Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

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 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, etc) or intrinsic causes (single gene disorders with autosomal dominant, recessive, or X-linked modes of inheritance; imprinting errors; chromosome abnormalities) [1]. In view of the large number of skeletal dysplasias (over 456 known types), a classification system was created that categorizes genetic bone disorders into 40 major groups by their cardinal features (eg, radiological findings, molecular etiology, inheritance) [2,3].

Prenatal diagnosis is based primarily upon fetal ultrasound findings, but magnetic resonance imaging (MRI), computed tomography (CT), radiography, and in some cases, molecular analysis, may be used to support the presumptive diagnosis. Skeletal dysplasias can usually be identified by prenatal ultrasound examination because most of the skeleton begins to ossify early in development (the clavicle, mandible, ileum, scapula, and long bones ossify by 12 weeks of gestation; the metacarpals and metatarsals are ossified by 12 to 16 weeks; the talus and calcaneus ossify at weeks 22 to 24; but the carpal bones ossify after birth; epiphyseal ossification centers are seen on radiographs at approximately 20 weeks of gestation) [4].

The lethal group of skeletal dysplasias typically have an earlier onset with more severe phenotypic features than the non-lethal group, thus lethal skeletal dysplasia are potentially more amenable to early diagnosis [5]. Diagnostic accuracy is critical, as it will significantly affect parental counseling and decision making regarding continuation of the current pregnancy, as well as their options for prenatal diagnosis in their future pregnancies. In retrospective studies, experienced ultrasonographers made accurate prenatal diagnosis of lethal skeletal dysplasias in 81 to 100 percent of cases versus 31 to 78 percent of all cases of skeletal dysplasia [5-8]. The most challenging diagnoses are the skeletal dysplasia with variable phenotypic expression, which are not always lethal.

After birth, postnatal radiographs, autopsy (in lethal cases), and molecular testing are crucial for making an accurate diagnosis [3,9,10].


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 [11,12]. The prevalence during pregnancy appears to be slightly higher at 7.5 per 10,000 ultrasound screened pregnancies [13].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Sep 08 00:00:00 GMT+00:00 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  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. Olsen BR, Reginato AM, Wang W. Bone development. Annu Rev Cell Dev Biol 2000; 16:191.
  5. 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.
  6. 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.
  7. Schramm T, Gloning KP, Minderer S, et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol 2009; 34:160.
  8. Tretter AE, Saunders RC, Meyers CM, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet 1998; 75:518.
  9. Doray B, Favre R, Viville B, et al. Prenatal sonographic diagnosis of skeletal dysplasias. A report of 47 cases. Ann Genet 2000; 43:163.
  10. Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002; 113:65.
  11. 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.
  12. 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.
  13. Weldner BM, Persson PH, Ivarsson SA. Prenatal diagnosis of dwarfism by ultrasound screening. Arch Dis Child 1985; 60:1070.
  14. Andersen PE Jr. Prevalence of lethal osteochondrodysplasias in Denmark. Am J Med Genet 1989; 32:484.
  15. 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.
  16. 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.
  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. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986; 23:328.
  19. Castilla EE, Orioli IM. Prevalence rates of microtia in South America. Int J Epidemiol 1986; 15:364.
  20. Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn 2011; 31:115.
  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. 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.
  25. Papageorghiou AT, Fratelli N, Leslie K, et al. Outcome of fetuses with antenatally diagnosed short femur. Ultrasound Obstet Gynecol 2008; 31:507.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. Wang DC, Shannon P, Toi A, et al. Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia. Ultrasound Obstet Gynecol 2014; 44:588.
  31. 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.
  32. Garjian KV, Pretorius DH, Budorick NE, et al. Fetal skeletal dysplasia: three-dimensional US--initial experience. Radiology 2000; 214:717.
  33. 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.
  34. Kanal E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol 2007; 188:1447.
  35. 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.
  36. 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.
  37. 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.
  38. Unger S, Korkko J, Krakow D, et al. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet 2001; 104:140.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. Rypens F, Metens T, Rocourt N, et al. Fetal lung volume: estimation at MR imaging-initial results. Radiology 2001; 219:236.
  46. Williams G, Coakley FV, Qayyum A, et al. Fetal relative lung volume: quantification by using prenatal MR imaging lung volumetry. Radiology 2004; 233:457.
  47. Chitayat D, Babul-Hirji R. Genetic counselling in prenatally diagnosed non-chromosomal fetal abnormalities. Curr Opin Obstet Gynecol 2000; 12:77.
  48. Sankar VH, Phadke SR. Clinical utility of fetal autopsy and comparison with prenatal ultrasound findings. J Perinatol 2006; 26:224.
  49. 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.
  50. Langer LO Jr, Yang SS, Hall JG, et al. Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl 1987; 3:167.
  51. 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.
  52. Thomas RL, Hess LW, Johnson TR. Prepartum diagnosis of limb-shortening defects with associated hydramnios. Am J Perinatol 1987; 4:293.
  53. 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.
  54. Taybi, H, Lachman, RS. Radiology of syndromes, metabolic disorders, and skeletal dysplasias, 3rd, Year Book Medical Publishers, Chicago 1990.
  55. 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.
  56. Latini G, De Felice C, Parrini S, et al. Polyhydramnios: a predictor of severe growth impairment in achondroplasia. J Pediatr 2002; 141:274.
  57. 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.
  58. 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.
  59. Munoz C, Filly RA, Golbus MS. Osteogenesis imperfecta type II: prenatal sonographic diagnosis. Radiology 1990; 174:181.
  60. 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.
  61. Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol 2008; 17:229.
  62. Mansour S, Hall CM, Pembrey ME, Young ID. A clinical and genetic study of campomelic dysplasia. J Med Genet 1995; 32:415.
  63. 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.
  64. Wu MH, Kuo PL, Lin SJ. Prenatal diagnosis of recurrence of short rib-polydactyly syndrome. Am J Med Genet 1995; 55:279.
  65. 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.
  66. Kulkarni ML, Matadh PS, Praveen Prabhu SP, Kulkarni PM. Fibrochondrogenesis. Indian J Pediatr 2005; 72:355.
  67. 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.
  68. Umranikar S, Glanc P, Unger S, et al. X-Linked dominant chondrodysplasia punctata: prenatal diagnosis and autopsy findings. Prenat Diagn 2006; 26:1235.
  69. Duff P, Harlass FE, Milligan DA. Prenatal diagnosis of chondrodysplasia punctata by sonography. Obstet Gynecol 1990; 76:497.
  70. Lefebvre M, Dufernez F, Bruel AL, et al. Severe X-linked chondrodysplasia punctata in nine new female fetuses. Prenat Diagn 2015; 35:675.