-Carpenter dysplasia (bone fragility with craniosynostosis)


    • n.

      Spondylo-ocular dysplasia


    • o.

      Osteopenia with radiolucent lesions of the mandible


    • p.

      Ehlers-Danlos syndrome, progeroid form


    • q.

      Geroderma osteodysplasticum


    • r.

      Cutis laxa, autosomal recessive form, type 2B (ARCL2B)


    • s.

      Cutis laxa, autosomal recessive form, type 2A (ARCL2A) (Wrinkly skin syndrome)


    • t.

      Singleton–Merten dysplasia




  • 26.

    Abnormal mineralization group



    • a.

      Hypophosphatasia, perinatal lethal, infantile and juvenile forms


    • b.

      Hypophosphatasia, juvenile and adult forms


    • c.

      Hypophosphatemic rickets, X-linked dominant


    • d.

      Hypophosphatemic rickets, autosomal dominant


    • e.

      Hypophosphatemic rickets, autosomal recessive, type 1 (ARHR1)


    • f.

      Hypophosphatemic rickets, autosomal recessive, type 2 (ARHR2)


    • g.

      Hypophosphatemic rickets with hypercalciuria, X-linked recessive


    • h.

      Hypophosphatemic rickets with hypercalciuria, autosomal recessive (HHRH)


    • i.

      Neonatal hyperparathyroidism, severe form


    • j.

      Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidism


    • k.

      Calcium pyrophosphate deposition disease (familial chondrocalcisnosis) type 2




  • 27.

    Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)



    • a.

      Mucopolysaccharidosis type 1H/1S (Hurler, Hurler-Scheie, Scheie)


    • b.

      Mucopolysaccharidosis type 2 (Hunter)


    • c.

      Mucopolysaccharidosis type 3A (Sanfilippo A)


    • d.

      Mucopolysaccharidosis type 3B (Sanfilippo B)


    • e.

      Mucopolysaccharidosis type 3C (Sanfilippo C)


    • f.

      Mucopolysaccharidosis type 3D (Sanfilippo D)


    • g.

      Mucopolysaccharidosis type 4A (Morquio A)


    • h.

      Mucopolysaccharidosis type 4B (Morquio B)


    • i.

      Mucopolysaccharidosis type 6 (Maroteaux-Lamy)


    • j.

      Mucopolysaccharidosis type 7 (Sly)


    • k.

      Fucosidosis


    • l.

      Alpha-mannosidosis


    • m.

      Beta-mannosidosis


    • n.

      Aspartylglucosaminuria


    • o.

      GMI gangliosidosis, several forms


    • p.

      Sialidosis, several forms


    • q.

      Sialic acid storage disease (SIASD)


    • r.

      Galactosialidosis, several forms


    • s.

      Multiple sulfatase deficiency


    • t.

      Mucolipidosis II (I-cell disease), alpha/beta type


    • u.

      Mucolipidosis III (pseudo–Hurler polydystrophy), alpha/beta type


    • v.

      Mucolipidosis III (pseudo–Hurler polydystrophy), gamma type



  • 28.

    Osteolysis group



    • a.

      Familial expansile osteolysis


    • b.

      Mandibuloacral dysplasia type A, B


    • c.

      Progeria, Hutchinson-Gilford type


    • d.

      Torg-Winchester syndrome


    • e.

      Hajdu-Cheney syndrome


    • f.

      Multicentric carpal-tarsal osteolysis with and without nephropathy



  • 29.

    Disorganized development of skeletal components group



    • a.

      Multiple cartilaginous exostoses 1, 2 , 3


    • b.

      Cherubism


    • c.

      Fibrous dysplasia, polyostotic form (McCune-Albright)


    • d.

      Progressive osseous heteroplasia


    • e.

      Gnathodiaphyseal dysplasia


    • f.

      Metachondromatosis


    • g.

      Osteoglophonic dysplasia


    • h.

      Fibrodysplasia ossificans progressiva (FOP)


    • i.

      Neurofibromatosis type 1 (NF1)


    • j.

      Carpotarsal osteochondromatosis


    • k.

      Cherubism with gingival fibromatosis (Ramon syndrome)


    • l.

      Dysplasia epiphysealis hemimelica (Trevor)


    • m.

      Lipomembranous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu-Hakola)


    • n.

      Enchondromatosis (Ollier) and enchondromatosis with hemangiomata (Maffucci)


    • o.

      Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria


    • p.

      Genochondromatosis


    • q.

      Gorham-Stout




  • 30.

    Overgrowth (tall stature) syndromes with skeletal involvement



    • a.

      Weaver syndrome


    • b.

      Sotos syndrome


    • c.

      Sotos-like syndrome


    • d.

      Marshall-Smith syndrome


    • e.

      Proteus syndrome


    • f.

      CLOVES


    • g.

      Marfan syndrome


    • h.

      Congenital contractural arachnodactyly


    • i.

      Loeys-Dietz syndrome types 1A,1B, 2A, 2B, 3, 4


    • j.

      Overgrowth syndrome with 2q37 translocations


    • k.

      Overgrowth with macrodactyly and NPR2 gain of function


    • l.

      Overgrowth syndrome with skeletal dysplasia (Nishimura-Schmidt, endochondral gigantism)



  • 31.

    Genetic inflammatory/rheumatoid-like osteoarthropathies



    • a.

      Progressive pseudorheumatoid dysplasia (PPRD; SED with progressive arthropathy)


    • b.

      Chronic infantile neurologic cutaneous articular syndrome (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)


    • c.

      Sterile multifocal osteomyelitis, periostitis, and pustulosis (CINCA/NOMID-like)


    • d.

      Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia (CRMO with CDA; Majeed syndrome)


    • e.

      Hyperostosis/hyperphosphatemia syndrome


    • f.

      Hyaline fibromatosis syndrome



  • 32.

    Cleidocranial dysplasia and related disorders



    • a.

      Cleidocranial dysplasia


    • b.

      CDAGS syndrome (craniosynostosis, delayed fontanelle closure, parietal foramina, imperforate anus, genital anomalies, skin eruption)


    • c.

      Yunis-Varon dysplasia


    • d.

      Parietal foramina (isolated)



  • 33.

    Craniosynostosis syndromes



    • a.

      Pfeiffer syndrome (FGFR1-related)


    • b.

      Apert syndrome


    • c.

      Craniosynostosis with cutis gyrata (Beare-Stevenson)


    • d.

      Crouzon syndrome


    • e.

      Bent bone dysplasia


    • f.

      Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal syndrome)


    • g.

      Craniosynostosis, Muenke type


    • h.

      Antley-Bixler syndrome


    • i.

      Craniosynostosis Boston type


    • j.

      Saethre-Chotzen syndrome


    • k.

      Shprintzen-Goldberg syndrome


    • l.

      Baller-Gerold syndrome


    • m.

      Carpenter syndrome


    • n.

      Coronal craniosynostosis


    • o.

      Complex craniosynostosis




  • 34.

    Dysostoses with predominant craniofacial involvement



    • a.

      Mandibulofacial dysostosis (Treacher-Collins, Franceschetti–Klein)


    • b.

      Oral-facial-digital syndrome type I (OFD1)


    • c.

      Weyers acrofacial (acrodental) dysostosis


    • d.

      Endocrine-cerebro-osteodysplasia (ECO)


    • e.

      Craniofrontonasal syndrome


    • f.

      Frontonasal dysplasia, types 1, 2, 3


    • g.

      Hemifacial microsomia


    • h.

      Miller syndrome (postaxial acrofacial dysostosis)


    • i.

      Acrofacial dysostosis, Nager type


    • j.

      Acrofacial dysostosis, Rodriguez type


    • k.

      Mandibulofacial dysostosis with microcephaly




  • 35.

    Dysostoses with predominant vertebral with and without costal involvement



    • a.

      Currarino triad


    • b.

      Spondylocostal dysostosis type 1 (SCDO1), type 2 (SCDO2), type 3(SCDO3), type 4 (SCDO4), type 5 (SCDO5)


    • c.

      Spondylothoracic dyostosis (STD)


    • d.

      Vertebral segmentation defect (congenital scoliosis) with variable penetrance


    • e.

      Klippel-Feil anomaly with laryngeal malformation


    • f.

      Cerebro-costo-mandibular syndrome (rib gap syndrome)


    • g.

      Cerebro-costo-mandibular-like syndrome with vertebral defects


    • h.

      Diaphanospondylodysostosis


    • i.

      Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD)



  • 36.

    Patellar dysostoses



    • a.

      Ischiopatellar dysplasia (small patella syndrome)


    • b.

      Nail-patella syndrome


    • c.

      Genitopatellar syndrome


    • d.

      Ear-patella-short stature syndrome (Meier-Gorlin)



  • 37.

    Brachydactylies (without extraskeletal manifestations)



    • a.

      Brachydactyly types A1, A2, B, B2, C, D, E


    • b.

      Brachydactyly with anonychia (Cooks syndrome)



  • 38.

    Brachydactylies (with extraskeletal manifestations)



    • a.

      Brachydactyly-mental retardation syndrome


    • b.

      Hyperphosphatasia with mental retardation, brachytelephalangy, and distinct face


    • c.

      Brachydactyly-hypertension syndrome (Bilginturan)


    • d.

      Microcephaly-oculo-digito-esophageal-duodenal syndrome (Feingold syndrome)


    • e.

      Hand-foot-genital syndrome


    • f.

      Rubinstein-Taybi syndrome


    • g.

      Brachydactyly, Temtamy type


    • h.

      Christian type brachydactyly


    • i.

      Coffin-Siris syndrome1


    • j.

      Adams-Oliver


    • k.

      Catel-Manzke syndrome




  • 39.

    Limb hypoplasia–reduction defects group



    • a.

      Ulnar-mammary syndrome


    • b.

      de Lange syndrome


    • c.

      Fanconi anemia


    • d.

      Thrombocytopenia–absent radius (TAR)


    • e.

      Thrombocythemia with distal limb defects


    • f.

      Holt-Oram syndrome


    • g.

      Okihiro syndrome (Duane–radial ray anomaly)


    • h.

      Cousin syndrome


    • i.

      Roberts syndrome


    • j.

      Split-hand-foot malformation with long bone deficiency (SHFLD3)


    • k.

      Tibial hemimelia


    • l.

      Tibial hemimelia-polysyndactyly-triphalangeal thumb


    • m.

      Acheiropodia


    • n.

      Tetra-amelia


    • o.

      Terminal transverse defect


    • p.

      Al-Awadi Raas-Rothschild limb-pelvis hypoplasia-aplasia


    • q.

      Fuhrmann syndrome


    • r.

      RAPADILINO syndrome


    • s.

      Femoral hypoplasia-unusual face syndrome (FHUFS)


    • t.

      Femur-fibula-ulna syndrome (FFU)


    • u.

      Hanhart syndrome (hypoglossia-hypodactylia)


    • v.

      Gollop-Wolfgang


    • w.

      Scapulo-iliac dysplasia (Kosenow)




  • 40.

    Ectrodactyly with and without other manifestations



    • a.

      Ectrodactyly with and without other manifestations


    • b.

      Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC)


    • c.

      Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 3 (EEC3)


    • d.

      Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 1 (EEC1)


    • e.

      Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM)


    • f.

      Limb-mammary syndrome (including ADULT syndrome)


    • g.

      Split hand-foot malformation, isolated form, type 4 (SHFM4)


    • h.

      Split hand-foot malformation, isolated form, type 1 (SHFM1)


    • i.

      Split hand-foot malformation, isolated form, type 3 (SHFM3)


    • j.

      Split hand-foot malformation, isolated form, type 5 (SHFM5)


    • k.

      Hartsfield syndrome



  • 41.

    Polydactyly-syndactyly-triphalangism group



    • a.

      Preaxial polydactyly type 1 (PPD1)


    • b.

      Postaxial polydactyly type A


    • c.

      Postaxial polydactyly type B


    • d.

      Triphalangeal thumb (TPT)-polydactyly syndrome


    • e.

      Preaxial polydactyly type 3 (PPD3)


    • f.

      Preaxial polydactyly type 4 (PPD4)


    • g.

      Greig cephalopolysyndactyly syndrome


    • h.

      Pallister-Hall syndrome


    • i.

      Synpolydactyly (complex, fibulin 1-associated)


    • j.

      Synpolydactyly


    • k.

      Townes-Brocks syndrome (renal-ear-anal-radial syndrome)


    • l.

      Lacrimo-auriculo-dento-digital syndrome (LADD Gene FGFR2)


    • m.

      Lacrimo-auriculo-dento-digital syndrome (LADD Gene FGFR3)


    • n.

      Lacrimo-auriculo-dento-digital syndrome (LADD Gene FGF10)







    • o.

      Acrocallosal syndrome


    • p.

      Acro-pectoral syndrome


    • q.

      Acro-pectoro-vertebral dysplasia (F-syndrome)


    • r.

      Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome)


    • s.

      Cenani-Lenz syndactyly


    • t.

      Cenani-Lenz-like syndactyly


    • u.

      Syndactyly, Malik-Percin type


    • v.

      STAR syndrome (syndactyly of toes, telecanthus, ano- and renal malformations)


    • w.

      Syndactyly type Lueken


    • x.

      Oculodentodigital dysplasia, syndactyly type 3 (IV-V)


    • y.

      Syndactyly Haas type


    • z.

      Syndactyly with metacarpal and metatarsal fusion


    • aa.

      Metacarpal 4-5 fusion syndrome


    • bb.

      Syndactyly with craniosynostosis (Philadelphia type)


    • cc.

      Syndactyly with microcephaly and mental retardation (Filippi syndrome)


    • dd.

      Meckel syndrome types 1, 2, 3, 4, 5, 6



  • 42.

    Defects in joint formation and synostoses



    • a.

      Multiple synostoses syndrome type 3


    • b.

      Proximal symphalangism type 1


    • c.

      Proximal symphalangism type 2


    • d.

      Radioulnar synostosis with amegakaryocytic thrombocytopenia


    • e.

      Liebenberg syndrome


    • f.

      Congenital clubfoot



Adapted from Bonafe L, Cormier-Daire V, Hall C, et al: Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 167(12):2869-2892, 2015.


Skeletal Dysplasias Seen at Birth


The molecular pathogenic classification 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 ). The authors acknowledge that for a full classification of skeletal anomalies the Nosology and Classification of Genetic Skeletal Disorders should be consulted.



TABLE 11-3

Well-Defined Skeletal Disorders Seen During the Neonatal Period


































































































































































































































































































































Group or Name of the Disorder Mode of Inheritance Gene Symbol
Fibroblast Growth Factor Receptor 3 (FGFR3) Disorders
Thanatophoric dysplasia AD FGFR3
Achonodroplasia AD FGFR3
Hypochondroplasia AD FGFR3
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) AD FGFR3
Type II Collagen Disorders
Achondrogenesis II AD COL2A1
Hypochondrogenesis AD COL2A1
Spondyloepiphyseal dysplasia congenita (SEDC) AD COL2A1
Kniest dysplasia AD COL2A1
Type XI Collagen Disorders
Fibrochondrogenesis AR COL11A1
Fibrochondrogenesis AD COL11A1, COL11A2
Otospondylomegaepiphyseal dysplasia (OSMED) AR COL11A2
Sulfation Disorders
Achondrogenesis IB AR SLC26A2
Atelosteogenesis II AR SLC26A2
Diastrophic dysplasia AR SLC26A2
Chondrodysplasia with congenital joint dislocations AR CHST3
Perlecan Disorders
Dyssegmental dysplasia AR PLC
Dyssegmental dysplasia, Silverman-Handmaker type AR PLC
Dyssegmental dysplasia, Rolland-Desbuquois type AR PLC
Filamin Disorders and Similar Disorders
Otopalatodigital syndrome I and II XLD FLNA
Osteodysplasty, Melnick-Needles XLD FLNA
Atelosteogenesis types I and III AD FLNB
Larsen syndrome AD FLNB
Spondylo-carpal-tarsal dysplasia AR FLNB
Serpentine fibula–polycystic kidney syndrome AD NOTCH2
TRPV4 Disorders
Metatropic dysplasia AD TRPV4
Short Rib Dysplasias (With and Without Polydactyly)
Chondroectodermal dysplasia (Ellis–van Creveld) AR DYNC2H1
Short rib–polydactyly syndrome I, II, III, and IV including asphyxiating thoracic dystrophy AR IFT80 NEK WDR35
Thoracolaryngeal dysplasia AD Unknown
Metaphyseal Dysplasias
Cartilage-hair hypoplasia AR RMRP
Metaphyseal dysplasia, Jansen type AD PTHR1
Spondylo-Epi-(Meta)-Physeal Dysplasia (SEMD)
SEMD, short limb abnormal calcification type AR DDR2
Severe Spondylodysplastic Dysplasias
Achondrogenesis 1A AR GMAP210
Schneckenbecken dysplasia AR SLC35D1
Opsismodysplasia AR INPPL1
Acromesomelic Disorders
Acromesomelic dysplasia, type Maroteaux AR NPR2
Mesomelic and Rhizomesomelic Dysplasias
Langer type (homozygous dyschondrosteosis) Pseudo-AR/XLD SHOX
Omodysplasia AR GPC6
Robinow syndrome, recessive AR ROR2
Robinow syndrome, dominant AD WNT5
Bent Bone Dysplasias
Campomelic dysplasia AD SOX9
Stuve-Wiedemann dysplasia AR LIFR
Bent bone dysplasia FGFR2 type AD FGFR2
Slender Bone Dysplasias
Microcephalic osteodysplastic primordial dwarfism (MOPD1) AR RNU4ATAC
Microcephalic osteodysplastic primordial dwarfism (MOPD2) AR PCNT
Dysplasias With Multiple Joint Dislocations
Desbuquois dysplasia AR CANT1, XYLT1
Pseudodiatrophic dysplasia AR Unknown
Chondrodysplasia Punctata Group (CDP)
CDP, X-linked dominant XLD EBP
Conradi-Hunermann type (CDPX2) XLR ARSE
Brachytelephalangic type (CDPX1) XLD NSDHL
Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome XLD EBP
Greenberg dysplasia AR LBR
Rhizomelic CDP type 1 AR PEX7
Rhizomelic CDP type 2 AR DHPAT
Rhizomelic CDP type 3 AR AGPS
Neonatal Osteosclerotic Dysplasias
Bloomstrand dysplasia AR PTHR1
Desmosterolosis AR DHCR24
Caffey disease (infantile) AD COL1A1
Raine dysplasia AR FAM20C
Increased Bone Density Group
Osteopetrosis (severe neonatal or infantile forms) AR TCIRG1
Osteopetrosis (severe neonatal or infantile forms) AR CLCN7
Dysosteosclerosis AR SLC29A3
Lenz-Majewski hyperostotic dysplasia SP PTDSS1
Osteogenesis Imperfecta and Decreased Bone Density Group
Osteogenesis imperfecta (OI), moderate, severe, and perinatal lethal AD COL1A1, COL1A2, IFITM5,
OI, moderate, severe, and perinatal lethal AR CRTAP, P3H1, PPBI, FKBP10, HSP47, SP7, WNT1, TMEM33B,
Bruck syndrome PLOD2, FKBP10,
Osteoporosis-pseudoglioma syndrome AR LRP5
Cole-Carpenter dysplasia SP LRP5, SEC24D, P4HB, CRTAP
Abnormal Mineralization Group
Hypophosphatasia, perinatal and infantile forms AR ALPL

From Krakow D: Skeletal dysplasias. Clin Perinatol 42:301-319, 2015.


Clinically Oriented Classification


A skeletal anomaly is suspected prenatally either by family history or by ultrasound findings, while after birth, the diagnosis is suspected based on family history and on clinical and radiographic findings. When a previous family member is affected, a gene panel can be offered to the mother (and if necessary to the father) to evaluate the risk to the fetus. Direct testing can also be performed and genetic panels evaluated on amniotic fluid or chorionic villus samples when sonographic findings suggestive of a skeletal anomaly are identified. Krakow and colleagues compiled a practical list of abnormal ultrasonographic findings seen in skeletal dysplasias along with a list of differential diagnoses for each finding ( Table 11-4 ). Once the differential diagnoses have been narrowed down to the most likely disorder(s), definitive genetic testing can be offered. Limitations of genetic panels include study cost, time to obtain the results, and that the genetic basis of all skeletal anomalies are not known. A benefit of molecular testing is that identification of the gene mutation can provide information on the severity of the disease.



TABLE 11-4

Common Abnormal Ultrasound Findings and Differential Diagnosis of Skeletal Disorders








































































































































































































































































Disorders MIM No. Gene Defect
Poor Mineralization of the Calvarium
Achondrogenesis IA 200600 Unknown
Cleidocranial dysplasia 119600 RUNX2
Hypophosphatasia 241500 ALPL
Osteogenesis imperfecta type II 166210 COL1A1
166210 COLIA2
610854 CRTAP
Fractures of Long Bones (Particular Femora)
Hypophosphatasia 241500 ALPL
Neurofibromatosis 162200 NF1
Osteogenesis imperfecta types II and III 166210 COL1A1
166210 COLIA2
610854 CRTAP
259440 P3H1
Bent/Bowed Bones by Ultrasound
Achondrogenesis IA 200600 Unknown
Achondrogenesis IB 600972 SLC26A2
Antley-Bixler syndrome 207410 FGFR2
Atelosteogenesis I 108720 FLNB
Atelosteogenesis II 256050 SLC26A2
Atelosteogenesis III 108721 FLNB
Campomelic dysplasia 114290 SOX9
Diastrophic dyplasia 222600 SLC26A2
Hypophosphatasia 241500 ALPL
Osteogenesis types II and III 166210 COL1A1
166210 COLIA2
610854 CRTAP
259440 P3H1
Short-rib polydactyly syndromes (types I-IV) 263530 Unknown
263520 Unknown
263510 Unknown
269860 Unknown
Stuve-Wiedemann syndrome 601559 LIFR
Thanatophoric dysplasia types I and II 187600 FGFR3
187601 FGFR3
Poor Mineralization of the Vertebrae
Achondrogenesis IA 200600 Unknown
Achondrogenesis IB 600972 SLC26A2
Achondrogenesis II 200610 COL2A1
Atelosteogenesis I 108720 FLNB
Atelosteogenesis II 256050 SLC26A2
Atelosteogenesis III 108721 FLNB
Opsismodysplasia 258480 Unknown
SMD—sedaghatian type 250220 Unknown
Thanatophoric dysplasia types I and II 187600 FGFR3
187601 FGFR3
Absent/Hypoplastic Scapula
Campomelic dysplasia 114290 SOX9
Equinovarus
Achondrogenesis IA 200600 Unknown
Achondrogenesis IB 600972 SLC26A2
Achondrogenesis II 200610 COL2A1
Atelosteogenesis I 108720 FLNB
Atelosteogenesis II 256050 SLC26A2
Atelosteogenesis III 108721 FLNB
Campomelic dysplasia 114290 SOX9
Desbuquois dysplasia 251450 Unknown
Diastrophic dyplasia 222600 SLC26A2
Ehler-Danlos syndrome types VIIA and B 130060 COL1A1, COL1A2
Hypophosphatasia 241500 ALPL
Larsen syndrome 150250 FLNB
Osteogenesis imperfecta types II and III 166210 COL1A1
166210 COLIA2
610854 CRTAP
259440 P3H1
Pseudodiastrophic dysplasia 264180 Unknown
Short-rib polydactyly syndromes (types I-IV) 263530 Unknown
263520 Unknown
263510 Unknown
269860 Unknown
Thanatophoric dysplasia types I and II 187600 FGFR3
187601 FGFR3

MIM, Mendelian Inheritance in Man; SMD, spondylometaphyseal dysplasia.

From Krakow D, Lachman RS, Rimoin DL: Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med 11:127-133, 2009.


Terminology Frequently Used to Describe Bone Dysplasias


Shortening of the extremities can involve the entire limb (micromelia), the proximal segment (rhizomelia), the intermediate segment (mesomelia), or the distal segment (acromelia) ( Fig. 11-6 ). The diagnosis of rhizomelia or mesomelia requires comparing the bony dimensions of the lower legs and forearms with those of the thighs and arms. Figures 11-7 and 11-8 display the relationships between the humerus and ulna, as well as the femur and tibia, which can be used for the objective assessment of rhizomelia and mesomelia. Table 11-5 presents a list of skeletal dysplasias characterized by rhizomelia, mesomelia, and micromelia.




FIG 11-6


Varieties of short limb dysplasia according to the involved segment.



FIG 11-7


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



FIG 11-8


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


TABLE 11-5

Skeletal Dysplasias Characterized by Rhizomelia, Mesomelia, and Micromelia








  • Rhizomelia




    • Thanatophoric dysplasia



    • Atelosteogenesis



    • Chondrodysplasia punctata (rhizomelic type)



    • Congenital short femur



    • Achondroplasia



    • Hypochondroplasia




  • Mesomelia




    • Mesomelic dysplasia (Langer, Reinhardt, and Robinow types)



    • Ellis–van Creveld syndrome (chondroectodermal dysplasia)




  • Acromesomelia




    • Ellis–van Creveld syndrome (chondroectodermal dysplasia)




  • Micromelia




    • Achondrogenesis



    • Atelosteogenesis



    • Short rib–polydactyly syndrome



    • Diastrophic dysplasia



    • Fibrochondrogenesis



    • Osteogenesis imperfecta (type II)



    • Kniest dysplasia



    • Dyssegmental dysplasia



    • Roberts syndrome




Several skeletal dysplasias feature alterations of the hands and feet. The term polydactyly refers to the presence of more than five digits. It is classified as postaxial if the extra digits are on the ulnar or fibular side, and preaxial if they are located on the radial or tibial side. Syndactyly refers to soft tissue or bony fusion of adjacent digits. Clinodactyly consists of deviation of a finger or fingers.


The most common spinal abnormality seen in skeletal dysplasias is platyspondyly, which consists of flattening of the vertebrae ( Fig. 11-9 ). Xyphosis, scoliosis ( Figs. 11-10 and 11-11 ), hemivertebra ( Fig. 11-12 ), and coronal clefting of vertebral bodies have been also reported.




FIG 11-9


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



FIG 11-10


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



FIG 11-11


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



FIG 11-12


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


Long bone biometry has been used extensively for the prediction of gestational age. Nomograms for this purpose display the distribution of bone lengths in relation to gestational weeks. For the proper use of these nomograms, the clinician must know the accurate gestational age of the fetus. Therefore, patients at risk for skeletal dysplasias are advised to seek prenatal care at an early gestational age in order to assess all clinical estimators of gestational age. Tables 11-6 and 11-7 present nomograms of the measurement of limb biometry for the upper and lower extremities, respectively. Comparisons between the limb dimensions and head circumference can be used for patients presenting with uncertain gestational age ( Figs. 11-13 and 11-14 ).



TABLE 11-6

Normal Values (3rd, 50th, 97th Percentiles) of the Lower Limb Bones (Millimeters)









































































































































































































































































































































































FEMUR TIBIA FIBULA
Week 3rd 50th 97th 3rd 50th 97th 3rd 50th 97th
12 4.4 7.7 11.1 4.4 7.6 10.8 3.6 6.8 10.0
13 7.5 10.9 14.4 5.8 9.2 12.5 5.2 8.5 11.8
14 10.6 14.1 17.6 8.0 11.4 14.8 7.4 10.8 14.2
15 13.6 17.2 20.8 10.6 14.1 17.6 10.0 13.5 17.0
16 16.5 20.3 24.0 13.3 16.9 20.5 12.8 16.4 20.0
17 19.4 23.3 27.2 16.2 19.9 23.5 15.6 19.3 23.0
18 22.3 26.3 30.2 19.0 22.8 26.6 18.4 22.2 26.0
19 25.1 29.2 33.3 21.8 25.7 29.6 21.2 25.1 29.0
20 27.9 32.1 36.3 24.5 28.5 32.5 23.9 27.9 31.8
21 30.6 34.9 39.2 27.2 31.2 35.3 26.4 30.5 34.6
22 33.2 37.6 42.0 29.7 33.8 38.0 28.9 33.1 37.3
23 35.8 40.3 44.8 32.1 36.4 40.6 31.2 35.5 39.8
24 38.3 42.9 47.6 34.4 38.8 43.1 33.5 37.9 42.3
25 40.8 45.5 50.2 36.6 41.0 45.5 35.6 40.1 44.6
26 43.1 48.0 52.8 38.7 43.2 47.8 37.6 42.2 46.8
27 45.4 50.4 55.3 40.7 45.3 49.9 39.6 44.3 49.0
28 47.6 52.7 57.8 42.6 47.3 52.0 41.4 46.2 51.0
29 49.8 55 60.1 44.4 49.2 54.0 43.1 48.0 52.9
30 51.8 57.1 62.4 46.1 51.0 55.9 44.8 49.8 54.8
31 53.8 59.2 64.6 47.7 52.7 57.7 46.4 51.5 56.6
32 55.7 61.2 66.7 49.3 54.4 59.5 47.9 53.1 58.3
33 57.5 63.1 68.7 50.8 55.9 61.1 49.3 54.6 59.9
34 59.2 64.9 70.6 52.2 57.5 62.7 50.7 56.1 61.5
35 60.8 66.6 72.4 53.5 58.9 64.3 52.0 57.5 63.0
36 62.3 68.2 74.1 54.8 60.3 65.7 53.2 58.8 64.4
37 63.7 69.7 75.8 56 61.6 67.2 54.4 60.1 65.8
38 64.9 71.1 77.3 57.2 62.9 68.5 55.5 61.3 67.1
39 66.1 72.4 78.7 58.3 64.1 69.8 56.6 62.5 68.4
40 67.2 73.6 79.9 59.4 65.2 71.1 57.6 63.6 69.6
41 68.1 74.6 81.1 60.4 66.4 72.3 58.6 64.7 70.8
42 69.0 75.6 82.2 61.4 67.4 73.5 59.5 65.8 72.0

From Chitty LS, Altman DG: Charts of fetal size: limb bones. Br J Obstet Gynaecol 109:919-929, 2002.


TABLE 11-7

Normal Values (3rd, 50th, 97th Percentiles) for the Upper Limb Bones (Millimeters)









































































































































































































































































































































































HUMERUS ULNA RADIUS
Week 3rd 50th 97th 3rd 50th 97th 3rd 50th 97th
12 3.7 7.1 10.6 3.9 7.3 10.7 2.2 5.5 8.8
13 7.2 10.7 14.2 6.2 9.6 13.1 4.8 8.2 11.6
14 10.5 14.1 17.7 8.8 12.4 15.9 7.6 11.0 14.5
15 13.7 17.3 21.0 11.6 15.3 18.9 10.3 13.9 17.4
16 16.7 20.4 24.2 14.5 18.2 22.0 13.0 16.7 20.3
17 19.6 23.4 27.2 17.3 21.2 25.0 15.6 19.3 23.1
18 22.3 26.2 30.1 20.1 24.0 28.0 18.1 21.9 25.7
19 24.9 28.9 32.9 22.8 26.8 30.8 20.4 24.4 28.3
20 27.4 31.5 35.5 25.3 29.4 33.5 22.7 26.7 30.7
21 29.8 34.0 38.1 27.8 32.0 36.2 24.8 28.9 32.9
22 32.1 36.3 40.5 30.1 34.4 38.7 26.8 30.9 35.1
23 34.3 38.6 42.9 32.3 36.6 41.0 28.6 32.9 37.1
24 36.4 40.7 45.1 34.3 38.8 43.3 30.4 34.7 39.1
25 38.4 42.8 47.2 36.3 40.9 45.5 32.0 36.5 40.9
26 40.3 44.8 49.3 38.2 42.8 47.5 33.6 38.1 42.6
27 42.1 46.7 51.3 39.9 44.7 49.5 35.1 39.7 44.3
28 43.9 48.5 53.2 41.6 46.5 51.3 36.5 41.2 45.8
29 45.5 50.2 55.0 43.2 48.2 53.1 37.8 42.6 47.3
30 47.1 51.9 56.7 44.7 49.8 54.8 39.0 43.9 48.7
31 48.6 53.5 58.4 46.2 51.3 56.4 40.2 45.1 50.1
32 50.0 55.0 59.9 47.5 52.7 58.0 41.3 46.4 51.4
33 51.4 56.4 61.5 48.8 54.1 59.4 42.4 47.5 52.6
34 52.7 57.8 62.9 50.0 55.4 60.8 43.4 48.6 53.8
35 53.9 59.1 64.3 51.2 56.7 62.2 44.3 49.6 54.9
36 55.1 60.3 65.6 52.3 57.9 63.5 45.2 50.6 56.0
37 56.2 61.5 66.8 53.4 59.1 64.7 46.1 51.6 57.0
38 57.2 62.6 68.0 54.4 60.2 65.9 46.9 52.5 58.0
39 58.2 63.7 69.2 55.4 61.2 67.1 47.7 53.3 59.0
40 59.1 64.7 70.3 56.3 62.2 68.2 48.4 54.2 59.9
41 60.0 65.6 71.3 57.2 63.2 69.3 49.1 55.0 60.8
42 60.8 66.5 72.2 58.0 64.1 70.3 49.8 55.7 61.6

From Chitty LS, Altman DG: Charts of fetal size: limb bones. Br J Obstet Gynaecol 109:919-929, 2002.



FIG 11-13


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



FIG 11-14


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


The nomograms and figures in this chapter provide the mean, 3rd, and the 97th percentiles of limb biometric parameters. The reader should be aware that approximately 6% of the general population will fall outside these boundaries. Ideally, a more stringent criterion, such as the 1st percentile of limb growth for gestational age, should be used for diagnosis. Unfortunately, none of the currently available nomograms has been based on a sufficient number of patients to provide an accurate discrimination between the 3rd and the 1st percentiles. However, most skeletal dysplasias diagnosed in utero or at birth are associated with dramatic long bone shortening, and under these circumstances, the precise boundary used (i.e., 1st or 3rd percentile) is not critical. An exception to this is achondroplasia, in which limb biometry is only mildly affected until the third trimester, when abnormal growth can be detected by examining the slope of growth of the femur length. In a study including 127 cases of 17 skeletal dysplasias, Gonçalves and Jeanty concluded, with the use of discriminant analysis, that the degree of femur length shortening can be used as the initial step in distinguishing among the five most common disorders: thanatophoric dysplasia, OI type II, achondrogenesis, achondroplasia, and hypochondroplasia. Gabrielli and coworkers reported the early diagnosis of skeletal dysplasias in eight women with previous pregnancies affected with skeletal dysplasias. Five recurrent cases were identified during the first trimester by the femur length/crown rump length ratio and the femur length/biparietal diameter ratio. The results of this study suggest that early evaluation of fetal structures might be helpful in the diagnosis of severe skeletal dysplasias. Nomograms for long bone measurements according to crown rump length in a large population of normal fetuses examined between 11 and 14 weeks of gestation have been published, but still their role in the early assessment of pregnancies at risk for skeletal dysplasias remains to be determined.


Clinical Presentation


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


Diagnostic Imaging and Prenatal Diagnosis of Skeletal Dysplasias


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


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



TABLE 11-8

Sensitivity of Ultrasound in the Prenatal Diagnosis of Skeletal Dysplasias



























































Author Year Number of Cases Sensitivity (%) ( n )
Gordienko et al 1996 26 73 (9)
Gaffney et al 1998 35 31 (11)
Tretter et al 1998 27 48 (13)
Hersh et al 1998 23 48 (11)
Doray et al 2000 47 60 (28)
Parilla et al 2003 31 65 (20)
Witters et al 2008 38 66 (25)
Schramm et al 2009 162 68 (110)
Yeh et al 2011 40 70 (28)
Khalil et al 2011 15 40 (6)

Superscript numbers indicate references listed at the end of the chapter.

Modified from Hall CM, Offiah AC, Forzano F, et al: Fetal and Skeletal Dysplasias; an Atlas of Multimodality Imaging. London, Radcliffe Publishing, 2012, p 11.


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




FIG 11-15


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


TABLE 11-9

Additional Phenotypic Findings and Improved Visualization in Skeletal Dysplasias Imaged by Prenatal Three-Dimensional Ultrasound (3DUS) as Compared to Two-Dimensional Ultrasound (2DUS)


















































Skeletal Dysplasia Phenotypic Characteristics Identified Better by 3DUS than 2DUS
Platyspondylic lethal chondrodysplasia Enhanced visualization of femoral and tibial bowing;
Better characterization of the facial soft tissues with surface rendering
Campomelic dysplasia Micrognathia, flat face, hypoplastic scapulae, bifid foot, fan-like position of the toes
Thanatophoric dysplasia Improved characterization of frontal bossing and depressed nasal bridge;
Demonstration of redundant skinfolds;
Low-set dysmorphic ears
Achondroplasia Improved characterization of frontal bossing and depressed nasal bridge;
Superior evaluation of the epiphyses and metaphyses of the long bones, with demonstration of a vertical metaphyseal slope;
Caudal narrowing of the interpedicular distance;
Clear visualization of trident hand;
Better visualization of disproportion between limb segments
Chondrodysplasia punctata, rhizomelic form Improved characterization of the Binder facies (depressed nasal bridge, midface hypoplasia, small nose with upturned alae);
Identification of laryngeal stippling
Achondrogenesis Panoramic demonstration of short neck and severe shortening of all segments of the limbs
Jarcho-Levin syndrome Vertebral defects with absence of ribs and transverse process
Spondylocostal dysostosis Fan-like rib cage with rib fusion
Larsen syndrome Genu recurvatum, midface hypoplasia, low-set ears
Cleidocranial dysplasia Widened cranial sutures, poor mineralization of the occipital bones, pseudoarthrosis of the clavicle
Apert syndrome Coronal craniosynostosis

Phenotypic characteristics of osteogenesis imperfecta, and short rib–polydactyly (SRP) syndrome, have also been described using 3DUS, although no additional findings to 2DUS were observed.

Superscript numbers indicate references listed at the end of the chapter.


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




FIG 11-16


Comparison of phenotypic features of osteogenesis imperfecta by three-dimensional helical computed tomography (3HCT), three-dimensional ultrasound (3DUS) images, two-dimensional ultrasound (2DUS) images, and postmortem radiographs. A, 2DUS: transverse section of fetal head with a skull fracture (f) deformed by the transducer pressure. B, 2DUS: coronal section of fetal thorax showing irregular ribs ( arrow ). C, 2DUS: sagittal section of the right superior limb showing a short and bowed arm. D, 2DUS: sagittal section of fetal femur with a fracture (f). E, 3DUS image showing lateral view of fetal skull with a fracture (f) that could be differentiated from a normal coronal suture (CS) by the location and the abnormal shape depending on the transducer pressure; this was confirmed by postmortem examination. F, 3DUS-rendered bone mode demonstrating posterior view of fetal thorax showing fractured and irregular ribs (f). G, 3DUS-rendered bone mode image showing short and bowed radius and ulna. H, 3DUS-rendered bone mode image showing a fractured femur (f). I, 3HCT: posterior view of entire fetus confirming fractures (f) of ribs and femur as well as decreased mineralization of the skull. J, Postmortem radiologic examination, confirming shortening, bowing, and fracture of long bones.

(From Ruano R, Molho M, Roume J, et al: Prenatal diagnosis of fetal skeletal dysplasias by combining two-dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography. Ultrasound Obstet Gynecol 24:134, 2004.)


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


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


Approach to the Diagnosis of Skeletal Dysplasias


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



TABLE 11-10

Checklist for Ultrasound Evaluation of a Fetus With Suspected Skeletal Dysplasia







  • 1.

    Long bones




    • Presence/absence



    • Length/shape



    • Mineralization/fractures



  • 2.

    Hands and feet




    • Presence/absence



    • Position/movements



    • Fingers and toes: number/position/movements



  • 3.

    Spine




    • Shape/curvatures



    • Mineralization



    • Clefts



    • Size and number of vertebral bodies



  • 4.

    Skull




    • Shape/mineralization/size



  • 5.

    Face




    • Profile



    • Hypertelorism/hypotelorism



    • Clefts



  • 6.

    Thorax




    • Shape



    • Lung and thoracic areas/volumes



    • Ribs: shape/fractures/number



    • Scapula/clavicle



  • 7.

    Fetal movements


  • 8.

    Complete anatomic evaluation


  • 9.

    Echocardiography


  • 10.

    Amniotic fluid



Evaluation of the Long Bones


Measurements.


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


Degree of Mineralization.


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




FIG 11-17


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


Degree of Long Bone Curvature.


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




FIG 11-18


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


Metaphyseal Flaring.


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


Femoral Angle.


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


Fractures.


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




FIG 11-19


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



FIG 11-20


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


Prediction of Pulmonary Hypoplasia


Skeletal dysplasias associated with a hypoplastic thorax frequently have lung hypoplasia, which is the most frequent cause of death for these conditions. When a severe skeletal dysplasia is diagnosed, the presence of marked thoracic involvement and pulmonary hypoplasia will allow the clinician to counsel the parents regarding prognosis, even though the specific type of skeletal dysplasia may be unknown. A number of sonographic parameters have been investigated for the prediction of pulmonary hypoplasia. They include measurements of the thorax and lungs, ratios between thoracic measurements and other biometric parameters, Doppler velocimetry of the pulmonary arteries, Doppler evaluation of tracheal fluid flow, and more recently, three-dimensional volumetric measurements of the fetal lungs by either sonography or MRI.


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




  • Is the thorax extremely small? (thanatophoric dysplasia)



  • Is the thorax long and narrow? (Jeune syndrome)



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



  • Are there rib fractures? (osteogenesis imperfecta type II)



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



  • Are there fused ribs? (spondylocostal dysplasia)



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



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



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


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



TABLE 11-11

Skeletal Dysplasias Associated With Altered Thoracic Dimensions























































Long, Narrow Thorax
Asphyxiating thoracic dysplasia (Jeune)
Chondroectodermal dysplasia (Ellis–van Creveld)
Metatropic dysplasia
Fibrochondrogenesis
Atelosteogenesis
Camptomelic dysplasia
Jarcho-Levin syndrome
Achondrogenesis
Osteogenesis imperfecta type II
Hypophosphatasia
Dyssegmental dysplasia
Cleidocranial dysplasia
Short Thorax
Osteogenesis imperfecta (type II)
Kniest dysplasia (metatropic dysplasia type II)
Pena-Shokeir syndrome
Hypoplastic Thorax
Short rib–polydactyly syndrome (type I, type II)
Thanatophoric dysplasia
Cerebrocostomandibular syndrome
Cleidocranial dysplasia syndrome
Homozygous achondroplasia
Melnick-Needles syndrome (osteodysplasty)
Fibrochondrogenesis
Otopalatodigital syndrome type II



FIG 11-21


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



FIG 11-22


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



FIG 11-23


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


TABLE 11-12

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
































































































































































































































































































































































































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

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


TABLE 11-13

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






























































































































































































































































































































































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

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Feb 16, 2019 | Posted by in ULTRASONOGRAPHY | Comments Off on Fetal Musculoskeletal System

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