medgenet velocardiofacial (shprintzen) syndrome:...

56 Med Genet 1991; 28: 596-604

Velocardiofacial (Shprintzen) syndrome: an

important syndrome for the dysmorphologist to

recognise

A H Lipson, D Yuille, M Angel, P G Thompson, J G Vandervoord, E J Beckenham

AbstractWe report the dysmorphological, genetic, andspeech therapy aspects of 38 cases of velocar-diofacial syndrome presenting to.a craniofa-cial clinic and a specialised children's hospi-tal, to indicate a relatively low incidence ofclefting, good response to pharyngoplasty,considerable variability of the syndrome, andtwo further familial cases. We emphasise thelow index of suspicion by paediatricians andpaediatric subspecialists which resulted indelayed diagnosis and delayed treatment forthe hypernasal speech and velopharyngealinsufficiency for periods of four months toseven years.

Velocardiofacial syndrome (VCFS) was first delin-eated in 12 children by Shprintzen et al,l thoughStrong2 had described a familial case previously.The features of the syndrome include overt andsubmucous clefting of the palate, cardiac anomalies,particularly of the conotruncal type, hypotonia,myopathic and dysmorphic facies, developmentaldelay and learning difficulties, small stature, velo-pharyngeal insufficiency, and a variety of other

The Cleft Palate Clinic, Genetics and Dysmorphol-ogy Unit, The Children's Hospital, PO Box 34,Camperdown, Sydney, NSW 2050, Australia.A H Lipson

Department of Speech Pathology, The Children'sHospital, Sydney, Australia.D Yuille, M Angel

Department of Plastic Surgery, The Children'sHospital, Sydney, Australia.P G Thompson, J G Vandervoord

Department of Otolaryngology, The Children'sHospital, Sydney, Australia.E J BeckenhamCorrespondence to Dr Lipson.

Received for publication 8 January 1991.Accepted for publication 5 February 1991.

anomalies.13 Patients may manifest overt or subclini-cal features of the Di George anomaly.245 Althoughfamilial cases have been described indicating domin-ant inheritance,3467 a consistent aetiology is notapparent, indicating that the condition may be het-erogeneous in aetiology. The great majority ofpatients have been described from one centre5where it has been reported to be the most commoncause of clefting.'

PatientsOf our 38 patients, 19 were male and 19 female. Arepresentative sample of facial features is shown infigs 1 to 8. The average age of referral was 6 years

Figure I Case 1 aged 5. Referred at the age of 4 withspeech problems from a developmental paediatrician.Hypotonia, undescended testes, mild intellectual impairment,and hypernasal speech. Height 10th centile. Note myopathicfacies, almond shaped palpebral fissures, deficient nasalalae, long narrow nose and prominent nasal bridge, andapparent micrognathia.

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Velocardiofacial (Shprintzen) syndrome: an important syndrome for the dysmorphologist to recognise

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Figure 2 Case 2 aged 4. Cleft of the posterior palate notedat birth and repaired at 9 months. Velopharyngealinsufficiency noted with speech. Hypotonia and learningdifficulties. Height 3rd centile. Note myopathic facies,almond shaped palpebral fissures, underdeveloped ears,deficient nasal alae, long narrow nose, prominent nasalbridge, and apparent maxillary and mandibular hypoplasia.

(range 9 months to 30 years). Ethnic distributionreflected the general population, with the majoritybeing white Caucasians with origins from theUnited Kingdom and Europe. Two were from Chi-nese, three Italian, two Yugoslav, one Greek, andone Lebanese backgrounds.Each patient was evaluated dysmorphologically

and genetically by AHL with a three generationfamily history, a standard questionnaire concerningmedications and other influences during pregnancy,and examination of other family members if appro-priate. All patients with hypernasal speech hadcinefluoroscopy to evaluate palatal length and move-ment. The patients were evaluated over a period of10 years, 1980 to 1990.Speech therapy assessments were performed

when possible before and after pharyngoplasty. As-sessment of the response was made six months aftersurgery and graded as excellent (normal speech,normal tone, no nasal airway escape, normal articu-lation), good (inconsistent nasal airway escape, mildtone discrepancy), fair (no considerable improve-ment in tone but improved intelligibility/articula-tion), poor (only marginal improvement in tone,articulation/intelligibility), and no response (nochange from preoperative status).

Figure 3 Case 3 aged 3f. Referredfrom a neurologist atthe age of 9 months for dysmorphic and genetic assessment.Hypotonia, nasal regurgitation offeeds, submucous cleftpalate, and umbilical hernia. No cardiac anomaly. Height3rd centile. Note subtle facial dysmorphic features.Velopharyngeal insufficiency was confirmed at the age of 3when hypernasal speech was obvious. Learning difficulties.

DysmorphologyCLEFT PALATE (TABLES 1 AND 2)Seven patients had overt and 15 submucous clefts ofthe palate. Two children had associated cleft of thelip with overt cleft of the palate.

CONGENITAL HEART DISEASE (TABLES 2 AND 3)Sixteen patients had congenital heart disease, themost common lesions being tetralogy of Fallot andventricular septal defect. Unusual defects such asvarious hypoplasias of pulmonary arteries, hemi-truncus, and interrupted aortic arch were seen. Onlyone child had a right sided aortic arch, the case withdouble aortic arch and vascular ring (case 28).

ASSOCIATED ANOMALIES (TABLE 4)Nineteen patients had anomalies other than cleftingand congenital heart disease.

TYPICAL FACIESAll patients had the typical face consisting of a longnose with a broad, squared root and deficient alae,narrow alveolar base, flattened malar eminences and

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Lipson, Yuille, Angel, Thompson, Vandervoord, Beckenham

Figure 4 Case 10 aged 15. Chinese parents. Tetralogy ofFallot corrected at the age of 3. Velopharyngealinsufficiency corrected by palatoplasty aged 5. Learningproblems at school needing remedial classes. Normal height.Hypotonia in first years. Now clumsy and poor at sports.Subclinical T cell subset deficiency and hypocalcaemiadetected at the age of 15. Note bulbous nasal tip often notedin mature cases.

small mandible, myopathic facies often associatedwith almond shaped palpebral fissures, and minormalformations and prominence of the auricles. Themouth was often small and open resulting in amisdiagnosis of 'adenoid' facies. A notable feature insome children was small nasal openings. Olderpatients had an appearance of a broad bulbar tip tothe nose.

OTHER FEATURES (TABLE 2)Other features included hypotonia, particularly inthe first years of life, learning difficulties, mild tosevere retardation, small stature, and taperingfingers. Ureteric reflux, hypocalcaemia, T cellanomalies, and abdominal hernias were seen.

VELOPHARYNGEAL INCOMPETENCEAll but one child had velopharyngeal incompetenceas assessed by a speech pathologist or videofluoros-copy or both. The exception was one of sibs (case 24)who was recognised because of the presentation ofhis sib with velopharyngeal incompetence. Hyper-nasal speech coupled with delayed expressivespeech, learning difficulties, retardation, small stat-ure, and secondary psychological overlay caused by

Figure 5 Case 27 aged 5. Submucous cleft of the palaterecognised and repaired at the age of 3. Developmentaldelay and hypotonia. Height between the 3rd and 10thcentiles. Velopharyngeal incompetence confirmed at the ageof 4. Note deficient nasal alae, small open mouth, almondshaped palpebral fissures, underdeveloped ears.

Figure 6 Case 30 aged 3. Diagnosed at 3 months bypaediatrician. Cleft soft palate repaired at 9 months.Perimembranous ventricular septal defect, bilateralcoloboma, hypocalcaemic fit at 3 weeks.?Hypoparathyroidism, small stature (height 3rd centile),and developmental delay.

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I.Figure 7 Case 32 aged 8. Interrupted aortic arch,ventricular septal defect, atrial septal defect.Hypocalcaemic fit aged 3 months. Nasal regurgitation offeeds in first year of life. Submucous cleft of palatediagnosed at the age of 4. Hypotonia. Aged 8, calciumnormal, T cell studies borderline abnormal result. Normalintelligence. Diagnosis of VCFS aged 8 and definitivetreatment of hypernasal speech offered after 4 years ofspeech therapy. Note almond shaped palpebral fissures, longnarrow nose, deficient nasal alae, apparent maxillary andmandibular hypoplasia, and prominent deficient ears.

decreased intelligibility combined to make thespeech very poor in many children. A history ofnasal regurgitation of feeds in the first year of lifewas very prominent in the children who did not havean overt cleft; at least 15 gave such a history. It wasoften misdiagnosed as oesophageal reflux. This set-tled after the first year of life in all cases. Twochildren had started sign language as a method ofcommunication. Both had a good response topharyngoplasty. The children and their familieswere frustrated by the lack of intelligibility and thisoften resulted in social withdrawal. The patientswere uniformally unresponsive to speech therapy,often continuing for some years with no success.

RESPONSE TO PHARYNGOPLASTYTwenty-four had a detailed speech therapy assess-ment at least six months after pharyngoplasty. Ofthese, 15 had an excellent response, four had a goodresponse, four a fair response, and one a poorresponse. Improvement occurred up to four yearsafter operation. No postoperative obstructive sleepapnoea was seen. Many children have not been

Figure 8 Case 38 aged 4j. Referredfrom speech therapistat the age of 4. Hypernasal speech. Submucous cleft palate.Velopharyngeal insufficiency. Note myopathic facies,almond shaped palpebral fissures, deficient nasal alae,maxillary and mandibular hypoplasia. Normal height anddevelopment. Very small nasal and external auditoryopenings.

assessed for this long, so that improvement couldstill occur. The oldest patient operated on was 15-2years when he had the procedure and had a poorresponse. One who was operated on at 14-4 years hada fair response. A strong clinical impression was thatoperation in infancy produced a quicker and betterresponse. In addition, a marked improvement inconfidence, vocabulary, and general ability wasnoted in many children who appeared to be sociallywithdrawn because of their lack of intelligibility.Two children who were using sign language beforeoperation had a good response, with rejection of

Table 1 Major features (n= 38).

No %

Overt cleft palate 7 18Associated with cleft lip 2 5Submucous cleft palate 15 39Congenital heart disease 16 42Other defects 21 55Hypotonia 29 76Learning deficiencies/retardation 31 82Small stature ( < 3rd centile) 24 63Dysmorphic face 38 100Pharyngoplasty 34 89

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Table 3 Congenital heart disease (n= 16).

No Case No

Pulmonary atresia with ventricularseptal defect, both left sided aorticarch 2 19, 34

Ventricular septal defect only 6 2, 14, 17, 18, 26, 30Ventricular septal defect and

hyoplastic pulmonary arteries 1 9Tetralogy of Fallot (one with

hemitruncus, all left sided aorticarch) 3 8, 10, 15

Vascular ring/double aortic arch 1 28Pulmonary stenosis, atrial septal

defect 1 29Interrupted aortic arch (associated

with VSD, ASD 1) 2 32, 33

Table 4 Associated anomalies.

No Case No %

Ureteric reflux 4 7, 19, 21, 23 10Umbilical hernia 2 22, 25 5Inguinal hernia 3 22, 33, 35 8Undescended testes 3 1, 7, 33 8Talipes 4 14, 20, 26, 33 10Hypocalcaemia 1st year 5 5, 30, 32, 33, 34 13Proven hypoparathyroidism 3 5, 33, 34 8Proven T cell deficiency 2 10, 33 5Vertical talus 1 34 3Hypospadias 1 6 3Sprengel's shoulder 1 4 3Hypermetropia 1 38 3Myopia 1 16 3Scoliosis 1 26 3Laryngeal web 1 29 3Bilateral coloboma of iris 1 30 3Bilateral preauricular sinus 1 4 3

signing after operation. Of the remaining cases whohad velopharyngeal incompetence but had not beenoperated on, one was mild and refused operationaged 34 (case 26). One was too retarded and had very

little speech (case 31), two still had to have theprocedure (cases 30 and 36), and one still had to beformally assessed (case 34). The nine remaining whohad pharyngoplasty with some response but no

formal assessment have either been lost to follow upafter reporting initial improvement, or have not hada formal assessment at the time of writing.

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Family historyTwo sibs and a probable twin brother and affectedmother of one patient were seen. The sibs hadnormal parents and normal twin first cousins withclefts of the palate. The second sib was ascertainedbecause of the diagnosis in his sister and response topalatal surgery. He had learning difficulties and

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retardation, hypotonia, myopathic facies, small stat-ure, and typical facies. He did not have velopharyn-geal incompetence. The second familial case was amild to moderately retarded 30 year old man withminimal hypernasal speech, typical facies, and con-genital heart disease, whose twin brother andmother had died of congenital heart disease (causeunknown). These two latter persons were not ex-amined and there are no photographs available. Thisfamilial case is therefore provisional.

PREVIOUS ASSESSMENTS AND TREATMENTEight patients were assessed by developmental pae-diatricians, three by geneticists, and four by paedi-atric neurologists for developmental, speech, anddysmorphic features during infancy and after speechhad started without a specific dysmorphological orspeech diagnosis. Treatment of the hypernasalspeech was delayed for periods ofone to seven years.Most had been treated during this time by speechtherapists on a medical referral with no response.Most had been seen by a paediatrician, or a cardi-ologist, if a cardiac lesion was present, a generalpractitioner, or ENT surgeon in the first years of lifeand before and after speech had started. Two chil-dren had had adenoidectomy because of the confu-sion between hypernasal and hyponasal speech andthe myopathic facies, exacerbating the hypernasalspeech. Two children had had extensive therapy forhypotonic cerebral palsy. Three children had had aprovisional diagnosis of VCFS made before speechstarted, one by a paediatrician at 3 months and twoby the dysmorphologist member of the cleft palateteam at 9 months and 2 years.

REFERRALSOther than referrals by the clinic team, nine childrenwere referred by speech therapists, eight by generalpaediatricians, two by developmental paediatricians,four by ENT surgeons, two by general practitioners,one by a general paediatrician, and one by a school.Two referred by developmental paediatricians andone by a general paediatrician had the diagnosis ofVCFS already made. Others were referred to clinicteam members because of palatal, speech, or dys-morphological problems. Treatment ofan overt cleftat the cleft palate clinic facilitated the diagnosis. Inthe latter part of the study period, clinical presenta-tions by clinic members caused confident referralsfrom speech therapists and developmental paediatri-cians.

DiscussionAlthough the velocardiofacial syndrome (VCFS) hasnow been delineated for over a decade' there is still a

relative paucity of reports from centres not associ-ated with the original reporting institution. Shprint-zen et al"2 have now reported 60 cases from NewYork City, Meinecke et a16 eight cases from Ger-many, Mackenzie-Stepner et al"3 three fromCanada, Stevens et at4 two cases from Salt LakeCity, and Wraith et al30 one case from Great Britain.In Shprintzen's clinic at the Montefiore MedicalCentre, New York City, 8-1% of children withpalatal clefts have VCFS.8 In our clinic, VCFSaccounts for 5% of the palatal cleft population. Thenumber of children has justified the establishment ofa VCFS parent support group over the last 12months. The ethnic background of our population isgenerally the same as North America, with apredominant white Caucasian population from theUnited Kingdom and Europe. Clearly the syndromeis either not recognised or not being reported. Ourexperience supports the former contention. Thecraniofacial and cleft palate clinic where this studywas undertaken serves a statewide population of 5million with 80 000 births per year seeing approxim-ately 90% of craniofacial and clefting disorders.VCFS appears to be very variable with incompleteforms being recognised. Twenty-two (57%) haveeither overt or submucous clefts in contradistinctionto the original reports of Shprintzen et al"3 whichcite up to 100% as having cleft palate. This may beassociated with the definition of submucous cleft atoperation, which has generally been conservative inour clinic. The fact that cardiac disease was uncom-mon, the presence of hypotonia and learning prob-lems inconstant, and a family history rare may havehindered the diagnosis. Shprintzen et all describedthe syndrome in 1978, three years before the firstcase was recognised at our clinic.

Diagnostic evaluation included exclusion of otherchromosomal, teratogenic, and genetic aetiologies.Differential diagnosis includes trichorhinophalan-geal syndrome,'4 Stickler syndrome,'5 the fetal alco-hol syndrome,'6 FG syndrome,'7 and myotonic dys-trophy.'8 The face has many features of a hypotonicor myopathic face and shares characteristics withother syndromes with hypotonia, such as the almondshaped palpebral fissures in Prader-Willi syndrome,the FG syndrome,'7 and even congenital facial para-lysis as seen in Moebius syndrome.'9 No patient wasseen with the Pierre-Robin syndrome though thishas been noted by Shprintzen et al.3

Shprintzen et al3 noted four unaffected motherswho had been given progestational agents during theearly first trimester and one mother was an operatingroom nurse who had been exposed to anaestheticgases during pregnancy. No cases in this series havereported a mother exposed to progestogens or anaes-thetic gases during pregnancy.

Five cases of hypocalcaemia were seen and thishas been reported before.4 Three had proven

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hypoparathyroidism and, of these, two had provenT cell dysfunction. Certainly the Di George se-quence is in the differential diagnosis of this syn-drome; in particular the association of complexcardiac defects of neural crest origin with some ofthe dysmorphic and developmental associations maymean that many reported cases of Di George se-quence may actually have the VCF syndrome.Stevens et a14 reported two families with Di Georgesequence and VCFS. Shimizu et a120 and Radford etal2 studied children with conotruncal congenitalheart disease and a dysmorphic face and found T cellabnormalities in the majority of those tested.Goldberg et a15 and Shprintzen et al"2 reported,among 60 patients with the VCFS, a high incidenceof infections, diminished lymphoid tissue, transienthypocalcaemia in the first year of life, and T cellabnormalities. Williams et al'0 subsequentlyreported a higher incidence of adenoidal hypoplasiain VCFS, which would further accentuate velophar-yngeal insufficiency. The association of dysmorphicfacies, palatal clefts, conotruncal cardiac anomalies,and other anomalies suggestive of VCFS have beenreported by Shimizu et al,20 Rohn et al,22 Kepper etal,23 and Radford.24 Wyse et al"2 noted the associ-ation of conotruncal congenital heart disease withclefts of the lip and palate. Kepper et a"23 and Rohnet a"22 described autosomal dominant transmissionand Shimizu et al20 recognised an affected parent insix of 36 patients with the conotruncal anomaly facesyndrome, which they recognised as probably analo-gous to VCFS.

Recent animal experimental work involving abla-tion of premigratory cranial neural crest has shownthat conotruncal2627 and thymic abnormalities2' mayresult. The cranial neural crest that participatesdirectly in heart development has been mappedusing quail to chick neural crest transfer in ViVO.2627The region called the cardiac neural crest extendsfrom the level of the midotic placode to the caudallimit of somite 3 and migrates into pharyngeal arches3, 4, and 6. These contribute to the development ofthe aortic arch and outflow tracts where they formthe aorticopulmonary septum and populate thetruncal folds. The thymus develops from pharyngealarches 3 and 4 and ablation of the premigratoryneural crest has been shown to result in reduction orabsence of the thymus in the experimental animal.28Abnormalities of neural crest migration are alsoinvolved in the development of the face and palate,including the muscles of the face.29 It is clear thatthere is an embryological basis for the VCFS.Stevens et at4 reported the association of Di Georgesequence and VCFS in two families, indicatingdominant inheritance, and presented data to indicatethat the familial cases of Di George syndromereported by Kepper et a"23 and Rohn et a"22 mayrepresent VCFS transmitted as a dominant trait.

This tends to support dominant inheritance, at leastwhen overt or subtle T cell changes are present.The type of congenital heart disease in our cases

was consistent with a conotruncal classification: vas-cular ring, interrupted aortic arch, hypoplastic pul-monary arteries, hemitruncus, tetralogy of Fallot,and ventricular septal defect. One child had a mus-cular ventricular septal defect, the others weremembranous or supracrystal. Young et al,9 fromShprintzen's clinic, reported 23 cardiac anomalies intheir first 27 cases, including ventricular septal de-fect, tetralogy of Fallot, and right sided aortic arch.No case with a cardiac lesion had a right sided aorticarch except the child with vascular ring (case 16).Truncus arteriosus was seen in case 1 of Stevens etat4 and the illustrations in the articles of Radford24and Shimizu et at20 of facial anomalies with cono-truncal congenital heart disease are very suggestiveof VCFS. The survival of children with severeconotruncal anomalies has improved dramatically inthe last 10 years owing to advances in cardiac sur-gery. The paucity of cases of truncus arteriosus andinterrupted aortic arch in the original series ofYoung et at9 may be because their cases werereported at least 10 years ago, before good survivalof this group was recorded.The family histories in cases 23 and 24 (sibs) and

case 26 (twin brother and mother) are of interest.Unfortunately, no further information is availableon the facial appearance or type of cardiac lesions inthe family of case 26. Dominant inheritance is likely.In the family with sib recurrence (cases 23 and 24),case 24 is an incomplete case only ascertainedbecause of the typical features in his sister. Theparents are normal and there are no other affectedfamily members. This could either indicate germinalmosaicism in a normal parent or recessive inherit-ance. The twin cousins of this case have cleft palateand are reported to be of normal height and intelli-gence and without dysmorphic features or otheranomalies. Several other familial cases have beenreported indicating dominant inheritance withtransmission from parent to child, including male tomale transmission by Williams et al,7 four familiesby Shprintzen et al,3 two families by Meinecke et al,6six by Shimizu et al,20 and two by Stevens et al.4Wraith et at30 reported a mother with tetralogy ofFallot and velocardiofacial syndrome having off-spring with tetralogy of Fallot and holoprosenceph-aly. This case must be considered as doubtful as themother's features, especially the absence or presenceof velopharyngeal incompetence, are not well docu-mented. No chromosomal anomalies have beenshown to be associated. No common environmentalagent or teratogen has been noted. It is likely thatthere is heterogeneity in the causes of VCFS andnon-genetic phenocopies to account for at least some

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of the other patients, and counselling should takethis into account.The cause of the severely hypernasal speech is

probably multifactorial, including pharyngeal hypo-tonia readily seen on videofluoroscopy, increasedpharyngeal width associated with platybasia,increased distance between the pterygoid plates,9and adenoidal hypoplasia.'0 A standard repair of anovert or submucous cleft was never adequate toprevent velopharyngeal insufficiency.The study of Arvystas and Shprintzen"3 reported

cephalometric evidence of platybasia indicating thatthe facial features of retrognathia, malar deficiency,and prominence of the nasal root may be not prim-ary but secondary to this feature. They wonderedwhether landmarks at the cranial base could bealtered by abnormally weak muscular forces in thenasopharynx, and posed a hypothesis that the cranialand facial findings of the syndrome could merely besecondary to neurogenic muscular weakness of apre- and postnatal time course. Almond shaped eyesare seen in other muscular hypotonic syndromesaffecting the face, such as the Prader-Willi and FGsyndromes and myotonic dystrophy. The associ-ation of inguinal and umbilical hernias, and perhapseven vesicoureteric reflux, may be further indicationfor a secondary effect of muscular deficiency.Talipes was seen in four patients, but none requiredoperative reduction. This may result from intrauter-ine deformation secondary to hypotonia, which isself-corrective after birth. Hypotonia of the mand-ible and tongue could cause retrognathia and pro-lapse of the tongue into the posterior pharynx,obstructing palate closure and resulting in a Ushaped posterior cleft palate. Hypotonia of the pala-topharyngeal structures in utero may give rise tosubmucous clefts of the palate and incomplete inser-tion of muscular fibres.

Studies of the cleft palate population have shownthat children with clefts tend to be smaller thanthose without,'2 suggesting nutritional deprivationas infants. These studies all assume that such apopulation was homogeneous when it has now beenshown to be highly heterogeneous by studies such asthat by Shprintzen et al.8 However, it is now likelythat these children, in fact, have syndromes such asthe velocardiofacial syndrome.The relative commonness of this syndrome in the

population of children with clefts and speech prob-lems seems at variance with an apparent failure todiagnose this dysmorphological syndrome. Under-diagnosis by therapists and paediatric subspecialistsoften resulted in prolonged and fruitless speechtherapy and the inadvertent withholding of a quiteeffective treatment of the hypernasal speech bypharyngeal surgery. There was no response tospeech therapy in any child until after pharyngo-plasty. Although the cause and definitive treatment

of VCFS may elude us in the majority of cases,surgery, speech therapy, developmental treatment,and genetic counselling provide a good quality of lifefor these children and their families. Diagnosisshould be considered in any child with a conotruncalcardiac anomaly, particularly if associated with cleft-ing, Di George sequence, or hypoparathyroidism.Nasal regurgitation of feeds in the first year of life,poor growth, hypotonia, and later developmentalproblems, as well as facial dysmorphism, should givea high index of suspicion of a diagnosis of VCFS.The children in whom the diagnosis is suspectedshould be followed carefully until speech starts as itis then that a functional palatal problem may first beevident, even if a cleft palate has been repairedpreviously. Expressive speech delay was commonand tended to delay the diagnosis. Facial dysmor-phism may also not be obvious in the first years oflife. There are subtle changes in the facial appear-ance with age, with the teenage and adult patientsdeveloping a bulbar and broad tip to the nose. Otherreports of adults have a similar bulbar nasal tip, suchas in case 7 of Meinecke et al.6 The absence ofcardiac disease should not deter the clinician from adiagnosis of VCFS. Only 42% of our cases hadcongenital heart disease. Differences in this seriesfrom those previously published"'32 included ab-sence of the Pierre-Robin sequence and the associ-ation of cleft lip in two cases and ureteric reflux infour cases. All those with ureteric reflux requiredantireflux surgery, though there was no associatedrenal malformation or damage. We did see cases oflaryngeal web, scoliosis, abdominal hernias, andundescended testes which have all been describedbefore. Genetic counselling should be approachedon a patient by patient basis and should includeexamination of other family members and studies ofT cell function. Abnormalities in T cell subsets andhypoparathyroidism may indicate a dominant in-heritance pattern,4 though this was not recognised infamilies of such children in this series. Manypatients with the Di George sequence may have theVCFS. Confident counselling of dominant inherit-ance in every case would presuppose an exception-ally high spontaneous mutation rate, which is unlik-ely. The known association of Di George sequencewith chromosomal anomalies, such as deletion of thelong arm of chromosome 22,33-3" and teratogenicinsults, such as ethanol36 and retinoic acid,'3739 maymean that monogenic VCFS probably accounts foronly a proportion of the total cases. However, atpresent no chromosomal or teratogenic associationwith VCFS has been described, although the over-lap with the fetal alcohol syndrome has been notedbefore.29

We wish to thank Miss Michelle Giaquinto andAnne Lyon for secretarial assistance, Lyndal Le Bas

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for case finding, our colleagues for referring theircases, and the families and children with VCFS fortheir cooperation.

1 Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syn-

drome involving cleft palate, cardiac anomalies, typical faciesand learning disabilities. Velo-cardio-facial syndrome. CleftPalate 1978;15:56-62.

2 Strong WB. Familial syndrome of right-sided aortic arch,mental deficiency and facial dysmorphism. Jf Pediatr1968;73:882-8.

3 Shprintzen RJ, Goldberg RB, Young D, Walford L. The velo-cardio-facial syndrome: a clinical and genetic analysis. Pedia-trics 1981;67:167-72.

4 Stevens CA, Carey JC, Shigeoka AO. Di George anomaly andvelocardiofacial syndrome. Pediatrics 1990;85:526-30.

5 Goldberg R, Marion R, Borderon M. Phenotypic overlapbetween velo-cardio-facial syndrome and Di George se-

quence. Am Hum Genet 1985;37:54A.6 Meinecke A, Beeomer FA, Schinzel A, Kushnick T. The velo-

cardio-facial (Shprintzen) syndrome. Eur Pediatr1986;145:539-44.

7 Williams MA, Shprintzen RJ, Goldberg RB. Male to maletransmission of the velo-cardio-facial syndrome: a case reportand review of 60 cases. J7 Craniofac Genet Dev Biol1985;5:175-80.

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