Dx Prenatal de Displasia Esqueleticas

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Ultrasound Obstet Gynecol2009; 34: 160170Published 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 andDepartment of Pathology, Bogenhausen Hospital, Munich andHeinrich Heine University, D usseldorf, Germany andUniversity Hospital, Bern, Switzerland

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

ABSTRACT

Objective To assess the types and numbers of cases,

gestational age at specific prenatal diagnosis anddiagnostic accuracy of the diagnosis of skeletal dysplasiasin a prenatal population from a single tertiary center.

Methods This was a retrospective database review oftype, prenatal and definitive postnatal diagnoses and

gestational age at specific prenatal diagnosis of allcases of skeletal dysplasias from a mixed referraland screening population between 1985 and 2007.Prenatal diagnoses were grouped into correct ultrasounddiagnosis (complete concordance with postnatal pediatricor pathological findings) or partially correct ultrasounddiagnosis (skeletal dysplasias found postnatally to be a

different one from that diagnosed prenatally).

Results We included 178 fetuses in this study, ofwhich 176 had a prenatal ultrasound diagnosis ofskeletal dysplasia. In 160 cases the prenatal diagnosisof a skeletal dysplasia was confirmed; two caseswith skeletal dysplasias identified postnatally had notbeen diagnosed prenatally, giving 162 fetuses withskeletal dysplasias in total. There were 23 differentclassifiable types of skeletal dysplasia. The specificdiagnoses based on prenatal ultrasound examinationalone 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 wasdiagnosed prenatally, but was not confirmed postnatally(n = 12 false positives) or the case was lost to follow-up (n = 4). The following skeletal dysplasias wererecorded: thanatophoric dysplasia (35 diagnosed correctly

prenatally of 40 overall), osteogenesis imperfecta (lethaland 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 orunclassifiable skeletal dysplasias.

Conclusion Prenatal diagnosis of skeletal dysplasias canpresent a considerable diagnostic challenge. However,a meticulous sonographic examination yields highoverall detection. In the two most common disorders,thanatophoric dysplasia and osteogenesis imperfecta(25% and 22% of all cases, respectively), typicalsonomorphology accounts for the high rates of completelycorrect prenatal diagnosis (88% and 89%, respectively)at the first diagnostic examination. Copyright 2009ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION

Congenital skeletal disorders comprise skeletal dysplasias,dysostoses and reduction deformities. Skeletal dysplasias(chondrodysplasias or osteochondrodysplasias) aredevelopmental disorders of chondro-osseous tissue.Dysostoses are malformations of single bones, alone orin combination (e.g. isolated polydactyly). Reductionsare secondary malformations of bones1,2. Advances inmolecular genetics have helped elucidate the biologicalbasis for many of the diseases in the first two groups,

making some of them amenable to molecular geneticdiagnosis in addition to the classical diagnostic approachof morphological assessment2. However, specific prenataldiagnosisof skeletal dysplasias still presents a considerablediagnostic challenge, not least because of their rarity3,4.

Prenatal series and diagnostic algorithms, based onsonographically detectable features of skeletal dysplasias,have been described57. We analyzed the data of allsuspected and confirmed cases of skeletal dysplasias from

Correspondence to: PD Dr T. Schramm, Pranatal-Medizin Munchen, Lachnerstrasse 20, D-80639 Munchen, Germany

(e-mail: [email protected])

Accepted: 19 February 2009

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


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Ultrasound in skeletal dysplasias 161

a mixed screening and referral population seen in ourinstitution between 1985 and 2007. The purpose of thisstudy was to report the types and proportions of skeletaldysplasias in this group and gestational ages at diagnosis,to carry out a detailed analysis of biometric parametersand to describe the characteristic sonographic features ofthe most common skeletal dysplasias.

P A T I E N T S A N D M E T H O D S

Between 1985 and2007, data were collectedprospectivelyfrom all fetuses with skeletal dysplasias diagnosed ina mixed screening and referral population in one largetertiary center. For this study, we sought and analyzeddetails of prenatal management and postnatal pediatricor pathological studies from all cases. Wherever possible,molecular diagnosis was sought.

We used the terms correct ultrasound diagnosis andpartially correct ultrasound diagnosis to describe the

accuracy of the first diagnostic examination done in ourcenter compared with the final pediatric or pathologicaldiagnosis. Either there was complete concordance of thespecific ultrasound diagnosis, or a skeletal dysplasia otherthan the one diagnosed by ultrasound was present, or thecases were false positive or false negative.

In all cases, the diagnostic ultrasound examinationincluded measurement of the long bones in all segmentsof all four extremities, examination of the hands, spineand head and assessment of mineralization and boneshapes, in addition to a full fetal anatomical survey57.Forthe purposes of this study, biometric data (femur length(FL), biparietal diameter (BPD), head circumference

(HC), thoracic circumference (ThC) and abdominalcircumference (AC)) were collected and analyzed inrelation to publishednormalvalues. Thepublished normaldata from Snijders and Nicolaides8 were used to providecentiles for FL, BPD, HC and AC. Those from Laudy andWladimiroff9 were used to provide centiles for ThC after20 weeks; prior to this age the centiles were extrapolatedfrom their normal data. In the graphs each fetus wasrepresented only once, at the gestational age of the firstdiagnostic examination.

For values beyond the typical normal ranges (such asthe 5th and 95th centiles), deviation from the gestational

age mean can be expressed best as multiples of the SD orZ-scores, enabling numerical quantification for extremevalues such as those encountered in skeletal dysplasias.This also allows comparison of different parameters overgestation on the same y-axis10. Z-scores were calculatedfor FL, ThC and HC for all affected fetuses. Values in mmand Z-scores were plotted across the gestational age rangefrom 12 to 40 weeks gestation. We assumed that thereported normal populations were normally distributed.

For the 10 most common skeletal dysplasias encoun-tered in our study, we describe diagnostic sonoanatomicalfeatures, derived from clinical experience gathered inthis study, a genetic textbook on skeletal dysplasias1, adigital dysmorphology database11 and the online catalogof human genes and genetic phenotypes, OMIM12.

RESULTS

Frequencies of skeletal dysplasias, detection rates andgestational ages at diagnosis

From the database, we identified 178 fetuses in which thediagnosis of skeletal dysplasia had been made. Of these,162 cases were confirmed as skeletal dysplasias, there

being 23 different classifiable types. Ten types of skeletaldysplasia occurred more than twice and accounted for137 of these 162 cases. The two most common typeswere thanatophoric dysplasia (TD, types 1 and 2; 40/162,24.7%) and osteogenesis imperfecta (OI types 2, 3 and4; 35/162, 21.6%). Another 13 known types of skeletaldysplasia occurred once or twice, and there were anothernine fetuses with unclassifiable skeletal dysplasias. Forthe 10 types of skeletal dysplasia that occurred morethan twice, the type, number of cases, proportion ofcompletely or partially correct diagnoses and gestationalage at diagnosis are shown in Table 1.

The overall prenatal detection rate for all cases withconfirmed skeletal dysplasias was 98.8% (160/162). Therates of completely and partially correct prenatal sono-graphic diagnosis at the first diagnostic examination were67.9%(110/162)and 30.9%(50/162), respectively.Therewere two false negatives: one case with chondroectoder-mal dysplasia Ellis-van Creveld (prenatally diagnosed at39 completed weeks as suspected genetic syndrome, shortlong bones) and one with achondroplasia (diagnosed at31 weeks as structurally normal fetus, suspect familiallarge head, intrauterine growth restriction (IUGR) affect-ing mainly extremities).

The less common types of skeletal dysplasia included

two cases with chondrodysplasia punctata (diagnosedcorrectly at 21 and 23 weeks), two cases of spondy-loepimetaphyseal dysplasia (one diagnosed correctly at12 weeks and one partially correctly at 32 weeks), twocases with lethal hypophosphatasia (diagnosed partiallycorrectly at 16 and 19 weeks), one case each of dysseg-mental dysplasia Rolland Desbuquois (diagnosed par-tially correctly as either OI or campomelic dysplasia at28 weeks), Kniest dysplasia (diagnosed partially correctlyat 19 weeks), kyphomelic dysplasia (diagnosed correctlyat 31 weeks), opsismodysplasia (misdiagnosed as TD at33 weeks), osteocraniostenosis (misdiagnosed as TD at

21 weeks), otopalatodigital syndrome type 2 (diagnosedcorrectly at 22 weeks), platyspondylic chondrodysplasiaShiraz type (diagnosed correctly at 28 weeks), spondy-loepiphyseal dysplasia (diagnosed partially correctly at35 weeks), sponastrimic dysplasia (diagnosed partiallycorrectly at 29 weeks), metaphyseal dysplasia McKusicktype (diagnosed partially correctly at 27 weeks) and nineskeletal dysplasias that remained unclear even at pediatricor pathological examination (diagnosedpartiallycorrectlyat 1330 weeks).

In addition to the 162 true skeletal dysplasia cases therewere another 16 cases in which the diagnosis skeletaldysplasia was made prenatally. Of these, four cases werelost to follow-up, and in 12 cases no skeletal dysplasiawas found postnatally. However, in seven of these 12

Copyright 2009 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol2009; 34: 160170.


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162 Schramm et al.

Table 1 Prenatal diagnosis of the 10 most common skeletal dysplasias in this study

Fetuses (n) with PD:* Fetuses (n) with specific PD at gestational age:

Skeletal dysplasia n CorrectPartiallycorrect

GA at PD(completed weeks)

Up to14+ 6

15+ 0 to19+ 6

20+ 0 to21+ 6

22+ 0 to28+ 6

29+ 0 to34+ 6

35+ 0 toterm

Thanatophoric

dysplasia

40 35/40 5/40 1635 7 10 13 8 2

Osteogenesisimperfecta 2, 3 or 4

35 31/35 4/35 1439 1 11 10 8 4 1

Short rib dysplasias 10 5/10 5/10 1634 (1 recurr. at18 weeks)

3 2 3 2

Ellis-van Creveld 9 4/9 4/9 14 33 (1 recurr. at14 weeks; 1 FNat 39 weeks)

1 3 1 2 2

Achondroplasia 9 7/9 1/9 2837 (1 FN at 31weeks)

2 6 1

Achondrogenesis 8 7/8 1/8 1217 1 7Campomelic dysplasia 8 6/8 2/8 1630 2 2 3 1ATD Jeune 7 3/7 4/7 1935 1 1 2 2 1Hypochondrogenesis 6 1/6 5/6 2132 1 3 2Diastrophic dysplasia 5 2/5 3/5 2025 3 2

*Cases diagnosed correctly or partially correct at the first diagnostic examination. ATD, asphyxiating thoracic dysplasia; FN, false-negativediagnosis; GA, gestational age; PD, prenatal diagnosis; Recurr., recurrent/familial case.

false positives there was significant morbidity: dysostoses(n = 2), IUGR (n = 3), unclear dysmorphic syndrome(n = 1) and IUGR with joint position anomalies andporencephaly (n = 1).

The gestational age (GA) at the first specific prenatalultrasound diagnosis depended on the type of skeletaldysplasia (Table 1 and Figure 1) and(more weakly) on theyear in which the case occurred (Figure 2). Figure 1 shows

the numbers of prenatally diagnosed cases according togestational age group for the 10 most common dysplasias.All fetuses with achondrogenesis, an extremely severeskeletal dysplasia, were diagnosed between 12 and 17completed weeks. In the two largest groups (TD andOI) there was a decrease in gestational age at diagnosis(Figure 2, solid and dashed lines) to about 20 weeks inthe more recent years, while achondroplasia consistentlybecame apparent only in late gestation. Overall, in theyears before 1995, the median GA at diagnosis was24 weeks, with 42% of the cases being diagnosed before24 weeks. After 1995, 62% of cases were diagnosedbefore 24 weeks and the median GA at diagnosis was

21 weeks.

Biometric parameters

The FL, BPD, HC and ThC data were available from177, 176, 167 and 137 fetuses, respectively, at thefirst diagnostic examination (AC data, which did notcontribute to diagnosis, are not included).

The FL was short (by definition (


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0

2

4

6

8

10

12

14

Up to 14+0 15+0 to 19+6 20+0 to 21+6

Gestational age (weeks)

Numberofcases

22+0 to 28+6 29+0 to 34+6 35+0 to term

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) ( ); osteogenesis imperfecta (all types) ( ); short rib dysplasias ( ); Ellis-van Creveld ( );achondroplasia ( ); achondrogenesis ( ); campomelic dysplasia ( ); asphyxiating thoracic dysplasia Jeune ( ); hypochondrogenesis ( )

and diastrophic dysplasia ( ). The peak of diagnoses is between 15 and 29 weeks, but some types are often first apparent in the thirdtrimester.

with asphyxiating thoracic dysplasia Jeune (ATD Jeune,or Jeune syndrome) was suspected to have a non-lethalskeletal dysplasia (the patient opted for termination) andone with Rolland-Desbuquois syndrome (misdiagnosed at28 weeks as OI, liveborn).

In 28 of 31 (90%) fetuses affected by non-lethalconditions this status was correctly diagnosed. Threewere misdiagnosed as having lethal skeletal dysplasias,but all of these resulted in live births; these included onefetus with achondroplasia first presenting at 37 weeks,one with either spondyloepiphyseal dysplasia or Kniestdysplasia presenting at 35 weeks and one with an unclearskeletal dysplasia presenting at 27 weeks.

Diagnostic sonographic criteria

TD was the most common skeletal dysplasia in our study(40 of 162). Its characteristics include severe micromeliaand brachydactyly. In TD1 the long bones are bowed(telephone receiver femur), while they are straight inTD2. In spite of severe platyspondyly, the trunk lengthis normal. The thorax is narrow, with short ribs anda prominent abdomen. The HC is large in half ofcases, with the nasal bridge depressed, and in some

(mainly TD2) there is craniosynostosis (cloverleaf skull)(see Figure S4 online for typical sonographic features).Some fetuses with TD have hydrocephaly. In the thirdtrimester, polyhydramnios is common. Figure 4a showsthe biometric parameters HC, ThC and FL in cases of TD.

Growth in FL slowed down with advancing gestation,leading to steadily decreasing Z-scores with advancingage. Fetuses with TD had ThC measurements markedlybelow the 5th centile with only three exceptions: one fetus

with TD1 at 16 completed weeks had a ThC at the 11

th

centile, one with TD1 at 21 weeks had a ThC at the 10th

centile and one with TD2 at 24 weeks had a ThC at the14th centile. There were several fetuses with TD diagnosedbelow the gestational age range of the normal curves weused for ThC (i.e. below 2040 weeks gestation, Laudyand Wladimiroff9). In 16 of 32 (50%; no measurementwas available in two cases) of the fetuses with TD1 and

in four of six of those with TD2, the HC was above the95th centile.

OI was the second most common skeletal dysplasia inour study (35 of 162). Characteristics of the lethal type2 (29 of 35) include severe micromelia, typically with

irregular bending of long bones and ribs due to mul-tiple intrauterine fractures. The affected bones are very



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164 Schramm et al.

0

5

10

15

20

25

Gestationalage(weeks)

30

35

40

1985 1990 1995

Year

2000 2005

Figure 2 Gestational age at diagnosis of skeletal dysplasias according to year of diagnosis, for the 10 most common dysplasias(thanatophoric dysplasia (types 1 and 2) ( ); osteogenesis imperfecta (all types) ( ); short rib dysplasias ( ); Ellis-van Creveld ( );achondroplasia ( ); achondrogenesis ( ); campomelic dysplasia (+); asphyxiating thoracic dysplasia Jeune ( ); hypochondrogenesis ( );

and diastrophic dysplasia ( )) and all other skeletal dysplasias ( ). Linear regression lines indicate possible trends of the gestational age atdiagnosis over the study period: thanatophoric dysplasia (types 1 and 2) ( ); osteogenesis imperfecta (all types) ( ); andachondroplasia ( ).

short and irregular and the thorax is narrow. The HC is

mostly normal; the skull, however, shows an abnormal

sonographic translucency and compressibility (see Figure

S4 online for typical sonographic features). The spine is

sometimes irregular in appearance, with platyspondyly

due to fractures of the vertebrae. It may be difficult to

distinguish OI type 2 from the lethal form of hypophos-

phatasia using sonography alone. In the non-lethal forms

of OI, usually only single tubular bones are affected and

the ThC and HC are normal (Figure 4b). In cases with

OI, the FL slowed down with advancing gestation, lead-

ing to steadily decreasing Z-scores with advancing age.

All fetuses with lethal OI had a FL below the 5 th centile

or below 2 SD for gestational age. Among the six cases

with non-lethal OI, only one fetus had a normal FL (at

25 weeks, with a FL at the 33rd centile and Z-score of

0.5). FL Z-scores decreased markedly with gestational

age in lethal OI, and the shortening was more pronounced

than in non-lethal forms. The ThC measurements in OI

were available for 27 of the 35 cases. In confirmed lethal

OI, 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

5.4th centile at 26 weeks). In the five cases with non-lethal

forms of OI and data on ThC available, it was normal in

two, low normal in two and abnormally small in one.

The short-rib dysplasias are a group of lethal skeletal

dysplasias with autosomal recessive inheritance, charac-

terized by micromelia with or without polydactyly (mostly

postaxial). The thorax is narrow with short, horizontally

oriented ribs and a protuberant abdomen, and there are

a variety of other possible malformations of the internal

organs. There are four types of short-ribdysplasia, butdif-

ferentiation is difficult because of overlapping symptoms.

Type 1 (SaldinoNoonan) is characterized by polydactyly

of the hands and sometimes of the feet, often congeni-

tal heart disease, sometimes facial clefts, brain anomalies

and anomalies of the kidneys and genital tract. Type 2

(Majewski) is characterized by pre- or postaxial poly-

dactyly and brachydactyly of the hands and sometimes of

the feet. The head is large, the nasal bridge is depressed,

the mandible is small (micrognathia) and there are often

facial clefts. Internal malformations include cystic dys-

plasia of the kidneys and hypoplasia of the cerebellar

vermis. Type 3 (VermaNaumoff) is characterized pre-

dominantly by postaxial polydactyly and brachydactyly

of the hands and feet and gastrointestinal, renal and



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0

10

20

30

40

50

60

(a)

12 14 16 18 20 22 24 26Gestational age (weeks)

28 30 32 34 36 38 40

Femurlength(mm)

0

50

100

150

Headcircumference(mm)

200

250

300

350(c)

12 14 16 18 20 22 24 26 28


30 32 34 36 38 40

other defects. Types 1, 2 and 3 can exhibit fetal hydropsand situs inversus. Type 4 (BeemerLanger) is charac-terized by bowed limbs, pre- and postaxial polydactylyin half of cases, facial clefts in nearly all cases, and,

0

50

Thoraciccircumference(mm)

100

150

200

250

(b)

12 14 16 18 20 22 24 26


28 30 32 34 36 38 40

Figure 3 Femur length (a), thoracic circumference (b) and headcircumference (c) plotted against gestational age in skeletaldysplasias (thanatophoric dysplasia (types 1 and 2) ( );osteogenesis imperfecta (all types) ( ); short rib dysplasias ( );Ellis-van Creveld ( ); achondroplasia ( ); achondrogenesis ( );campomelic dysplasia ( ); asphyxiating thoracic dysplasia Jeune( ); hypochondrogenesis ( ); and diastrophic dysplasia ( )) andfor all other skeletal dysplasias ( ). The 5th and 95th centiles areindicated8,9; for thoracic circumference, centiles before 20 weeksgestation were extrapolated from normal data9. Each fetus isplotted only once, at the gestational age of the first diagnosticexamination.

less commonly, cardiac, cerebral, gastrointestinal or renalanomalies and omphalocele. In this study there weretwo cases of short-rib dysplasia Type 3, one of Type2, two of Type 4 and a further five other cases includ-ing one recurrent case (diagnosed at a targeted scan at18 weeks).

Chondroectodermal dysplasia Ellis-van Creveld andATD Jeune are also grouped with the short-rib dysplasiasand are mostly lethal. In Ellis-van Creveld, there isan acromesomelic micromelia with polydactyly of thehands in most cases and of the feet in some cases. Halfof the fetuses have structural heart disease (atrial orventricular septal defect) and some have a Dandy Walkermalformation. In ATD, the thorax is long and narrow,the long bones have mild rhizomelia and some havepolydactyly. Most affected fetuses have cystic dysplastickidneys. We diagnosed eight cases of Ellis-van Creveld (at14 33 weeks plus one false-negative at 39 weeks) andseven cases of ATD Jeune (at 1935 weeks).

All eight cases of achondrogenesis were diagnosedbetween 12 and 17 weeks. In achondrogenesis there is



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166 Schramm et al.

0

50

100

150

200

250

300

350(a)

(b)

12 14 16 18 20 22



Biometric

parameter(mm)

Biometricparame

ter(mm)

24 26 28 30 32 34 36 38 40

0

50

100

150

200

250

300

350

12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Figure 4 Head circumference (filled symbols), thoraciccircumference (open symbols) and femur length (+ and symbols)in thanatophoric dysplasia Type 1 (,

, ) and Type 2 (, , +)

(a) and in osteogenesis imperfecta lethal (, ,) and non-lethal

(, , +) forms (b), with 5th and 95th centiles indicated8,9. Forthoracic circumference, centiles before 20 weeks gestation wereextrapolated from normal data9.

early hydrops and a short trunk (short crownrumplength), with a very narrow barrel-shaped thorax and amarkedly prominent abdomen. In achondrogenesis typesIA/B, both of which are autosomal recessive, there isextreme micromelia, with short hands and feet, poor min-eralization, a large head, a flat face and a short neck.Achondrogenesis Type II (autosomal dominant) is less

severe, presenting somewhat later in gestation than doesTypeI and frequentlyhaving polyhydramnios.Hypochon-drogenesis (autosomal dominant) represents a clinicalvariant within the achondrogenesishypochondrogenesisspectrum, with a small thorax, short limbs, a flat facewith micrognathia, a short trunk and macrocephaly. Thenose is flat and the nasal bridge is depressed, resem-bling TD. The six cases of hypochondrogenesis in ourstudy were diagnosed between 21 and 32 weeks. Bothachondrogenesis and hypochondrogenesis are lethal.

Campomelic dysplasia (autosomal dominant) is char-acterized by mesomelia and mild to moderate bowingof the legs and, less commonly, of the arms. Anteriorangulation of the tibia (see Figure S4f online) and theshort fibula are a pathognomonic feature of campomelic

dysplasia. The fingers and toes are short and the feet areclubbed. The face is flat, with micrognathia and low-setears, and there may be nuchal edema. The thorax is smalland bell-shaped, with 11 pairs of ribs, and the scapu-lae and claviculae are hypoplastic. Occasionally there ishydronephrosis. In some affected chromosomally malefetuses sex reversal occurs, as the mutated gene, SOX9,

is also involved in gonadal development. Our eight caseswere diagnosed between 16 and 30 weeks.

Diastrophic dysplasia (autosomal recessive) is a non-lethal skeletal dysplasia without mental impairment. Thelong bones are thick, markedly shortened and straight.The fingers are short, with ulnar deviation and hitch-hiker thumbs. There are clubfeet and micrognathia. Inour cohort there were five cases diagnosed between 20and 25 weeks.

Achondroplasia (autosomal dominant) is a non-lethal skeletal dysplasia without mental impairment. Allnine of our cases were diagnosed after 27 weeks (at2837 weeks). At around 20 weeks gestation, fetuseswith achondroplasia had normal biometric parameters,including FL, which became abnormally short only inthe third trimester. The micromelia is rhizomelic and theheads tend to be large. Typical facial features includeprominent forehead, depressed nasal bridge and mid-facehypoplasia. The phalanges are short; typical gaps betweenthe fingers and digital deviation lead to the appearance ofa trident hand.

The chondrodysplasia punctata group contains 11skeletal dysplasias, some of which have been detectedprenatally. The mostly lethal type, the rhizomelic form(autosomal recessive), is characterized by a moderate

rhizomelic shortening of the otherwise straight longbones, exhibiting typical hyperechogenicareas (prematurecalcification) in the cartilaginous skeletal parts, i.e. theepiphyses of the long bones (see Figure S4g) or thecalcaneus. The face is flat and there is micrognathiaand sometimes microcephaly. The thorax is normal insize. The rhizomelic form is associated with severe mentalretardation. The two cases in our cohort were diagnosedat 19 and 21 weeks.

DISCUSSION

To the best of our knowledge this is the largest single-center study of sonographically diagnosed fetal skeletaldysplasias: we investigated 162 affected fetuses withconfirmed clinical genetic, pathological or moleculardiagnosis. Prenatal sonographic diagnosis of fetal skeletaldysplasias is challenging because of their rarity (2147per 100 000 deliveries3,4), the multitude of differentialdiagnoses with overlapping features and the phenotypicvariability. With the discovery of the molecular basis ofmany of the skeletal dysplasias their classification hasevolved, from being based initially on morphological,mostly radiological features only, to being based largelyon pathogenesis2. In fact, molecular genetics is the goldstandard for an increasing number of skeletal dysplasias,and it may be the only diagnosis if the pregnant woman



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opts for termination or when pathological diagnosis is notpossible4,7. A revised classification of skeletal dysplasias,incorporating newly recognized disorders, pathogeneticconcepts and molecular and biochemical properties wasrecently provided by Superti-Furga and Unger2. Webresources can aid in the selection of appropriate moleculargenetic tests (for an example and selection of links, see

Goncalves et al.7 and Superti-Furga and Unger2).

Classification and frequencies of skeletal dysplasias

The most recent classification of genetic skeletal disordersincludes 372 different conditions in 37 groups definedby molecular, biochemical and/or radiological criteria2.Of them, 215 have been found to be associated withmutations in 145 genes, but there are still some entitieswhich are not clinically classifiable. Prenatal identificationof the specific type of a particular skeletal dysplasiarequires a detailed and structured examination, for

which protocols have been suggested5,7

. Besides the 23different types of skeletal dysplasia that we diagnosedin our series, nine of the 162 (5%) cases could not beclassified. Rasmussen et al.4, Gaffney et al.14 and Dorayet al.15 reported 16%, 20% and6% unclassifiable skeletaldysplasias, respectively, in their cohorts.

Our cases were from a mixed screening and referralpopulation. We thereforecould notcalculate the incidenceof individual skeletal dysplasias, and the true detectionrate wasdifficult to establish. However, themost commontypes of skeletal dysplasia in this fetal population andtheirfrequencies were similar to those found in previous studies(Table 2).

Diagnostic accuracy of prenatal diagnosis

We described the accuracy of our prenatal diagnosis withregard to the final diagnosis, as previously reported1416,as either correctultrasounddiagnosisor partially correctultrasound diagnosis. There are few reports with data on

the diagnostic accuracy of prenatal diagnosis of skeletaldysplasias1419 (Table 3), not all of which include num-bers of false negatives and false positives. The accuracy ofprenatal diagnosis seems to have improved in recentyears.

In the studies listed in Table 3, the false positives weremainly fetuses with dysmorphic syndromes or IUGR.Sharony et al.16, for example, reported that among

54 false positives in their study, 36 had dysmorphicsyndromesand 15 were structurallynormal IUGR fetuses.In our study, among 12 false positives, there were twofetuses with dysostoses, two with dysmorphic syndromesand eight with IUGR or which were normal small babies.

So far only a few studies have discussed false-negativediagnoses of skeletal dysplasias. Tretter et al.17 andParilla et al.19 report that they had no false negatives.We had two false-negative diagnoses: one fetus withachondroplasia was wrongly diagnosed as structurallynormal fetus, suspect familial large head, IUGR affectingmainly extremities and one with Ellis-van Creveld wasdiagnosed as suspected genetic syndrome, short longbones. Ascertainment of the false negatives was limitedbecause of incomplete follow-up in suspected normals.Our overall follow-up for (supposedly) normal cases overthe study period was about 80%. Also, some familiesof affected cases did not respond spontaneously; in ourlost-to-follow-up group there was one fetus with a clearskeletal dysplasia whose parents refused to provide anypostnatal data to us.

The ability to achieve the correct specific diagnosisby prenatal ultrasound depends on the type of skeletaldysplasia. The two most common skeletal dysplasias inour study, TD and OI, were diagnosed correctly in 88%

and 89% of cases, respectively. The data for the othermost common skeletal dysplasias and for previous studiesare shown in Table 4.

Lethality

Lethality in skeletal dysplasias is caused mainly by pul-monary hypoplasia secondary to thoracic hypoplasia13.

Table 2 Frequencies of skeletal dysplasias reported in different prenatal series

Final diagnosisThis study(n = 162)

Sharony et al.16

(1993)(n = 172)

Goncalves

and Jeanty20

(1994)(n = 139)

Gaffney et al.14

(1998)(n = 25)

Doray et al.15

(2000)(n = 42)

Thanatophoric dysplasia 40 (25) 27 (16) 43 (31) 5 (20) 4 (10)Osteogenesis imperfecta 2, 3 or 4 35 (22) 37 (22) 39 (28) 8 (32) 13 (31)Short-rib dysplasia 10 (6) 8 (5) 6 (4) 2 (8) 1Ellis-van Creveld 9 (6) 0 2 (1) 0 3 (7)Achondroplasia 9 (6) 4 (2) 15 (11) 4 (16) 7 (17)Achondrogenesis 8 (5) 17 (10) 9 (6) 3 (12) 5 (12)Campomelic dysplasia 8 (5) 14 (8) 4 (3) 1 1ATD Jeune 7 (4) 3 (2) 0 0 2 (5)Hypochondrogenesis 6 (4) 0 0 0 0Diastrophic dysplasia 5 (3) 2 (1) 3 (2) 0 1

Values are given as n (%) for cases with true skeletal dysplasias. Goncalves and Jeanty20

: 127 from multiple centers plus 12 from previouspublications; Sharony et al.16: 54 false-positives; Doray et al.15 five false-positives; Gaffney et al.14 three false-positives plus seven lost tofollow-up. ATD, asphyxiating thoracic dysplasia.



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Table 3 Studies reporting the diagnostic accuracy of prenatal ultrasound of skeletal dysplasias

Ultrasound diagnosisFalse False

Study Single/multicenter n Correct (%)Partially

correct (%)positive

(n)negative

(n)

Sharony et al.16 (1993) Multi 172 35 65 54 ND

Tretter et al.17 (1998)* Single 26 48 52 1 0Gaffney et al.14 (1998) Single 25 44 56 3 NDHersh et al.18 (1998) Single 26 50 50 ND NDDoray et al.15 (2000) Multi 42 62 38 5 NDParilla et al.19 (2003) Single 20 65 35 7 0This study Single 162 68 31 12 2

*Included only lethal skeletal dysplasias. ND, not done/data not given.

Table 4 Diagnostic accuracy of prenatal ultrasound for the 10 most common skeletal dysplasias in this study

Final diagnosisThis study(n = 162)

Sharony et al.16

(1993) (n = 172)Tretter et al.17

(1998) (n = 26)Gaffney et al.14

(1998) (n = 25)Doray et al.15

(2000) (n = 42)

Overall 110/162 (68) 60/172 (35)* 13/26 (50) 11/25 (44) 30/42 (71)Thanatophoric dysplasia 35/40 (88) (70) 6/12 (50) 2/5 (40) 3/4 (75)Osteogenesis imperfecta 2, 3 or 4 31/35 (89) (50) 5/6 (83) 5/8 (63) 9/13 (69)Short-rib dysplasia 5/10 (50) NA 1/3 (33) 0/2 0/1Ellis-van Creveld 4/9 (44) NA 0 0 3/3 (100)Achondroplasia 7/9 (78) NA 0 2/4 (50) 7/7 (100)Achondrogenesis 7/8 (88) NA 1/2 (50) 1/3 (33) 3/5 (60)Campomelic dysplasia 6/8 (75) NA 0/2 0/1 1/1 (100)ATD Jeune 3/7 (43) NA 0 2/2 (100)Hypochondrogenesis 1/6 (17) NA 0/1 0 0Diastrophic dysplasia 2/5 (40) NA 0 0 0/1

Values are given as n (%). *Detailed evaluation not possible (figures shown here calculated from Sharony et al.16, as exact numbers were not

given by the authors). Figures quoted in the text. Included in short-rib dysplasia. ATD, asphyxiating thoracic dysplasia; NA, data notavailable.

The discrimination between lethal and non-lethal formsof skeletal dysplasias is, of course, of major clinical impor-tance. In our study, with one exception, all fetuses with

lethaldisease were correctlyclassified(113/114,99%); themisdiagnosis occurred in a fetus with hypophosphatasiaand a normal ThC (Z-score,0.1) examined at 19 weeks.

Among the mostly lethal conditions, Ellis-van Creveldwas the most difficult to classify correctly: in five of nine

affected fetuses the sonographic assessment of lethalitywas imprecise. Three of 31 fetuses with non-lethal skeletaldysplasias were misdiagnosed (at 27, 35 and 37 weeks),but all three cases resulted in live births.

Four other studies have addressed the ability todiscriminate between lethal and non-lethal skeletaldysplasias: Hersh et al.18 predicted lethality correctly in

92% of cases (23 fetuses with lethal and three with non-lethal conditions). Gaffney et al.14 correctly identified all20 cases with lethalandtwoof fivewith non-lethal skeletal

dysplasias. Doray et al.15 identified 17 of 21 lethal cases,five of eight mostly lethal cases and all eight non-lethalcases; in five cases they could not determine lethality.

Parilla et al.19 only report on their 16 lethal cases ofskeletal dysplasia, all of which were diagnosed correctly.

Morphology

In the two most common skeletal dysplasias, TD andOI, their typical sonomorphological signs accounted forthe high rate of overall and correct specific diagnosis.In addition, for some skeletal dysplasias, there arealmost always subtle but pathognomonic signs whichcan be found within the skeletal apparatus, the faceor the internal organs. Examples include the angulated

tibia in campomelic dysplasia or polydactylies. In theResults section we provide descriptionsof the sonographicmorphology of the 10 most common skeletal dysplasias.

There are, of course, pitfalls in this sonomorpho-logical approach. For example, in one case in whichTD was diagnosed at 33 weeks (ThC Z-score, 2.4;FL Z-score, 7.8), the fetus actually had opsismodys-plasia (micromelic dwarfism, frontal bossing and shortmetacarpals).

Gestational ages at diagnosis

For many reasons, including termination laws, a timelyspecific prenatal diagnosis is important. In Germany,



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compulsory routine measurement of the fetal FL wasintroduced in 1995. In our cohort, there was a trendtowards earlier prenatal diagnosis over the years, raisingthe percentage of correct prenatal diagnosis before24 weeks from 42% to 62% in the last 10 years, mainlydue to earlier diagnosis of TD and lethal OI. For Franceand the UK, both with ultrasound screening programs,

the reported percentages of diagnosis before 24 weeksare similar (62% and 71%14,15). In the USA, whereultrasound screening is not universal, these percentagesrange from 37%4 to 58%16 or 62%17.

In our study, achondroplasia was the only skeletaldysplasia that was not detected before 24 weeks. In allnine cases, the FLs at 20 weeks had been reported asnormal by the referring gynecologists. In most studiesachondroplasia is detected late in pregnancy: Gaffneyet al.14 reported four cases detected at 3147 weeks,while Doray et al.15 reported seven fetuses detected at2835 weeks. Goncalvesand Jeanty20 reported 15 fetuseswith achondroplasia: twohadfemur measurementsbefore24 weeks and both were normal, while another twomeasured at 25 and 36 weeks also had normal FL. Thereis only one recent report, by Tonni et al.21, in whichrhizomelic shortening of the long bones (


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170 Schramm et al.

ultrasound diagnosis. In the most common fetal skeletaldysplasias ultrasound diagnosis can be confirmed bymolecular genetic testing, which should be sought forquality assurance.

R E F E R E N C E S

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3. Stoll C, Dott B, Roth MP, Alembik Y. Birth prevalence rates ofskeletal dysplasias. Clin Genet1989; 35: 8892.

4. Rasmussen SA, Bieber FR,Benacerraf BR, Lachman RS,RimoinDL, Holmes LB. Epidemiology of osteochondrodysplasias:changing trends due to advances in prenatal diagnosis. Am

J Med Genet1996; 61: 4958.5. Meizner I. Fetal skeletal malformations revisited: steps in the

diagnostic approach. Ultrasound Obstet Gynecol 1997; 10:202206.

6. Jeanty P, Valero G, Bircher AM, Garcia Cavazos G. Skele-tal dysplasias. In Diagnostic Imaging of Fetal Anomalies,Nyberg DA, McGahan JP, Pretorius D, Pilu G (eds). Lippincott,Williams and Wilkins: Philadelphia, PA, 2003; 661 711.

7. Goncalves LF, Espinoza J, Mazor M, Romero R. Newer imag-ing modalities in the prenatal diagnosis of skeletal dysplasia.Ultrasound Obstet Gynecol2004; 24: 115120.

8. Snijders RJM, Nicolaides KH. Fetal biometry at 1440 weeksgestation. Ultrasound Obstet Gynecol1994; 4: 3448.

9. Laudy JAM, Wladimiroff JW. The fetal lung (2): pulmonaryhypoplasia. Ultrasound Obstet Gynecol2000; 16: 482494.

10. World Health Organization (WHO). Physical Status: The Useand Interpretation of Anthropometry (WHO Technical Report

Series No. 854). WHO: Geneva, Switzerland, 1995.11. Winter R, Baraitser M. Winter-Baraitser Dymorphology Data-

base. London medical databases Ltd: London, UK, 2006.12. OMIM- Online Mendelian Inheritance in Man. http://www.

ncbi.nlm.nih.gov/sites/entrez?db=omim [Accessed 19 February2008].

13. Merz E, Miric-Tesanic D, Bahlmann F, Weber G, Haller-mann C. Prenatal sonographic chest and lung measurements forpredicting severe pulmonary hypoplasia. Prenat Diagn 1999;19: 614619.

14. Gaffney G, Manning N, Boyd PA, Rai V, Gould S, Chamber-lain P. Prenatal sonographic diagnosis of skeletal dysplasias areport of the diagnostic and prognostic accuracy in 35 cases.Prenat Diagn 1998; 18: 357362.

15. Doray B, Favre R, Viville B, Langer B, Dreyfus M, Stoll C.Prenatal sonographic diagnosis of skeletal dysplasias. A reportof 47 cases. Ann Genet2000; 43: 163169.

16. Sharony R, Browne C, Lachman RS, Rimoin DL. Prenataldiagnosis of the skeletal dysplasias. Am J Obstet Gynecol1993;169: 668675.

17. Tretter AE, Saunders RC, Meyers CM, Dungan JS, Grum-bach K, Sun CC, Campbell AB, Wulfsberg EA. Antenatal diag-nosis of lethal skeletal dysplasias. Am J Med Genet 1998; 75:

518522.18. Hersh JH, Angle B, Pietrantoni M, Cook VD, Spinnato JA,Clark AL, Kurtzman JT, Bendon RW, Gerassimides A. Predic-tive value of fetal ultrasonography in the diagnosis of a lethalskeletal dysplasia. South Med J1998; 91: 11371142.

19. Parilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor SN.Antenatal detection of skeletal dysplasias. J Ultrasound Med2003; 22: 255258.

20. Goncalves L, Jeanty P. Fetal biometry of skeletal dysplasias: amulticentric study. J Ultrasound Med1994; 13: 977985.

21. Tonni G, Ventura A, De Felice C. First trimester increasednuchal translucency associated with fetal achondroplasia. Am JPerinatol2005; 22: 145148.

S U P P O R T I N G I N F O R M A T I O N O N T H E I N T E R N E T

The following supporting information may be found in the online version of this article:

Normal ranges were taken from Snijders and Nicolaides8 for femur length, head circumference and abdominalcircumference (for 1440 weeks) and from Laudy and Wladimiroff9 for thoracic circumference after 20 weeks;prior to 20 weeks, the thoracic circumference normal range was extrapolated from Laudy and Wladimiroff9. Eachfetus is plotted only once at thegestational ageof thefirst diagnostic examination.TD, thanatophoric dysplasia; OI,osteogenesis imperfecta; AP, achondroplasia; AG, achondrogenesis; EvC, Ellis-van Creveld; Jeune, asphyxiatingthoracic dysplasia Jeune; SR, Short rib dysplasia; HG, hypochondrogenesis; CD, campomelic dysplasia.

Figure S1 Femur length in skeletal dysplasias expressed as Z-scores against gestational age.

Figure S2 Thoracic circumference in skeletal dysplasias expressed as Z-scores against gestational age.

Figure S3 Head circumference in skeletal dysplasias expressed in Z-scores against gestational age.

Figure S4 Characteristic sonographic appearances of skeletal dysplasias encountered during the study.

Figure S5 Biometric parameters in thanatophoric dysplasia Types 1 and 2, expressed in Z-scores.

Figure S6 Biometric parameters in osteogenesis imperfecta lethal and non-lethal forms, expressed in Z-scores.

Table S1 Molecular diagnosis in the 10 most common skeletal dysplasias in this study.


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