D'ARMIENTO, MARIA

Leone F

MARTINELLI, PASQUALE

Maruotti GM

PALADINI, DARIO

Penner I

Sglavo G

English

Archivio della ricerca - Università degli studi di Napoli Federico II

Ultrasound Obstet Gynecol 2007; 30: 354–358Published online 2 August 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.4080Diagnosis of femoral hypoplasia–unusual facies syndromein the fetusD. PALADINI*, G. M. MARUOTTI*, G. SGLAVO*, I. PENNER*, F. LEONE*,M. R. D’ARMIENTO† and P. MARTINELLI**Fetal Cardiology Unit, Department of Obstetrics and Gynecology and †Department of Pathology, University Federico II of Naples,Naples, ItalyKEYWORDS: cleft lip; femoral focal hypoplasia; prenatal diagnosis; ultrasound; unusual faciesABSTRACTFemoral hypoplasia–unusual facies syndrome (FHUFS)is a rare condition characterized by a variable degreeof unilateral or bilateral femoral hypoplasia associatedwith facial clefting and other minor malformations. Theprenatal diagnosis of this condition is possible, but sofar has been reported prospectively in only two cases.We review all cases of FHUFS reported in the literatureand also describe three cases detected prenatally in themid-trimester, underlining the variable expression ofthe syndrome. The reported association with maternaldiabetes mellitus and differential diagnosis with othersyndromes characterized by femoral hypoplasia are alsodiscussed. Copyright  2007 ISUOG. Published by JohnWiley & Sons, Ltd.CASE REPORTSCase 1A 30-year-old primigravida was referred to our unit at21 weeks’ gestation because of a suspicion of severe bilat-eral femoral hypoplasia in her male fetus. The familyhistory was negative for congenital anomalies. The patientdid not have insulin-dependent diabetes mellitus. Ultra-sound examination showed fetal biometry consistent witha gestational age of 21 weeks, with the exception of thefemora, which appeared severely hypoplastic. The leftfemur was completely absent whereas the right one mea-sured only a few millimeters (Figure 1a and b). Ultrasoundimaging of the fetal face revealed the presence of unilat-eral right cleft lip and palate (Figure 1d). Unilateral rightrenal agenesis was also observed. In the counseling ses-sion, the couple was informed of the putative diagnosisand outcome of femoral hypoplasia–unusual facies syn-drome (FHUFS), and the possible management options.After counseling, the couple opted for termination of thepregnancy. The diagnosis of FHUFS was confirmed atautopsy. In particular, severe bilateral and asymmetricfemoral hypoplasia (Figure 1c), unilateral cleft lip/palate(Figure 1e) and unilateral renal agenesis were found. Inaddition, the face showed the typical features of FHUFS: along philtrum, thin upper lip, moderate micrognathia andlow-set ears (Figure 1e). Other features consistent withthe diagnosis of FHUFS found at autopsy included a shortneck and a pelvis with vertically orientated iliac blades.Case 2A 28-year-old obese woman (gravida 2, para 1) withinsulin-dependent diabetes mellitus was referred to ourunit at 21 weeks’ gestation because of an abnormalsecond-trimester anomaly scan. The family history wasunremarkable, with no consanguinity reported. Onultrasound examination, severe hypoplasia of the leftfemur was observed (Figure 2a), whereas the contralateralfemoral shaft appeared unremarkable, with length in thenormal range1. Examination of the fetal face revealedsevere micrognathia (Figure 2c) and the ears appeared lowset. No other abnormalities were observed. A diagnosisof FHUFS was made. After counseling, the coupleopted for termination of the pregnancy. At autopsy,severe unilateral hypoplasia of the left femur, severemicrognathia and low-set ears were confirmed (Figure 2band d). Also noted were a short nose with a broad tip,a thin upper lip and a cleft palate (Figure 2d, inset),confirming the diagnosis of FHUFS.Case 3A 24-year-old primigravida was referred to our unit at13 weeks’ gestation after the detection of abnormal lowerlimbs at the nuchal translucency scan. There was noCorrespondence to: Prof D. Paladini, University Federico II of Naples, Via S. Pansini 5, 80133 Naples, Italy (e-mail: paladini@unina.it)Accepted: 19 April 2007Copyright  2007 ISUOG. Published by John Wiley & Sons, Ltd. CASE REPORTFemoral hypoplasia–unusual facies syndrome 355Figure 1 Case 1 at 21 weeks’ gestation. (a, b) Ultrasound images showing symmetrical femoral hypoplasia; the femur is completely absenton the left side (a; ??) and severely hypoplastic on the right (b; arrowheads and F). (c) Confirmation of the diagnosis at necropsy; note alsothe talipes. (d) Axial view of the fetal head showing the wide cleft of lip and palate (arrow). (e) Confirmation of the diagnosis at necropsy;note also the additional subtle facial features, including upslanting palpebral fissures, long philtrum and thin upper lip.history of either insulin-dependent diabetes mellitus orcongenital anomalies. Ultrasound examination revealeda nuchal translucency thickness consistent with gesta-tional age and confirmed the presence of symmetricallyhypoplastic femora with normal tibiae and an abnor-mal left foot (Figure 3a and b). Transvaginal ultrasoundexamination further confirmed these findings and, inaddition, suggested the presence of moderate microg-nathia (Figure 3b). Termination was carried out in sucha way that an intact specimen was obtained for post-mortem examination. The pathologist confirmed thediagnosis of FHUFS and described severely hypoplasticfemora, an abnormal left foot and moderate micrognathia(Figure 3c). No additional facial dysmorphisms or otherassociated anomalies were detected at necropsy at suchan early gestational age, but the pathologist felt confidentwith the diagnosis of FHUFS.DISCUSSIONFemoral–facial syndrome, or FHUFS, is a rare syndrome,described for the first time in 19752. The pathogenesis ofCopyright  2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 354–358.356 Paladini et al.Figure 2 Case 2 at 21 weeks’ gestation. (a) Ultrasound image showing severe asymmetrical femoral hypoplasia; note the severely shortenedfemoral shaft (arrowheads) and the normal tibia (Ti) and foot (H, heel). (b) Confirmation of the diagnosis at necropsy. (c) Sagittal view ofthe facial profile, showing severe micrognathia (arrow). (d) Confirmation of the diagnosis at necropsy (arrow). Note also the low-set ears,long philtrum and thin upper lip. The associated cleft palate is shown in the inset.Figure 3 Case 3 at 13 weeks’ gestation. (a) Two-dimensional ultrasound image of the severely hypoplastic femora. (b) Three-dimensionalsurface-rendered image of the whole fetus demonstrating the severe bilateral femoral defect and the abnormal left foot (arrowhead);moderate micrognathia (arrow) was also suspected. (c) Confirmation of the diagnosis at necropsy; the arrow indicates the moderatemicrognathia and the arrowhead points to the abnormal foot. The abdominal wall lesion with bowel herniation was traumatic and occurredduring expulsion of the fetus following rupture of the membranes.the syndrome is unknown, although an association withmaternal insulin-dependent diabetes is well documented2,as are the large number of similarities with caudalregression syndrome, another condition frequently seenin infants of diabetic mothers. Most cases of FHUFShave been sporadic, although a few cases of Mendelianinheritance have been reported.The key features of this condition are bilateraland often asymmetric focal femoral hypoplasia andfacial dysmorphism, the latter ranging from evidentCopyright  2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 354–358.Femoral hypoplasia–unusual facies syndrome 357Table1Timeofdiagnosisandultrasoundandpathologicalfindingsinfetusesdiagnosedwithfemoralhypoplasia–unusualfaciessyndromeUltrasoundfindingsReferenceGA(weeks)FemoralhypoplasiaoraplasiaHypoplasiaoraplasiaofotherbonesFacialsignsOtheranomaliesAdditionalmajorfindingsatnecropsyTimeofdiagnosisTadmoretal.432++CLP−−ProspectiveRobinowetal.525+−Micrognathia−−ProspectiveCampbellandVujanic619+−−−Micrognathia,cleftpalate,unilateralpelvickidneyNecropsyUrbanetal.721++−−Micrognathia,cleftpalate,abnormalspinesegmentation,unilateralrenalagenesisNecropsyGillerotetal.325+−−−Micrognathia,cleftpalate,distalarthrogryposis,hemivertebra,brainheterotopia,partialACCNecropsyFillyetal.820+−−ClubfeetMicrognathia,depressednasalbridgeNecropsyThisstudyCase121+−CLP,micrognathiaUnilateralrenalagenesisLongphiltrum,thinupperlip,upslantingpalpebralfissuresProspectiveCase221+−Micrognathia−Cleftpalate,mandibularasymmetry,longphiltrum,thinupperlip,low-setearsProspectiveCase313+−Micrognathia?−MicrognathiaProspectiveACC,agenesisofthecorpuscallosum;CLP,cleftlip/palate;GA,gestationalage.micrognathia/cleft lip and palate to more subtle fea-tures such as upslanting palpebral fissures, short nosewith broad tip, long philtrum, thin upper lip, max-illary asymmetry and isolated cleft palate (Figures 1eand 2d). A number of additional malformations havebeen described occasionally in neonates with FHUFS,including lumbar spine and pelvic abnormalities, absenceor hypoplasia of the fibulae, talipes and genitourinaryanomalies2. Furthermore, severe central nervous system(CNS) malformations have been reported in neonateswith fatal FHUFS, including brain heterotopia, age-nesis of the corpus callosum and ventriculomegaly3.It can therefore be said that there is moderate vari-ation in the phenotypic expression of FHUFS, withoccasional reporting of associated CNS and spinalanomalies.Prenatal ultrasound diagnosis of FHUFS is feasiblegiven that its most consistently reported findings, namelyfemoral hypoplasia and major facial anomalies, can berecognized in utero. However, a prospective diagnosis ofFHUFS, based upon the concurrent detection of femoraland facial anomalies, has been reported in very fewcases4,5; in most published reports the diagnosis wasmade at autopsy following prenatal diagnosis of thefocal femoral defect only (Table 1)3,6–8. This is probablybecause prenatal recognition of the femoral defect,unlike facial anomalies, is relatively straightforward onultrasound examination. In addition, it should be notedthat it is the facial dysmorphisms, although subtlein some cases, that need be recognized to supporta prospective diagnosis of FHUFS in the fetus. Infact, the focal femoral defect can occur as an isolatedanomaly or represent one of multiple abnormalitiescharacteristic of a number of rare disorders, suchas caudal regression sequence, camptomelic dysplasia,Antley–Bixler syndrome and kyphomelic dysplasia9. Thedifferential diagnosis of these pathologic entities maypresent some difficulties. However, in focal femoralhypoplasia the skeletal anomaly is not associated withany malformation of the craniofacial area, whereasin FHUFS micrognathia and/or cleftings are frequentlypresent and recognizable in utero (Figures 1d and 2c).As for caudal regression sequence, which is alsoassociated with maternal insulin-dependent diabetes andfetal urogenital abnormalities, a major lower spinaldefect is usually present at the same time, which isextremely rare in FHUFS10. Camptomelic dysplasia ischaracterized by bowed and moderately short (ratherthan severely hypoplastic) femora and tibiae, scapularhypoplasia, micrognathia and sex reversal in males10.Antley–Bixler syndrome features multiple synostoses,in addition to bowed long bones9,10. Finally, theautosomal recessive disorder kyphomelic dysplasia ischaracterized by symmetrically hypoplastic and bowedfemora and micrognathia9; we consider this to be theonly condition that may be difficult to distinguish fromFHUFS prenatally.In view of the differential diagnosis described above,we believe that, for a prospective prenatal diagnosis ofCopyright  2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 354–358.358 Paladini et al.FHUFS, at least one other major anomaly of the skeletalor craniofacial region should be detected in addition tofocal femoral hypoplasia. If a third malformation is alsofound, such as unilateral renal agenesis or a spinal orCNS anomaly, then the diagnosis is virtually certain.Despite this relatively simple diagnostic algorithm, onlytwo prospective diagnoses of FHUFS in the fetus havebeen described to date (Table 1)4,5. Here we reportanother three cases detected at 21, 21 and 13 weeks’gestation, in which the facial features were carefullysought following the detection of the femoral defect. Thisreport demonstrates that prenatal diagnosis of FHUFS isfeasible with a high degree of accuracy if expert ultrasoundexamination is performed. To the best of our knowledge,the case detected at 13 weeks’ gestation represents theearliest prenatal diagnosis of FHUFS and the first withthree-dimensional imaging.Regarding three-dimensional ultrasound examination,this approach is of no additional value in the diagno-sis of femoral hypoplasia, which is easily detected ontwo-dimensional ultrasonography (Figures 1a and b, 2aand 3a). However, it can be speculated that its use mightenhance the diagnostic capability of ultrasound in rela-tion to minor facial dysmorphisms, such as upslantingpalpebral fissures and, especially, nasal dysmorphismsincluding short nose with broad tip, long philtrum andthin upper lip. We were not able to provide evidence tosupport this hypothesis because the index fetus examinedwith three-dimensional ultrasonography was at a veryearly gestational age (13 weeks); at this early age, the finefacial features are not fully developed and thus the capac-ity of ultrasound to detect these subtle features is lessthan that at 20 weeks’ gestation. However, despite theselimitations, moderate micrognathia was apparent on thethree-dimensional surface-rendered image (Figure 3b).Another important consideration is that the develop-ment of femoral hypoplasia may also occur relatively late,although this bizarre finding was reported in only onecase. In this case, described by Tadmor et al.4, long bonebiometry was unremarkable at scans performed at 19 and24 weeks’ gestation, with facial clefting and shortness ofthe humeri and femora identified at 32 weeks. At thisgestational age, the femur length was described to be atthe 50th centile for 24 weeks’ gestation. Follow-up exami-nations at 34 and 37 weeks’ gestation showed resumptionof normal femoral growth, suggesting that an in-uteroinsult leading to a transient arrest of femoral growth hadoccurred after the 24th gestational week4.Finally, as far as terminology is concerned, we agreewith Tadmor et al.4 and Urban et al.7, who suggestedthat FHUFS should be considered as an association ofmalformations rather than a syndrome because of thewide range of anomalies observed (Table 1). Generally,the definition of an association is the idiopathic occurrenceof multiple congenital anomalies during blastogenesis11,whereas a syndrome is characterized by a cluster ofmalformations that are known or causally related12.In conclusion, we believe that the diagnosis ofFHUFS can be reliably established prenatally if at leastone major skeletal or craniofacial anomaly is foundin addition to asymmetric femoral hypoplasia. Otherassociated anomalies amenable to ultrasound diagnosisinclude major CNS (agenesis of the corpus callosum,hydrocephaly), spinal (hemivertebra) and renal (unilateralagenesis) malformations.REFERENCES1. Paladini D, Rustico MA, Viora E, Giani U, Bruzzese D, Cam-pogrande M, Martinelli P. Fetal size charts for the Italianpopulation. Normative curves of head, abdomen and longbones. Prenat Diagn 2005; 25: 456–464.2. Daentl DL, Smith DW, Scott CI, Hall BD, Gooding CA.Femoral hypoplasia–unusual facies syndrome. J Pediatr 1975;86: 107–111.3. Gillerot Y, Fourneau C, Willems T, Van Maldergem L. Lethalfemoral–facial syndrome: a case with unusual manifestations.J Med Genet 1997; 34: 518–519.4. Tadmor OP, Mannerman C, Rabinowitz R, Fisher D, Itz-chaki M, Aboulafia Y, Diamant YZ. Femoral hypoplasia–unusual facies syndrome: prenatal ultrasonographic observa-tions. Fetal Diagn Ther 1993; 8: 279–284.5. Robinow M, Sonek J, Buttino L, Veghte A. Femoral–facial syn-drome – prenatal diagnosis – autosomal dominant inheritance.Am J Med Genet 1995; 57: 397–399.6. Campbell F, Vujanic GM. Bilateral femoral agenesis in femoralfacial syndrome in a 19-week-old fetus. Am J Med Genet 1997;72: 315–318.7. Urban JE, Ramus RM, Stannard MW, Rogers BB. Autopsy,radiographic and prenatal ultrasonographic examination of astillborn fetus with femoral facial syndrome. Am J Med Genet1997; 71: 76–79.8. Filly AL, Robnett-Filly B, Filly RA. Syndromes with focaldeficiency: strengths and weaknesses of prenatal sonography.J Ultrasound Med 2004; 23: 1511–1516.9. Pryde PG, Zelop C, Pauli RM. Prenatal diagnosis of isolatedfemoral bent bone skeletal dysplasia: problems in differentialdiagnosis and genetic counselling. Am J Med Genet A 2003;117: 203–206.10. Lyons Jones K. Smith’s Recognizable Patterns of HumanMalformation (6th edn). W. B. Saunders Company: Philadelphia,PA, 2006; 350–353.11. Opitz JM. Blastogenesis and the ‘primary field’ in human devel-opment. Birth Defects Orig Artic Ser 1993; 29: 3–37.12. Opitz JM, Czeizel A, Evans JA, Hall JG, Lubinsky MS, Spran-ger JW. Nosologic groupings in birth defects. In HumanGenetics. Proceedings of VII International Congress onHuman Genetics, Berlin, Vogel F, Sperling K (eds). Springer:Heidelberg, 1987; 382–385.Copyright  2007 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2007; 30: 354–358.

Diagnosis of femoral hypoplasia-unusual facies syndrome in the fetus.

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Diagnosis of femoral hypoplasia-unusual facies syndrome in the fetus.

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