PRENATAL DIAGNOSISPrenat Diagn 2009; 29: 715–717.Published online 1 April 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2268

RESEARCH LETTER

Platyspondylic lethal skeletal dysplasia San Diego type(thanatophoric dysplasia type 1) associated with trisomy 21presenting with nuchal translucency: a case report

Takahiro Yamada1* , Hideaki Sawai2, Gen Nishimura3, Hironao Numabe2, Kazutoshi Cho1 andHisanori Minakami1

1Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan2Genetic Counselling and Clinical Research Unit, School of Public Health, Graduate School of Medicine, Kyoto University,Kyoto, Japan3Department of Radiology, Tokyo Metropolitan Kiyose Children’s Hospital, Kiyose, Japan

KEY WORDS: platyspondylic lethal skeletal dysplasia (PLSD); thanatophoric dysplasia (TD); trisomy 21; nuchaltranslucency (NT); FGFR3

Thanatophoric dysplasia (TD) is one of the two mostcommon types of lethal skeletal dysplasia. TD is causedby heterozygous mutations of FGFR3, and is thereforean allelic disorder of achondroplasia which is the mostcommon form of nonlethal skeletal dysplasia (Tavorminaet al., 1995). The prevalence of TD is estimated to be 1in 20 000, and affected individuals show macrocephaly,severe micromelia, and a narrow thorax, and succumbto pulmonary hypoplasia in the neonatal period. TDis subdivided into two major categories, TD types 1and 2 (TD 1 and TD 2). The former is characterizedby bent femora (telephone receiver femora), while thelatter by straight femora and a cloverleaf skull. The twosubtypes are also different at the molecular level. TD 2is due to a single missense mutation (K650E), while 12distinct missense mutations have been identified in TD1 (Tavormina et al., 1995; Brodie et al., 1999).

Prenatal diagnosis should be possible in screeningprogrammes, as limb shortening is normally picked upreadily in the first and second trimester (Sawai et al.,1999; De Biasio et al., 2005; Wong et al., 2008). More-over, nuchal translucency, a widely known sonographicmarker for chromosomal abnormalities and other con-genital defects during early pregnancy, is commonlyencountered in TD (Snijders et al., 1998; Souka et al.,2001; Ferreira et al., 2004; De Biasio et al., 2005; Wonget al., 2008). The clinical and radiological manifesta-tions of TD are well-established, certainly in late preg-nancy or at birth (Table 1). However, a new variantof TD 1, termed platyspondylic lethal skeletal dys-plasia San Diego (PLSD-SD) type, presents a diag-nostic dilemma (Brodie et al., 1999). Although PLSD-SD shows the same FGFR3 mutations as those seenin TD 1, PLSD-SD presents with relatively straightfemora, ragged metaphyses, and much more severe

*Correspondence to: Takahiro Yamada, Department of Obstet-rics and Gynecology, Hokkaido University Graduate School ofMedicine, Sapporo, Japan. E-mail: taka0197@med.hokudai.ac.jp

platyspondyly than that seen in classical TD. It is thoughtthat PLSD-SD is actually a second trimester or ear-lier fetal phenotype of TD 1. It remains unclear howand when PLSD-SD evolves into TD 1. The phenotypeof TD 1 (PLSD-SD) in the early stages of the sec-ond trimester has not yet been firmly established. Thus,the diagnosis of TD 1 (PLSD-SD) in early pregnancymay not be easy. This report describes a case of PLSD-SD associated with trisomy 21. The concurrence causedsome confusion in diagnosis.

A 28-year-old primigravida was referred followingabnormal nuchal translucency (NT = 17 mm) scan. Shewas in a nonconsanguineous marriage and had neitherrelevant medical history nor significant family history.Ultrasound examination at 16 weeks revealed a smallthorax, short femora of 10 mm (−3.30 SD), and shorthumeri of 10 mm (−3.30 SD) with normal amnioticfluid volume. These findings led to a tentative diagno-sis of a lethal skeletal dysplasia, particularly suspect-ing TD. After genetic counseling including an offerof genetic testing, both mother and spouse elected toterminate the pregnancy without further prenatal diag-nostic steps. A male fetus weighing 290 g was deliv-ered at 18 weeks. Craniofacial manifestations includeda flat facial profile with macrocephaly (head circumfer-ence: 16.4 mm, +2.0 SD), mid-face hypoplasia, a shortnose with a depressed nasal bridge, low placement ofdeformed small ears, epicanthic folds, and blepharophi-mosis. There were loose folds in the posterior neck.Features of the body and extremities consisted of a nar-row thorax, a protruding abdomen with rectus abdominisdiastasis, and very short limbs (Figure 1, Table 1). Radi-ological examination showed many characteristics sug-gestive of TD1 (Figure 1, Table 1). However, markedplatyspondyly, relatively straight femora, and raggedmetaphyses led to a more specific diagnosis of PLSD-SD. On the other hand, the facial gestalt and looseposterior neck were inconsistent with the typical featuresof PLSD-SD or TD 1. The parents declined autopsy butconsented to skin sampling.

Copyright 2009 John Wiley & Sons, Ltd. Received: 14 October 2008Revised: 16 February 2009

Accepted: 18 February 2009Published online: 1 April 2009

716 T. YAMADA ET AL.

Figure 1—Macroscopic view of the fetus and radiographic findings. Craniofacial features showed a flat facial profile with macrocephaly, mid-facehypoplasia, a short nose with depressed nasal bridge, low placement of deformed small ears, epicanthic folds, blepharophimosis, and loose foldson the posterior neck. The fetus had a narrow thorax, a protuberant abdomen with rectus abdominis diastasis, and shortened limbs (left). Apostmortem radiograph showed macrocephaly, a narrow thorax with short ribs, severe platyspondyly, short and small iliac bones, accessoryossification centers lateral to iliac wings, marked micromelia, irregularity and flaring of most metaphyses, and relatively straight femora withdistal metaphyseal cupping (right)

To establish the diagnosis, skin fibroblasts were sub-jected to genetic testing (University of Colorado Denver,DNA Diagnostic Laboratory, Aurora, CO). An A > G

transition was detected at nucleotide 1118 in the FGFR3gene by polymerase chain reaction (PCR) and restric-tion enzyme digestion with BsgI. This common missense

Table 1—Observed phenotypic features in the present case that are compatible with TD and/or trisomy 21

Trisomy 21 TDPresent

case

Appearance

(Head and face)Macrocephaly ++ ++Frontal bossing ++Mid-face hypoplasia + + +Short nose with depressed nasal bridge + + +Flat face + +Low placement of deformed small ears + +Epicanthic folds and blepharophimosis + +Excessive nuchal folds + −/+ ++(Body and extremities)Shortened limbs + ++ ++Narrow thorax ++ ++Protrudent abdomen ++ ++Rectus abdominis diastasis + +RadiographMacrocephaly ++ ++Shortening of long bones + ++ ++Irregularity and flaring of metaphyses with cupping of some long bones ++ ++Flattening of vertebral bodies ++ ++Short ribs and hypoplastic thorax ++ ++Short and small iliac bones, with a separate ossification center on lateral/inferior surfaces ++ ++11 pairs of ribs + (++ in female)

+: characteristic, ++: prominent

Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 715–717.DOI: 10.1002/pd

THANATOPHORIC DYSPLASIA ASSOCIATED WITH TRISOMY 21 717

mutation of TD1 leads to Y373C transition in the FGFR3protein (Rousseau et al., 1996). Karyotyping was alsoperformed using fetal skin, and revealed 47,XY,+21.Therefore, the final diagnosis was a variant of TD 1(PLSD-SD) associated with trisomy 21.

A fetus with the combination of TD and trisomy 21has not been reported previously. On the other hand,there have been five cases reported with both trisomy21 and achondroplasia (Chen et al., 2000; Dabir et al.,2008). Chen et al. (2000) reported craniofacial featurestypical of Down syndrome (trisomy 21), but had skeletalfindings characteristic of achondroplasia. Likewise, thefetus described here exhibited the craniofacial gestaltconsistent with trisomy 21, including a flat facial profilewith low placement of deformed small ears, epicanthicfolds, and blepharophimosis, as well as loose folds onthe posterior neck. Macrocephaly was observed as inTD, while frontal bossing was absent as in trisomy 21.The short nose with depressed nasal bridge and mid-face hypoplasia in the present fetus are manifestationsseen in both TD and trisomy 21. The body proportionand radiological findings in the present fetus werecharacteristic of TD (PLSD-SD). Unfortunately, thefamily did not consent to autopsy, so no other associateddefects, such as cardiac or digestive anomalies, could beruled out.

We have reported here an unusual case of thanato-phoric dysplasia associated with trisomy 21. This casecould have been diagnosed as an unclassifiable TD-like skeletal dysplasia if chromosome analysis and/orgenetic testing were not performed. As exemplified inthis report, the possibility of concurrence of commondisorders should always be considered.

ACKNOWLEDGEMENTS

We thank Dr Noriaki Sakuragi, Dr Hideto Yamada,Dr Takashi Yamada, Dr Mamoru Morikawa, and Dr.Shigeki Shimada for helpful discussion.

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Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 715–717.DOI: 10.1002/pd