PDF
ePub
Citation
Print
Abstract
Objective
To determine the accuracy and usefulness of prenatal ultrasonographic and molecular genetic diagnosis in detection of skeletal dysplasia.
Methods
This study was based upon data of the 17 cases of skeletal dysplasia diagnosed by prenatal ultrasound and 7 cases by molecular diagnosis performed among the 17 cases and the 2 cases who has familial skeletal dysplasia by molecular diagnosis during the first trimester at Ewha and Eulji University from March 1998 to August 2005. A final diagnosis was sought on the basis of radiographic studies, molecular testing, or both.
Results
The mean gestational age at diagnosis was 24.9 weeks (range, 17 to 35 weeks). Nine cases were diagnosed before 24 weeks. A final diagnosis was obtained in 16 cases (94.1%). There was 1 false-positive diagnosis. The antenatal diagnosis was correct in 14 cases (82.4%). The 8 cases were prenatally confirmed and 1 case was postpartum confirmed using molecular genetic testing and accurate antenatal diagnosis and prediction was done. We were able to rule out skeletal dysplasia through chorionic villus sampling during the first trimester in the 2 cases with the family history with skeletal dysplasia.
Conclusion
Prenatal diagnosis of skeletal dysplasia can be a considerable diagnostic challenge. However, skeletal dysplasia is correctly diagnosed on the basis of prenatal meticulous ultrasound and antenatal prediction of lethality was highly accurate. Using prenatal molecular diagnosis, skeletal dysplasia can be diagnosed at first trimester of pregnancy and nonlethal skeletal dysplasia can be confirmed when prenatal ultrasound was nonspecific.
Figures and Tables
Figure 1
Infantograms of skeletal dysplasia. (A) Jarco-Levin syndrome. There are kyphoscoliosis and dyssegmentation of thoracic spines, agenesis of right upper ribs and fan-like appearance of right lower ribs. (B) Camptomelic dysplasia. There are bowing of both femur and hypoplastic scapula. (C) Achondroplasia. The long bones are rhizomelic shortening and mild bowing. Head is enlarged. (D) Osteogenesis imperfecta. There are severe micromelia, multiple fracture, brittle bone. (E) Thanatophoric dysplasia, type 1. Marked limb shortening and characteristic bowed telephone receiver femur are demonstrated.
Figure 3
Molecular studies of the osteogenesis imperfecta mother and the normal fetus. (A) Osteogenesis imperfecta mother : Col 1A2:G982A heterozygote (red arrow), (B) Normal baby
Table 1
Genes that can be screened or diagnosed in uterus
For a more detailed list of biochemical and molecular tests available for the diagnosis of skeletal dysplasia, see the University of Washington-sponsored WorldWideWeb page GeneTests (http://www.genetests.org).
COL1A1: Collagen Type1 Alpah 1, COL1A2: collagen type 1 alpha 2, COL2A1: collagen type 2 alpha 1, COL9A1: collagen type IX alpha 1, COL9A2: collagen type IX alpha 2, COL9A3: collagen type IX alpha 3, COMP: cartilage oligomeric matrix protein gene, EVC: Ellis-van Creveld, DTDST (SLC26A2): diastrophic dysplasia sulfate transporter (solute carrier family 26[sulfate transporter] member 2), MATN3: matrilin 3, RUNX2: runt-related transcription factor 2, FGFR: fibroblast growth factor receptor, SADDAN: severe achondroplasia with developmental delay and acanthosis nigricans.
References
1. Parilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med. 2003. 22:255–258.
2. Rimon DL, Lachman RS. Rimoin DL, Connor JM, Pyeritz RE, Korf B, editors. The chondrodysplsias. Emery and Rimoin's principles and practice of medical genetics. 1983. New York: Churchill Livingstone;703–733.
3. Savarirayan R, Rimoin DL. The skeletal dysplasias. Best Pract Res Clin Endocrinol Metab. 2002. 16:547–560.
4. Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet. 2002. 113:65–77.
5. Dighe M, Fligner C, Cheng E, Warren B, Dubinsky T. Fetal skeletal dysplasia: an approach to diagnosis with illustrative cases. Radiographics. 2008. 28:1061–1077.
6. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986. 23:328–332.
7. Kaufman RL, Rimoin DL, McAlister WH, Kissane JM. Thanatophoric dwarfism. Am J Dis Child. 1970. 120:53–57.
8. Spranger J, Maroteaux P. The lethal osteochondrodysplasias. Adv Hum Genet. 1990. 19:1–103. 331–332.
9. Romero R, Athanassiadis AP, Jeanty P. Fetal skeletal anomalies. Radiol Clin North Am. 1990. 28:75–99.
10. Mortier GR, Rimoin DL, Lachman RS. The scapula as a window to the diagnosis of skeletal dysplasias. Pediatr Radiol. 1997. 27:447–451.
11. Tretter AE, Saunders RC, Meyers CM, Dungan JS, Grumbach K, Sun CC, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet. 1998. 75:518–522.
12. Lee JY, Park SW, Park JH, Baek MJ, Lee MG, Song SA, et al. A case of the type I thanatophoric dysplasia diagnosed in the 2nd trimester. Korean J Obstet Gynecol. 2005. 48:2217–2222.
13. Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet. 1997. 70:427–436.
14. Jones KL. Jones KL, Smith DW, editors. Thanatophoric dysplasia. Smith's recognizable patterns of human malformation. 2006. 6th ed. Philadelphia: Elsevier Saunders;382–383.
15. Doray B, Favne R, Viville B, Langer B, Dreyfus M, Stoll C. A repot of the diagnosis and dysplasia. Presented at the 4th International Skeletal Dysplasia Meeting. 1999. 1999 Jul 29- Aug 1; . Baden-Baden, Germany: 49.
16. Cohen MM Jr. Short-limb skeletal dysplasias and craniosynostosis: what do they have in common? Pediatr Radiol. 1997. 27:442–446.
17. Martinez-Frias ML, Ramos-Arroyo MA, Salvador J. Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet. 1988. 31:815–820.
18. Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI Jr, Gusella JF, Tsipouras P. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nat Genet. 1994. 6:314–317.
19. Le Merrer M, Rousseau F, Legeai-Mallet L, Landais JC, Pelet A, Bonaventure J, et al. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nat Genet. 1994. 6:318–321.
20. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004. 363:1377–1385.
21. Ruvolo KA, Filly RA, Callen PW. Evaluation of fetal femur length for prediction of gestational age in a racially mixed obstetric population. J Ultrasound Med. 1987. 6:417–419.
22. Mahoney MJ, Hobbins JC. Prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with fetoscopy and ultrasound. N Engl J Med. 1977. 297:258–260.
23. Merz E, Grussner A, Kern F. Mathematical modeling of fetal limb growth. J Clin Ultrasound. 1989. 17:179–185.
24. Shalev E, Feldman E, Weiner E, Zuckerman H. Assessment of gestational age by ultrasonic measurement of the femur length. Acta Obstet Gynecol Scand. 1985. 64:71–74.
25. Warda AH, Deter RL, Rossavik IK, Carpenter RJ, Hadlock FP. Fetal femur length: a critical reevaluation of the relationship to menstrual age. Obstet Gynecol. 1985. 66:69–75.
26. Brons JT, van der Harten HJ, Wladimiroff JW, van Geijn HP, Dijkstra PF, Exalto N, et al. Prenatal ultrasonographic diagnosis of osteogenesis imperfecta. Am J Obstet Gynecol. 1988. 159:176–181.
27. Stephens JD, Filly RA, Callen PW, Golbus MS. Prenatal diagnosis of osteogenesis imperfecta type II by real-time ultrasound. Hum Genet. 1983. 64:191–193.
28. Munoz C, Filly RA, Golbus MS. Osteogenesis imperfecta type II: prenatal sonographic diagnosis. Radiology. 1990. 174:181–185.
29. Wenstrup RJ, Cohn DH, Cohen T, Byers PH. Arginine for glycine substitution in the triple-helical domain of the products of one alpha 2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype. J Biol Chem. 1988. 263:7734–7740.
30. Barsh GS, Byers PH. Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta. Proc Natl Acad Sci U S A. 1981. 78:5142–5146.
31. Byers PH, Tsipouras P, Bonadio JF, Starman BJ, Schwartz RC. Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet. 1988. 42:237–248.
32. Steiner RD, Pepin M, Byers PH. Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta. J Pediatr. 1996. 128:542–547.
33. Pepin M, Atkinson M, Starman BJ, Byers PH. Strategies and outcomes of prenatal diagnosis for osteogenesis imperfecta: a review of biochemical and molecular studies completed in 129 pregnancies. Prenat Diagn. 1997. 17:559–570.
34. Fauci A, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison's Principles of Internal Medicine. 1998. 14th ed. New York: McGraw-Hill.
35. Seol HJ, Kim MJ, Kim MK, Park HJ, Shin JH, An HS, et al. A Case of osteogenesis imperfecta: diagnosis in uterus by ultrasonogram. Korean J Obstet Gynecol. 2003. 46:1246–1249.
36. Ferreira JC, Carter SM, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, et al. Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol. 1999. 14:426–430.
37. Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg JS, Dufresne C, et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet. 1995. 57:321–328.
XML Download