PRENATAL DIAGNOSISPrenat Diagn 2005; 25: 535–538.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.801

CASE REPORT

Prenatal diagnosis of Bruck syndrome

C. Berg1*, A. Geipel1, F. Noack2, J. Smrcek3, M. Krapp3, U. Germer5, G. Bender4 and U. Gembruch1

1Department of Obstetrics and Prenatal Medicine, Center for Obstetrics and Gynecology, RheinischeFriedrich-Wilhelms-Univeristat Bonn, Germany2Department of Pathology, University Hospital Schleswig-Holstein, Campus Lubeck, Germany3Division of Prenatal Medicine, Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein, CampusLubeck, Germany4Department of Obstetrics and Gynecology, District Hospital, Oldenburg, Germany5Division of Prenatal Medicine, University of Regensburg, Germany

Bruck syndrome is an autosomal recessive connective tissue disorder combining features of osteogenesisimperfecta and arthrogryposis multiplex congenita. There are only few reports describing this rare syndromeof multiple fractures and joint contractures that is thought to be a subtype of osteogenesis imperfecta. We reportthe first case of prenatal diagnosis of this syndrome in a fetus at 23 weeks of gestation. Ultrasound findingsincluded brachycephaly, retrognathia marked shortening and bowing of both femurs, bilateral fixed flexion ofthe elbows, bilateral fixed extension of the wrists and partially fixed flexion of the knees. The parents opted fortermination of pregnancy. Macroscopic and radiologic examination of the aborted fetus confirmed the prenataldiagnosis, whereas morphological studies of the bone tissue found no hard evidence of osteogenesis imperfecta,probably due to the early stage of pregnancy and the heterogeneity of the syndrome itself. Copyright 2005John Wiley & Sons, Ltd.

KEY WORDS: Bruck syndrome; osteogenesis imperfecta; arthrogryposis multiplex congenita; prenatal diagnosis;ultrasound; fetus

INTRODUCTION

Bruck syndrome [BS; Online Mendelian Inheritance inMan #259450] is a rare autosomal recessive disease firstdescribed in the late nineteenth century (Bruck, 1897)that combines features of osteogenesis imperfecta (OI)and arthrogryposis multiplex congenita. Patients with BSusually present as neonates with multiple joint contrac-tures and pterygia as found in arthrogryposis multiplexcongenita. In the subsequent weeks, multiple fracturesof ribs and long bones are detected, as well as dia-physeal bending, kyphoscoliosis and persistent wormianbones in the calvarium, features strongly reminiscentof osteogenesis imperfecta (Leroy et al., 1998). In con-trast to osteogenesis imperfecta, these patients do nothave blue sclerae or hearing loss. Mental development isnormal. Reports of multiple occurrence in siblings sug-gest an autosomal recessive inheritance pattern (Breslau-Siderius et al., 1998; Viljoen et al., 1989).

Worldwide, only 13 families comprising 18 patientshave been reported (Blacksin et al., 1998; Brady andPatton, 1997; Brenner et al., 1993; Breslau-Sideriuset al., 1998; Bruck, 1897; Leroy et al., 1998; McPhersonand Clemens, 1997; Sharma and Anand, 1964; Viljoen

*Correspondence to: C. Berg, Abteilung fur Geburtshilfe undPranatale Medizin, Zentrum fur Frauenheilkunde und Geburtshilfe,Rheinische Friedrich-Wilhelms-Univeristat, Sigmund-Freud-Str.25, 53105 Bonn, Germany.E-mail: christoph.berg@ukb.uni-bonn.de

et al., 1989); all of them were detected in infancy oradulthood.

Here, we report a case with the clinical manifestationof bowed femurs and multiple joint contractures detectedin a fetus at 22 weeks of pregnancy by means ofultrasound. The prenatal sonographic findings as wellas the postnatal imaging studies are presented.

CASE REPORT

A 34-year-old women, gravida 1, para 0, was referredbecause of an abnormal ultrasound examination at22 weeks’ gestation, including short femurs, polyhy-dramnios and a single umbilical artery. The patientand her husband denied consanguinity. The family his-tory was uneventful. The repeat scan in our institutionat 23 weeks’ gestation showed a fetus with brachy-cephaly and marked shortening and bowing of bothfemurs (Figure 1). The other biometric values were nor-mal. Both elbows and knees were fixed in flexion,while the wrists were fixed in extension (Figure 2). Theposition of the feet appeared normal; however, therewas a marked skin edema of the heels on both sides.Other findings were polyhydramnios and a single rightumbilical artery. There were no visceral anomalies andechocardiography demonstrated normal cardiac anatomyand function. All Doppler measurements were normal.Fetal blood sampling revealed a normal male karyotype.The combination of bowed femurs and multiple jointcontractures prompted the diagnosis of BS. Following

Copyright 2005 John Wiley & Sons, Ltd. Received: 23 April 2003Revised: 27 October 2003

Accepted: 10 November 2003

536 C. BERG ET AL.

Figure 1—Sonogram of the fetus with Bruck syndrome at 23 weeksof gestation showing marked bowing of the femur

Figure 2—Sonogram of the fetus with Bruck syndrome at 23 weeksof gestation showing the wrist fixed in extension

interdisciplinary counseling, the parents opted for termi-nation of pregnancy.

The aborted fetus weighed 520 g and showed facialdysmorphy with retrognathia, bowed femurs, joint con-tractures of the knees, ankles, shoulders and elbows.There were no pterygia. Postnatal imaging studies per-formed with conventional X ray (Figure 3), magneticresonance imaging (MRI) and computerised tomography(CT) confirmed these findings. There were no fracturesof the limbs and no wormian bones in the calvariumcould be detected. Microscopic examination of a carti-lage sample of the proximal and distal femurs revealedno evidence of disturbed ossification as is often seen inpatients with OI in infancy. However, no consent of theparents could be obtained for additional samples of thebones or for complete postmortem examination.

DISCUSSION

There is little overlap in the clinical features of BS apartfrom multiple joint contractures at birth and recurrent

fractures of long bones in infancy. This becomes evenmore apparent, when neonatal findings are analyzed.Table 1 summarizes the clinical and radiological featuresof 11 cases of BS for which neonatal informationis available and of our own prenatal case. The mostconsistent symptoms are multiple joint contractures andclubbed feet, while brachycephaly, persistent wormianbones, facial dysmorphy and connatal fractures areonly present in a subset of patients. This is in partexplained by the slowly progressive nature of thedisease itself, which is in most cases misinterpretedas arthrogryposis multiplex congenita at birth until thefirst fractures occur in infancy. In our case, the earlyoccurrence of bowed femurs together with multiple jointcontractures enabled a prenatal diagnosis. Other diseasespossibly associated with diaphyseal bending of femursincluding hypophosphatasia and camptomelic dysplasiawere unlikely to be the cause as there were no additionalanomalies of the skull, the heart, the thorax or other longbones. A review of the radiological findings in neonateswith BS revealed no case of bowing of the long boneswithout evidence of healing fractures. In our case, therewas isolated marked bowing of the femurs, which is inkeeping with the early gestational age at diagnosis andthe smooth bone structure at that gestational age.

Since its first description, it remains unsolved whetherto consider BS as a subtype of OI or as a distinctsyndrome. This is due to the rarity of the syndromeitself and the limited and contradictory information onthe ultrastructural changes in tissues of patients with BS.Brenner et al. provided the first and only morphologicdescription of a bone sample from a 12-year-old boywith BS (Brenner et al., 1993). Analysis of corticalbone revealed typical characteristics of OI, includingvarying width of the osteoid, swollen mitochondria anda dilated endoplasmatic reticulum of the osteoblasts.However, the collagen fibrils of the osteoid were ofvarying diameter, a feature not typically found in OIpatients. Analysis of compact bone showed that theextractability of collagen I with pepsin and the size ofthe apatite crystals was increased compared to controlsand other OI type III and type IV patients, suggestingan underlying defect in fibril formation of collagen typeI (Brenner et al., 1993). In contrast, collagen studieson skin fibroblasts in other patients reported to haveBS were found to be normal (Breslau-Siderius et al.,1998; McPherson and Clemens, 1997). Although anabnormality in the bone collagen network in BS wasassumed, the underlying defect remained unknown untilBank et al. reported aberrant cross-linking of collagentype I because of altered telopeptide hydroxylation inone previously described case of BS. The responsiblegene was located in a single region on chromosome17p12. The authors proposed that this might be the BSlocus (Bank et al., 1999; Breslau-Siderius et al., 1998).

In our case, no morphological abnormalities in bonestructure could be detected. This might as well be due tothe early stage of gestation at detection as to the hetero-geneity of the syndrome itself. Unfortunately, no consentfor further molecular studies could be obtained from theparents. However, the diagnosis of BS has to focus on

Copyright 2005 John Wiley & Sons, Ltd. Prenat Diagn 2005; 25: 535–538.

BRUCK SYNDROME 537

Figure 3—X rays of the aborted fetus showing the bowed femurs and the abnormal position of the hands

Table 1—Findings in 11 previously reported neonates later diagnosed to have Bruck syndrome in comparison to our own prenatalcase

Brachy-cephaly

Facialdysmorphy

Wormianbones

Connatalfractures

Bowingof longbones

Symmetriccontractures

Pesequinovarus

Present case + + − − + + −Sharma and Anand, 1964 NM NM NM + − + +Viljoen et al., 1989 Case 1 − − NM − − + +

Case 2 − − NM − − + +Case 3 − − NM − − + +

Brenner et al., 1993 − − + − − + −McPherson and Clemens,1997

− − NM + − + +Brady and Patton, 1997 − + + + − + +Leroy et al., 1998 Case 1 + − + − − + +

Case 2 − − − + − + +Case 3 − − + + − + +

Blacksin et al., 1998 + + + − − + −NM, not mentioned; +, present; −, absent.

Copyright 2005 John Wiley & Sons, Ltd. Prenat Diagn 2005; 25: 535–538.

538 C. BERG ET AL.

the main clinical findings until more information is avail-able on the morphologic and ultrastructural findings intissue of patients with BS and their genetic origin.

In conclusion, the prenatal diagnosis of BS willremain reserved for cases with intrauterine manifestationof fractures or bowing of long bones in combinationwith multiple joint contractures. Future studies have toconfirm the proposed underlying genetic defect (Banket al., 1999) and index families should be offered geneticcounseling.

ACKNOWLEDGEMENT

We thank Prof. Dr A. Schulz (med.), Institute of Pathol-ogy, University of Giessen, for the morphological stud-ies on the cartilage samples of our patient.

REFERENCES

Bank RA, Robins SP, Wijmenga C, et al. 1999. Defective collagencrosslinking in bone, but not in ligament or cartilage, inBruck syndrome: indications for a bone-specific telopeptide lysyl

hydroxylase on chromosome 17. Proc Natl Acad Sci U S A 96:1054–1058.

Blacksin MF, Pletcher BA, David M. 1998. Osteogenesis imperfectawith joint contractures: Bruck syndrome. Pediatr Radiol 28:117–119.

Brady AF, Patton MA. 1997. Osteogenesis imperfecta with arthrogry-posis multiplex congenita (Bruck syndrome)–evidence for possibleautosomal recessive inheritance. Clin Dysmorphol 6: 329–336.

Brenner RE, Vetter U, Stoss H, Muller PK, Teller WM. 1993.Defective collagen fibril formation and mineralization inosteogenesis imperfecta with congenital joint contractures (Brucksyndrome). Eur J Pediatr 152: 505–508.

Breslau-Siderius EJ, Engelbert RH, Pals G, van der Sluijs JA. 1998.Bruck syndrome: a rare combination of bone fragility and multiplecongenital joint contractures. J Pediatr Orthop B 7: 35–38.

Bruck A. 1897. Uber eine seltene Form von Erkrankung der Knochenund Gelenke. Dtsch Med Wochenschr 23: 152–155.

Leroy JG, Nuytinck L, De Paepe A, et al. 1998. Bruck syndrome:neonatal presentation and natural course in three patients. PediatrRadiol 28: 781–789.

McPherson E, Clemens M. 1997. Bruck syndrome (osteogenesisimperfecta with congenital joint contractures): review and reporton the first North American case. Am J Med Genet 70: 28–31.

Sharma NL, Anand JS. 1964. Osteogenesis imperfecta with arthrogry-posis multiplex congenita. J Indian Med Assoc 43: 124–126.

Viljoen D, Versfeld G, Beighton P. 1989. Osteogenesis imperfectawith congenital joint contractures (Bruck syndrome). Clin Genet36: 122–126.

Copyright 2005 John Wiley & Sons, Ltd. Prenat Diagn 2005; 25: 535–538.