� 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:488–491 (2008)

Clinical Report

Adams–Oliver Syndrome in SiblingsWith Central Nervous System Findings,

Epilepsy, and Developmental Delay:Refining the Features of a Severe Autosomal Recessive Variant

Robin R. McGoey1,2 and Yves Lacassie2,3*1Department of Pathology, Louisiana State University Health Science Center, New Orleans, Louisiana

2Department of Pediatrics, Division of Genetics, Children’s Hospital of New Orleans, New Orleans, Louisiana3Department of Pediatrics, Louisiana State University Health Science Center, New Orleans, Louisiana

Received 9 July 2007; Accepted 15 October 2007

Adams–Oliver syndrome (AOS) is a well-known raresyndrome of cutis aplasia in combination with limb defects.Recent reports have been published discussing the clinicalvariability and apparent genetic heterogeneity seen in someaffected individuals and families with particular attentionmade to the possible existence of an autosomal recessivevariant of AOS. We report on sisters as the ninth report ofsuch an autosomal recessive-variant and review previouslypublished similar sibships for observed comparisons re-lative to clinical features. Review of these cases is initially

suggestive of an increased frequency of both central nervoussystem involvement as well as epilepsy in the autosomalrecessive variant of AOS. Full case reports and a review ofneurological involvement in the autosomal recessive AOScases are presented. � 2008 Wiley-Liss, Inc.

Key words: Adams–Oliver syndrome; limb reductiondefect; cutis aplasia; autosomal recessive; central nervoussystem; epilepsy

How to cite this article: McGoey RR, Lacassie Y. 2008. Adams–Oliver syndrome in siblings with centralnervous system findings, epilepsy, and developmental delay: Refining the features of a severe autosomal

recessive variant. Am J Med Genet Part A 146A:488–491.

INTRODUCTION

Adams–Oliver syndrome (AOS) (OMIM 100300)was first described in 1945 as a syndrome of scalpdefects and distal limb reduction with probableautosomal dominant inheritance [Adams and Oliver,1945]. Clinical variability has been described andincludes variation in the degree of both the scalpand limb defects. In a review of 102 AOS cases inthe literature, Farrell et al. [1993] report that while78% of patients have lower limb defects, the upperextremities are also involved in 59%. Additionally,scalp defects are observed in 73% of cases andrange in severity from cutaneous lesions to calvarialdefects and acrania. In infancy, calvarial defects canbe inapparent and present simply as an enlargedanterior fontanelle [Whitley and Gorlin, 1991]. AOS isalso manifest in various combinations with a largenumber of additionally associated features such ascutis marmorata and dilated scalp veins.

The infrequently reported associated defects aremany and include congenital heart malformations,

polythelia, cryptorchidism, wooly hair, and oligohy-dramnios [Kuster et al., 1988; Santos et al., 1989;Whitley and Gorlin, 1991; Zapata et al., 1995]. Centralnervous system abnormalities have rarely been re-ported in associationwith classicAOSand intelligenceis reportedly normal in the majority of cases.

The vast majority of reports document autosomaldominant inheritance including several instancesof nonpenetrance. Recently publications, however,introduce the possible existence of an AOS-variantwherein autosomal recessive inheritance is dis-played. Amor et al. [2000] published a sib pair bornto consanguineous parents who both manifestpsychomotor delay, lower extremity lymphedema,

*Correspondence to: Yves Lacassie, M.D., FACMG, Division ofGenetics, Department of Pediatrics, Louisiana State University HealthScience Center, New Orleans and Children’s Hospital of New Orleans,200 Henry Clay Avenue, New Orleans, Louisiana 70118.E-mail: ylacas@lsuhsc.edu

DOI 10.1002/ajmg.a.32163

polymicrogyria, and seizure activity. Only one sibadditionally displayed aplasia cutis with reductiondefects of the toes while the other sib showedno scalp aplasia but brachydactyly and prominentcutaneous vasculature. Orstavik et al. [1995] reporteda sib pair with aplasia cutis in combination withnot only transverse limb anomalies but also centralnervous system anomalies including agenesis ofthe corpus callosum, cerebral atrophy, and bilateralperiventricular calcifications. The parents were non-consanguineous. Temtamy et al. [2007] publish threeadditional patients. All three had scalp defects aswell as terminal transverse lower extremity defects,with one patient additionally having central nervoussystem abnormalities and delayed developmentalmilestones. All three patients were born to consan-guineous parents and two were said to have similarlyaffected siblings.

We report on a new sib pair whose constellation offeatures provides additional evidence for clinicalvariability and further support the existence of anautosomal recessive variant of AOS. We also assertthat central nervous system abnormalities may bemore commonly seen in those cases of AOS whereinthe probable inheritance pattern is autosomalrecessive.

CLINICAL REPORT

Patient 1

The proposita is a female who was born at36 weeks’ gestation via cesarean secondary to fetaldistress, to a 30-year-old mother and 26-year-oldfather following a pregnancy complicated only bypreterm labor beginning at 24 weeks and requiringbed rest. The parents were nonconsanguineous andhealthy, reporting only a history of vitiligo, psoriasis,and asthma in the mother. The couple also reportedtwopriormiscarriages aswell as apreterm(35weeks’gestation) male infant who died at 1 day withpulmonary hypertension. Additional family historyrevealed a sister who was similarly affected to theproposita (Patient 2) but was otherwise noncontri-butory. Her BW was 1,919 g (3rd centile), BL 44.5 cm(5th centile), and OFC 30 cm (<3rd centile). Apgarswere 8 and 9 at 1 and 5 min, respectively. Featuresnoted at birth included anomalies of all four extre-mities with rudimentary fingers with hypoplasticnails, near total adactyly on the left foot andsyndactyly of toes 2–3 on the right with umbilicationof the nails (Figs. 1 and 2). Additional featuresincluded two hairwhorls, micrognathia, a high-pitched cry, prominent xiphoid, and sacrococcygealdimple. At 8 months, she was also noted to have cutismarmorata, prominent veins on the forehead and anenlarged, 4 cm� 4 cm, anterior fontanelle along withpersistent microcephaly (OFC 40 cm, <3rd centile;Fig. 3). Length was 66 cm (10–25th centile) andweight was 6.6 kg (3rd centile). Developmental

milestones are currently appropriate. Seizure activitybegan at 7 months of age at which time a cranial MRIrevealednear total agenesis of the corpus callosumaswell as periventricular gliosis with calcificationsin the subcortical white matter adjacent to the rightfrontal horn of the lateral ventricle. The seizuresweredescribed as multiple daily complex partial seizuresfor which she is being treated with Levetiracetam andoxcarbazepime. Chromosomes at the 500–550 bandlevel were normal.

Patient 2

Patient 2 was the older sister of the proband. She wasborn at 38 weeks’ gestation following an uncompli-catedpregnancy.BWwas2200g(<3rdcentile).BLandOFC were not recalled. Terminal transverse limbdefects were noted at birth and amniotic bandsyndrome was considered. At 6-years of age she hadmicrocephaly (OFC 46.5 cm,<2nd centile), epicanthalfolds, blue sclerae, hemangiomata of the forehead andocciput and a gluteal cafe-au-lait spot (Fig. 4). Height

FIG. 1. Patient 1 with near total adactyly of left foot. [Color figure can beviewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 2. Patient 1 with 2–3 syndactyly of right foot and umbilicatednails. [Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

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was 116 cm (50–75th centile) and weight was 19.8 kg(25–50th centile). There was extreme bilateral short-ening of the radioulnar bones with four hypoplasticdigits present at the elbow on the right and five on theleft (Fig. 5). Toes are asymmetrically absent with neartotal adactyly on the left (Fig. 6). Developmentalmilestones are delayed. Ambulation began at19 months. She has had epilepsy since 9 months ofage for which she is treated with oxcarbazepime andvalproate. Cranial CT revealed bilateral linear periven-tricular calcifications. The karyotype at the 500–550band resolution level was normal.

DISCUSSION

AOS was first described as a syndrome of scalpdefects and distal limb reduction with probable

autosomal dominant inheritance [Adams and Oliver,1945]. Three subsequent reports in recent press havesuggested the potential existence of an AOS-variantwith autosomal recessive inheritance [Orstavik et al.,1995; Amor et al., 2000; Temtamy et al., 2007]. Areviewof publishedAOScases revealsfive additionalreports wherein autosomal recessive inheritance islikely [Kahn and Olmedo, 1950; Koiffmann et al.,1988; Klinger and Merlob, 1998; Tekin et al., 1999;Unay et al., 2001].

The report here of a similar sibship furtherreinforces the observed clinical variability of AOSeven in regards to classic features described in theoriginal cases by Adams and Oliver in 1945. The mainfeature of AOS seen in both sibs of the current reportis the limb reduction defect. Patient 1 also has apersistently large anterior fontanelle as well as anabnormal growth pattern of scalp hair over thevertex. Cutis marmorata, prominent veins andhemangiomata are additional findings. This reportalso supports the existence of an autosomal recessive

FIG. 3. Patient 1 with hypertelorism, cutis marmorata, micrognathia, andprominent forehead veins. [Color figure can be viewed in the online issue,which is available at www.interscience.wiley.com.]

FIG. 4. Patient 2 with hypertelorism, epicanthal folds, blue sclerae, andmicrognathia. [Color figure can be viewed in the online issue, which is availableat www.interscience.wiley.com.]

FIG. 5. Patient 2 with bilaterally short forearms, four rudimentary digits onthe right, and five on the left. [Color figure can be viewed in the online issue,which is available at www.interscience.wiley.com.]

FIG. 6. Patient 2 with near total adactyly of lower extremities. [Colorfigure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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variant of AOS and brings the total number ofdescribed AOS kindreds with probable autosomalrecessive inheritance to nine.

Particular attention is deserved to the possibilitythat central nervous system anomalies may occurmore frequently in the autosomal recessive variantform of AOS. A review of these autosomal recessivevariant cases, including the two described here,reveals twelve patients wherein diagnostic neuro-imaging was performed (Table I). Of the 12 patients,8 have multiple, complex central nervous systemfindings including idiopathic intracranial calcifica-tions, polymicrogyria, and agenesis of the corpuscallosum. Eight patients had a history of seizureactivity. Seven had microcephaly; and six haddelayed developmental milestones. This compiledevidence suggests that phenotypic severity, speci-fically in regards to cranial malformations, may bemore significant in cases of recessively inheritedAOS. It also may add evidence for such casesbeing considered as an AOS-variant wherein centralnervous system involvement is a discriminatoryfeature between classic and variant AOS. Additionalreports are needed to document these observationsand comprehensive medical workups to includeappropriate brain imaging are recommended.

REFERENCES

Adams FH, Oliver CP. 1945. Hereditary deformities in man due toarrested development. J Hered 36:3–7.

Amor DJ, Leventer RJ, Hayllar S, Bankier A. 2000. Polymicrogyriaassociated with scalp and limb defects: Variant of Adams-Oliver syndrome. Am J Med Genet 93:328–334.

Farrell SA, Warda LJ, LaFlair P, Szymonowicz W. 1993. Adams-Oliver syndrome: A case with juvenile chronic myelogenousleukemia and chylothorax. Am J Med Genet 47:1175–1179.

Kahn EA, Olmedo L. 1950. Congenital defect of the scalp: With anote on the closure of the scalp defects in general. PlastReconstr Surg 6:435–440.

Klinger G, Merlob P. 1998. Adams-Oliver syndrome: Autosomalrecessive inheritance and new phenotypic-anthropometricfindings. Am J Med Genet 79:197–199.

Koiffmann CP, Wajntal A, Huyke BJ, Castro RM. 1988. Congenitalscalp skull defects with distal limb anomalies (Adams-Oliver syndrome–McKusick 10030): Further suggestion ofautosomal recessive inheritance. Am J Med Genet 29:263–268.

Kuster W, Lenz W, Kaarianinen H, Majewski F. 1988. Congenitalscalp defects with distal limb anomalies (Adams-Oliversyndrome): Report of ten cases and review of the literature.Am J Med Genet 31:99–115.

Orstavik KH, Stromme P, Spetalen S, Flage T, Wesstvik J, VesterhusP, Skjeldal O. 1995. Aplasia cutis congenita associated withlimb, eye, and brain anomalies in sibs: A variant of the Adams-Oliver Syndrome? Am J Med Genet 59:92–95.

Santos H, Cordeiro I, Menezes I. 1989. Aplasia cutis congenitaassociatedwith congenital heart defect, not a coincidence? AmJ Med Genet 34:614–615.

Tekin M, Bodurtha J, Ciftci E, Arsan S. 1999. Further family withpossible autosomal recessive inheritance of Adams-Oliversyndrome. Am J Med Genet 86:90–91.

Temtamy SA, Aglan MS, Ashour AM, Zaki MS. 2007. Adams-Oliversyndrome: Further evidence of an autosomal recessivevariant. Clin Dysmorph 16:141–149.

Unay B, Sarici SU, Gul D, Akin R, Gokcay E. 2001. Adams-Oliversyndrome: Further evidence for autosomal recessive inher-itance. Clin Dysmorph 10:223–225.

Whitley CB, Gorlin RJ. 1991. Adams-Oliver syndrome revisited.Am J Med Genet 40:319–326.

Zapata H, Sletten LJ, Pierpont MEM. 1995. Congenital cardiacmalformations in Adams-Oliver syndrome. Clin Genet 47:80–84.

TABLE I. Cranial and CNS Findings in AOS Patients With Autosomal Recessive Inheritance

Case KindredScalp/skull

defects CNS findings Microcephaly SeizuresDevelopmental

delay

1 1a þ/þ Normal CT þ No No2 2a �/þ Normal CT No No No3 3a �/þ Retrocerebellar cyst, cerebellar hypoplasia þ þ þ4 4b þ/� Periventricular calcification þ þ þ

þ5 5c þ/� Cortical malformation, ventriculomegaly,

pachy-/polymicrogyriaNo þ þ

6 5 �/� Polymicrogyria, hypoplastic corpus, callosum, gliosis,ventriculomegaly, small pons

No þ þ

7 6d þ/þ Normal CT No h h

8 7e þ/� Normal ultrasound No � No9 8f þ/þ Periventricular and thalamic calcifications, cerebral atrophy þ þ þ

10 8 þ/� Ventriculomegaly, partial agenesis of corpus callosum,ischemic changes

þ i i

11 9g �/� Agenesis corpus, callosum, gliosis, periventricularcalcifications

þ þ No

12 9 �/� Periventricular calcifications þ þ þaTemtamy et al. [2007].bUnay et al. [2001].cAmor et al. [2000].dTekin et al. [1999].eKlinger and Merlob [1998].fOrstavik et al. [1995].gCurrent case report.hDied at 4 months.iDied at 1 week.

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