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  Assessement of the Fetus with Suspected
  Osteochondroplasia

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    Skeletal dysplasias are a heterogeneous group of more than 200 disorders characterized by abnormalities of cartilage and bone growth

    CONSIDERATIONS
    • A primary objective in the evaluation of skeletal dysplasias is to determine lethal from non lethal dysplasias, since cesarean section for fetal indications would not be indicated in the case of a lethal dysplasia.
    • Appropriate genetic counseling should follow confirmation of the diagnosis by a clinician experienced in skeletal dysplasias. Since the diagnosis of skeletal dyplasias is made for the most part by radiological evaluation, an attempt should be made to deliver the fetus intact if the patient chooses to have elective termination.
    • Cesarean section has been recommended for fetuses with achondroplasia or osteogenesis imperfecta to reduce the theoretical risk of possible CNS complications from vaginal delivery. However, patients should be informed that retrospective studies have failed to show a significant improvement in the outcomes of fetuses with skeletal dyplasias delivered by cesarean section [1,2].
    TERMS
    • Rhizomelia: Small proximal extremities ( femur, humerus).
    • Mezomelia: Small intermediate segments of long bones ( ulna, radius etc.).
    • Acromelia: Shortening of the distal segment (hands or feet).
    • Micromelia: Shortening of all segment of the extremities.
    • Campomelia: Bowing of the long bones.
    • Preaxial: Located on the radial or thumb side or the tibial side
    • Postaxial: Located on the ulnar or little finger side or the fibular side
    • Syndactyly: Digits stuck together or fused (webbed)
    • Scoliosis: Laterally curved or bent spine.
    • Kyphosis: Abnormal posterior curvature of the thoracic spine (hunchback)
    • Lordosis: Abnormal anterior curvature of the lumbar spine (swayback or saddle back)
    • Hemivertebrae: Partially formed vertebral body
    • Platyspondyly: Flattening of the vertebral body
    ASSESSMENT
    The assessment should include measurement of:
    • All extremities to detect predominantly shortened segments. Report of hypoplasia, absence of bones, degree of mineralization, bowing, angulation, fractures or thickening secondary to callus formation.
      Evaluation of:
    • The shape of the thorax and number and appearance of the ribs.
      • The TC/AC ratio may be used either alone or in addition to the TC and peak systolic velocity (PSV) of the proximal artery branch to estimate the risk of pulmonary hypoplasia.
      • A TC/AC of < 0.76 , TC < 2 SD below the mean, and a PSV < 40 cm/sec of the proximal arterial pulmonary branch are indicative of lethal pulmonary hypoplasia [3,4].
    • The fetal spine assessing the degree of ossification, hemivertebrae, scoliosis, gross vertebral disorganization, and platyspondylia.
    • Hands and feet for polydactyly, missing digits, and postural deformities including clubfoot and hypoplastic or hitchhiker thumbs.
    • Fetal craniofacial structures for membranous ossification, orbits (evaluate to exclude ocular hypertelorism), retrognathia/micrognathia, facial or lip clefting, frontal bossing, and cloverleaf skull deformity.
    • Fetal movement. Movement usually is decreased in fetuses with bone dysplasias, especially lethal types.
    • Associated anomalies including maternal hydramnios, fetal hydrops, congenital heart defects and cystic renal malformation.
       

    ESTABLISH A DIFFERENTIAL
    • Once the fetus has undergone ultrasound evaluation, Table 1 may be used to guide additional cytogenetic and DNA testing [5-11].
    • Fetal radiography may be considered to obtain more information about bone shape and mineralization.
    • Serial sonograms may help to establish the diagnosis more firmly [12]
    • Consider the following consultation
        The International Skeletal Dysplasia Registry
        Cedars-Sinai Medical Center
        444 S. San Vicente Boulevard, Suite 1001
        Los Angeles, CA 90048
        MaryAnn Priore, Program Coordinator, at (310) 423-9915.
    POSTPARTUM
    • Obtain radiograms of the entire skeleton including anterior, posterior, and Towne views of the skull and antero-posterior views of the spine and extremities with separate films of the hands and feet.
    • Consider the following consultations:
      • Clinical geneticist
      • Orthopedist
      • Radiologist
      • Pediatric surgeon
      • Ophthalmologist
      • Otolaryngologist
      • Neurologist
      • Physical and occupational therapists
      • The International Skeletal Dysplasia Registry
        Cedars-Sinai Medical Center
    • Contacts Patient and Family Support
    TABLE 1. DIFFERENTIAL DIAGNOSIS OF SELECTED OSTEOCHONDRODYSPLASIAS
    Condition Relative Frequency

    Most Common Features

    Mutation

    Inheritance

    Viability

    Thanatophoric dysplasia

    Common

    Macrocephaly
    Frontal bossing
    Severe micromelia
    Narrow thorax with short ribs
    Platyspondyly
    Brachydactyly
    Polyhydramnios
    Occasional: Agenesis of the corpus callosum,hydrocephalus, cardiac defect, kidney malformation

    FGFR3

    AD

     

         Type I (most common)

     

    Telephone receiver femora,

    normal skull

     

     

    Lethal

         Type II

     

    Cloverleaf-shaped skull

     

     

    Lethal

    Achondroplasia  

    Common

     

    FGFR3

    AD

     

         Heterozygous

     

    Macrocephaly
    Rhizomelia
    Trident hand
    Brachydactyly

    Occasional: Hydrocephalus

     

     

    Nonlethal

         Homozygous

     

    Severe micromelia
    Narrow thorax with short ribs

     

     

    Lethal

    Osteogenesis imperfecta

    Common

     

    COL1A1, COL1A2

     

     

         Type I  

     

    Blue sclera
    Not usually diagnosed prenatally.

     

    AD

    Nonlethal

         Type II

     

    Poor ossification of skull
    Blue sclera
    Micromelia
    with fractures and campomelia
    Narrow thorax with or without rib fractures
    Platyspondyly
    Generalized demineralization
    Hydrops

     

    AD

    Lethal

         Type III

     

    Poor ossification of skull
    Sclera may be blue at birth
    Micromelia
    with variable fractures and campomelia
    Generalized demineralization

     

    AD or AR

    Nonlethal

         Type IV 

     

    Normal sclera
    Not usually diagnosed prenatally.

     

    AD

    Nonlethal

    Achondrogenesis

    Common

     

     

     

     

         Type IA

     

    Macrocephlay
    Micrognathia
    Narrow thorax, rib fractures
    Severe micromelia
    Poor ossification of skull, spine and pelvis
    Polyhydramnios

    Hydrops

     

    AR

    Lethal

         Type IB 

     

    Macrocephlay
    Micrognathia
    Narrow thorax, occasional rib fractures
    Severe micromelia
    Poor ossification of skull, spine and pelvis

    DTDST

    AR

    Lethal

         Type II 

     

    Relatively normal ossification of the skull
    No rib fractures
    Occasional: cleft palate, hydrops

    COL2A1

    AD

    Lethal

    Asphyxiating thoracic dysplasia (Jeune syndrome)

    Uncommon

    Mild rhizomelia
    Narrow thorax with short ribs
    Brachydactyly
    Occasional: Polydactyly, cardiac defect

     

    AR

    Usually lethal

    Chondrodysplasia punctata

    Uncommon

    Group of bone dysplasias with common characteristic is  stippling of the epiphyses.

     

     

     

         Rhizomelic form      
         autosomal recessive

     

    Microcephaly
    Cleft palate
    Coronal cleft of vertebrae
    Kyphoscoliosis
    Rhizomelia

    PEX

    AR

    Usually lethal
    by age of 2 years

        Nonrhizomelic form  
        autosomal dominant
       (Conradi-Hunermann)

     

    Asymmetric mild shortening of extremities
    Kyphoscoliosis

     

    AD

    Nonlethal

    Diastrophic dysplasia

    Uncommon

    Scoliosis
    Micromelia
    Hitchhiker thumb
    Clubfoot
    Occasional: Small thoracic cage, cardiac defect (found mostly in lethal cases)

    DTDST

    AR

    Usually
    Nonlethal

    Short rib polydactyly  syndrome

    Uncommon

    Narrow thorax with short ribs
    Micromelia

     

     

     

    Type I

     

    Cardiac defects:Transposition of great vessels
    Polycystic kidneys

     

    AR

    Lethal

    Type II

     

    Cleft palate
    Polydactyly
    Disproportionate shortening of the tibia
    Polycystic kidneys
    Ambiguous geniltalia

     

    AR

    Lethal

    Chondroectodermal dysplasia

    (Ellis-Van Creveld Syndrome)

    Uncommon

    Mild micromelia or mesomelic
    Narrow thorax
    Postaxial polydactyly
    Cardiac defects: Atrial septal defect or single atrium
    Occasional: Dandy-Walker Malformation, renal agenesis

     

    AR

    ~ 50% of cases are lethal

    Hypochondroplasia

    Uncommon

    Macrocephlay
    Mild rhizomelia

    Brachydactyly

    FGFR3

    AD

    Nonlethal

    Campomelic dysplasia

    Rare

    Macrocephaly
    Cleft  palate
    Narrow thorax
    Severe hypoplasia of the scapula
    Eleven pairs of ribs
    Mild micromelia
    Mild bowing of femur and tibia
    Sex reversal in some karyotypic males
    Occasional: Hydronephrosis hydrocephalus,  cardiac defects

    SOX9

    AD

    Usually lethal

    Mesomelic dysplasia, Langer type

    Rare

    Mesomelia

    SHOX

    AR

    Nonlethal

    Kniest dysplasia

    Rare

    Cleft palate
    Platyspondyly
    Kyphoscoliosis
    Coronal vertebral clefts
    Micromelia
    Dumbbell-shaped femur

    COL2A1

    AD

    Nonlethal

    Dyssegmental dysplasia

    Rare

    Cleft palate
    Hydrocephalus
    Narrow thorax
    Abnormally segmented vertebrae
    Micromelia

     

    AR

    Lethal

    Hypophosphatasia , perinatal lethal

    Rare

    Poor ossification of skull
    Generalized demineralization.
    Micromelia
    Bowed lower extremities
    Other: Craniosynostosis, blue sclera

    ALPL

     

    AR

    Lethal

    Atelosteogenesis I

    Rare

    Narrow thorax
    Eleven pairs of ribs
    Severe rhizomelia
    Absent or hypoplastic fibula

    DTDST (typeII)

    Sporadic

    Lethal

    Focal femoral deficiency

    Rare

    Fibular hemimelia
    When bilateral usually does not demonstrate femoral head or acetabulum

     

     

    Nonlethal

    Fibroblast growth factor receptor 3 gene = FGFR3 ; diastrophic dysplasia sulfate transporter gene= DTDST ; procollagen II gene=COL2A1 peroxisomal biogenesis factors=PEX ; SRY-box 9 protein =SOX9; procollagen I genes =COL1A1, COL1A2; liver alkaline phosphatase gene=ALPL Short stature homeobox protein = SHOX; ; Autosomal dominant=AD; Autosomal recessive=AR

    CLINICAL TESTING LABORATORIES

    Condition

    Clinical Testing Laboratory

    Achondrogenesis Type 1B

    Centre Hospitalier Universitaire Vaudois
    Division of Molecular Pediatrics Lausanne, Switzerland
    Director: Andrea Superti-Furga, MD
    Contact: Luisa Bonafe, MD
    email: luisa.bonafe@hospvd.ch
    phone:
    (+41) 21-314-3483
    fax:
    (+41) 21-314-3546

    Achondrogenesis type 2

    Tulane University Health Sciences Center
    Matrix DNA Diagnostics Laboratory New Orleans, LA 

    co-Contact: James Hyland, MD, PhD
    email: jhyland@tulane.edu
    phone:
    (504) 988-7061
    fax:
    (504) 988-7704

    Achondroplasia, Hypochondroplasia

    Stanford Hospital and Clinics
    Molecular Pathology Laboratory Stanford, CA 
    Contact: Dana Bangs
    email: dana.bangs@medcenter.stanford.edu
    phone: (650) 725-7476
    fax:
    (650) 498-5649

    Comprehensive Genetic Services, SC, Molecular Diagnostic Laboratory; Milwaukee, WI 
    Director: Anthony T Garber, PhD
    email: dnadoc@worldnet.att.net
    phone:
    (414) 393-1000
    phone2:
    (877) 266-7436
    ax:
    (414) 393-1399

    Atelosteogenesis Type 2

    Centre Hospitalier Universitaire Vaudois

    Camptomelic Dysplasia

    Institute of Human Genetics
    Scherer Laboratory Freiburg, Germany
    Director: Gerd Scherer, PhD
    email: scherer@ukl.uni-freiburg.de
    phone:
    (+49) 761-270-7030
    phone2:
    (+49) 761-270-7029
    fax:
    (+49) 761-270-7041

    Diastrophic Dysplasia

    Centre Hospitalier Universitaire Vaudois

    Osteogenesis Imperfecta Type I

     Osteogenesis Imperfecta Type II

     Osteogenesis Imperfecta Type III

     Osteogenesis Imperfecta Type IV

    University of Washington Health Sciences Center
    Collagen Diagnostic Laboratory Seattle, WA
    Contact: Melanie G Pepin, MS
    email: mpepin@u.washington.edu
    phone:
    (206) 543-5464 f
    ax:
    (206) 616-1899

    Tulane University Health Sciences Center
    Matrix DNA Diagnostics Laboratory New Orleans, LA 

    Multiple Epiphyseal Dysplasia, Recessive

    Centre Hospitalier Universitaire Vaudois

    Kniest Dysplasia

    Tulane University Health Sciences Center
    Matrix DNA Diagnostics Laboratory New Orleans, LA

    Langer Mesomelic Dwarfism

    Esoterix
    Molecular Endocrinology Calabasas Hills, CA

    Director: Samuel H Pepkowitz, MD
    Contact: Mark Stene, PhD
    email: mark.stene@esoterix.com
    phone: (800) 444-9111
    fax:
    (818) 880-5121

    Metaphyseal Chondrodysplasia, Schmid Type

    Tulane University Health Sciences Center
    Matrix DNA Diagnostics Laboratory New Orleans, LA

    Rhizomelic Chondrodysplasia Punctata Type 1

    Rhizomelic Chondrodysplasia Punctata Type 2

    Rhizomelic Chondrodysplasia Punctata Type 3

    Kennedy Krieger Institute
    Genetics Laboratory, Peroxisomal Disorders Section
    Baltimore, MD 
    co-Contact: Ann B Moser
    email: mosera@kennedykrieger.org
    phone: (443) 923-2760 fax: (443) 923-2755
    co-Contact:Steven J Steinberg, PhD
    email: steinbergs@kennedykrieger.org
    phone: (443) 923-2760 fax: (443) 923-2755

    Spondyloepiphyseal Dysplasia, Congenita

    Tulane University Health Sciences Center
    Matrix DNA Diagnostics Laboratory New Orleans, LA

    Thanatophoric Dysplasia Type IThanatophoric Dysplasia Type II

    Comprehensive Genetic Services, SC,
    Molecular Diagnostic Laboratory; Milwaukee, WI 

     

    REFERENCES:
    1. Kuller JA, Katz VL, Wells SR, Wright LN, McMahon MJ. Cesarean delivery for fetal malformations. Obstet Gynecol Surv. 1996;51:371-5. MEDLINE
    2. Cubert R, Cheng EY, Mack S, Pepin MG, Byers PH.Osteogenesis imperfecta: mode of delivery and neonatal outcome.Obstet Gynecol. 2001 ;97:66-9. MEDLINE
    3. Yoshimura S, Masuzaki H, Gotoh H, Fukuda H, Ishimaru T. Ultrasonographic prediction of lethal pulmonary hypoplasia: comparison of eight different ultrasonographic parameters. Am J Obstet Gynecol. 1996;175:477483 MEDLINE
    4. Laudy JA, Tibboel D, Robben SG, de Krijger RR, de Ridder MA, Wladimiroff JW.
    Prenatal prediction of pulmonary hypoplasia: clinical, biometric, and Doppler velocity correlates.
    Pediatrics. 2002;109:250-8. MEDLINE
    5.Kozlowski K, Beighton P. Gamut Index of Skeletal Dysplasias : An Aid to Radiodiagnosis. Berlin: Springer-Verlag, 1984
    6. Camera G, Mastoiacovo P. Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects. In Papadatos CJ, Bartsocas CS, eds. Skeletal dysplasia. New York: Alan R Liss;1982:441-449.
    7. Connor JM, Connor RAC, Sweet EM et al. Lethal neonatal chondrodysplasias in West Scotland, 1970-1983 with a description of a thanatophoric, dysplasia-like autosomal recessive disorder. Am J Med Genet 1985;22:243 MEDLINE
    8. Jones, KL. Smith's Recognizable Patterns of Human Deformation, 5th ed W. B. Saunders, Philadelphia, 1997
    9. Benacerraf, BR. Ultrasound of Fetal Syndromes, 1st ed Churchill Livingstone, Philadelphia, 1998, pp159-199.
    10. Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000.
    World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/
    11. Callen PW. Ultrasonography in obstetrics and gynecology. Wb. Saunders, 4th edition, 2000. The fetal musculoskeletal system. pp 359
    12. Goncalves L, Jeanty P.Fetal biometry of skeletal dysplasias: a multicentric study.
    J Ultrasound Med. 1994;13:977-85. MEDLINE

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    Created: 3/9/2003
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