Cerebral Cortical Dysplasia and DigitalConstriction Rings in Adams-Oliver Syndrome
Ravi Savarirayan,1 Elizabeth M. Thompson,2* Kimball J. Abbott,3 and Mark H. Moore41Victorian Clinical Genetics Service, Parkville, Victoria, Australia2South Australian Clinical Genetics Service, Womens & Childrens Hospital, North Adelaide, South Australia3Department of Neurology, Womens & Childrens Hospital, North Adelaide, South Australia4Australian Cranio Facial Unit, Womens & Childrens Hospital, North Adelaide, South Australia
Adams-Oliver syndrome (AOS) is character-ised by aplasia cutis congenita of the scalpand variable degrees of terminal transverselimb defects. Short fingers and hypoplasticnails also occur in this predominantly auto-somal dominant syndrome which displaysmarked variability of expression and lack ofpenetrance in some cases. We describe a boywith AOS whose sister is also mildly af-fected. Their mother has hypoplastic fifthtoenails which may represent very mild ex-pression of the syndrome. Brain (computedtomography) imaging to investigate mildleft hemiparesis in the boy demonstrated se-vere cortical dysplasia of central, occipitaland anterior regions of the right cerebralhemisphere. A variety of brain and cranialmalformations has been reported in AOSbut dysplasia of the cerebral cortex has notbeen noted previously. In addition, the boyand his sister have apparent constrictionrings present on the toes which are uncom-mon in AOS. Am. J. Med. Genet. 86:1519,1999. 1999 Wiley-Liss, Inc.
KEY WORDS: Adams-Oliver syndrome; cor-tical dysplasia; constrictionring
Adams-Oliver syndrome (AOS, MIM 100300) com-prises congenital scalp defects with terminal trans-verse limb defects [Adams and Oliver, 1945]. The con-dition exhibits a remarkable degree of inter- and intra-familial variability [Bamforth et al., 1994; Kuster etal., 1988]. We report on 2 sibs affected with AOS, whose
mother may have a very mild clinical expression of thedisorder. Significant cerebral cortical dysplasia waspresent in one of the affected children and is a struc-tural brain anomaly not previously described in AOS.Digital constriction rings were also present in bothchildren, a finding rarely recognized in AOS.
The propositus was the product of his mothers sec-ond pregnancy. Cytomegaloviral (CMV) infection wasdiagnosed serologically at 38 weeks of gestation, afteran illness with fatigue and enlarged cervical lymphnodes. Ultrasound scans were done at 18, 34, and 36weeks for suspected IUGR (intrauterine growth retar-dation) and borderline oligohydramnios. He moved nor-mally in utero and there was no bleeding or amnioticfluid loss during pregnancy. The child weighed morethan expected at birth; 2700 g at 38.5 weeks gestation(just below 10th centile). The birth was normal and nomanifestations of congenital CMV were present. Thechild subsequently tested negative for CMV.
He was noted at birth to have hypoplasia of the skinoverlying the large anterior fontanelle, a palpably wid-ened sagittal suture, an area of absent skin on the palmof the left hand, and apparent ring constriction abnor-malities of the toes. A skull radiograph showed areas ofpatchy mineralization along the line of the sagittal su-ture. The coronal and sagittal sutures were wide, andthe mandible was hypoplastic. No other abnormalitieswere seen. A cranial ultrasound study showed no ab-normality.
When seen in the genetic clinic at age 5 weeks, hisweight was on the 10th centile, length was on the 3rd,and head circumference (OFC) was just above the 2ndcentile for age. At the site of the anterior fontanelle,there was a circular reddened area of skin and therewas a red line in the skin overlying the sagittal suture.Mother described these red areas as having been rawat birth. The left middle and ring fingers were small,especially the distal phalanx of the middle finger. Theleft index, middle, and ring fingernails were small. Onthe ulnar border of the left palm, there was a smallcircular scar which represented the site of the skin de-fect noted at birth.
*Correspondence to: Dr. E.M. Thompson, South AustralianClinical Genetics Service, Womens & Childrens Hospital, NorthAdelaide, South Australia 5006. E-mail: email@example.com
Received 29 September 1998; Accepted 8 April 1999
American Journal of Medical Genetics 86:1519 (1999)
1999 Wiley-Liss, Inc.
The right hand was normal. All the toes were abnor-mal, being small with hypoplastic or absent nails. Theleft second and third and right second to fourth toeshad constriction bands around them. The physical find-ings were otherwise normal.
At 7 months, the child was referred to a pediatricneurologist because the parents had noted that he per-sistently held his left hand fisted and did not reach outwith this hand. Leg movement was also noted to beasymmetric. He was able to roll, could almost sit, andwas otherwise developmentally age appropriate. Neu-rological findings were consistent with mild left hemi-paresis. A CT scan showed mild hypoplasia of the righthemisphere and slight asymmetrical dilatation of thelateral ventricles, the right being larger than the left.There was a reduction in the number of cortical whitematter interdigitations in the right cerebral hemi-sphere, most apparent in the right parietal lobe nearthe vertex. A superficial cleft lined by heterotopic greymatter about 1 cm thick was present in the right pari-etal lobe posteriorly, just above the level of the lateralventricle (Fig. 1). These appearances were consistentwith a severe cortical dysplasia and extended towardthe central and frontal area in some slices. The left sideshowed no definite abnormality. There was no abnor-mal enhancement with use of contrast media.
At 11 months (Fig. 2), he was able to sit unaided but
was not crawling. He was vocalizing and saying dad.His head circumference was on the 50th centile, lengthbetween the 3rd and 10th, and weight between the10th and 25th centiles. The anterior fontanelle mea-sured 4 cm 2 cm. When assessed by a developmentalpediatrician at 19 months, the boy still had signs of amild left hemiparesis, was nearly able to walk unaided,and had appropriate cognitive and language abilitiesfor his age. The head circumference was still trackingat the 50th centile and the anterior fontanelle wasnearly closed.
The boy had one sib, a girl 2 years older, who wasalso examined (Fig. 3). She had documented pulmonaryvalve stenosis and abnormal toes. Her toenails weresmall, especially the left second and third toenails,which were almost absent. The third left toe had aconstriction ring present. The hands and scalp ap-peared normal at the first examination, but at review ayear later, her mother pointed out several small areas1 cm in diameter on the scalp which lacked hair andhad a shiny, atrophic appearance. She had no otheranomalies. The mother had hypoplastic fifth toenailson examination and reported that these were absentuntil 10 years ago, when she was 20 years old. Herscalp was normal. The father, who was not seen, wasreported to have normal hands, feet, and scalp. Theparents were unrelated.
DISCUSSIONIs This AOS?
Adams-Oliver syndrome is a well-delineated, geneti-cally determined entity comprising scalp defects anddistal limb anomalies. The propositus and his sisterreported here have the characteristic scalp and distaldigital lesions consistent with the diagnosis, whereastheir mother only has hypoplasia of her fifth toenails.This finding in the mother may represent a very mildphenotypic expression of AOS as the limb manifesta-tions reported in the condition have varied from virtualabsence of limbs [Adams and Oliver, 1945] to isolatedmild nail hypoplasia [Sybert, 1985] to completely nor-mal individuals [Whitley and Gorlin, 1991]. Alterna-tively, as hypoplastic fifth toenails are not uncommonlyseen in the normal population, the possibility existsthat she could be unaffected, with gonadal mosaicismexplaining two affected children. Gonadal mosaicismhas not, to our knowledge, been described previously inAOS. A congenital heart defect, present in the sister, isa well-recognized component of AOS and estimated tooccur in 13.4% of cases [Zapata et al., 1995].
What is the Mode of Inheritance?AOS is an autosomal dominant trait [Sybert, 1985;
Kuster et al., 1988] with variable expressivity and sev-eral instances of nonpenetrance [Kahn and Olmedo,1950; Scribanu and Temtamy, 1975]. Previous authorshave suggested that a proportion of AOS cases may berecessively inherited. Koiffmann et al.  reportedon 3 affected brothers whose parents are first cousins.This report does not provide a compelling argument forrecessive inheritance as the parents of these childrenwere not available for examination and may have hadsubtle manifestations of the condition. The docu-
Fig. 1. CT brain scan of the propositus. Note mild hypoplasia of theentire right hemisphere. The arrow indicates the 1 cm thick heterotopicgrey matter lining the superficial cleft in the right parietal lobe.
16 Savarirayan et al.
mented occurrence of nonpenetrance in AOS and thepossibility of gonadal mosaicism are other plausible ex-planations in this family that are not discussed in theabove report.
Various theories have been proposed to explain thepathogenesis of the observed defects seen in AOS.Early embryonic vascular disruption/insufficiency ap-pears to be the most tenable of these theories. The pres-ence in AOS of scalp and limb defects, cutis mamorata,tortuous scalp veins [Scribanu and Temtamy, 1975],abnormal cerebral vessels [Chitayat et al., 1992; Frynset al., 1996], and association with Poland anomaly [DerKaloustian et al., 1991] are all findings that could theo-retically be reconciled by this hypothesis.
The absent skin observed in the left palm of the pro-positus at birth may have been caused by such a vas-cular insult and be analogous to the localized cutisaplasia congenita of the scalp seen in the condition.
Apparent Constriction Rings
The presence of digital constriction rings in the pro-positus and his sister is a rare finding in AOS andseveral authors have noted other similarities betweenAOS and amniotic band sequence [Kuster et al., 1988;Whitley and Gorlin, 1991]. The human homologue ofthe mouse mutant disorganization has been implicatedin the pathogenesis of the amniotic band sequence andheterozygous mutations of this gene appear to affectthe development of structures derived from all germlayers during embryogenesis [Donnai and Winter,
Fig. 2. (a) The propositus at 11 months. (b & c) The feet of the pro-positus. Note small toes with small, dysplastic or absent nails and con-striction rings around the left second and third and right second to fourthtoes.
Cortical Dysplasia in AOS 17
1989]. Given the similarities in clinical phenotype be-tween certain cases of AOS and amniotic band se-quence, this gene may also have a role in the patho-genesis of the former condition and may mediate itseffects via a predisposition to embryonic vascular in-sufficiency.
Cerebral Cortex Dysplasia
A variety of intracranial abnormalities have been de-scribed in AOS (Table I). The propositus in this reportwas found to have cerebral cortical dysplasia involvingcentral, occipital, and anterior regions of the right ce-rebral hemisphere which was visualized by computedtomography. The possibilty that the thickened area ofcortex lining the cleft represented pachygyria was con-sidered, but clarification would have required an MRIscan under general anesthesia, which was not felt to bejustified. This abnormality would be expected to havearisen in the first half of pregnancy, when the processof cerebral cortical development takes place, and istherefore unlikely to be related to the maternal CMVinfection in late pregnancy. Although vascular disrup-tion/insufficiency may explain the abnormal corticaldevelopment seen in this child, it is conceivable thatabnormalities in a gene critical for regulation of normalcortical development could underlie this finding. Re-cently, germline mutations in the homeobox gene,EMX2, have been shown to underlie schizencephaly[Brunelli et al., 1996], a disorder of cortical develop-ment thought initially to be secondary to a vasculopa-thy [Landrieu and Lacroix, 1994].
This is the first report of an abnormality of cerebralcortical development in AOS. This finding in the pro-positus, combined with the reports of other intracranialanomalies in AOS, suggests that intellect may not al-ways be preserved in the condition. This is an impor-tant fact to bear in mind when counseling families andprovides an argument for neuroimaging in this groupof patients to search specifically for intracranial mani-festations.
The authors thank Dr. Lloyd Morris, Consultant Ra-diologist, Womens and Childrens Hospital, North Ad-elaide for reviewing the radiology and for helpful dis-cussions.
Fig. 3. (a) The sister of the proband. (b) The feet of the sister. Notesmall, dysplastic toenails. The left second and third toenails are almostabsent, and there is a constriction ring on the left third toe.
TABLE I. Intracranial Manifestations in Adams-Oliver Syndrome
Authors Sex Age Scalp defect Limb anomalies Intracranial anomaly
Kuster et al. (1988) Female Died 6 weeks Present Present EncephaloceleChitayat et al. (1992) Male 10 years Present Present Acrania; abnormal intracerebral
vasulature; prominent ventriclesBamforth et al. (1994) Female 2 years Present Present Microcephaly
Female 22 years Present Present MicrocephalyFemale 3 months Present Present Communicating hydrocephalus;
arrhinencephalyFryns et al. (1996) Male 18 years Present Present Hypoplasia of left cerebral hemisphere,
pons, and medulla; hypoplasia of theleft middle cerebral artery
18 Savarirayan et al.
REFERENCESAdams FH, Oliver CP. 1945. Hereditary deformities in man due to arrested
development. J Hered 36:37.
Bamforth JS, Kaurah P, Byrne J, Ferreira P. 1994. Adams-Oliver syn-drome: a family with extreme variability in clinical expression. Am JMed Genet 49:393396.
Brunelli S, Faiella A, Capra V, Nigro V, Simeone A, Cama A, Boncinelli E.1996. Germline mutations in the homeobox gene EMX2 in patientswith severe schizencephaly. Nat Genet 12:9496.
Chitayat D, Meunier C, Hodgkinson KA, Robb L, Azouz M. 1992. Acrania:a manifestation of Adams-Oliver syndrome. Am J Med Genet 44:562566.
Der Kaloustian VM, Hoyme HE, Hogg H, Entin MA, Guttmacher AE. 1991.Possible common pathogenetic mechanisms for Poland sequence andAdams-Oliver syndrome. Am J Med Genet 38:6973.
Donnai D, Winter RM. 1989. Disorganization: a model for early amnionrupture? J Med Genet 26:421425.
Fryns JP, Legius E, Demaerel P, van den Berghe H. 1996. Congenital scalpdefect, distal limb reduction anomalies, right spastic hemiplegia andhypoplasia of the left arteria cerebri media. Clin Genet 50:505509.
Kahn EA, Olmedo L. 1950. Congenital defect of the scalp, with a note onthe closure of the scalp defect. Plast Reconstr Surg 6:435440.
Koiffmann CP, Wajntal A, Huyke BJ, Castro RM, 1988. Congenital scalpdefects with distal limb anomalies (Adams-Oliver syndrome-McKusick10030): further suggestion of autosomal recessive inheritance. Am JMed Genet 29:263268.
Kuster W, Lenz W, Kaariainen H, Majewski F. 1988. Congenital scalpdefects with distal limb anomalies (Adams-Oliver syndrome): report of10 cases and review of the literature. Am J Med Genet 31:99115.
Landrieu P, Lacroix C. 1994. Schizencephaly, consequence of a develop-mental vasculopathy? A clinicopathological report. Clin Neuropath 13:192196.
Scribanu N, Temtamy SA. 1975. The syndrome of aplasia cutis congenitawith terminal, transverse defects of the limbs. J Pediatr 87:7982.
Sybert VP. 1985. Aplasia cutis congenita: a report of 12 new families andreview of the literature. Pediatr Dermatol 3:114.
Whitley CB, Gorlin RJ. 1991. Adams-Oliver syndrome revisited. Am J MedGenet 40:319326.
Zapata HH, Sletten LJ, Pierpont MEM. 1995. Congenital cardiac malfor-mations in Adams-Oliver syndrome. Clin Genet 47:8084.
Cortical Dysplasia in AOS 19