Sonographic Detection of Severe Skeletal Dysplasias
The prevalence of skeletal dysplasias is between 1 and 2000 and 1 and 4000 livebirths1. While there are over 125 skeletal dysplasias2, approximately 4 disorders comprise 70% of the total: achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, and achondrogenesis. The appropriate identification of lethal skeletal dysplasias is important not only for current pregnancy management, but also for genetic counseling concerning future pregnancies. Table I provides the genetic inheritance for but a few of the more common skeletal dysplasias.
The severity of the effect on the skeletal system with lethal skeletal dysplasias makes 2nd trimester diagnosis possible. Additional testing is necessary to confirm or exclude a specific skeletal dysplasia. For example, amniocentesis can be used to confirm a diagnosis of achondroplasia3. Usually a definitive diagnosis cannot be made until a pediatric or pathologic evaluation of the neonate is undertaken.
Table I. Inheritance of skeletal dysplasias.
|Usually Lethal Dysplasia||Mode of Inheritance|
|Osteogenesis imperfecta||AD*, AR|
|Usually Non-lethal Dysplasia|
|Asphyxiating thoracic dysplasia||AR|
|Derived from: Wigglesworth JS, Singer DB. Textbook of Fetal and Perinatal Pathology. Oxford:Blackwell Scientific, 1991;1176.|
|*Majority of cases are new mutations.|
As with any suspected congenital anomaly, a detailed fetal anatomic survey is required whenever a skeletal dysplasia is suspected. Ancillary sonographic findings frequently provide the clues that are necessary to narrow the differential diagnosis.
The measurement of the femur length (FL) is part of standard 2nd and 3rd trimester biometry. Since the long bones are invariably affected in the severe skeletal dysplasias, this measurement provides the first clue that bone formation or growth is abnormal. Even in patients with established dating criteria, a FL < 2 SD of the mean is not necessarily diagnostic for a skeletal dysplasia. The differential diagnosis of a short femur includes a normal physiologic variation, intrauterine growth restriction, a focal shortening of one femur and an abnormal karyotype. However, when the femur length is 3 5 mm below 2 SD of the mean, a significant skeletal dysplasia is almost certain4.
If the femur length is between 2 SD of the mean and 5 mm below 2 SD, interval growth of the FL can be evaluated. During the 2nd trimester the femur length normally increases 2.5 mm/week. The time of onset and degree to which FL growth is inhibited is specific for each skeletal dysplasia. For example, a fetus with heterozygous achondroplasia may have an abnormal FL between 21 and 27 weeks' menstrual age; the femur length of fetuses with osteogenesis imperfecta type II is already abnormal at 15 weeks' menstrual age5.
As the fetus grows and develops, there is an inherent proportionality between all of the body parts. Hence, a comparison of femur length with another independently growing body part can help to confirm the diagnosis of a skeletal dysplasia.
FL/Head Circumference (HC)
An FL/HC ratio < 3 SD below the mean suggests a skeletal dysplasia6.
FL/Abdominal Circumference (AC)
The FL/AC ratio is normally between 0.20 and 0.247. A ratio < 0.16 is diagnostic for a skeletal dysplasia8,9. However, this cut-off should only be utilized in patients with a suspected skeletal dysplasia. In the normal population an FL/AC ratio < 0.16 would have a high false positive rate for the detection of a severe skeletal dysplasia.
In a normal fetus the FL and foot are generally of equivalent length. The growth of the foot is not affected by severe skeletal dysplasias10. Hence, with a severe skeletal dysplasia, the FL/foot ratio is decreased to < 0.8711(Fig. 1).
The chest circumference is measured perpendicular to the fetal spine at the level of the 4-chamber view (Fig. 2). In order to ensure an appropriate cross-section, only one rib should be imaged on either side of the chest. The normal thoracic/AC ratio (+ 2 SD) is 0.89 + 0.06. This ratio does not vary with gestational age11,12.
The normal chest circumference/HC ratio (+ 2 SD) is 0.80 (+ 0.12). This ratio is also not gestational age dependent11.
Normally, the 4th rib extends two-thirds around the thorax (Fig. 3). In lethal skeletal dysplasias the chest cavity is characteristically narrowed. Hence, the heart fills the chest cavity. On a sagittal view the marked narrowing of the chest results in the abdomen appearing protuberant (Fig. 4).
A sagittal view of the face can be used to diagnosis frontal bossing (Fig. 5), a depressed nasal bridge (Fig. 5) or micrognathia (Fig. 6). Fetuses with thanatophoric dysplasia or osteogenesis imperfecta will characteristically have frontal bossing. A cloverleaf skull (Fig. 7) may be detected with 14% of fetuses with thanatophoric dysplasia or fetuses with homozygous achondroplasia13. Three-dimensional imaging is particularly useful in evaluating facial dysmorphology14.
Which Long Bones Are Affected?
Proximal long bone shortening (rhizomelia) is present in achondroplasia. With osteogenesis imperfecta type II and achondrogenesis there is a generalized shortening (micromelia) of all of the long bones.
Long Bone Appearance
Multiple long bone fractures occur with osteogenesis imperfecta type II. Bowed extremities are characteristic for camptomelic dysplasia, thanatophoric dysplasia, and osteogenesis imperfecta type II (Fig. 8).
While it is difficult to appreciate sonographically, widening of the intervetebral spaces and flattening of the spine (platyspondyly) occurs with achondroplasia and thanatophoric dyplasia15.
Acoustic shadowing is normally present from the edges of the calvarium, as well as from the long bones. In skeletal dysplasias associated with hypomineralization, acoustic shadowing is not present. Flattening of the skull with compression by the ultrasound transducer is an indication of the hypomineralization associated with osteogenesis imperfecta type II. Hypomineralization of the spine is characteristic of achondrogenesis type II.
Hands and Feet
Whenever a skeletal dysplasia is suspected, the hands and feet should be carefully evaluated. Pre-axial (thumb side) or post-axial (5th finger side) polydactyly may occur. The extra digit could be a skin tag or contain bone. When the fist is clenched, post-axial polydactyly may not be detectable. Both hands should be evaluated when extended. A three-dimensional sweep is helpful when attempting to accurately evaluate the hands and/or feet16 (Fig. 9). While neither diagnostic nor specific, clubbed feet (Fig. 10) have been reported with osteogenesis imperfecta and diastrophic dysplasia.
Polyhydramnios may be present in approximately 50% of fetuses with thanatophoric dysplasia and 25% of fetuses with achondroplasia17. Other skeletal dysplasias are associated with a much lower prevalence of polyhydramnios18,19.
Non-immune Hydrops (Fig. 11)
Chest compression has been hypothesized as the reason for the higher frequency of non-immune hydrops with short-rib polydactyly18 and achondrogenesis19. What differentiates those fetuses with a specific skeletal dysplasia that have non-immune hydrops from those who do not have non-immune hydrops has not yet been determined.
Specific Skeletal Dysplasias
Thanatophoric Dysplasia (Fig. 5)
Thanatophoric dysplasia is the most common lethal skeletal dysplasia with an incidence of 1 in 4000 to 1 in 30,0001,20,21. Mutations in gene 3 fibroblast growth factor result in thanatophoric dysplasia. This growth factor is also present in the central nervous system. Those infants with thanatophoric dysplasia who survive the neonatal period consequently have profound mental handicaps22. Molecular diagnostic methods permit the prenatal diagnosis of thanatophoric dysplasia through chorionic villus sampling or amniocentesis23.
With thanatophoric dysplasia the limbs are markedly shortened and the femurs have a "telephone receiver" appearance. There is macrocephaly. The chest is significantly narrowed due to the extremely short ribs. The abdomen is protuberant. There is a generalized redundancy in subcutaneous tissue. 3D surface imaging in the second and third trimester provides an excellent view of all of the external stigmata of thanatophoric dysplasia24. Polyhydramnios is a frequent 3rd trimester finding. Neonatal death from respiratory failure is the usual outcome for those fetuses that survive to term.
Two forms of thanatophoric dysplasias have been identified. Type I is characterized by short curved femurs. These fetuses rarely have a cloverleaf skull. Type II thanatophoric dysplasia is characterized by shortened, but straight femurs and is usually associated with a cloverleaf skull25.
Camptomelic dysplasia must be considered in the differential diagnosis with thanatophoric dysplasia. Camptomelic dysplasia is characterized by shortened bowed lower extremities, hypoplastic fibulas and hypoplastic scapulas. Other features associated with camptomelic dysplasia include hypertelorism, cleft palate, ventriculomegaly and clubbed feet26, 27. Phenotypic female fetuses with camptomelic dysplasia may have a male karyotype. Fetal karyotyping may, therefore, be helpful in differentiating thanatophoric dysplasia from camptomelic dysplasia28.
Mutation in the two genes that encode the chains of type I collagen results in the wide phenotypic expression of osteogenesis imperfecta29. Most cases of osteogenesis imperfecta are new mutations; autosomal recessive inheritance has also been described.
Osteogenesis imperfecta has been divided into 4 predominant types. Types I and IV have fractures, but survive; type II is lethal in utero, or during the early neonatal period. Because of its severity, type II osteogenesis imperfecta may be diagnosed in the 1st trimester30.
Type II is further subdivided into subgroup A with short fractured long bones (Fig. 12) and fractured ribs (Fig. 13). Subgroup B has short fractured long bones without rib fractures. Subgroup C has thin and fractured long bones along with thin ribs31.
The absence of skull calcification permits enhanced visualization of the cerebral cortex nearest to the transducer (Fig. 14). The lack of mineralization permits compression of the skull with the ultrasound transducer.
Third trimester polyhydramnios has been described.
A 2nd or 3rd trimester three-dimensional profile may help to distinguish the normal facies of osteogenesis imperfecta type IIA from the hypertelorism and broad base nose of short-rib polydactyly32.
In some cases of osteogenesis imperfecta type II, there is significant bowing of the lower extremities rather than fractures. Type III OI may also have significant long bone bowing. However, osteogenesis imperfecta type III has normal bone mineralization and a normal chest circumference. In these specific cases osteogenesis imperfecta can mimic camptomelic dysplasia26, 33.
Type III has variable expression; long bone shortening may only become apparent after 24 weeks' menstrual age.
Type IV is between types I and III in severity - most fractures occur before puberty. These individuals have short stature and an increased prevalence of kyphoscoliosis. Subgroups of type IV have been described. In 2006 two additional forms of osteogenesis imperfecta with AR inheritance were described34.
Severe micromelia and a narrow chest are also characteristic features of achondrogenesis. Defective cartilage formation results in poor ossification. Achondrogenesis is due to an autosomal dominant mutation35.
Achondrogenesis type I has almost a complete lack of skull ossification. These fetuses have a short neck and trunk. Type IA has associated rib fractures, while fetuses with achondrogenesis type IB do not have rib fractures36. The inheritance pattern is autosomal recessive.
Achondrogenesis type II makes up 80% of cases37. It is characterized by a greater degree of calcification of the spine and pelvis than fetuses with type I. Fetuses with type II achondrogenesis have normal skull ossification. Polyhydramnios and hydrops are common with type II achondrogenesis.
An evaluation of a fetus for a suspected skeletal dysplasia begins with the recognition of a significantly shortened femur length. The majority of lethal skeletal dysplasias will have markedly shortened long bones certainly by the 20 week ultrasound examination and sometimes even in the 1st trimester. The remainder of the extended fetal anatomic survey outlined above is performed primarily to determine the possibility of lethality. The sonographic parameters that have been discussed are able to predict lethality in between 92%8 and 100% of cases38. However, an accurate prenatal diagnosis is made only 48%39 to 65%22 of the time.
- Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence ratios for the skeletal dysplasias. J Med Genet 1986; 23(4):328-332.
- Meizner I, Bar-Ziv J. In utero Diagnosis of Skeletal Disorders. An atlas of prenatal sonographic and postnatal radiologic correlation. CRC Press, Inc 1993, Chap 2.
- Shiang R, Thompson LM, Zhu Y-Z et al. Mutations in the transmember domain of FGFR3 causes the most common genetic form of dwarfism, achondroplasia. Cell 1994;78(2):335-342.
- Kurtz AB, Needleman L, Wapner RJ et al. Usefulness of a short femur in the in utero detection of skeletal dysplasia. Radiology 1990;177(1):197-200.
- Kurtz AB, Filly RA, Wapner RJ et al. In utero analysis of heterozygous achondroplasia: variable time of onset as detected by femur length measurements. J Ultrasound Med 1986;5(3):137-140.
- Hadlock FL, Harrist RB, Shah Y et al. The femur length/head circumference relation in obstetric sonography. J Ultrasound Med 1984;3(10):439-442.
- Hadlock FP, Harrist RB, Fearneyhough TC et al. Use of femur length/abdominal circumference ratio in detecting the macrosomic fetus. Radiology 1985;154(2):530-505.
- Barilla BV, Leeth EA, Kambich MP et al. Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003;22(3):255-258.
- Ramus RM, Martin LB, Twickler DM. Ultrasonographic prediction of fetal outcome in suspected skeletal dysplasias with use of the femur length-to-abdominal circumference ratio. Am J Obstet Gynecol 1998;179(5):1348-1352.
- Campbell J, Henderson RGN, Campbell S. The femur/foot length ratio: a new parameter to assess dysplastic limb reduction. Obstet Gynecol 1988;72(2):181-184.
- Brons JTJ, Van der Harten JJ, Van Geijn HP et al. Ratios between growth parameters for the prenatal ultrasonographic diagnosis of skeletal dysplasias. Eur J Obstet Gynecol Reprod Biol 1990;34(1-2):37-46.
- DeVore GR, Horenstein J, Platt LD. Fetal echocardiography VI. Assessment of cardiothoracic disproportion: a new technique for the diagnosis of thoracic dysplasia. Am J Obstet Gynecol 1986;155(5):1066-1071.
- Mahony BS, Filly RA, Callen PW et al. Thanatophoric dwarfism with the cloverleaf skull: a specific antenatal sonographic diagnosis. J Ultrasound Med 1985;4(3):151-154.
- Machado LE, Osborne NG, Bonilla-Musoles F. Antley-Bixler syndrome. Report of a case. J Ultrasound Med 2001;20(1):73-77.
- Rouse GA, Filly RA, Toomey F et al. Short-limb skeletal dysplasia: evaluation of the fetal spine with sonography and radiography. Radiology 1990;174(1):177-180.
- Viora E, Sciarrone A, Bastonero S et al. Three-dimensional ultrasound evaluation of short-rib polydactyly syndrome type II in the second trimester: a case report. Ultrasound Obstet Gynecol 2002;19(1):88-91.
- Thomas RL, Hess LW, Johnson TRB. Prepartum diagnosis of limb shortening defects with associated hydramnios. Am J Perinatol 1987;4(4):293-299.
- Meizner I, Bar-Ziv J. Prenatal ultrasonic diagnosis of short-limb polydactyly syndrome (SRPS) type III: a case report and a proposed approach to the diagnosis of SRPS and related conditions. J Clin Ultrasound 1985;13(4):284-287.
- Benacerraf B, Ustharundth r, Rieber FR. Achondrogenesis type I: ultrasound diagnosis in utero. J Clin Ultrasound 1984;12(6):357-359.
- Saunders RC, Blahemore K. Lethal fetal anomalies. Sonographic demonstration. Radiology 1989;172:1-6.
- Camera G, Mastoiacovo P. Birth prevalence of skeletal dysplasias in the Italian multicentric monitoring system for birth defects. In: Papadatos CJ, Bartsocos CS eds. Skeletal dysplasia. New York: Alan R Liss;1982:441-449.
- Tavormine 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(3):321-328.
- Elejalde BR, deElejalde MM. Thanatophoric dysplasia: fetal manifestations and prenatal diagnosis. Am J Med Genet 1984;22(4):669-683.
- Machado LE, Bonilla-Musoles F, Osborne NG. Thanatophoric dysplasia. Ultrasound Obstet Gynecol 2001;18:85-86.
- Schild RL, Hunt GH, Moore J, Davis H, Harwell DH. Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol 1996;8:62-67.
- Sanders RC, Greyson-Fleg RT, Hogge WA, Blakemore KJ, McGowan KD et al. Osteogenesis Imperfecta and Camptomelic dysplasia: Difficulties in prenatal diagnosis. J Ultrasound Med 1994;13:691-700.
- Cordone M, Littiana M, Zampatti C. In utero ultrasonographic features of camptomelic dysplasia. Prenat Diagn 1989;9(11):745-750.
- Turner GM, Twinning P. The antenatal diagnosis of skeletal dysplasias: a simplified approach. BMUS Bulletin 1994;11:32-38.
- Byers PH, Wallis GA, Willing MC. Osteogenesis imperfecta: translation of mutation to phenotype. J Med Genet 1991;28:433-442.
- 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(7):589-596.
- Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101-116.
- Azumendi G, Kurjak A. Three-dimensional and four-dimensional sonography in the study of the fetal face. Ultrasound Rev. Obstet Gynecol 2003;3:160-169.
- Bulas DI, Stern HJ, Rosenbaum KN, Fonda JA, Glass RB, Tiffa C. Variable prenatal appearance of osteogenesis imperfecta. J Ultrasound Med 1994;13:419-427.
- Martin E, Shapiro JR. Osteogenesis imperfecta: epidemiology and pathophysiology. Curr Osteoporosis Rep 2007;5:91-97.
- Van de Harten JJ, Brons JTJ, Dijkstra PE et al. Achondrogenesis-hypochondrogenesis, the spectrum of chondrogenesis imperfecta: A radiographic, ultrasonographic and histopathologic study of 23 cases. Paediatr Pathol 1988;8:571-597.
- Borochowitz Z, Lachman R, Adomian GE et al. Achondrogenesis type I delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr 1988;112:23-32.
- Beighton P, Giedion A, Corlin R et al. International classification of osteochondrodysplasias. Am J Med Genet 1992;44(2):223-229.
- Doray B, Favre R, Viville B et al. Prenatal sonographic diagnosis of skeletal dysplasias. A report of 47 cases. Amales de Génét 2000;43(3-4):163-169.
- 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(12):1137-1142.