Assessement of the Fetus with Osteochondroplasia

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

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
- Little People of America, Inc.
  P.O. Box 65030
  Lubbock, TX 79464-5030
  (888) LPA-2001 (English and Spanish)
  E-mail: LPADataBase@juno.com
- University of Kansas Genetic and Rare Conditions

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;175:477�483 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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