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Approach to prenatal diagnosis of the lethal skeletal dysplasias

Phyllis Glanc, MD, FRCPC
Section Editors
Deborah Levine, MD
Louise Wilkins-Haug, MD, PhD
Deputy Editor
Vanessa A Barss, MD, FACOG


Skeletal dysplasias or osteochondrodysplasia are a large, heterogeneous group of conditions involving the formation and growth of bone. Some skeletal dysplasias are associated with abnormalities in other organ systems.

These disorders begin to manifest in the early stages of fetal development. They can be due to extrinsic causes (eg, teratogen exposure, maternal autoimmune disorders) or intrinsic causes (single gene disorders with autosomal dominant, recessive, or X-linked modes of inheritance; imprinting errors or chromosome abnormalities) [1]. In view of the large number of skeletal dysplasias (over 436 known types), a nosology and classification system was developed that categorizes genetic bone disorders into 42 major groups based on their cardinal features (eg, radiological findings, molecular etiology, inheritance) [2-4] to facilitate diagnosis [5].

The lethal group of skeletal dysplasias typically has an earlier onset with more severe phenotypic features than the non-lethal group, thus lethal skeletal dysplasia are potentially more amenable to prenatal diagnosis [6]. Diagnostic accuracy is critical, as it will significantly affect parental counseling and decision-making regarding continuation of the current pregnancy, as well as options for prenatal or preimplantation genetic diagnosis in future pregnancies. After birth, postnatal radiographs, autopsy (in lethal cases), and molecular testing are crucial for making an accurate diagnosis [3,7,8].

This topic will discuss lethal skeletal dysplasias that present prenatally. The majority of skeletal dysplasias will present postnatally with obvious clinical manifestations. Postnatal evaluation, clinical findings, and diagnosis of skeletal dysplasias are reviewed separately. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)


Although each type of skeletal dysplasia is rare, the overall birth prevalence of skeletal dysplasias is estimated to be 2.4 per 10,000 births [1,9,10]. The prevalence during pregnancy appears to be slightly higher at 7.5 per 10,000 ultrasound-screened pregnancies [11].

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Literature review current through: Nov 2017. | This topic last updated: Dec 20, 2016.
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  1. Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med 2009; 11:127.
  2. Superti-Furga A. Growing bone knowledge. Clin Genet 2004; 66:399.
  3. Warman ML, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011; 155A:943.
  4. Stevenson DA, Carey JC, Byrne JL, et al. Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A 2012; 158A:1046.
  5. Bonafe L, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015; 167A:2869.
  6. Ngo C, Viot G, Aubry MC, et al. First-trimester ultrasound diagnosis of skeletal dysplasia associated with increased nuchal translucency thickness. Ultrasound Obstet Gynecol 2007; 30:221.
  7. Doray B, Favre R, Viville B, et al. Prenatal sonographic diagnosis of skeletal dysplasias. A report of 47 cases. Ann Genet 2000; 43:163.
  8. Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002; 113:65.
  9. Rasmussen SA, Bieber FR, Benacerraf BR, et al. Epidemiology of osteochondrodysplasias: changing trends due to advances in prenatal diagnosis. Am J Med Genet 1996; 61:49.
  10. Camera G, Mastroiacovo P. Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. Prog Clin Biol Res 1982; 104:441.
  11. Weldner BM, Persson PH, Ivarsson SA. Prenatal diagnosis of dwarfism by ultrasound screening. Arch Dis Child 1985; 60:1070.
  12. Andersen PE Jr. Prevalence of lethal osteochondrodysplasias in Denmark. Am J Med Genet 1989; 32:484.
  13. Waller DK, Correa A, Vo TM, et al. The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US. Am J Med Genet A 2008; 146A:2385.
  14. Connor JM, Connor RA, Sweet EM, et al. Lethal neonatal chondrodysplasias in the West of Scotland 1970-1983 with a description of a thanatophoric, dysplasialike, autosomal recessive disorder, Glasgow variant. Am J Med Genet 1985; 22:243.
  15. Krakow D, Alanay Y, Rimoin LP, et al. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: a retrospective and prospective analysis. Am J Med Genet A 2008; 146A:1917.
  16. Tretter AE, Saunders RC, Meyers CM, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet 1998; 75:518.
  17. Källén B, Knudsen LB, Mutchinick O, et al. Monitoring dominant germ cell mutations using skeletal dysplasias registered in malformation registries: an international feasibility study. Int J Epidemiol 1993; 22:107.
  18. Schramm T, Gloning KP, Minderer S, et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34:160.
  19. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986; 23:328.
  20. Castilla EE, Orioli IM. Prevalence rates of microtia in South America. Int J Epidemiol 1986; 15:364.
  21. Sharony R, Browne C, Lachman RS, Rimoin DL. Prenatal diagnosis of the skeletal dysplasias. Am J Obstet Gynecol 1993; 169:668.
  22. Parilla BV, Leeth EA, Kambich MP, et al. Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003; 22:255.
  23. Gaffney G, Manning N, Boyd PA, et al. Prenatal sonographic diagnosis of skeletal dysplasias--a report of the diagnostic and prognostic accuracy in 35 cases. Prenat Diagn 1998; 18:357.
  24. Krakow D. Skeletal dysplasias. Clin Perinatol 2015; 42:301.
  25. Barkova E, Mohan U, Chitayat D, et al. Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases. Clin Genet 2015; 87:330.
  26. Olsen BR, Reginato AM, Wang W. Bone development. Annu Rev Cell Dev Biol 2000; 16:191.
  27. Mathiesen JM, Aksglaede L, Skibsted L, et al. Outcome of fetuses with short femur length detected at second-trimester anomaly scan: a national survey. Ultrasound Obstet Gynecol 2014; 44:160.
  28. Papageorghiou AT, Fratelli N, Leslie K, et al. Outcome of fetuses with antenatally diagnosed short femur. Ultrasound Obstet Gynecol 2008; 31:507.
  29. Kurtz AB, Needleman L, Wapner RJ, et al. Usefulness of a short femur in the in utero detection of skeletal dysplasias. Radiology 1990; 177:197.
  30. Campbell J, Henderson A, Campbell S. The fetal femur/foot length ratio: a new parameter to assess dysplastic limb reduction. Obstet Gynecol 1988; 72:181.
  31. Kumar M, Thakur S, Haldar A, Anand R. Approach to the diagnosis of skeletal dysplasias: Experience at a center with limited resources. J Clin Ultrasound 2016; 44:529.
  32. Rouse GA, Filly RA, Toomey F, Grube GL. Short-limb skeletal dysplasias: evaluation of the fetal spine with sonography and radiography. Radiology 1990; 174:177.
  33. Wang DC, Shannon P, Toi A, et al. Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia. Ultrasound Obstet Gynecol 2014; 44:588.
  34. Pugash D, Lehman AM, Langlois S. Prenatal ultrasound and MRI findings of temporal and occipital lobe dysplasia in a twin with achondroplasia. Ultrasound Obstet Gynecol 2014; 44:365.
  35. Ruano R, Molho M, Roume J, Ville Y. Prenatal diagnosis of fetal skeletal dysplasias by combining two-dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography. Ultrasound Obstet Gynecol 2004; 24:134.
  36. Chen CP, Chern SR, Shih JC, et al. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn 2001; 21:89.
  37. Garjian KV, Pretorius DH, Budorick NE, et al. Fetal skeletal dysplasia: three-dimensional US--initial experience. Radiology 2000; 214:717.
  38. Vergani P, Andreani M, Greco M, et al. Two- or three-dimensional ultrasonography: which is the best predictor of pulmonary hypoplasia? Prenat Diagn 2010; 30:834.
  39. Gonçalves LF. Three-dimensional ultrasound of the fetus: how does it help? Pediatr Radiol 2016; 46:177.
  40. Arthurs OJ, Thayyil S, Addison S, et al. Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children. Prenat Diagn 2014; 34:1254.
  41. Cassart M, Massez A, Cos T, et al. Contribution of three-dimensional computed tomography in the assessment of fetal skeletal dysplasia. Ultrasound Obstet Gynecol 2007; 29:537.
  42. Macé G, Sonigo P, Cormier-Daire V, et al. Three-dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia. Ultrasound Obstet Gynecol 2013; 42:161.
  43. Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 2000; 21:23.
  44. Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 1995; 9:321.
  45. Geister KA, Camper SA. Advances in Skeletal Dysplasia Genetics. Annu Rev Genomics Hum Genet 2015; 16:199.
  46. Akolekar R, Beta J, Picciarelli G, et al. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2015; 45:16.
  47. Unger S, Korkko J, Krakow D, et al. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet 2001; 104:140.
  48. Yeh P, Saeed F, Paramasivam G, et al. Accuracy of prenatal diagnosis and prediction of lethality for fetal skeletal dysplasias. Prenat Diagn 2011; 31:515.
  49. Hersh JH, Angle B, Pietrantoni M, et al. Predictive value of fetal ultrasonography in the diagnosis of a lethal skeletal dysplasia. South Med J 1998; 91:1137.
  50. Dugoff L, Coffin CT, Hobbins JC. Sonographic measurement of the fetal rib cage perimeter to thoracic circumference ratio: application to prenatal diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 1997; 10:269.
  51. Yoshimura S, Masuzaki H, Gotoh H, et al. Ultrasonographic prediction of lethal pulmonary hypoplasia: comparison of eight different ultrasonographic parameters. Am J Obstet Gynecol 1996; 175:477.
  52. Rypens F, Metens T, Rocourt N, et al. Fetal lung volume: estimation at MR imaging-initial results. Radiology 2001; 219:236.
  53. Williams G, Coakley FV, Qayyum A, et al. Fetal relative lung volume: quantification by using prenatal MR imaging lung volumetry. Radiology 2004; 233:457.
  54. Weaver KN, Johnson J, Kline-Fath B, et al. Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia. Prenat Diagn 2014; 34:1326.
  55. Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn 2011; 31:115.
  56. Chitayat D, Babul-Hirji R. Genetic counselling in prenatally diagnosed non-chromosomal fetal abnormalities. Curr Opin Obstet Gynecol 2000; 12:77.
  57. Sankar VH, Phadke SR. Clinical utility of fetal autopsy and comparison with prenatal ultrasound findings. J Perinatol 2006; 26:224.
  58. Lemyre E, Azouz EM, Teebi AS, et al. Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J 1999; 50:185.
  59. Langer LO Jr, Yang SS, Hall JG, et al. Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 1987; 3:167.
  60. Chitayat D, Fernandez B, Gardner A, et al. Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. Am J Med Genet 1999; 84:401.
  61. Thomas RL, Hess LW, Johnson TR. Prepartum diagnosis of limb-shortening defects with associated hydramnios. Am J Perinatol 1987; 4:293.
  62. Blaas HG, Vogt C, Eik-Nes SH. Abnormal gyration of the temporal lobe and megalencephaly are typical features of thanatophoric dysplasia and can be visualized prenatally by ultrasound. Ultrasound Obstet Gynecol 2012; 40:230.
  63. Taybi H, Lachman RS. Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, 3rd ed, Year Book Medical Publishers, Chicago 1990.
  64. DiMaio MS, Barth R, Koprivnikar KE, et al. First-trimester prenatal diagnosis of osteogenesis imperfecta type II by DNA analysis and sonography. Prenat Diagn 1993; 13:589.
  65. Latini G, De Felice C, Parrini S, et al. Polyhydramnios: a predictor of severe growth impairment in achondroplasia. J Pediatr 2002; 141:274.
  66. Sillence DO, Barlow KK, Garber AP, et al. Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet 1984; 17:407.
  67. Barnes AM, Carter EM, Cabral WA, et al. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med 2010; 362:521.
  68. Munoz C, Filly RA, Golbus MS. Osteogenesis imperfecta type II: prenatal sonographic diagnosis. Radiology 1990; 174:181.
  69. Meizner, I, Bar-Ziv, J. In utero diagnosis of skeletal disorders: an atlas of prenatal sonographic and postnatal radiologic correlation, CRC Press, Boca Raton FL 1993.
  70. Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol 2008; 17:229.
  71. Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet 1995; 32:415.
  72. Velagaleti GV, Bien-Willner GA, Northup JK, et al. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet 2005; 76:652.
  73. Wu MH, Kuo PL, Lin SJ. Prenatal diagnosis of recurrence of short rib-polydactyly syndrome. Am J Med Genet 1995; 55:279.
  74. Whitley CB, Langer LO Jr, Ophoven J, et al. Fibrochondrogenesis: lethal, autosomal recessive chondrodysplasia with distinctive cartilage histopathology. Am J Med Genet 1984; 19:265.
  75. Kulkarni ML, Matadh PS, Praveen Prabhu SP, Kulkarni PM. Fibrochondrogenesis. Indian J Pediatr 2005; 72:355.
  76. Chitayat D, Keating S, Zand DJ, et al. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases. Am J Med Genet A 2008; 146A:3038.
  77. Umranikar S, Glanc P, Unger S, et al. X-Linked dominant chondrodysplasia punctata: prenatal diagnosis and autopsy findings. Prenat Diagn 2006; 26:1235.
  78. Duff P, Harlass FE, Milligan DA. Prenatal diagnosis of chondrodysplasia punctata by sonography. Obstet Gynecol 1990; 76:497.
  79. Lefebvre M, Dufernez F, Bruel AL, et al. Severe X-linked chondrodysplasia punctata in nine new female fetuses. Prenat Diagn 2015; 35:675.
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