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Ultrasound Obstet Gynecol 2009; 34: 160–170 Published online 22 June 2009 in Wiley InterScience (www.interscience.wiley.

com). DOI: 10.1002/uog.6359

Prenatal sonographic diagnosis of skeletal dysplasias
¨ T. SCHRAMM*†, K. P. GLONING*, S. MINDERER*, C. DAUMER-HAAS*, K. HORTNAGEL*, A. NERLICH‡ and B. TUTSCHEK§¶
*Prenatal Medicine Munich, †Ludwig Maximilian University Munich and ‡Department of Pathology, Bogenhausen Hospital, Munich and §Heinrich Heine University, Dusseldorf, Germany and ¶University Hospital, Bern, Switzerland ¨

K E Y W O R D S: hypoplastic thorax; malformation syndromes; micromelia; osteochondrodysplasias; prenatal diagnosis; skeletal dysplasias

ABSTRACT
Objective To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal population from a single tertiary center. Methods This was a retrospective database review of type, prenatal and definitive postnatal diagnoses and gestational age at specific prenatal diagnosis of all cases of skeletal dysplasias from a mixed referral and screening population between 1985 and 2007. Prenatal diagnoses were grouped into ‘correct ultrasound diagnosis’ (complete concordance with postnatal pediatric or pathological findings) or ‘partially correct ultrasound diagnosis’ (skeletal dysplasias found postnatally to be a different one from that diagnosed prenatally). Results We included 178 fetuses in this study, of which 176 had a prenatal ultrasound diagnosis of ‘skeletal dysplasia’. In 160 cases the prenatal diagnosis of a skeletal dysplasia was confirmed; two cases with skeletal dysplasias identified postnatally had not been diagnosed prenatally, giving 162 fetuses with skeletal dysplasias in total. There were 23 different classifiable types of skeletal dysplasia. The specific diagnoses based on prenatal ultrasound examination alone were correct in 110/162 (67.9%) cases and partially correct in 50/162 (30.9%) cases, (160/162 overall, 98.8%). In 16 cases, skeletal dysplasia was diagnosed prenatally, but was not confirmed postnatally (n = 12 false positives) or the case was lost to followup (n = 4). The following skeletal dysplasias were recorded: thanatophoric dysplasia (35 diagnosed correctly prenatally of 40 overall), osteogenesis imperfecta (lethal and non-lethal, 31/35), short-rib dysplasias (5/10), chondroectodermal dysplasia Ellis-van Creveld (4/9), achondroplasia (7/9), achondrogenesis (7/8), campomelic

dysplasia (6/8), asphyxiating thoracic dysplasia Jeune (3/7), hypochondrogenesis (1/6), diastrophic dysplasia (2/5), chondrodysplasia punctata (2/2), hypophosphatasia (0/2) as well as a further 7/21 cases with rare or unclassifiable skeletal dysplasias. Conclusion Prenatal diagnosis of skeletal dysplasias can present a considerable diagnostic challenge. However, a meticulous sonographic examination yields high overall detection. In the two most common disorders, thanatophoric dysplasia and osteogenesis imperfecta (25% and 22% of all cases, respectively), typical sonomorphology accounts for the high rates of completely correct prenatal diagnosis (88% and 89%, respectively) at the first diagnostic examination. Copyright  2009 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION
Congenital skeletal disorders comprise skeletal dysplasias, dysostoses and reduction deformities. Skeletal dysplasias (‘chondrodysplasias’ or ‘osteochondrodysplasias’) are developmental disorders of chondro-osseous tissue. Dysostoses are malformations of single bones, alone or in combination (e.g. isolated polydactyly). Reductions are secondary malformations of bones1,2 . Advances in molecular genetics have helped elucidate the biological basis for many of the diseases in the first two groups, making some of them amenable to molecular genetic diagnosis in addition to the classical diagnostic approach of morphological assessment2 . However, specific prenatal diagnosis of skeletal dysplasias still presents a considerable diagnostic challenge, not least because of their rarity3,4 . Prenatal series and diagnostic algorithms, based on sonographically detectable features of skeletal dysplasias, have been described5 – 7 . We analyzed the data of all suspected and confirmed cases of skeletal dysplasias from

¨ ¨ ¨ Correspondence to: PD Dr T. Schramm, Pranatal-Medizin Munchen, Lachnerstrasse 20, D-80639 Munchen, Germany (e-mail: schramm@praenatal-medizin.de) Accepted: 19 February 2009

Copyright  2009 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

34: 160–170. The two most common types were thanatophoric dysplasia (TD. suspect familial large head. intrauterine growth restriction (IUGR) affecting mainly extremities’). OMIM12 .8% (160/162).9% (110/162) and 30.9% (50/162). two cases with lethal hypophosphatasia (diagnosed partially correctly at 16 and 19 weeks). Ten types of skeletal dysplasia occurred more than twice and accounted for 137 of these 162 cases. For the 10 types of skeletal dysplasia that occurred more than twice. BPD. spine and head and assessment of mineralization and bone shapes. Of these. Published by John Wiley & Sons. In all cases. Of these. For this study. The less common types of skeletal dysplasia included two cases with chondrodysplasia punctata (diagnosed correctly at 21 and 23 weeks).6%). In the graphs each fetus was represented only once. This also allows comparison of different parameters over gestation on the same y-axis10 . a digital dysmorphology database11 and the online catalog of human genes and genetic phenotypes. biometric data (femur length (FL). Those from Laudy and Wladimiroff9 were used to provide centiles for ThC after 20 weeks. 162 cases were confirmed as skeletal dysplasias. For values beyond the typical normal ranges (such as the 5th and 95th centiles). Either there was complete concordance of the specific ultrasound diagnosis. Copyright  2009 ISUOG. Values in mm and Z-scores were plotted across the gestational age range from 12 to 40 weeks’ gestation. enabling numerical quantification for extreme values such as those encountered in skeletal dysplasias. examination of the hands. we identified 178 fetuses in which the diagnosis of ‘skeletal dysplasia’ had been made. 161 RESULTS Frequencies of skeletal dysplasias. deviation from the gestational age mean can be expressed best as multiples of the SD or Z-scores. Wherever possible. For the 10 most common skeletal dysplasias encountered in our study. We assumed that the reported normal populations were normally distributed. the type. respectively.Ultrasound in skeletal dysplasias a mixed screening and referral population seen in our institution between 1985 and 2007. the diagnostic ultrasound examination included measurement of the long bones in all segments of all four extremities. 24. biparietal diameter (BPD). sponastrimic dysplasia (diagnosed partially correctly at 29 weeks). head circumference (HC). opsismodysplasia (misdiagnosed as TD at 33 weeks). Ultrasound Obstet Gynecol 2009.7%) and osteogenesis imperfecta (OI types 2. we sought and analyzed details of prenatal management and postnatal pediatric or pathological studies from all cases. types 1 and 2. to carry out a detailed analysis of biometric parameters and to describe the characteristic sonographic features of the most common skeletal dysplasias. Kniest dysplasia (diagnosed partially correctly at 19 weeks). kyphomelic dysplasia (diagnosed correctly at 31 weeks). However. derived from clinical experience gathered in this study. The purpose of this study was to report the types and proportions of skeletal dysplasias in this group and gestational ages at diagnosis. four cases were lost to follow-up. data were collected prospectively from all fetuses with skeletal dysplasias diagnosed in a mixed screening and referral population in one large tertiary center. metaphyseal dysplasia McKusick type (diagnosed partially correctly at 27 weeks) and nine skeletal dysplasias that remained unclear even at pediatric or pathological examination (diagnosed partially correctly at 13–30 weeks). HC and AC. Ltd. For the purposes of this study. two cases of spondyloepimetaphyseal dysplasia (one diagnosed correctly at 12 weeks and one partially correctly at 32 weeks). osteocraniostenosis (misdiagnosed as TD at 21 weeks). proportion of completely or partially correct diagnoses and gestational age at diagnosis are shown in Table 1. 3 and 4. Z-scores were calculated for FL. ThC and HC for all affected fetuses. or a skeletal dysplasia other than the one diagnosed by ultrasound was present. there being 23 different classifiable types. and there were another nine fetuses with unclassifiable skeletal dysplasias. The overall prenatal detection rate for all cases with confirmed skeletal dysplasias was 98. There were two false negatives: one case with chondroectodermal dysplasia Ellis-van Creveld (prenatally diagnosed at 39 completed weeks as ‘suspected genetic syndrome. in addition to a full fetal anatomical survey5 – 7 . platyspondylic chondrodysplasia Shiraz type (diagnosed correctly at 28 weeks). 35/162. or the cases were false positive or false negative. at the gestational age of the first diagnostic examination. detection rates and gestational ages at diagnosis From the database. molecular diagnosis was sought. prior to this age the centiles were extrapolated from their normal data. We used the terms ‘correct ultrasound diagnosis’ and ‘partially correct ultrasound diagnosis’ to describe the accuracy of the first diagnostic examination done in our center compared with the final pediatric or pathological diagnosis. The published normal data from Snijders and Nicolaides8 were used to provide centiles for FL. Another 13 known types of skeletal dysplasia occurred once or twice. short long bones’) and one with achondroplasia (diagnosed at 31 weeks as ‘structurally normal fetus. 40/162. we describe diagnostic sonoanatomical features. a genetic textbook on skeletal dysplasias1 . thoracic circumference (ThC) and abdominal circumference (AC)) were collected and analyzed in relation to published normal values. The rates of completely and partially correct prenatal sonographic diagnosis at the first diagnostic examination were 67. in seven of these 12 PATIENTS AND METHODS Between 1985 and 2007. spondyloepiphyseal dysplasia (diagnosed partially correctly at 35 weeks). otopalatodigital syndrome type 2 (diagnosed correctly at 22 weeks). 21. In addition to the 162 true skeletal dysplasia cases there were another 16 cases in which the diagnosis ‘skeletal dysplasia’ was made prenatally. . one case each of dyssegmental dysplasia Rolland Desbuquois (diagnosed partially correctly as ‘either OI or campomelic dysplasia’ at 28 weeks). and in 12 cases no skeletal dysplasia was found postnatally. number of cases.

FN. at the first diagnostic examination (AC data. are not included). Ltd. asphyxiating thoracic dysplasia. at 18 weeks) 14–33 (1 recurr. 62% of cases were diagnosed before 24 weeks and the median GA at diagnosis was 21 weeks. were diagnosed between 12 and 17 completed weeks.9 SD) at 27 weeks. prenatal diagnosis. There were 17 cases of mostly lethal skeletal dysplasias. 3 or 4 Short rib dysplasias Ellis-van Creveld n 40 35 10 9 Correct 35/40 31/35 5/10 4/9 Partially correct 5/40 4/35 5/10 4/9 GA at PD (completed weeks) 16–35 14–39 16–34 (1 recurr. Fetuses (n) with specific PD at gestational age: 15 + 0 to 19 + 6 20 + 0 to 21 + 6 22 + 0 to 28 + 6 29 + 0 to 34 + 6 35 + 0 to term 7 11 3 1 3 10 10 2 1 13 8 3 2 8 4 2 2 2 1 Achondroplasia Achondrogenesis Campomelic dysplasia ATD Jeune Hypochondrogenesis Diastrophic dysplasia 9 8 8 7 6 5 7/9 7/8 6/8 3/7 1/6 2/5 1/9 1/8 2/8 4/7 5/6 3/5 2 1 7 2 1 6 1 2 1 1 3 3 2 3 2 1 2 2 1 *Cases diagnosed correctly or partially correct at the first diagnostic examination.4 SD) at 23 weeks.3 SD) at 31 weeks and a prenatal/final diagnosis of ‘structurally normal fetus. one case Copyright  2009 ISUOG. suspected IUGR’/achondroplasia. and a prenatal/final diagnosis of ‘complex syndrome’/hypochondrogenesis.162 Table 1 Prenatal diagnosis of the 10 most common skeletal dysplasias in this study Fetuses (n) with PD:* Skeletal dysplasia Thanatophoric dysplasia Osteogenesis imperfecta 2. in two of the nine such cases of achondroplasia and in two of the 10 such cases of short-rib dysplasia. with 42% of the cases being diagnosed before 24 weeks. Biometric parameters The FL. unclear dysmorphic syndrome (n = 1) and IUGR with joint position anomalies and porencephaly (n = 1). GA. Figure 1 shows the numbers of prenatally diagnosed cases according to gestational age group for the 10 most common dysplasias. IUGR (n = 3). The HC was typically increased in some skeletal dysplasias: in 20 of the 38 cases of TD with HC measurement. All fetuses with achondrogenesis. Overall. 34: 160–170. After 1995. The FL was short (by definition (< 5th centile) as well as Z-scores < −2) in all cases of skeletal dysplasia except in four fetuses: one with FL at the 8th centile (−1. while achondroplasia consistently became apparent only in late gestation. recurrent/familial case. PD. In Figure 3a the FLs are expressed as absolute measures in mm (and in Figure S1 online they are expressed as Z-scores) according to gestational age. in the years before 1995. of ‘unclassifiable skeletal dysplasia’. 113 were correctly diagnosed as lethal (99%) and one with hypophosphatasia (Z-score for FL was −3. an extremely severe skeletal dysplasia.1) was misdiagnosed as having non-lethal skeletal dysplasia. false-negative diagnosis. 167 and 137 fetuses. Achondrogenesis and TD showed the most severely abnormal FL. one with FL at the 8th centile (−1. at 14 weeks. in which the prenatal/final diagnosis was mesomelic campomelia.1 and for ThC was −0. gestational age. of which 10 (59%) had a correct specific diagnosis. In Figure 3b ThCs are expressed as absolute values (and in Figure S2 online they are expressed as Z-scores). 176. solid and dashed lines) to about 20 weeks in the more recent years. in four of the eight such cases of campomelic dysplasia. respectively. Lethality in skeletal dysplasias is typically caused by impaired lung development secondary to a narrow thorax13 . In the two largest groups (TD and OI) there was a decrease in gestational age at diagnosis (Figure 2. and one with FL at the 9th centile (−1. Ultrasound Obstet Gynecol 2009. Five fetuses with Ellis-van Creveld were misdiagnosed (three as lethal and two as non-lethal skeletal dysplasia). Recurr. BPD.4 SD) at 18 weeks. ATD. which did not contribute to diagnosis. false positives there was significant morbidity: dysostoses (n = 2). Published by John Wiley & Sons. . HC and ThC data were available from 177. one with FL at the 81st centile (+ 0. and a prenatal/final diagnosis Sonographic assessment of lethality There were 114 fetuses with lethal skeletal dysplasias. The gestational age (GA) at the first specific prenatal ultrasound diagnosis depended on the type of skeletal dysplasia (Table 1 and Figure 1) and (more weakly) on the year in which the case occurred (Figure 2).. the median GA at diagnosis was 24 weeks. 1 FN at 39 weeks) 28–37 (1 FN at 31 weeks) 12–17 16–30 19–35 21–32 20–25 1 Up to 14 + 6 Schramm et al. In Figure 3c the HCs are expressed as absolute measurements (and in Figure S3 online they are expressed as Z-scores). Of these.

OI was the second most common skeletal dysplasia in our study (35 of 162).Ultrasound in skeletal dysplasias 14 163 12 10 Number of cases 8 6 4 2 0 Up to 14 + 0 15 + 0 to 19 + 6 20 + 0 to 21 + 6 22 + 0 to 28 + 6 29 + 0 to 34 + 6 35 + 0 to term Gestational age (weeks) Figure 1 Prenatally diagnosed skeletal dysplasias: numbers of cases by gestational age groups for the 10 most common dysplasias: thanatophoric dysplasia (types 1 and 2) ( ). polyhydramnios is common. liveborn). the HC was above the 95th centile. no measurement was available in two cases) of the fetuses with TD1 and in four of six of those with TD2. Ltd. There were several fetuses with TD diagnosed below the gestational age range of the normal curves we used for ThC (i. In the third trimester. campomelic dysplasia ( ). one with TD1 at 21 weeks had a ThC at the 10th centile and one with TD2 at 24 weeks had a ThC at the 14th centile. leading to steadily decreasing Z-scores with advancing age. achondrogenesis ( ). . with asphyxiating thoracic dysplasia Jeune (ATD Jeune. hypochondrogenesis ( ) and diastrophic dysplasia ( ). Figure 4a shows the biometric parameters HC. The thorax is narrow. The HC is large in half of cases. The peak of diagnoses is between 15 and 29 weeks. with the nasal bridge depressed. Three were misdiagnosed as having lethal skeletal dysplasias.e. The affected bones are very Copyright  2009 ISUOG. Its characteristics include severe micromelia and brachydactyly. these included one fetus with achondroplasia first presenting at 37 weeks. Fetuses with TD had ThC measurements markedly below the 5th centile with only three exceptions: one fetus with TD1 at 16 completed weeks had a ThC at the 11th centile. with short ribs and a prominent abdomen. ThC and FL in cases of TD. the trunk length is normal. Characteristics of the lethal type 2 (29 of 35) include severe micromelia. Ultrasound Obstet Gynecol 2009. but some types are often first apparent in the third trimester. achondroplasia ( ). In spite of severe platyspondyly. typically with irregular bending of long bones and ribs due to multiple intrauterine fractures. 34: 160–170. below 20–40 weeks’ gestation. and in some (mainly TD2) there is craniosynostosis (‘cloverleaf skull’) (see Figure S4 online for typical sonographic features). osteogenesis imperfecta (all types) ( ). asphyxiating thoracic dysplasia Jeune ( ). Growth in FL slowed down with advancing gestation. Some fetuses with TD have hydrocephaly. or Jeune syndrome) was suspected to have a non-lethal skeletal dysplasia (the patient opted for termination) and one with Rolland-Desbuquois syndrome (misdiagnosed at 28 weeks as OI. Published by John Wiley & Sons. while they are straight in TD2. In 28 of 31 (90%) fetuses affected by non-lethal conditions this status was correctly diagnosed. one with either spondyloepiphyseal dysplasia or Kniest dysplasia presenting at 35 weeks and one with an unclear skeletal dysplasia presenting at 27 weeks. In 16 of 32 (50%. short rib dysplasias ( ). Diagnostic sonographic criteria TD was the most common skeletal dysplasia in our study (40 of 162). In TD1 the long bones are bowed (‘telephone receiver femur’). but all of these resulted in live births. Ellis-van Creveld ( ). Laudy and Wladimiroff9 ).

achondroplasia ( short and irregular and the thorax is narrow. low normal in two and abnormally small in one. 35 30 Gestational age (weeks) 25 20 15 10 5 0 1985 1990 1995 Year 2000 2005 Figure 2 Gestational age at diagnosis of skeletal dysplasias according to year of diagnosis. brain anomalies and anomalies of the kidneys and genital tract. leading to steadily decreasing Z-scores with advancing age. usually only single tubular bones are affected and the ThC and HC are normal (Figure 4b). Ltd. . achondroplasia ( ). the ThC (data available on 22 cases) was below the 5th centile in all but one of the fetuses (which had a ThC at the 5. hypochondrogenesis ( ). Among the six cases with non-lethal OI. with a FL at the 33rd centile and Z-score of −0. The HC is mostly normal. In the five cases with non-lethal forms of OI and data on ThC available. only one fetus had a normal FL (at 25 weeks.164 40 Schramm et al. The head is large. shows an abnormal sonographic translucency and compressibility (see Figure S4 online for typical sonographic features). The thorax is narrow with short. It may be difficult to distinguish OI type 2 from the lethal form of hypophosphatasia using sonography alone. Linear regression lines indicate possible trends of the gestational age at diagnosis over the study period: thanatophoric dysplasia (types 1 and 2) ( ). characterized by micromelia with or without polydactyly (mostly postaxial). often congenital heart disease. achondrogenesis ( ). Internal malformations include cystic dysplasia of the kidneys and hypoplasia of the cerebellar vermis. The spine is sometimes irregular in appearance.5). Ultrasound Obstet Gynecol 2009. the mandible is small (micrognathia) and there are often facial clefts. osteogenesis imperfecta (all types) ( ). The short-rib dysplasias are a group of lethal skeletal dysplasias with autosomal recessive inheritance. 34: 160–170. and there are a variety of other possible malformations of the internal organs. and diastrophic dysplasia ( )) and all other skeletal dysplasias ( ). and the shortening was more pronounced than in non-lethal forms. the nasal bridge is depressed. it was normal in two. for the 10 most common dysplasias (thanatophoric dysplasia (types 1 and 2) ( ). Type 2 (Majewski) is characterized by pre. In the non-lethal forms of OI. campomelic dysplasia (+). asphyxiating thoracic dysplasia Jeune ( ). Ellis-van Creveld ( ). In cases with OI. osteogenesis imperfecta (all types) ( ). short rib dysplasias ( ). All fetuses with lethal OI had a FL below the 5th centile or below −2 SD for gestational age. There are four types of short-rib dysplasia. but differentiation is difficult because of overlapping symptoms. Type 1 (Saldino–Noonan) is characterized by polydactyly of the hands and sometimes of the feet. horizontally oriented ribs and a protuberant abdomen. In confirmed lethal OI. sometimes facial clefts. renal and Copyright  2009 ISUOG.or postaxial polydactyly and brachydactyly of the hands and sometimes of the feet. Type 3 (Verma–Naumoff) is characterized predominantly by postaxial polydactyly and brachydactyly of the hands and feet and gastrointestinal. and ). FL Z-scores decreased markedly with gestational age in lethal OI. the FL slowed down with advancing gestation. however. Published by John Wiley & Sons.4th centile at 26 weeks). with platyspondyly due to fractures of the vertebrae. the skull. The ThC measurements in OI were available for 27 of the 35 cases.

In achondrogenesis there is Copyright  2009 ISUOG. Ellis-van Creveld ( ). pre. 2 and 3 can exhibit fetal hydrops and situs inversus. two of Type 4 and a further five other cases including one recurrent case (diagnosed at a targeted scan at 18 weeks). and. cerebral. All eight cases of achondrogenesis were diagnosed between 12 and 17 weeks. Types 1. In Ellis-van Creveld. The 5th and 95th centiles are indicated8. thoracic circumference (b) and head circumference (c) plotted against gestational age in skeletal dysplasias (thanatophoric dysplasia (types 1 and 2) ( ). Published by John Wiley & Sons. Half of the fetuses have structural heart disease (atrial or ventricular septal defect) and some have a Dandy–Walker malformation.Ultrasound in skeletal dysplasias (a) 60 (b) 250 165 50 Thoracic circumference (mm) 200 Femur length (mm) 40 150 30 100 20 50 10 0 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks) (c) 350 0 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks) 300 250 Head circumference (mm) Figure 3 Femur length (a). We diagnosed eight cases of Ellis-van Creveld (at 14–33 weeks plus one false-negative at 39 weeks) and seven cases of ATD Jeune (at 19–35 weeks). the thorax is long and narrow. In this study there were two cases of short-rib dysplasia Type 3.and postaxial polydactyly in half of cases. Ltd. . short rib dysplasias ( ). one of Type 2. gastrointestinal or renal anomalies and omphalocele. centiles before 20 weeks’ gestation were extrapolated from normal data9 . hypochondrogenesis ( ). for thoracic circumference. achondrogenesis ( ). Each fetus is plotted only once. Most affected fetuses have cystic dysplastic kidneys. less commonly. In ATD. campomelic dysplasia ( ). and diastrophic dysplasia ( )) and for all other skeletal dysplasias ( ). at the gestational age of the first diagnostic examination. there is an acromesomelic micromelia with polydactyly of the hands in most cases and of the feet in some cases. asphyxiating thoracic dysplasia Jeune ( ). 34: 160–170. facial clefts in nearly all cases. cardiac. 200 150 100 50 0 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks) other defects. achondroplasia ( ).9 . osteogenesis imperfecta (all types) ( ). Ultrasound Obstet Gynecol 2009. Type 4 (Beemer–Langer) is characterized by bowed limbs. the long bones have mild rhizomelia and some have polydactyly. Chondroectodermal dysplasia Ellis-van Creveld and ATD Jeune are also grouped with the short-rib dysplasias and are mostly lethal.

With the discovery of the molecular basis of many of the skeletal dysplasias their classification has evolved. The long bones are thick. less commonly. In our cohort there were five cases diagnosed between 20 and 25 weeks. −) and Type 2 ( .9 . The rhizomelic form is associated with severe mental retardation. The fingers are short. The nose is flat and the nasal bridge is depressed. Anterior angulation of the tibia (see Figure S4f online) and the short fibula are a pathognomonic feature of campomelic DISCUSSION To the best of our knowledge this is the largest singlecenter study of sonographically diagnosed fetal skeletal dysplasias: we investigated 162 affected fetuses with confirmed clinical genetic. The fingers and toes are short and the feet are clubbed. with 5th and 95th centiles indicated8. . presenting somewhat later in gestation than does Type I and frequently having polyhydramnios. a flat face and a short neck. Our eight cases were diagnosed between 16 and 30 weeks. 34: 160–170. All nine of our cases were diagnosed after 27 weeks (at 28–37 weeks). Achondrogenesis Type II (autosomal dominant) is less severe. The micromelia is rhizomelic and the heads tend to be large. +) (a) and in osteogenesis imperfecta lethal ( .4 ). −) and non-lethal ( . with short hands and feet. dysplasia. The chondrodysplasia punctata group contains 11 skeletal dysplasias. a short trunk and macrocephaly. pathological or molecular diagnosis. as the mutated gene. mostly radiological features only.e. the multitude of differential diagnoses with overlapping features and the phenotypic variability. Diastrophic dysplasia (autosomal recessive) is a nonlethal skeletal dysplasia without mental impairment. a flat face with micrognathia. and it may be the only diagnosis if the pregnant woman Copyright  2009 ISUOG. For thoracic circumference. with 11 pairs of ribs. to being based largely on pathogenesis2 . Hypochondrogenesis (autosomal dominant) represents a clinical variant within the achondrogenesis–hypochondrogenesis spectrum. with ulnar deviation and ‘hitchhiker’ thumbs. Both achondrogenesis and hypochondrogenesis are lethal. a large head. and the scapulae and claviculae are hypoplastic. with a very narrow barrel-shaped thorax and a markedly prominent abdomen. some of which have been detected prenatally. thoracic circumference (open symbols) and femur length (+ and − symbols) in thanatophoric dysplasia Type 1 ( . There are clubfeet and micrognathia. molecular genetics is the gold standard for an increasing number of skeletal dysplasias. . is also involved in gonadal development. The thorax is normal in size. . the rhizomelic form (autosomal recessive). with micrognathia and low-set ears. Campomelic dysplasia (autosomal dominant) is characterized by mesomelia and mild to moderate bowing of the legs and. typical gaps between the fingers and digital deviation lead to the appearance of a ‘trident’ hand. In fact. The phalanges are short. The face is flat and there is micrognathia and sometimes microcephaly. . Ltd. ž °ž ° early hydrops and a short trunk (short crown–rump length). resembling TD. markedly shortened and straight. exhibiting typical hyperechogenic areas (premature calcification) in the cartilaginous skeletal parts. from being based initially on morphological. At around 20 weeks’ gestation. centiles before 20 weeks’ gestation were extrapolated from normal data9 . . both of which are autosomal recessive. Ultrasound Obstet Gynecol 2009. with a small thorax. fetuses with achondroplasia had normal biometric parameters. The six cases of hypochondrogenesis in our study were diagnosed between 21 and 32 weeks. The thorax is small and bell-shaped. i. depressed nasal bridge and mid-face hypoplasia. of the arms. and there may be nuchal edema. which became abnormally short only in the third trimester. Figure 4 Head circumference (filled symbols). Published by John Wiley & Sons. there is extreme micromelia. The mostly lethal type. Occasionally there is hydronephrosis. including FL.166 (a) 350 Biometric parameter (mm) 300 250 200 150 100 50 0 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks) (b) 350 Biometric parameter (mm) 300 250 200 150 100 50 0 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Gestational age (weeks) Schramm et al. Prenatal sonographic diagnosis of fetal skeletal dysplasias is challenging because of their rarity (21–47 per 100 000 deliveries3. Achondroplasia (autosomal dominant) is a nonlethal skeletal dysplasia without mental impairment. SOX9. Typical facial features include prominent forehead. In achondrogenesis types IA/B. the epiphyses of the long bones (see Figure S4g) or the calcaneus. is characterized by a moderate rhizomelic shortening of the otherwise straight long bones. poor mineralization. short limbs. +) forms (b). The face is flat. In some affected chromosomally male fetuses sex reversal occurs. The two cases in our cohort were diagnosed at 19 and 21 weeks.

7 . 215 have been found to be associated with mutations in 145 genes. but there are still some entities which are not clinically classifiable. pathogenetic concepts and molecular and biochemical properties was recently provided by Superti-Furga and Unger2 .16 . biochemical and/or radiological criteria2 . the most common types of skeletal dysplasia in this fetal population and their frequencies were similar to those found in previous studies (Table 2). in their cohorts. two with dysmorphic syndromes and eight with IUGR or which were normal small babies. incorporating newly recognized disorders. Table 2 Frequencies of skeletal dysplasias reported in different prenatal series Goncalves and Jeanty20 (1994) (n = 139) 43 (31) 39 (28) 6 (4) 2 (1) 15 (11) 9 (6) 4 (3) 0 0 3 (2) Final diagnosis Thanatophoric dysplasia Osteogenesis imperfecta 2. Doray et al. A revised classification of skeletal dysplasias.7 . as either ‘correct ultrasound diagnosis’ or ‘partially correct ultrasound diagnosis’. Web resources can aid in the selection of appropriate molecular genetic tests (for an example and selection of links.7 and Superti-Furga and Unger2 ).14 three false-positives plus seven lost to follow-up. Ultrasound Obstet Gynecol 2009. for which protocols have been suggested5. some families of affected cases did not respond spontaneously. nine of the 162 (5%) cases could not be classified. 20% and 6% unclassifiable skeletal dysplasias. the false positives were mainly fetuses with dysmorphic syndromes or IUGR. However. The accuracy of prenatal diagnosis seems to have improved in recent years.Ultrasound in skeletal dysplasias opts for termination or when pathological diagnosis is not possible4. Prenatal identification of the specific type of a particular skeletal dysplasia requires a detailed and structured examination.14 (1998) (n = 25) 5 (20) 8 (32) 2 (8) 0 4 (16) 3 (12) 1 0 0 0 Doray et al. 3 or 4 Short-rib dysplasia Ellis-van Creveld Achondroplasia Achondrogenesis Campomelic dysplasia ATD Jeune Hypochondrogenesis Diastrophic dysplasia This study (n = 162) 40 (25) 35 (22) 10 (6) 9 (6) 9 (6) 8 (5) 8 (5) 7 (4) 6 (4) 5 (3) Sharony et al.4 . We therefore could not calculate the incidence of individual skeletal dysplasias. Besides the 23 different types of skeletal dysplasia that we diagnosed in our series. 36 had dysmorphic syndromes and 15 were structurally normal IUGR fetuses. in our lost-to-follow-up group there was one fetus with a clear skeletal dysplasia whose parents refused to provide any postnatal data to us. for example. Sharony et al. and the true detection rate was difficult to establish. 34: 160–170. In the studies listed in Table 3. were diagnosed correctly in 88% and 89% of cases. TD and OI. Goncalves and Jeanty20 : 127 from multiple centers plus 12 from previous publications. Published by John Wiley & Sons.19 report that they had no false negatives. The data for the other most common skeletal dysplasias and for previous studies are shown in Table 4. ATD.16 : 54 false-positives. . Gaffney et al. Ascertainment of the false negatives was limited because of incomplete follow-up in ‘suspected normals’.15 five false-positives.16 (1993) (n = 172) 27 (16) 37 (22) 8 (5) 0 4 (2) 17 (10) 14 (8) 3 (2) 0 2 (1) Gaffney et al. reported that among 54 false positives in their study. as previously reported14 – 16 .17 and Parilla et al. respectively. Our overall follow-up for (supposedly) normal cases over the study period was about 80%. Tretter et al. So far only a few studies have discussed false-negative diagnoses of skeletal dysplasias. short long bones’. There are few reports with data on the diagnostic accuracy of prenatal diagnosis of skeletal dysplasias14 – 19 (Table 3). respectively. Also. suspect familial large head. among 12 false positives. We had two false-negative diagnoses: one fetus with achondroplasia was wrongly diagnosed as ‘structurally normal fetus. not all of which include numbers of false negatives and false positives. Diagnostic accuracy of prenatal diagnosis We described the accuracy of our prenatal diagnosis with regard to the final diagnosis. Copyright  2009 ISUOG. Gaffney et al. Our cases were from a mixed screening and referral population. The ability to achieve the correct specific diagnosis by prenatal ultrasound depends on the type of skeletal dysplasia. there were two fetuses with dysostoses. Rasmussen et al. The two most common skeletal dysplasias in our study. Ltd.15 (2000) (n = 42) 4 (10) 13 (31) 1 3 (7) 7 (17) 5 (12) 1 2 (5) 0 1 Values are given as n (%) for cases with true skeletal dysplasias. Sharony et al. see Goncalves et al.15 reported 16%. IUGR affecting mainly extremities’ and one with Ellis-van Creveld was diagnosed as ‘suspected genetic syndrome. 167 Classification and frequencies of skeletal dysplasias The most recent classification of genetic skeletal disorders includes 372 different conditions in 37 groups defined by molecular. Of them. asphyxiating thoracic dysplasia. In our study. Lethality Lethality in skeletal dysplasias is caused mainly by pulmonary hypoplasia secondary to thoracic hypoplasia13 .14 and Doray et al.

with one exception. *Detailed evaluation not possible (figures shown here calculated from Sharony et al. as exact numbers were not given by the authors).15 identified 17 of 21 lethal cases. the misdiagnosis occurred in a fetus with hypophosphatasia and a normal ThC (Z-score. Among the mostly lethal conditions.18 (1998) Doray et al. five of eight mostly lethal cases and all eight non-lethal cases. all of which were diagnosed correctly. all fetuses with lethal disease were correctly classified (113/114. ‡Included in short-rib dysplasia. Correct (%) 35 48 44 50 62 65 68 Partially correct (%) 65 52 56 50 38 35 31 False positive ( n) 54 1 3 ND 5 7 12 False negative ( n) ND 0 ND ND ND 0 2 172 26 25 26 42 20 162 *Included only lethal skeletal dysplasias. In the Results section we provide descriptions of the sonographic morphology of the 10 most common skeletal dysplasias.16 . data not available.14 correctly identified all 20 cases with lethal and two of five with non-lethal skeletal dysplasias. Ellis-van Creveld was the most difficult to classify correctly: in five of nine affected fetuses the sonographic assessment of lethality was imprecise. ND. . There are.1) examined at 19 weeks.16 (1993) Tretter et al. not done/data not given. In addition. including termination laws.4. but all three cases resulted in live births. Published by John Wiley & Sons.16 (1993) (n = 172) 60/172 (35)* (70)† (50)† NA NA NA NA NA NA NA NA Tretter et al. of course.19 (2003) This study Single/multicenter Multi Single Single Single Multi Single Single n Schramm et al.17 (1998) (n = 26) 13/26 (50) 6/12 (50) 5/6 (83) 1/3 (33) 0 0 1/2 (50) 0/2 ‡ 0/1 0 Gaffney et al. FL Z-score. Gestational ages at diagnosis For many reasons. For example. 34: 160–170. Doray et al. In Germany. their typical sonomorphological signs accounted for the high rate of overall and correct specific diagnosis. in one case in which ‘TD’ was diagnosed at 33 weeks (ThC Z-score. there are almost always subtle but pathognomonic signs which can be found within the skeletal apparatus. 99%). a timely specific prenatal diagnosis is important. Copyright  2009 ISUOG. asphyxiating thoracic dysplasia. in five cases they could not determine lethality. Ltd. The discrimination between lethal and non-lethal forms of skeletal dysplasias is. frontal bossing and short metacarpals). −7. −2. pitfalls in this sonomorphological approach.15 (2000) (n = 42) 30/42 (71) 3/4 (75) 9/13 (69) 0/1 3/3 (100) 7/7 (100) 3/5 (60) 1/1 (100) 2/2 (100) 0 0/1 Final diagnosis Overall Thanatophoric dysplasia Osteogenesis imperfecta 2. the fetus actually had opsismodysplasia (micromelic dwarfism.14 (1998) Hersh et al. ATD. for some skeletal dysplasias. 3 or 4 Short-rib dysplasia Ellis-van Creveld Achondroplasia Achondrogenesis Campomelic dysplasia ATD Jeune Hypochondrogenesis Diastrophic dysplasia Values are given as n (%). Table 4 Diagnostic accuracy of prenatal ultrasound for the 10 most common skeletal dysplasias in this study This study (n = 162) 110/162 (68) 35/40 (88) 31/35 (89) 5/10 (50) 4/9 (44) 7/9 (78) 7/8 (88) 6/8 (75) 3/7 (43) 1/6 (17) 2/5 (40) Sharony et al. of major clinical importance. Three of 31 fetuses with non-lethal skeletal dysplasias were misdiagnosed (at 27.18 predicted lethality correctly in 92% of cases (23 fetuses with lethal and three with nonlethal conditions). the face or the internal organs. 35 and 37 weeks). Morphology In the two most common skeletal dysplasias. Gaffney et al.15 (2000) Parilla et al. Four other studies have addressed the ability to discriminate between lethal and non-lethal skeletal dysplasias: Hersh et al. Ultrasound Obstet Gynecol 2009.14 (1998) (n = 25) 11/25 (44) 2/5 (40) 5/8 (63) 0/2 0 2/4 (50) 1/3 (33) 0/1 0 0 0 Doray et al. †Figures quoted in the text. Parilla et al. TD and OI. Examples include the angulated tibia in campomelic dysplasia or polydactylies. NA. In our study.19 only report on their 16 lethal cases of skeletal dysplasia.168 Table 3 Studies reporting the diagnostic accuracy of prenatal ultrasound of skeletal dysplasias Ultrasound diagnosis Study Sharony et al. of course.17 (1998)* Gaffney et al. −0.8).

15 reported seven fetuses detected at 28–35 weeks. However. This can be seen particularly well in the Z-score plots. In particular. three with hypochondroplasia and one with OI). This is evident. for example. these percentages range from 37%4 to 58%16 or 62%17 . for some skeletal dysplasias. In our study. We performed additional molecular studies for suspected skeletal dysplasias prenatally or postnatally as available at that time (data not shown).14 reported four cases detected at 31–47 weeks. In our study. Additionally. but included only the sonographic information in our analysis of detection rates and diagnostic accuracy. the FLs at 20 weeks had been reported as normal by the referring gynecologists. Signalling genes (e. mostly symmetrical. By how much the diagnostic accuracy can be improved by integrating molecular studies into the prenatal diagnostic approach remains to be determined. For example. both with ultrasound screening programs. achondroplasia was the only skeletal dysplasia that was not detected before 24 weeks. Our data agree with this. which can accurately assess recurrence risks. by Tonni et al. Molecular genetics can contribute essential diagnostic information and complement prenatal sonographic assessment4. Table S1 (online) lists the known genetic causes for the most common skeletal dysplasias in our study. OI Type 4 (FL. We therefore decided to analyze and display the quantitative data both in the ‘conventional’ way of plotting the affected values on normal ranges and to display them as Z-scores. mutated fibroblast growth factor receptor FGFR-3 leading to reduced enchondral chondrocyte proliferation in achondroplasia) and genes regulating cell structure and function such as production or removal of matrix components (e. mainly due to earlier diagnosis of TD and lethal OI. we have analyzed the largest prenatal single-center series of skeletal dysplasias. with either a fully or at least a partially correct diagnosis. the final molecular diagnosis revealed lethal hypophosphatasia. there was a trend towards earlier prenatal diagnosis over the years. Genetically determined growth changes. which therefore cannot be expressed meaningfully as centiles or graphically in typical ‘normal ranges’ with centiles. For France and the UK. In the majority of cases the initial ultrasound examination was diagnostic. the diagnostic accuracy with regard to lethality was high. the FL is the best parameter for the detection of skeletal dysplasias20 . while Doray et al.2 . There is only one recent report. Thus we chose this approach over the one used in another large biometry study of fetal skeletal dysplasias.7 . in the biometric synopsis of FL. −1. In our cohort. Biometry In ultrasound screening. ThC and HC for TD and OI (Figure 4 and Figures S5 and S6 online). In the USA. not all cases of skeletal dysplasia have shortening below −2 SD. in a fetus with the sonographic features of OI Type 2. are apparent in all skeletal segments in which the particular gene is expressed.g. In addition to showing the quantitative excess of an affected parameter more clearly. Genetic analysis Defects of both pre. Published by John Wiley & Sons. Goncalves and Jeanty20 reported nine of 137 fetuses (6. −0.Ultrasound in skeletal dysplasias compulsory routine measurement of the fetal FL was introduced in 1995. including molecular genetic analysis7 . Extreme deviations of biometric measurements are typical for many skeletal dysplasias. Biometric parameters in skeletal dysplasias are best expressed as Z-scores.4 SD at 23 weeks).21 . In this study. which grouped affected fetuses by percentages of the mean20 . raising the recurrence risk from around 5% (empirically for OI Type 2) to 25% (autosomal recessive). hypochondrogenesis (FL. faulty collagen COL1A1 and COL1A2 in OI) can be involved. the measurements of the other long bones and the head and thorax circumferences contributing mainly to the differential diagnoses.4 SD at 18 weeks) and one with an unclear skeletal dysplasia (FL. examining 162 fetuses and at least 23 different types of dysplasia.and postnatally expressing genes can lead to skeletal dysplasias. for example in the FL Z-score curves for TD and OI (Figures S5 and S6 online). there were five cases with a FL greater than −2 SD: one case each of achondroplasia (FL.9 SD at 27 weeks). 34: 160–170. but the severity of the effect may vary in the affected segments1.3 SD at 31 weeks).g. In most studies achondroplasia is detected late in pregnancy: Gaffney et al. −1. Goncalves and Jeanty20 reported 15 fetuses with achondroplasia: two had femur measurements before 24 weeks and both were normal. Typical morphology often allows a specific prenatal Copyright  2009 ISUOG. while another two measured at 25 and 36 weeks also had normal FL. Ltd. where ultrasound screening is not universal. In all nine cases. the reported percentages of diagnosis before 24 weeks are similar (62% and 71%14. Ultrasound Obstet Gynecol 2009.6%) with a FL above the 5th centile (five with achondroplasia. The World Health Organization (WHO) recommends Z-scores for comparison of anthropometric measurements with the normal ranges10 . . raising the percentage of correct prenatal diagnosis before 24 weeks from 42% to 62% in the last 10 years. 169 gestational age in the same clear x-y plot. we have shown that a specific diagnosis is possible by prenatal ultrasound alone in the majority of cases. Z-scores allow comparison of multiple biometric parameters over CONCLUSION In conclusion. −0.15 ). −1. in which rhizomelic shortening of the long bones (< −2 SD) was diagnosed at 17 weeks in a fetus with achondroplasia. In inconclusive cases ultrasound can be used to narrow the possible diagnoses down in order to select appropriate further tests. the biometric measurements deviated progressively from the expected mean as the gestational age advanced. They commented that the FL is the best parameter to distinguish at least among the five most common skeletal dysplasias.5 SD at 32 weeks) and short-rib dysplasia (FL.

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