506 CASE REPORT
Ultrasound Obstet Gynecol 2002; 20: 506510
Blackwell Science, LtdAutosomal recessive type of AdamsOliver syndrome: prenatal diagnosis
R. BECKER*, J. KUNZE, D. HORN, A. GASIOREK-WIENS*, M. ENTEZAMI*, R. ROSSI, M. GUSCHMANN and N. SARIOGLU*Department of Obstetrics and Gynaecology, Klinikum Benjamin Franklin, Free University of Berlin, Department of Human Genetics, Klinikum Rudolf Virchow, Humboldt University, Department of Pediatrics and Neonatology, Klinikum Neuklln and Department of Paidopathology and Placentology, Virchow Klinikum, Humboldt University, Berlin, Germany
KEYWORDS : AdamsOliver syndrome, Inheritance, Prenatal diagnosis, Ultrasound
We report on three pregnancies complicated by AdamsOliver syndrome in a consanguineous Turkish couple. Twocases were correctly diagnosed prenatally at 22+3 and13+0 weeks gestation following the first case of AdamsOliver syndrome in which severe anomalies of the extremitieswere observed at 26+5 weeks gestation. In this first case, thediagnosis of AdamsOliver syndrome was made followingtermination of pregnancy at 27+2 weeks gestation. In allthree cases, autopsy was performed. All fetuses showedanomalies of the extremities, aplasia cutis and symmetricdefects of the skull, with bone being replaced by collagenoustissue. Although there have been numerous cases of thepostnatal diagnosis of AdamsOliver syndrome followingtermination of pregnancy, this is the first description of theprenatal diagnosis of this disorder.
AdamsOliver syndrome (AOS) is characterized by a combi-nation of congenital scalp defects (aplasia cutis congenita)and terminal transverse limb defects. Following the firstdescription1, more than 100 postnatal cases have beenreported24 in association with a large number of additionalfeatures but, as yet, prenatal diagnosis of the condition hasnot been described. We report on a consanguineous healthycouple with four pregnancies, one ending in the birth of ahealthy child, and three cases ending in termination of preg-nancy because of prenatally detected anomalies compatiblewith the diagnosis of AOS. While, in the first affected fetus,the prenatal findings of severe limb anomalies led to termi-nation of pregnancy and the correct diagnosis of AOS wasmade following termination, the sonographic features of the
second and third affected fetuses were consistent with AOSand the diagnosis was made prenatally.
A 20-year-old primigravida was referred to our center forprenatal diagnosis for the first time in 1997 at 26+5 weeks ofgestation. The consanguineous Turkish couple were secondcousins but there was no family history of abnormalities. Thehistory of this pregnancy included attempted suicide by drugintoxication at 5 weeks gestation.
Ultrasound examination revealed fetal growth restrictionas well as severe reduction anomalies of all limbs (Figures 1and 2). No further abnormalities could be demonstrated.
Correspondence: Prof. Rolf Becker, Free University of Berlin, Klinikum Benjamin Franklin, Kurfrstendamm 199, D-10719 Berlin, Germany (e-mail: email@example.com)
Figure 1 First affected fetus: sonographic picture of the right arm at 26+5 weeks gestation. The missing forearm is replaced by tissue containing areas of calcification (rudimentary bones).
Ultrasound in Obstetrics and Gynecology 507
AdamsOliver syndrome Becker et al.
Amniocentesis and fetal blood analysis revealed a normalfemale karyotype (46,XX). Following genetic counseling,the patient opted for termination of pregnancy which wasperformed at 27+2 weeks gestation. The clinical findingsreported by the neonatologists were consistent with AOS.The newborn died after 36 min.
For the growth-restricted female fetus, weighing 488 g, thesonographic findings of tetraperomelia were confirmed:severely shortened forearms with absence of both hands, aseverely shortened right leg with missing lower leg and a leftlower leg with tibia/fibula fragments of 1 cm (Figure 3); bothfeet were missing. All findings were demonstrated by X-ray.In addition, we found large areas of aplasia cutis of the head(approximately 65 cm2) and the trunk (Figure 3). Histologyshowed necrosis and deposits of calcification. The stumps ofthe upper and lower limbs also were hemorrhagic with somesmall areas of calcification. In addition, the skull cap showedtwo symmetric osseous defects, which were replaced by thincollagenous tissue. The inner organs, especially the brainand the heart, displayed no malformations. These findingsconfirmed the clinical diagnosis of AOS. A causal correlation
with the intoxication during the early stage of pregnancywas suspected, and the probability of recurrence in furtherpregnancies was assessed to be low.
The patient again was referred to our center at age 21 yearswith her second pregnancy at 22+0 weeks gestation forultrasound examination which revealed normal findings.The pregnancy ended with the birth of a healthy femalebaby.
At age 23 years, the woman was referred in her third preg-nancy at 22+3 weeks gestation. Ultrasound findings revealedabnormalities of the fetal limbs and scalp. The hands and feethad an atypical appearance, being shortened and with the feetending at the middle phalanx and rudimentary fingers beingpresent on the hands (Figure 4). In addition, the fetal scalpwas partially elevated from the skull, and the fetal skullshowed areas of reduced echogenicity (Figure 5). Theseresults led to the sonographic diagnosis of AOS. Followinggenetic counseling, the patient opted for termination ofpregnancy which was performed at 23+4 weeks gestation.Autopsy of the male fetus with a weight of 495 g (Figure 3)confirmed the sonographic findings of abnormalities of the
Figure 2 First affected fetus: sonographic picture of the left leg. A fragment of a lower leg contains two rudimentary bones.
Figure 3 Autopsy pictures of the three affected fetuses after termination of pregnancy at 27+2 (I, left), 23+4 (II, middle) and 14+2 (III, right) weeks gestation with abnormalities of the limbs in all fetuses and hemorrhage of the abdominal wall in fetus I and fetus II.
Figure 4 Second affected fetus: sonographic picture of one lower arm with abnormal shortness of middle hand bones and rudimentary fingers.
Figure 5 Second affected fetus: sonographic picture of the head with echo-free space between scalp and bone. The underlying skull shows reduced echogenicity.
AdamsOliver syndrome Becker et al.
508 Ultrasound in Obstetrics and Gynecology
limbs, scalp and skull. We found aplasia cutis of the head(approximately 35 cm2), calcification defects of the under-lying skull (Figure 6), hemorrhage of the abdominal wall(Figure 3) and acral aplasia of all four extremities: a rudimen-tary right hand, a left severely hypoplastic hand with shortfragments of metacarpals and very small fragments of somephalanges; both feet were hypoplastic with complete absenceof toes. All findings were demonstrated by X-ray. The skin ofthe hands and feet was atrophic and hemorrhagic. The innerorgans, especially the brain and the heart, displayed nomalformations. Examination of the parents, as well as the2-year-old sister, did not reveal any clinical abnormalities,especially anomalies of the limbs and skin.
The patient again was referred to our center at the age of24 years with her fourth pregnancy at 13+0 weeks gestation.Ultrasound examination again revealed severe abnormalitiesof the fetal arms (Figure 7) and legs (Figure 8). With the sono-graphic diagnosis of AOS, the parents opted for terminationof pregnancy which was performed at 14+1 weeks gestation.
Autopsy of the male fetus with a weight of 23 g (Figure 3)confirmed the diagnosis of another case of AOS with severeanomalies of the fetal limbs: hypoplasia of both arms, a left
arm with cutaneous pterygium and fixed contracturebetween upper arm and forearm, a right arm with aplasiaradii, kinked hand and syndactylia of all fingers. Both legswere severely hypoplastic with campomelic bent lower legsand syndactyly of all toes. All findings were demonstrated byX-ray. Furthermore, in this case, the inner organs, especiallythe brain and the heart, displayed no malformations. Addi-tional findings were symmetric areas of aplasia cutis of thefetal scalp, ossification defects of the underlying skull cap andareas of calcification in a papillary muscle of the left ventricle.Histological examination of other organs, including thebrain, revealed no further malformations.
The patient again was referred to our center at the age of25 years with her fifth pregnancy. Sonography at 12+0 and14+0 weeks gestation showed normal results.
The three cases presented here exhibited the classical featuresof AOS with abnormalities of the limbs, the scalp and theskull. The severity of limb defects varied from transversereduction anomaly involving only the hands and feet (secondaffected fetus) to severe anomalies with absence or severemalformation of the lower arms and lower legs (first andthird affected fetuses). They all showed circumscribed defectsof the scalp and skull.
The variability in presence and severity of symptoms is typ-ical for AOS5. Following the first description1, numerousadditional abnormalities have been described in addition tolimb and scalp anomalies. They include the cardiovascu-lar system, including various cardiac malformations4,6,7 oranomalies of vessels8. Possible anomalies of the brain associ-ated with AOS are polymicrogyria9, arrhinencephaly5, hydro-cephaly5, cerebral cortical dysplasia10, or even acrania10.Anomalies with low frequency include bronchial and renalanomalies4, chylothorax and leukemia12. Our cases showeda constant pattern of anomalies involving the limbs, scalp,calvaria and skin with varying degrees of severity. In noneof our cases did the inner organs, especially the brain and theheart, display any malformations.
Figure 6 Second affected fetus: autopsy picture of the skull with two symmetric areas of missing calcification.
Figure 7 Third affected fetus: sonographic picture of one arm at 13+0 weeks gestation. The fingers are dysplastic.
Figure 8 Third affected fetus: sonographic picture of the legs. While the thighs can be demonstrated, the lower legs are rudimentary.
Ultrasound in Obstetrics and Gynecology 509
AdamsOliver syndrome Becker et al.
Several cases of the familial appearance of AOS withaffected or unaffected parents have been described3,7,9,1322.In the majority of familial cases of AOS, the inheritancewas autosomal dominant3,7,1315,22,23. In seven of thesefamilies, autosomal recessive inheritance was more likelythan autosomal dominant inheritance9,1621. Clinicaldifferences between the autosomal dominant and thepostulated autosomal recessive types are not evident.Multiple affected offspring of unaffected parents andparental consanguinity in the family reported here provideadditional support for autosomal recessive inheritance.Indirect support for the hypothesis that recessive inherit-ance is possible in some families with AOS is provided bythe frequency of inbreeding. Including the family in ourcase, reported parental consanguinity was present infour of them, and so the high rate of consanguineousmarriages in the Turkish and Brazilian populations shouldbe considered.
Although the presence of affected siblings with unaffectedparents is often considered to indicate autosomal recessiveinheritance, it should be kept in mind that other explanationsare possible, such as dominant inheritance with incompletepenetrance in the parents or germline mosaicism. Charac-terization of the molecular basis accounting for the AOSphenotype will be a precondition to prove the hypothesis ofautosomal recessive inheritance.
To date, the pathogenesis of the disease remains unclear.Various mechanisms have been discussed. One of them isinterruption of early embryonic blood supply24. It has alsobeen speculated that local impairment of circulation mightoccur later in intrauterine life25. A generalized abnormality insmall vessels causing disruption of blood flow also has beensuggested8. A common pathogenetic mechanism for Polandsequence and AOS has been discussed26,27.
In our first affected fetus, a disturbance of blood supply inearly embryonic life because of maternal intoxication mighthave been possible as an underlying condition. However, thepresence of two affected siblings of these healthy consanguin-eous parents strongly suggests that there was autosomalrecessive inheritance in our case. Sporadic appearance andgerm cell mosaicism appear unlikely.
The theory of abnormality of small vessels8 and hereditarytransmission must not necessarily be contradictory butmight be additive. It is possible that the common patho-genetic mechanism is a hereditary disorder of perfusion withvarying penetration. Our third affected fetus shows that theunderlying problem may affect the fetus as early as in the firsttrimester.
The broad spectrum of symptoms and possible hetero-geneity of AOS make genetic counseling difficult. It has beensuggested that the severity of symptoms should be deter-mined by fetoscopy15. The cases presented here show thatprenatal diagnosis, as well as the assessment of severity ofAOS, may be possible even in the first trimester.
We thank Mrs Gisela Krantz for producing the photos of theautoptic specimen.
1 Adams FH, Oliver CP. Hereditary deformities in man due to arresteddevelopment. J Hered 1945; 36: 27
2 Whitley CB, Gorlin RJ. AdamsOliver syndrome revisited. Am JMed Genet 1991; 40: 31926
3 Kster W, Lenz W, Kriinen H, Majewski F. Congenital scalpdefects with distal limb anomalies (AdamsOliver syndrome): reportof ten cases and review of the literature. Am J Med Genet 1988; 31:99115
4 Zapata HH, Sletten LJ, Pierpont MEM. Congenital cardiac malfor-mations in AdamsOliver syndrome. Clin Genet 1995; 47: 804
5 Bamforth JS, Kaurah P, Byrne J, Ferreira P. Adams Oliver syndrome:a family with extreme variability in clinical expression. Am J MedGenet 1994; 49: 3936
6 Ishikiriyama S, Kaou B, Udagawa A, Niwa K. Congenital heartdefect in a Japanese girl with AdamsOliver syndrome: one of themost important complications. Am J Med Genet 1992; 43: 9001
7 Lin AE, Westgate M-N, van der Velde ME, Lacro RV, Holmes LB.AdamsOliver syndrome associated with cardiovascular malforma-tions. Clin Dysmorphol 1998; 7: 23541
8 Swartz EN, Sanatani S, Sandor GGS, Schreiber RA. Vascular abnor-malities in AdamsOliver syndrome: cause or effect? Am J MedGenet 1999; 82: 4952
9 Amor DJ, Leventer RJ, Hayllar S, Bankier A. Polymicrogyria associ-ated with scalp and limb defects: variant of AdamsOliver syndrome.Am J Med Genet 2000; 93: 32834
10 Savarirayan R, Thompson EM, Abbott KJ, Moore MH. Cerebralcortical dysplasia and digital constriction rings in AdamsOliversyndrome. Am J Med Genet 1999; 86: 159
11 Chitayat D, Meunier C, Hodgkinson KA, Robb L, Azouz M. Acra-nia. a manifestation of the AdamsOliver syndrome. Am J MedGenet 1992; 44: 5626
12 Farrell SA, Warda LJ, LaFlair P, Szymonowicz W. AdamsOliversyndrome: a case with juvenile chronic myelogenous leukaemia andchylothorax. Am J Med Genet 1993; 47: 11759
13 Burton BK, Hauser L, Nadler HL. Congenital scalp defects withdistal limb anomalies. Report of a family. J Med Genet 1976; 13:4668
14 Jaeggi E, Kind C, Morger R. Congenital scalp and skull defects withterminal transverse limb anomalies (AdamsOliver syndrome):report of three additional cases. Eur J Pediatr 1990; 149: 5656
15 Bonafede RP, Beighton P. Autosomal dominant inheritance of scalpdefects with ectrodactyly. Am J Med Genet 1979; 3: 3541
16 Kahn EA, Olmedo I. Congenital defect of the scalp with a note onthe closure of large scalp defects in general. Plast Reconstr Surg 1950;6: 43540
17 Koiffman CP, Wajntal A, Huyke BJ, Castro RM. Congenital scalpdefect with distal limb anomalies (AdamsOliver syndrome McKu-sick 10030): further suggestion of autosomal recessive inheritance.Am J Med Genet 1988; 29: 2638
18 Sybert VP. Congenital scalp defects with distal limb anomalies(AdamsOliver syndrome-McKusick 10030): further suggestion ofautosomal recessive inheritance. Am J Med Genet 1989; 32: 2667
19 Klinger G, Merlob P. AdamsOliver syndrome: autosomal recessiveinheritance and new phenotypic-anthropometric findings. Am J MedGenet 1998; 79: 1979
20 Tekin M, Bodurtha J, Ciftici E, Arsan S. Further family with possibleautosomal recessive inheritance of AdamsOliver syndrome. Am JMed Genet 1999; 86: 901
21 nay B, Sarici S, Gl D, Akin R, Gokcay E. AdamsOliver syn-drome: further evidence for autosomal recessive inheritance. ClinDysmorphol 2001; 10: 2235
22 Torielle HV, Graff RG, Florentine MF, Lacina S, Moore WD. Scalpand limb defects with cutis marmorata telangiectatica congenita.AdamsOliver syndrome? Am J Med Genet 1988; 29: 26976
23 Martinez-Frias MS, Herranz I, Salvador J, Prieto L, Ramos-ArroyoMA, Rodriquez-Pinilla E, Cordero JF. Prevalence of dominant muta-tions in Spain: effect of changes in maternal age distribution. Am JMed Genet 1988; 31: 84552
24 Fryns JP, Legius E, Demaerel P, van den Berghe H. Congenital scalp
AdamsOliver syndrome Becker et al.
510 Ultrasound in Obstetrics and Gynecology
defect, distal limb reduction anomalies, right spastic hemiplegia andhypoplasia of the left arteria cerebri media. Further evidence thatinterruption of early embryonic blood supply may result in AdamsOliver (plus) syndrome. Clin Genet 1996; 50: 5059
25 Pereira-da-Silva L, Leal F, Cassiano Santos G, Videira Amaral JM,Feijo MJ. Clinical evidence of vascular abnormalities at birth inAdamsOliver syndrome: report of two further cases. Am J MedGenet 2000; 94: 756
26 Vazken M, Der Kaloustian H, Hoyme E, Hogg H, Entin MA, Gutt-macher AE. Possible common pathogenetic mechanisms for Polandsequence and AdamsOliver syndrome. Am J Med Genet 1991; 38:6973
27 Hoyme HE, Der Kaloustian VM, Hogg H, Entin MA, GuttmacherAE. Possible common pathogenetic mechanisms for Poland sequenceand AdamsOliver syndrome: an additional clinical observation. AmJ Med Genet 1992; 42: 3989