I Med Genet 1997;34:79-82

Anal anomalies: an uncommon feature ofvelocardiofacial (Shprintzen) syndrome?

S Worthington, A Colley, K Fagan, Kang Dai, A H Lipson*

AbstractWe report three cases of velocardiofacialsyndrome (VCFS) with anal anomalieswho have deletions of the 22qll regionand a further case where the proband hasVCFS clinically and her father has an analanomaly. It is important to consider VCFSin the differential diagnosis of childrenwith anal anomalies and to look for otherfeatures of the syndrome, such as asym-metrical crying facies, submucous cleft ofthe palate, developmental delay, cardiacanomalies, and hypoparathyroidism.(J Med Genet 1997;34:79-82)

Keywords: anal anomalies; velocardiofacial syndrome;22ql deletion.

Department ofClinical Genetics,Sydney Children'sHospital, High Street,Randwick, NSW 2031,AustraliaS Worthington

CytogeneticsDepartment, HunterArea PathologyService, Newcastle,NSW, AustraliaK FaganK Dai

Department ofClinical Genetics,Liverpool, NSW,AustraliaA Colley

Department ofClinical Genetics,Royal AlexandraHospital for Children,PO Box 3515,Paramatta NSW 2124,AustraliaA H Lipson (*deceased)

Correspondence to:Dr Worthington.Received 12 January 1996Revised version acceptedfor publication6 August 1996

The 22q1 1 deletion disorders include velo-cardiofacial syndrome (VCFS),' the DiGeorgesequence (DGS),23 conotruncal anomaly facesyndrome,4 Cayler's cardiofacial or asym-metrical crying facies syndrome,5 and"CATCH 22".6 They consist of a wide spec-trum of clinical manifestations some of whichare explained by abnormal migration of neuralcrest cells.7Anal anomalies occur in approximately 1 in

5000 live births.8 They occur in many syn-dromes and have been commonly described inassociation with other malformations.9 Cardio-vascular (CVS) anomalies, most commonlyventricular septal defect and tetralogy of Fallot,are reported to occur in 7-22% of cases withimperforate anus.'0 Other associated anomaliesinclude spina bifida, genitourinary ab-normalities, limb defects, and tracheo-oeso-phageal fistulae.9"0 Anal anomalies have beenreported infrequently in the 22qll deletiondisorders."1-13We report three cases of VCFS with anal

anomalies who have deletions of the 22qllregion detected using fluorescent in situ hy-bridisation (FISH). A further case is presentedwhere the proband has VCFS clinically and herfather an anal anomaly and mental retardation,presumably because of VCFS.

Case reportsCASE 1Case 1, a male, the second child of unrelatedparents, was born at 38 weeks' gestation bycaesarean section with a birth weight of 2640 g(1Oth centile), length 40 cm (<3rd centile), andOFC 32.8 cm (1Oth centile). The pregnancywas uneventful. Chromosomal analysis of am-niocytes at 16 weeks' gestation, performed for

advanced maternal age, was reported as a nor-mal male karyotype. The neonatal period wascomplicated by hypotonia and feeding diffi-culties and gastro-oesophageal reflux. Con-stipation owing to anal stenosis was a problemfrom the first month of age. At 7 monthsof age he underwent an anoplasty which wassuccessful in treating the constipation.He had significant global developmental and

expressive speech delay with a normal hearingassessment. A skeletal survey showed spinabifida occulta. At 4 years of age he was referredto a child development unit where the diagnosisof VCFS was suggested. Review by a geneticistconfirmed facial dysmorphic features (fig 1) ofmicrognathia, almond shaped palpebral fis-sures, deficient alae nasi, broad nasal bridge,prominent dysplastic ears, and a short, hy-potonic palate with a single uvula. Cardio-vascular examination was normal and his heightwas on the 3rd centile. A diagnosis of VCFSwas made clinically and FISH studies with theOncor N25 probe confirmed a deletion of thechromosome 22q 1 1 region. The family historywas unremarkable with neither parent havingVCFS clinically. FISH studies are not availableon the parents.

Figure 1 Case 1: congenital anal stenosis. Notemicrognathia, almond shaped palpebral fissures, deficientalae nasi, and broad nasal bridge.

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excision of the fistula. The family history wasunremarkable.

His subsequent course was complicated byslow growth, and expressive speech delay withhypernasal speech. He was referred to a cleftpalate clinic for speech review where he wasseen by a geneticist who noted myopathic fa-cies, deficiency of the alae nasi, almond shapedpalpebral fissures, maxillary and mandibularhypoplasia, and small dysplastic ears (fig 2).His palate was short and the uvula grooved.Cardiovascular examination was normal andhis height was on the 3rd centile. These featureswere consistent with VCFS and FISH studieswith the Oncor N25 probe confirmed a deletionof the chromosome 22ql 1 region. His parentsdid not have VCFS clinically; FISH studies ofthe parents are not available. At 5 years of age,during induction of anaesthesia for pharyn-goplasty, a diagnosis of anterior laryngeal web,subglottic stenosis, and thickened cricoid car-tilage was made.

Figure 2 Case 2: covered anus with perineal fistula.Note almond shaped palpebral fissures, maxillary andmandibular hypoplasia, and small dysplastic ears.

CASE 2Case 2, a 5 year old male, the second child ofnon-consanguineous parents, was born at 40weeks' gestation by normal vaginal delivery.Labour was complicated by fetal distress withmeconium stained liquor. Apgar scores were 5and 7 at one and five minutes respectively. Hewas resuscitated at birth, then intubated andventilated for 24 hours. Birth weight was 3000 g(1Oth centile). Hypothyroidism was detectedby newborn screening and treatment with thyr-oxine was started. He was noted to have acovered anus and a perineal fistula at birth,which were treated surgically by anoplasty and

0 d_

Figure 3 Case 3: congenital anal stenosis. His older female sib (left) is shown to indicatefamilial resemblance. Note almond shaped palpebral fissures, myopathic facies, broadnasal bridge, and deficient alae nasi.

CASE 3Case 3 was the second child of non-con-sanguineous, healthy, Dutch parents. He wasborn at 40 weeks' gestation by normal vaginaldelivery following an uneventful pregnancy.Gastro-oesophageal reflux, poor oral motorfunction, and hypotonia were significant prob-lems from birth. At 3 months of age he de-veloped constipation which persisted despitemedical treatment. Anal stenosis was diagnosedat 10 months of age and was initially treatedwith anal dilatation but without success. Onexamination under anaesthesia there was a tightfibrous anal ring which required surgical treat-ment. Surgery consisting of sphincterotomyand anoplasty was performed at 17 months ofage.At 3 years of age, he was referred to a ge-

neticist for syndrome identification because ofsevere expressive speech delay, mild global de-velopmental delay, and hypotonia. He had hy-pernasal speech with a bifid uvula andhypotonic palate. His height, weight, and OFCmeasurements were all on the 50th centile forage. His facial appearance consisted of almondshaped palpebral fissures, epicanthic folds, abroad nasal bridge with small alae nasi, and asmooth philtrum, as shown in fig 3. He hadjoint laxity and tapering fingers with narrowdistal phalanges. His ears were normally situ-ated but had thickened helices. Hearing testswere normal. A sacral pit was noted but xrays showed no associated abnormalities ofthe vertebrae. An echocardiogram was normalapart from an aberrant subclavian artery. Adiagnosis of VCFS was made clinically andFISH studies with the Oncor N25 probe con-firmed a deletion (de novo) of the chromosome22ql1 region.

His older sister was healthy with no learningproblems. There was a strong familial facialappearance (fig 3).

CASE 4

Case 4, a 4 year old female, the second childof a young, non-consanguineous couple, was

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Anal anomalies: an uncommon feature of velocardiofacial (Shprintzen) syndrome?

born at term following an uneventful preg-nancy. She was delivered by caesarean sectionfor cephalopelvic disproportion and fetal dis-tress. Apgar scores were 9 and 9 at one and fiveminutes respectively. Birth weight was 3370 g(50th centile), length 53 cm (90th centile), andOFC 34 cm (50th centile). The neonatal periodwas complicated by hypoglycaemia, transienthypoparathyroidism, and cyanosis associatedwith a cardiac murmur. The absent pulmonaryvalve syndrome consisting of an absent pul-monary valve, pulmonary artery aneurysm,ventricular septal defect, and bronchomalaciawas diagnosed on day 3. This cardiovascularanomaly was associated with a right aortic arch.

Surgery consisted of homograft re-construction of the pulmonary artery and clos-ure of the ventricular septal defect at 5 monthsof age. The thymus gland was absent at oper-ation but subsequent T cell subsets were nor-mal. At 16 months of age she was seen in theimmunology clinic because ofpoor weight gainassociated with recurrent upper respiratorytract and ear infections. Facial dysmorphic fea-tures included an expressionless face, smallmouth, almond shaped palpebral fissures, mid-face hypoplasia, and protuberant ears with ab-sent ear lobes. Short stature was present withheight less than the 3rd centile. At 22 monthsof age when seen by a geneticist she also hadgross motor and expressive speech delay and aclinical diagnosis of VCFS was made.The family history was complex. A sib was

developmentally delayed with hypemasalspeech. The father had an imperforate anus andattended a special school because of learningdifficulties. Congenital heart disease, im-perforate anus, and intellectual handicap oc-curred in other family members. Karyotypestudies of the proband were normal, but FISHstudies were not performed because the familyhas been lost to follow up.

DiscussionVCFS was described in 1978 by Shprintzen etal"4 and was characterised by a cleft palate inassociation with congenital heart disease, facialdysmorphism, and learning disabilities.'4 Thephenotypic spectrum was later expanded as thevariability of this syndrome was recognised.'5The discovery that deletions of chromosome22qll were associated with DGS, and thatDGS and VCFS were a spectrum of the samedisorder led not only to further expansion ofthe clinical spectrum but to hypotheses re-garding the role ofgenes from this chromosomeregion in neural cell migration and the patho-genesis of the associated birth defects.'6The cases presented have the typical facial

features of VCFS and abnormalities of thepalate resulting in hypernasal speech. The chil-dren with anal anomalies do not have cardio-vascular anomalies, although the latter is acommon manifestation of VCFS. All exceptcase 4 have proven 22qll deletions. Case 4has the typical facial features and cardiovascularlesion but it is her retarded father who hasan anal anomaly. Anal anomalies have beeninfrequently reported in children who have fea-

tures of the 22ql 1 deletion syndromes. Aninfant with a clinical diagnosis of DGS wasreported with a ventricular septal defect (VSD),cleft lip and palate, bilateral hydroureters, hy-pocalcaemia, and anal atresia."l Anteriorlyplaced anus was reported by Wilson et alt in oneof 44 cases with a 22ql 1 deletion, McDonald-McGinn et all2 in two of 52 cases with VCFS,and DeSilva et al" in one of three cases offamilial 22q deletion. Deletions of the chro-mosome 22ql 1 region have also been reportedin Cayler syndrome,5 the association of con-genital hypoplasia of the depressor anguli orismuscle with congenital heart disease. Im-perforate anus and anal stenosis have occurredin four patients with Cayler syndrome; how-ever, they were not investigated for the pos-sibility of a 22ql 1 deletion."718Anal anomalies occur in many syndromes

including the VATER association,19 caudal re-gression syndrome,20 FG syndrome,2' cat eyesyndrome (CES),22 Kabuki syndrome,2'Townes-Brocks syndrome,24 and Opitz G syn-drome.25 CES is characterised by ocular col-oboma, anal atresia, preauricular skin tags andpits, heart defects, and facial dysmorphic fea-tures.22 CES is caused by partial tetrasomy forthe 22q11.2 region.22 Although DGS and CESmap to the same cytogenetic region, the distalboundary of the CES critical region is proximalto that of DGS.22 The significance of the closeproximity of these gene loci, one deleted, theother overexpressed, in the pathogenesis of analand cardiovascular anomalies is uncertain. The22ql 1 deletion syndromes and CES share somefeatures in common. McPherson et al26 re-ported a girl with features of cat eye syndromebut with a normal karyotype. She had an im-perforate anus, facial dysmorphism, iris colo-bomata, bilateral cleft lip, hip dislocation, andtalipes calcaneovalgus. Her father had milderbut similar features with a broad nasal bridge,low set, posteriorly rotated ears, mild mi-crognathia, anal stenosis, and brachydactyly.VCFS could be considered as a possible diag-nosis for this family.The Opitz G syndrome is an autosomal dom-

inant disorder characterised by facial dys-morphism and multiple congenital anomalies.Many of these features also occur in VCFS.Anal anomalies have been reported in this syn-drome.25 Christodoulou et al27 described a babywith Opitz G syndrome who had a hoarse cry,hypertelorism, low set ears with a prominentcrus helix, a cleft of the soft palate, patentductus arteriosus, hypotonia, hypospadias, un-descended testes, and an imperforate anus.This infant had a ring chromosome 22 karyo-type on G banding reported as 46,XY,r(22)(pl3;q13.3). It is not known if the 22q11region was deleted as more detailed analysis ofthe breakpoints was not available and thepatient is now dead. McDonald-McGinn et al'2reported three cases with Opitz G syndromethat had a 22qll.2 deletion shown by FISHstudies. None of these cases, however, had analanomalies.The structures involved in the 22q1 1 deletion

syndromes, the parathyroids, thymus, face, andthe conotruncal region of the heart are derived

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from the pharyngeal pouches. The neural crestmakes important mesenchymal contributionsto the derivatives of the pharyngeal pouchesand this led to the hypothesis that many of themanifestations of the DGS and VCFS were

caused by abnormalities of neural cellmigration.816 The development of the anorectalregion may also be influenced by neural crest

cell migration.28 Most anorectal anomaliesresult from abnormal development of a wedgeof mesenchyme called the urorectal septum.29It is possible that the pathogenesis of anomaliesin VCFS is related to a defect in mesenchymecell migration. The defect could be in theprogramming of cell migration, an abnormalityof the cell matrix that contains the migratingcells,28 or because of a faulty cell adhesionmolecule.

Deletions of22ql 1 result in a variable clinicalpicture which may include anal anomalies. Vari-ation in the phenotype is considerable, andthe presence of cleft palate or cardiovascularanomalies is not obligatory.30 Only one case

had a cardiac anomaly and two a submucouscleft of the palate. Indeed the initial pre-

sentation in these cases was because of the analanomalies. Constipation is not an uncommon

symptom in children with developmental delayand hypotonia. Anal anomalies such as con-

genital stenosis need to be considered in VCFSas effective treatment is available. Similarly,awareness of the occurrence of anal anomaliesin VCFS may lead to the recognition of pre-

viously undiagnosed anomalies such as sub-mucous cleft of the palate, developmentaldelay, cardiac anomalies, and hypo-parathyroidism. The mechanism by whichdeletion of the genes in the 22q1 1 region causes

anal anomalies with such a variable clinicalpicture is unknown, but may be related to an

abnormality of mesenchymal cell migration.

We thank the children and their families for their cooperation,our colleagues for referring the cases, and Pixie Maloney andAmir Saguiguit for the photographs. This work was supportedby a National Health and Medical Research Council of AustraliaDevelopmental Grant. We report with regret the untimely death,since this paper was written, of Tony Lipson. We would like to

dedicate this paper to TonyLipson to reflect his enthusiasm andcontribution to the understanding ofVCFS and his dedication tochildren with VCFS and their families.

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