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Keywords:

  • skeletal dysplasias;
  • prenatal diagnosis;
  • first-trimester fetal ultrasound;
  • molecular genetics

Abstract

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Objective

To review experience of early prenatal diagnosis of skeletal dysplasias, and to explore diagnostic accuracy and improve management.

Methods

A retrospective review of fetal medicine unit (FMU) records was performed to identify cases where a skeletal dysplasia was suspected by 14 weeks' gestation. A literature review was undertaken to ascertain cases with a diagnosis of a skeletal dysplasia in the late first or early second trimester.

Results

Fifteen cases were identified from review of FMU records, including ten different dysplasias with a variety of inheritance patterns. Accurate prenatal diagnosis was made only in cases with a positive family history, and in one case each of thanatophoric dysplasia and Roberts syndrome. Review of the literature identified further cases. Increased nuchal translucency was reported in other cases subsequently diagnosed as having a skeletal dysplasia. In early pregnancy, common presenting features included short femora, abnormal skull shape and mineralisation, profile or chest.

Conclusion

Increasing use of first-trimester combined screening for Down's syndrome, with or without detailed anomaly scanning, will result in early detection of more skeletal dysplasias. Parents must be made aware that detailed postnatal pathological and radiological examination is usually required for accurate diagnosis and prediction of recurrence risks. Copyright © 2011 John Wiley & Sons, Ltd.


BACKGROUND

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

With the demonstration of the effectiveness of first-trimester combined screening for Down syndrome, there is an increasing use of early ultrasound as a routine part of obstetric care. For example, in UK the national guidelines have mandated that by the end of 2010 all women booking for prenatal care before 14 weeks' gestation should be offered combined screening (National Screening Committee, 2010) and in the Netherlands this has been national policy since 2007. This test includes measurement of the nuchal translucency (NT) which, when increased, is associated not only with an increased risk of aneuploidy but also other congenital anomalies, predominantly cardiac abnormalities (Hafner et al., 1998; Clur et al., 2009; Bilardo et al., 2010) and skeletal dysplasias (Souka et al., 1998; Makrydimas et al., 2001; Ngo et al., 2007). Improved technology and ready availability of transvaginal scanning allows detailed examination of the fetal anatomy in early pregnancy with the subsequent detection of many structural abnormalities (Syngelaki et al., 2011; Hernadi et al., 1997; Economides et al., 1998; Ebrashy et al., 2010; Saltvedt et al., 2006). The first trimester is a good time to examine the fetal skeleton as long bones and many other bony parts are formed by 11 weeks' gestation (Timor-Tritsch et al., 1992; Brown et al., 1996; van Zalen-Sprock et al., 1997) and charts of fetal limb length are available from this gestation (Rosati et al., 1997; Chitty and Altman, 2002). All these factors contribute to the potential for increasing detection in early pregnancy of serious skeletal dysplasias, including those which are lethal, carry a significant risk of early mortality, significant degrees of short stature and/or serious orthopaedic problems. Here, we report the experience of two fetal medicine units (FMUs) for the diagnosis of skeletal dysplasias by 14 weeks' gestation and highlight the need for careful and detailed description of sonographic features and accurate postnatal examination to confirm diagnosis and inform parental counselling.

METHODS

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Our computerised FMU records were searched to ascertain all cases seen since 1995 with a diagnosis of a skeletal dysplasia confirmed postnatally. The FMU databases, neonatal records and, where appropriate, pathology records were reviewed to determine the prenatal features, including increased NT, the gestational age at which a skeletal dysplasia was suspected, and the final diagnosis confirmed postnatally. All cases where a skeletal dysplasia was identified by 14 weeks' gestation were reviewed in detail. In addition, a search of the literature was performed using Medline (1976 through February 2010) with the following Mesh terms: ‘skeletal dysplasia’ and ‘prenatal or fetal ultrasound diagnosis’ to identify all articles describing early prenatal diagnosis of skeletal dysplasias. We also hand-searched reference lists of all potentially relevant case reports and series. Articles were reviewed and cases included where details of the gestational age at diagnosis and sonographic features observed in early pregnancy were clearly defined.

RESULTS

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Fifteen cases where a skeletal dysplasia was suspected by 14 weeks' gestation in our units were ascertained (Table 1). Four cases were scanned in detail and the diagnosis suspected because of an affected parent [spondyloepiphyseal dysplasia congenita (SEDC)] or history of a previous affected pregnancy [two cases of short rib-polydactyly syndrome (SRPS) type II and one of Jeunes asphyxiating thoracic dystrophy (ATD)]. Others were scanned in detail in early pregnancy because of an increased NT with or without generalised oedema, an enlarged bladder and echogenic kidneys (SRPS II) or suspicion of abnormal long bones (Roberts syndrome). In cases arising de novo, a definitive diagnosis was made in only two cases in early pregnancy. One case of thanatophoric dysplasia was diagnosed when scanned at 13 weeks following detection of an increased NT and short limbs in the routine ultrasound department. The features identified include an abnormal head shape, short limbs, frontal bossing, small chest and short ribs (Figure 1). Invasive diagnostic testing by chorionic villus sampling (CVS) confirmed the presence of the Lys650Glu disease-causing mutation in the FGFR3 gene. In a second case, the finding of short limbs with oligodactyly and talipes (Figure 2) was suggestive of Roberts syndrome, which was confirmed by the demonstration of premature separation of the centromeres.

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Figure 1. Images of a fetus with thanatophoric dysplasia type II presenting at 13 weeks' gestation. Note the abnormal head shape (A), profile demonstrating frontal bossing (B) and small chest with bulging abdomen. In (C) the short ribs are seen which contract the chest making it appear considerably smaller than the abdomen (D) when viewed in the transverse plane. The champagne cork appearance of the thorax and abdomen can be seen the parasagittal view of the whole fetus (E)

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Figure 2. The arm(A) and leg (B) in the case of Roberts syndrome seen at 14 weeks' gestation. Amniocentesis and examination of the chromosomes revealed centromeric puffing confirming the diagnosis

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Table 1. Sonographic features of skeletal dysplasias identified by ultrasound by 14 weeks of gestation
ConditionNT (mm)aFLHCThoraxSkullOther featuresInheritanceGene (s)bLethalAuthorsc
  • NT, nuchal translucency; FL, femur length; N, normal; AR, autosomal recessive; AD, autosomal dominant; SRPS, short rib-polydactyly syndrome.

  • a

    Where possible the NT measurements recorded in our cases or given in the literature are detailed to show the range/degree of increased NT, where details are not given but it is clear from the text that the NT is increased we have noted this.

  • b

    This list is not exhaustive and for some conditions there is evidence of locus heterogeneity which means that the gene list does not account for every case.

  • c

    Only includes articles where gestation and details of sonographic findings in early pregnancy are clearly defined.

  • d

    Diagnosed because of affected parent/previous affected pregnancy.

Achondrogenesis IIncreased< 5thNSmallN/Poor ossificationHydrops, hypomineralised vertebral bodiesAR1A—TRIP11, 1B—DTDST or SLC26A2YesMeizner and Barnhard (1995)
Achondrogenesis IIIncreased, 9.5, 13.7< 5th Narrow, short ribsNo ossificationNo/minimal ossification of vertebral bodies, poorly ossified long bones, generalised oedemaADCOL2A1yesFisk et al. (1991),d Soothill et al. (1993), Ngo et al. (2007), our cases (2)
Ellis van Creveld (EVC)N, 3.1< 5thNSmallNCardiac anomaly, polydactyly, posterior fossa cystAREVC1,ECV2NoDugoff et al. (2001)d, our case
Osteogenesis imperfecta II3.7, 3.8, 4.4, 7.7< 5th fractures/no fracturesNSmallHypomineralised/ normalShort ribs, crumpled long bones, acute angling of femoraAD (AR)COL1A1/COL1A2, CRTAP, P3H1, FKBP65, HSP47YesBronshtein et al. (1993),d Dimaio et al. (1993), Bronshtein and Weiner (1992), Makrydimas et al. (2001), Buisson et al. (2002), Viora et al. (2002), Ruano et al. (2003), Viora et al. (2003),d Cho et al. (2005),; our cases (2)
Thanatophoric dysplasia3.4, 3.6, 3.7, 4.9, 5.2, 6.55th/< 5thN/> 95thNarrow, short ribsN/abnormal shape (cloverleaf)Frontal bossing, bowed femoraADFGFR3YesBenacerraf et al. (1988), Ferreira et al. (2004), De Biasio et al. (2005), Ngo et al. (2007), Wong et al. (2008); our cases (2)
Campomelic dysplasia2.9, 3.9, 5.6, 6.0, 11.0< 5th bowedNSmallNClub feet, tibial spikes, arms normal length and appearanceADSOX9YesMichel-Calemard et al. (2004), Massardier et al. (2008), Gentilin et al. (2010)
Diastrophic dysplasiaN, 3.8< 5thNNNHitch-hiker thumb, clubfoot, all long bones < 5thARSLC26A2NoSeveri et al. (2003),d Ngo et al. (2007)d
Congenital hypophosphatasiaN, 2.5, 4.1< 5th/10thNN/narrow, short ribsHypomineralisedPoorly ossified ribs, vertebrae and long bones, polyhydramnios, short long bones, talipesARTNSALPYesTongsong et al. (2000), Souka et al. (2002), Simon-Bouy et al. (2008)
Greenberg skeletal dysplasia4.2, 8.3≪ 3rdNNarrowNHydrops, hepatomegaly, severe generalised micromeliaARLBRYesKonstantinidou et al. (2008)d; our case
Spondyloepiphyseal dysplasia congenita4.0, 4.5N—5thNShort Hypomineralised vertebral bodiesADCOL2A1NoChitty et al. (2006); our case
Boomerang dysplasia6.5≪ 5th Short, small Some long bones not visible X-linked unknownFLNBYesOur case
Jeunes asphyxiating thoracic dystrophyN, 3.1, 5.8< 5thNNarrow, short ribsNPolydactylyARDYNCH2H1 IFT8030%Ben Ami et al. (1997),d den Hollander et al. (2001); our case
SRPS I (Saldino-Noonan)Increased≪ 3rdNSmall Generalised skin oedema, severe micromelia, polydactylyAR YesHill and Leary, (1998)
SRPS II (Majewski)3.0, 3.5, 4.7, 4.45th/≪ 3rdNSmall, short ribs Exomphalos, bladder outflow obstruction, polydactyly, generalised oedemaAR YesWitters et al. (2008); our cases (1 + 2d)
SRPS III (Verma-Naumoff syndrome)3.2< 10th Small Postaxial polydactyly DYNCH2H1YesNgo et al. (2007)
SRPS IV (Beemer Langer)Increased< 5th SmallNTibia > fibula, exomphalosAR Yesden Hollander et al. (1998)
Blomstrand dysplasiaIncreased< 5th   Flared metaphyses, generalised rhizo-meso-acromelic limb shorteningARPTHR1Yesden Hollander et al. (1997)d
Roberts syndrome3.8< 5th   Oligodactyly, all long bones short, talipesARESCO2Yes/NoOur case
Schneckenbecken dysplasia11.8< 5th, severe angulationNSmall Poor vertebral mineralisation, generalised skin oedema, angulation of long bonesARSLC35D1YesVarkey and Jones (2004)
Cleidocranial dysplasiaNN  HypomineralisedPoor ossification of the vertebral spine, hypoplastic clavicleADRUNX2NoStewart et al. (2000),d Hove et al. (2008)

The diagnosis of achondrogenesis was suspected in both cases seen in our units following identification of very short limbs together with hypomineralisation of the skull and vertebral bodies, but the diagnosis was only confirmed after delivery by radiology and identification of the mutation in the COL2A1 gene in one case. No confirmation of diagnosis was available in the other case as the pregnancy was terminated surgically in the private sector. In both cases with osteogenesis imperfecta (OI), the diagnosis was suspected based on the sonographic findings but only confirmed after delivery. In all other cases, the definitive diagnosis was made following postnatal radiological or pathological examination.

The literature review revealed further dysplasias with sonographic features described in early pregnancy (Table 1). In general, a definitive diagnosis was made early in pregnancy only in cases with a relevant family history (Table 1). In other cases while specific diagnoses were sometimes suspected, definitive diagnosis was not usually made until later in pregnancy or after birth when more extensive radiological, pathological or molecular genetic investigations were undertaken.

In addition to cases where detailed sonographic findings were reported in early pregnancy (Table 1), we also identified cases seen in our units or reported in the literature where an increased NT was found in early pregnancy but the diagnosis of a skeletal dysplasia was only made later in pregnancy or after birth. These included achondroplasia, hypochondroplasia and Kneist syndrome.

DISCUSSION

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The data presented here together with the review of the literature indicate that the sonographic features of a wide variety of skeletal dysplasias present early in pregnancy. While all carry significant risks of orthopaedic problems, not all are universally lethal (Table 1). Accurate diagnosis tends to be made in cases presenting with a known family history, for example cleidocranial dysostosis, SEDC, the SRPSs and Ellis van Creveld syndrome. In others, while the diagnosis of a skeletal dysplasia was suspected in all the cases we describe, definitive diagnosis was only made after delivery; the exceptions were thanatophoric dysplasia (Figure 1) and Roberts syndrome (Figure 2) where the presenting features were such that targeted molecular or cytogenetic diagnosis was possible after invasive testing to facilitate definitive early prenatal diagnosis.

While the disease-causing genes for many skeletal dysplasias are known, rapid definitive molecular prenatal diagnosis is currently not possible in most cases arising de novo as there is allelic and genetic heterogeneity for many of these conditions with many possible mutations, some of which can sometimes be specific to individual families (Pepin et al., 1997). Thus, postnatal radiology and/or histology are required. Thanatophoric dysplasia is the exception and molecular diagnosis is possible in cases presenting in low-risk pregnancies if the sonographer is alert to the classical features of short limb, frontal bossing, trident fingers and short ribs (Chen et al., 2001) as there are only a few known mutations in the FGFR3 gene which cause this condition (Wilcox et al., 1998). Indeed, with advances in molecular diagnostic technology and the ability to analyse cell-free fetal DNA in maternal plasma, this diagnosis no longer requires an invasive test as it is possible from a maternal blood sample (Raymond et al., 2010). Availability of rapid molecular prenatal testing is also useful to distinguish thanatophoric dysplasia, one of the most commonly occurring lethal skeletal dysplasias (Krakow et al., 2008), from the SRPSs which are less common but are all inherited in an autosomal recessive fashion while thanatophoric dysplasia is a new dominant mutation. These conditions have several features in common, for example short ribs and short limbs, and sometimes abnormal skull shape when considering SRPS II (Majewski). More subtle distinguishing features do exist but may be difficult to identify; these include polydactyly, which does not occur in thanatophoric dysplasia, and short trident fingers or frontal bossing which are not seen in SRPS.

In both cases of OI seen in our units, as well as those reported in the literature (Bronshtein et al., 1993; DiMaio et al., 1993; Bronshtein and Weiner, 1992; Makrydimas et al., 2001; Buisson et al., 2002; Viora et al., 2002; Ruano et al., 2003; Viora et al., 2003; Cho et al., 2005), the diagnosis was suspected on the basis of the sonographic features including a profoundly hypomineralised skull, small chest with evidence of beaded (fractured) ribs and short angulated long bones (Figure 3). While these features are highly typical of OI types IIA and IIC, there is some overlap with features seen in achondrogenesis types I and II, hypophosphatasia and Boomerang dysplasia. There are distinguishing features such as short straight long bones and hypomineralisation of the vertebral bodies in achondrogenesis (Fisk et al., 1991; Soothill et al., 1993; Meizner and Barnhard, 1995; Ngo et al., 2007) and apparent absence of long bones in Boomerang dysplasia (Figure 4; Table 1). However, these features may be subtle and difficult to define clearly in early pregnancy, rendering postnatal pathology and radiology essential to determine the underlying pathology. This is particularly important in facilitating accurate genetic counselling as recurrence risks for these conditions range from 25% for achondrogenesis type I and congenital hypophosphatasia which are inherited in an autosomal recessive fashion (Superti-Furga et al., 1996; Simon-Bouy et al., 2008) to around 5% for OI which is usually sporadic except in occasional cases of parental germline mosaicism or recessive inheritance (Thompson et al., 1987; Pepin et al., 1997). Furthermore, definitive postnatal diagnosis allows for targeted molecular testing to determine the disease-causing mutation in many dysplasias which can then allow accurate, early invasive diagnosis from 11 weeks' gestation, if requested in subsequent pregnancies (Dimaio et al., 1993).

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Figure 3. Sonographic features seen in osteogenesis imperfecta (OI) when rescanned at 15 weeks showing the profoundly hypomineralised skull (A), beading of the ribs (B) and short fractured femur (C) and lower leg (D)

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Figure 4. Images of a fetus with Boomerang dysplasia demonstrating the small chest (A), short ribs (B), very short and absent long bones in the arm (C) and leg (D) with the postnatal radiograph (E)

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Other conditions presenting in the first trimester in our units included Jeune's ATD and EVC syndrome. These can be difficult to differentiate prenatally in the absence of a relevant family history as they have very similar features: a small chest with moderate shortening of the ribs, mild to moderate shortening of long bones and polydactyly (Figure 5) (Brueton et al., 1990; Krakow et al., 2000). Although both are inherited in an autosomal recessive fashion, thus carrying a significant risk of recurrence, accurate postnatal diagnosis is important as these conditions may vary in severity (Tüysüz et al., 2009). This variation may impact on the gestation at sonographic presentation, making molecular prenatal diagnosis the preferred option should parents request early diagnosis in subsequent pregnancies.

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Figure 5. A fetus with Ellis van Creveld syndrome scanned at 13 weeks' gestation. Note the short ribs and abnormal four-chamber view of the heart (A), short femur with the appearance of fat legs (B), short lower limb (C) and polydactyly (D). The diagnosis was confirmed by postnatal radiology and identification of the mutation in the EVC gene

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Increased NT or hydrops are common features of serious skeletal dysplasias presenting in early pregnancy (Table 1; Figure 6), suggesting that at minimum the femur should be measured all cases seen with these features. If this is short then referral to a FMU for a more detailed examination, which may reveal further abnormalities suggestive of a skeletal dysplasia, is recommended (Chitty and Griffin, 2008; Krakow et al., 2009)

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Figure 6. Transverse section through the fetal abdomen (A) and head (B) in a fetus scanned at 12 weeks' gestation with Greenberg dysplasia. The chest was very small even at this gestation (C) with a bulging abdomen (arrow). The parents elected to continue the pregnancy and at 20 weeks (D) there was significant hydrops with an extremely small thorax

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In conclusion, the sonographic features of many serious skeletal dysplasias are present by 14 weeks' gestation. Accurate prenatal diagnosis is often difficult in the absence of a relevant family history. When parents choose to interrupt the pregnancy they should be encouraged to undergo medical termination to allow detailed pathological and radiological examination to inform accurate diagnosis and genetic counselling.

Acknowledgements

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

LSC is partially funded by NHS and NIHR Biomedical Centre Funding and the Great Ormond Street Hospital Charity for Children.

REFERENCES

  1. Top of page
  2. Abstract
  3. BACKGROUND
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES