9JMed Genet 1997;34:798-804

Spectrum of clinical features associated withinterstitial chromosome 22ql 1 deletions: a

European collaborative study

Department ofHumanGenetics, University ofNewcastle upon Tyne,19/20 Claremont Place,Newcastle upon TyneNE2 4AA, UKA K RyanJ A GoodshipD I Wilson

Centre De GenetiqueMedicale, Marseille,FranceN PhilipA Levy

Abteilung PadiatrischeGenetik,Kinderpolidlinik,LMU, Munchen,GermanyH SeidelS Schuffenhauer

Kinderklink,DeutschesHerzzentrum, TU,Munchen, GermanyH Oechsler

Dr von HaunerschenKinderspital, LMU,Munchen, GermanyB Belohradsky

Hopital des EnfantsMalades, Paris, FranceM Prieur

Institut Curie, Paris,FranceA Aurias

S E Thames RegionalGenetics Centre, Guy'sHospital, London, UKF L Raymond

Department ofMedical Genetics, StMary's Hospital,Manchester, UKJ Clayton-Smith

Wessex ClinicalGenetics Service,Princess AnneHospital,Southampton, UKE Hatchwell

Clinical Genetics Unit,Birmingham Women'sHospital,Birmingham, UKC McKeown

Clinical GeneticsCentre, Utrecht, TheNetherlandsF A Beemer

A K Ryan, J A Goodship, D I Wilson, N Philip, A Levy, H Seidel, S Schuffenhauer,H Oechsler, B Belohradsky, M Prieur, A Aurias, F L Raymond, J Clayton-Smith,E Hatchwell, C McKeown, F A Beemer, B Dallapiccola, G Novelli, J A Hurst, J Ignatius,A J Green, R M Winter, L Brueton, K Br0ndum-Nielsen, F Stewart, T Van Essen,M Patton, J Paterson, P J Scambler

AbstractWe present clinical data on 558 patientswith deletions within the DiGeorge syn-

drome critical region of chromosome22qll. Twenty-eight percent of the cases

where parents had been tested had inher-ited deletions, with a marked excess ofmaternally inherited deletions (maternal61, paternal 18). Eight percent of thepatients had died, over half ofthese withina month ofbirth and the majority within 6months. All but one of the deaths were theresult of congenital heart disease. Clini-cally significant immunological problemswere very uncommon. Nine percent ofpatients had cleft palate and 32% hadvelopharyngeal insufficiency, 60% of pa-

tients were hypocalcaemic, 75% of pa-

tients had cardiac problems, and 36% ofpatients who had abdominal ultrasoundhad a renal abnormality. Sixty-two per-

cent of surviving patients were develop-mentally normal or had only mildlearning problems. The majority of pa-

tients were constitutionally small, with36% of patients below the 3rd centile foreither height or weight parameters.(JMed Genet 1997;34:798-804)

Keywords: DiGeorge syndrome; velocardiofacial syn-

drome; chromosome 22ql 1 deletion

It is now well documented that the majority ofcases of DiGeorge syndrome (DGS) and velo-cardiofacial syndrome (VCFS) result fromdeletions within chromosome band 22q1 1.There have been good reviews of each of thesesyndromes'3 and many case reports drawingattention to new clinical features.47 The

acronym "CATCH 22" (Cardiac, Abnormalfacies, Thymic hypoplasia, Cleft palate, andHypocalcaemia resulting from 22ql 1 dele-tions) has been proposed to describe thephenotype. There is wide variability in theclinical spectrum, ranging from problems lead-ing to death in the neonatal period to presenta-tion with isolated hypernasal speech or tran-

sient hypoparathyroidism."'0 However, it hasbeen difficult to glean figures for general coun-

selling from published reports. There is a

tendency to report atypical cases and publishedseries have been ascertained according to theauthors' speciality." 12 Even the largest of the

published series are still too small to providereliable data for counselling. We have com-bined data from 23 European centres in anattempt to decrease ascertainment bias and toincrease the clinical information on whichmanagement and counselling can be based.

Data collectionParticipating centres from Europe were sentdata questionnaires relating to cases of provendeletions within chromosome band 22ql 1.The probes and microsatellite markers usedvaried between centres but all mapped withinthe DGS region.2 Centres were asked to sendinformation on all their cases, whether previ-ously published or not. The data for all UKcentres was collected by one person (AR) whoalso entered information into the databasefrom the returned questionnaires. Data wererequested on heart, palate, renal, and thymusabnormalities, parathyroid function, growth,developmental status, behaviour, and psychiat-ric illness. All available patient information wasentered into an anonymous central database.Some questionnaires did not provide infor-mation on all sections, for example, the heartsection was completed in more questionnairesthan the renal section. Hence, the total numberof patients for which data were recorded isspecified in each section of the results.

Patient dataA total of 558 patients were included in thestudy. In 399 patients, sex was recorded. Ofthese, 197 (49.4%) were male and 202(50.6%) were female. Excluding the 10 fetuseson which postmortem details were given, ageswere available in 534 patients and ranged frombirth to 51 years: 286/534 (54%) were aged 0-5years, 115 (22%) were aged 6-10 years, 72(13%) were aged 11-17 years, and 61 (11%)were aged 18 years and over. The averagematernal and paternal ages at birth were 27.5and 30.4 years, respectively.

All the people in the study had a deletionwithin chromosome band 22ql 1, detected byeither fluorescent in situ hybridisation (FISH)or by use of microsatellite polymorphismsmapping within the DGS region. The majorityof patients were tested with only one probe.Therefore, no conclusions can be drawnbetween the size of the deletion and phenotype.

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Spectrum of clinicalfeatures associated with interstitial chromosome 22ql 1 deletions

Universita "TorVergata", Rome, ItalyB DallapiccolaG Novelli

Department of ClinicalGenetics, Oxford, UKJ A Hurst

Department ofMedicalGenetics, Vaestoliitto,The Family Federationof Finland, Helsinki,FinlandJ Ignatius

Department ofMedicalGenetics, Addenbrook'sNHS Trust, Cambridge,UKA J Green

Institute of ChildHealth, London, UKR M WinterP J Scambler

The Kennedy GaltonCentre, Middlesex, UKL Brueton

The John F KennedyInstitute, Glostrup,DenmarkK Brondum-Nielsen

Northern IrelandRegional GeneticsCentre, Belfast,Northern IrelandF Stewart

Department ofMedicalGenetics, Groningen,The NetherlandsT Van Essen

Department ofMedicalGenetics, St George'sHospital MedicalSchool, London, UKM Patton

Duncan GuthrieInstitute ofMedicalGenetics, Glasgow, UKJ Paterson

Correspondence to:Dr Ryan.

Received 5 December 1996Revised version accepted forpublication 17 April 1997

Table 1 Origin of deletions of285 patients whose parentswere also testedfor deletions

Parent of origin Paternal MaternalNo unknown origin origin

De novo 204 167 24 13Inherited 81 2 18 61

For 285 patients, information regarding paren-tal deletion status was available. For 204/285(72%) patients, both parents were not deletedand therefore these patients had de novo dele-tions (table 1). Parent of origin de novodeletions were determined in 37/204- (18%)patients using three microsatellite markers,D22S264, D22S944, and D22S941. Therewere no unexplained bands that would haveraised the suspicion of non-paternity. De novodeletions of the paternally derived chromo-some 22 (24) exceeded those from thematernally derived chromosome (13). Inher-ited deletions occurred in 81/285 (28%). Forthe 81 patients with inherited deletions, the sexof the deleted parent was given in 79 cases.Inherited maternal deletions (61) far out-weighed paternal deletions (18). In this group,there were 13 sib pairs, nine with maternaldeletions and four with paternal deletions. Inthe majority of patients with inherited dele-tions, no information was given regardingwhether the normal parent was tested in addi-tion to the deleted parent. In 253 patients,neither parent was tested. There were 20 caseswhere only one parent had been tested and thatparent was not deleted (18 maternal, twopaternal).

NEONATAL DETAILSBirth weight, gestation, and sex were availablefor 205 patients. A total of 31/205 (15%) ofbabies were born before 37 weeks' gestation.Although 172/205 (84%) of babies were bornwithin the normal weight range (between the3rd and 97th centiles), 147/205 (72%) hadbirth weights less than the 50th centile and32/205 (16%) were below the 3rd centile.Average birth weight was 2960 g at 38 weeksfor males and 2760 g at 38 weeks for females.Neonatal problems included feeding difficul-ties, often related to palatal abnormalities,complications secondary to CHD, and seizuressecondary to hypocalcaemia.

GROWTHGrowth data (sex, height, weight, head circum-ference) were available in 158 patients (table2). Growth retardation was common; 131/158(83%) of patients had heights/weights less thanthe 50th centile, and 57/158 (36%) were belowthe 3rd centile for either height or weightparameters. In the few cases where there was adiscrepancy between height and weight para-meters, the height measurement was used;46/120 (38%) of patients with congenital heartdisease (CHD) were below the 3rd centile foreither height or weight compared to 11/38(29%) of patients without CHD. This was notstatistically significant. Head circumferencemeasures were in keeping with those for heightand weight.

Table 2 Comparison ofgrowth parameters in 158 childrenwith and without significant cardiac disease

Congenital heartNormal hearts disease

Total 38 120<75% ht/wt 36 (95%) 115 (96%)<50% ht/wt 27 (71%) 104 (87%)<25% ht/wt 19 (50%) 67 (56%)<3% ht/wt 11 (29%) 46 (38%)

SURVIVALForty-four patients (8%) had died, but the ageof death was not given for 15 of these. Of theremaining 29 patients, 16/29 (55%) diedwithin one month, and 25/29 (86%) had diedwithin six months, as a consequence of CHD.There was one death from severe immune defi-ciency.

DEVELOPMENT AND BEHAVIOURInformation on developmental status was givenfor 363 patients, but 25 children less than 1year of age were excluded from analysis as wefelt they were too young to exclude mild motorand language delay (table 3); 107/338 (32%)were reported to be developmentally normal,although 37 of these had speech delay and231/338 (68%) had abnormal developmentalprogress, with severity of delay not recorded in69/338 (20%) patients. One hundred and twopatients had mild delay. Therefore, 209/338patients (62%) were either normal or had onlymild learning problems and 60/338 (18%) ofpatients had either moderate or severe learningdifficulties.Of the 252 children aged between 3 and 18

years in our study, 22 (9%) were reported tohave either behavioural or psychiatric prob-lems. This included 13 with behavioural prob-lems, six with attention deficit disorder, twowith psychosis, and one with mood changes.There were 61 adults (aged >= 18 years) in ourseries and 11/61 (18%) had a psychiatricdisorder. This included 4/61 patients (6.5%)who had had at least one episode of psychosis,three patients had a neurotic illness, and fourhad unspecified psychiatric problems.

CONGENITAL HEART DISEASEIn 545 patients, cardiac status was recorded.Patients with more than one structural abnor-mality were grouped under their most clinicallysignificant cardiac abnormality, unless theheart was of very complex arrangement (table4).One hundred and ten patients had normal

hearts by clinical examination or echocardio-gram or both. A further 26 patients hadclinically insignificant heart abnormalities,which included five aberrant subclavian arter-ies and five right sided aortic arches. Therefore,136/545 patients (25%) had no cardiac compli-cations and 409/545 patients (75%) hadsignificant cardiac pathology. The group of"other significant abnormalities" includeddouble aortic arch (2), absent pulmonary valve(2), aortic valve stenosis (1), aortic valve hypo-plasia (1), coarctation of the aorta (4), doubleoutlet right ventricle (4), atrial isomerism (1),left hypoplastic heart (1), patent ductus

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Table 3 Development of children and adults (n=338)

Normal=107 (32%)Normal motor and speech development 70 21Normal motor development with speech delay 37 11

Abnormal=231 (68%)Mild motor development delay 102 30Moderate motor development delay 51 15Severe motor development delay 9 3Unknown degree of developmental delay 69 20

Table 4 The spectrum of heart defects seen in 545 patients

No %

Normal 110 20Other clinically non-significant 26 5Tetralogy of Fallot 95 17Ventricular septal defect 75 14Interrupted aortic arch 74 14Pulmonary atresia/ventricular septal defect 55 10Truncus arteriosis 51 9Pulmonary valve stenosis 13 2Atrial septal defect 8 1Atrioventricular septal defect 5 <1Transposition of great arteries 4 <1Complex heart disease 3 <1Other significant abnormalities 26 5

arteriosis (7), tricuspid valve hypoplasia (1),and unspecified CHD which required opera-tion (2).

OTOLARYNGEAL ABNORMALITIESA total of 242/496 (49%) patients hadotolaryngeal abnormalities (table 5). Seventy-two patients had either an overt cleft palate(hard/soft) or submucous cleft. Cleft lip waspresent in four patients; two had bilateral cleftlip and palate and two had isolated cleft lip; 161patients had velopharyngeal insufficiency(VPI) without a cleft.Data on hearing were available in only 159

patients; 52/159 (33%) had abnormal hearingand 107/159 had normal hearing (67%). Of the52 patients with documented hearing loss therewere no further details for 35 cases. In theremaining 17 cases the hearing loss wasconductive and most of these patients hadpalatal abnormalities or recurrent otitis mediaor both.

GENITOURINARY ABNORMALITIESRenal information was given for 136 patients.Abnormalities were present in 49/136 (36%)patients, including absent, dysplastic, or multi-cystic kidneys (23), obstructive abnormalities(14), vesicoureteric reflux (6), nephrocalcinosis(1), duplex kidney (1), and unspecified anoma-lies (4).

Sixteen males had undescended testes (8%of total males). The gestation at birth was givenfor 13 and only two of them were born prema-

Table 5 The spectrum of otolaryngeal complications in496 patients

No %

Cleft palate (hard/soft) ± VPI 45 9Submucous cleft 25 5Velopharyngeal insufficiency 161 32Recurrent glue ear/grommets 11 2Tracheomalacia/laryngomalacia 9 2Laryngeal web 6 1Choanal stenosis/atresia 5 1Other 13 3

turely at 36 weeks' gestation. Six males had asmall penis, three had hypospadias, and onehad a shawl scrotum.

PARATHYROID FUNCTIONThe parathyroid function and calcium statuswas recorded for 340 patients; 203/340 (60%)had been hypocalcaemic. Of the 108/203hypocalcaemic patients whose seizure historywas documented, 42/108 (39%) had seizuressecondary to hypocalcaemia. Where infor-mation was available, the majority of patientsresponded well to calcium supplements, withcessation of seizures. Although most patientswere hypocalcaemic in the neonatal period,several patients were first known to behypocalcaemic in childhood and one patientpresented at 18 years of age. The hypocalcae-mia resolved in 45/64 (70%) patients and theremainder continue on calcium supplements.

NEUROLOGICAL ABNORMALITIESNeurological details were available for 548patients and 44/548 (8%) had neurologicalabnormalities. Sixteen patients (3%) had struc-tural brain abnormality, consisting of cerebralatrophy (7), cerebellar hypoplasia (2), cerebralvascular abnormality (1), septum pellucidumcyst (2), hydrocephalus (2), hypoplastic corpuscallosum (1), and enlarged ventricles (1).Eleven patients had asymmetrical crying facies(Cayler syndrome), three had 7th cranial nervepalsies, and two had facial asymmetry. Onepatient, who had had cardiac surgery, had aparalysed hemidiaphragm.

Seizure information was available in 290patients; 62/290 (21%) had seizures and in 42patients these were hypocalcaemic in origin. Ofthe other 20 patients, seven were normocalcae-mic and in 13 calcium status was unknown.The aetiology of seizures in these 20 patientswere unspecified (1 1), febrile convulsions (6),structural malformations (2), and hyponatrae-mia (1).

IMMUNE STATUSData on immune function were given for 263patients, although details were incomplete inmany cases (table 6). Patients' white cell count,lymphocyte count, T cell numbers, and clinicalhistory of infections were reviewed. Thelaboratory data were classified into threegroups: major abnormality, minor abnormality,or normal. Those cases in which a clinical his-tory of frequent infections was not recordedwere assumed to be clinically normal. Where apatient was reported as having frequentinfections (usually of the upper respiratorytract), this was classified as clinically signifi-cant. Two patients with severe immune defi-ciency had died, this being the cause of death inone patient. Presence or absence of the thymusas noted at operation or necropsy was alsorecorded.

OTHER ABNORMALITIESA total of 94/548 (17%) patients had minorabnormalities of the skeletal system (table 7).Talipes equinovarus and general bone abnor-malities were the most frequently seen abnor-

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Table 6 Laboratory and clinical immune and thymusstatus in 218 patients

Clinical history of infectionAbsent

Laboratory result thymus - +

Major abnormality 1 1 2Minor abnormality 30 132 10Normal 6 70 3

Table 7 Range of skeletal abnormalities in 548 patients

No %

Talipes equinovarus 22 4Other abnormal bones 22 4Scoliosis 15 3Abnormal vertebrae 8 1Polydactyly 7 1Syndactyly 6 1Craniosynostosis 5 < 1Other 1 < 1

malities, present in 22 patients (4%) each, and39/548 (7%) patients had ocular anomalies.Fourteen patients had abnormal teeth, consist-ing primarily of poor tooth enamel and excessdental caries. Ten patients (2%) had analabnormalities, consisting of anal atresia (2),imperforate anus (3), anteriorly placed anus(2), Hirschsprung disease (2), and constipation(1). Other abnormalities consisted of colo-boma (4), hypothyroidism (4), pigmentaryabnormalities (2), idiopathic thrombocyto-penic purpura (2), and many other isolatedstructural abnormalities (not listed). While themajority of patients were said to be dysmor-phic, there was marked variation, which isshown in fig 1. The mother and son in fig 1Ahave very subtle dysmorphic features while themother and son in fig 1B, C, and D have thetypical facies. We have made no attempt toanalyse these dysmorphic features in detail.

COMPARISON OF PHENOTYPE WITHIN FAMILIESParent-offspring comparisonTwenty-seven parents with interstitial deletionsof chromosome band 22ql 1 had 35 deletedoffspring. Twenty parents had one affectedchild, six had two affected children, and onehad three affected children. The cardiac defect,palatal abnormality, and developmental statuswere compared between child and deleted par-ent when information was available for both.CHD was more severe in 27/35 (77%) of chil-dren compared to their parents, and of thesame degree of severity in 8/35 (23%). In nocase was the child's CHD less severe than his/her parents. Developmental status was better in1/17 (6%), the same in 7/17 (41%), and worsein 9/17 (53%). In eight of the nine cases wheredevelopmental status was worse, the delay inthe child was mild, and in one case the delaywas moderate. The palatal abnormalities werebetter in 10/22 (45%) children and similar tothe parent's in 12/22 (55%) children.

Sibship comparisonIn addition to the seven sibships describedabove, there were five sibships for whom therewas no parental information (four with twoaffected children and one with three affectedchildren). In these 26 sibs from 12 families,

there was considerable variation in heartabnormalities between sibs. For example, inthree sibships, one child had a normal heartand the other sib had significant CHD. Withinthe sibships where all affected children hadCHD there was variability in severity; forexample, one sibship of three children hadventricular septal defect, coarctation of theaorta, and interrupted aortic arch type B,'3 andanother sibship had two children with patentductus arteriosis (not related to prematurity)and one with transposition of the great arteries,atrial septal defect, and dextrocardia. Develop-mental status was similar for sibs in all but onecase, where there was a marked difference; onesib required minimal help with schooling com-pared to her brother who had severe develop-mental delay. This sib pair are not in theparent/child group as there was no informationavailable on their parents.

DiscussionThe aim of this study was to provide data onwhich to base answers to questions in clinicalpractice, for example, the prognosis for chil-dren with a deletion within chromosome band22ql 1 or the outlook following prenataldiagnosis. Clinicians from 23 European centreswere sent a standard questionnaire which theycompleted after review of the patient or theirnotes. Usually the questionnaires were com-pleted from notes held at the genetic centreswhere the laboratory diagnosis of the deletionwas made. Often, no information was availablefor one or more sections of the questionnaireand this is reflected in the wide variation inpatient numbers for the different sections'results. Absent data may mean that the testshad not been done or simply that the resultswere not available. For example, it is likely thatmost children will have had white cell countsthough these were not recorded in half of thequestionnaires. In contrast, we suspect that theabsent data in the renal section is because alower proportion ofchildren will have had renalultrasound. Unfortunately there is no way ofdistinguishing between these two situations forthe data gathered. Missing data and paucity ofclinical detail in some of the sections, forexample, the behaviour and psychiatric sec-tions, are disadvantages of the questionnaireapproach. However, the large amount of datacollected will be useful in counselling situa-tions.The proportion of inherited deletions within

this series was 28%, stressing the importance ofstudying both parents when a child is found tohave a deletion. However, it is possible thatsome of these parents were tested because ofclinical suspicion and that the proportion ofinherited deletions would have been lower hadall parents been tested. Of the 81 patients withan inherited deletion, there was a large mater-nal origin excess (61 maternal, 18 paternal).

In the majority of cases where the deletionwas known to be de novo, the informationcame from FISH analysis and the parent oforigin was not known. Of the 37 patients forwhom parent of origin studies had been carriedout, there was a paternal excess (24 paternal,

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Figure 1 This figure shows two affected mothers and their affected sons. The mother and son in (A) have very subtledysmorphic features, while the mother and son in (B), (C), and (D) have more typicalfeatures, including small mouth,nose with bulbous tip, hypertelorism, and low set, simple ears.

13 maternal). In contrast, Demczuk et al,'combining their data with previous reports,found an excess of deletions of maternal origin(eight paternal, 24 maternal). Four cases (twopaternal, two maternal) are in both series.When we pool data from this and the series ofDemczuk et al,3 counting those four patientsonly once, there are 30 maternal and 35 pater-nal deletions. We conclude that there is not amajor difference between parent of origin of denovo deletions.Although most babies were born within the

normal size range, 33/205 (16%) are less thanthe 3rd and 147/205 (72%) are less than the50th centile. This suggests there is an intrinsicproblem causing growth retardation. For themajority of patients in the study we have birthweight and one set of subsequent childhoodmeasurements, with serial information avail-able on very few. Such data could be recordedon this database prospectively. The childhood

measurements were frequently on a lower cen-tile than birth weight, with 57/158 (36%) <3rdand 131/158 (83%) <50th centile. This mayberelated to feeding problems in the neonatalperiod or CHD. Recurrent infection is unlikelyto play a role as this was a complication in onlya small number of patients. Comparing thesubgroups of patients with/without significantheart disease, 46/120 (38%) were <3rd versus11/38 (29%), suggesting that, while CHD maycontribute to growth failure, it is not the soleexplanation and that these children are consti-tutionally small.From the completed questionnaires, 209/

338 patients (62%) had either normal develop-ment or mild learning problems and 60/338(18%) had moderate or severe learning prob-lems. However, for 69/338 (20%) developmen-tal status was unknown. It seems likely thatpatients with mild learning problems accountfor more of these "unknown" cases than

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children with significant learning problems, asthese would almost certainly have been re-corded.A total of 6.5% of adults had at least one

episode of psychosis, a figure which is lowerthan recent papers4"15 would suggest. Thiscompares to a baseline population prevalenceof psychosis in 5% of the adult population.'6 Itis generally accepted that the percentage ofpsychosis in the learning disabled population ishigher than in the general population but it isdifficult to find a reliable figure. There was lit-tle detail about the psychiatric and behaviouralproblems in children or adults, highlightingthis as an area in which more detailed studiesare required.The spectrum of heart defects seen in the

study is similar to that previously reported,affecting predominantly both right and leftoutflow tracts. This is consistent with thehypothesis that the abnormal development issecondary to aberrant migration of neural crestinto the branchial arches and outflow septumof the heart. It is of interest, however, that a fewpeople had defects of structures that arethought not to be derived from the outflowtract, for instance, atrioventricular septal de-fect, atrial septal defect, and isomerism. All butone of the 44 deaths in our series were theresult of CHD; death usually occurred withinthe first month (55%) and in the majority(86%) within six months. The study alsoprovides an estimate of the proportion of sub-jects with deletions within chromosome band22ql l who do not have cardiac problems(25%). Included in the group of defects thatwere clinically insignificant were those childrenwith isolated aberrant right or left subclavianartery and a right sided aortic arch. These werealso found in association with other heartdefects (for example, interrupted aortic arch orpulmonary atresia/ventricular septal defect).The presence of such defects has considerablediagnostic importance as they represent evi-dence ofabnormal outflow tract/branchial archartery development and should alert a clinicianto the possible diagnosis of 22ql 1 deletion.

Renal abnormalities were a frequent finding,present in 49/136 (36%) of patients. Many ofthese abnormalities require surgical or medicalintervention to prevent complications such ashypertension and renal nephropathy. The highfrequency of renal abnormalities suggests thatrenal ultrasounds should be a standard part ofthe investigations of these patients. Anothergenitourinary abnormality requiring surgicalintervention is undescended testes, present in8% of males.Hypocalcaemia was present in 203/340

(60%) of our patients, and was generally asso-ciated with presentation in the neonatal period.However, several patients presented with hy-pocalcaemia in childhood and one patient pre-sented at the age of 18 years. In this group, it isnot clear whether samples were taken followinga seizure or for some other reason. Neonatalcalcium measurements were not available forany of these children. The hypocalcaemia hadresolved in 45/64 (70%) of patients. In thepatients remaining on calcium supplements, it

was not known if parathyroid function hadbeen reassessed.The original description of the syndrome by

DiGeorge" was of a child with hypoparathy-roidism and recurrent infections and necropsyfindings of three cases of absent thymus andparathyroid glands. Paediatric textbooks em-phasise these aspects of the syndrome. How-ever, in this large series of patients withdeletions within chromosome 22ql 1, onlythree children had severe immunodeficiency,one previously reported by Wilson et al.'8 Evenin those cases where the thymus was absent orwhere there were abnormal laboratory results,clinically significant immunological problemswere uncommon.Asymmetrical crying face has been reported

previously as a common complication ofpatients with 22qll deletions,6 but was re-ported in only 11 patients from four centres inthis study. Either this is not as common as sug-gested or it is under-reported. All of thefeatures of CHARGE association (Coloboma,Heart defects, Atresia choanae, Retardedgrowth and development, Genital hypoplasia,Ear anomalies), including facial asymmetryand facial nerve palsy, occur in this series ofpatients who have deletions within chromo-some band 22ql 1. Cerebellar hypoplasia hasbeen reported once before4 and there were twonew cases in this series; it has been suggestedthat some cases of the 3C (craniocerebellocar-diac) syndrome may in fact have deletionswithin chromosome band 22ql 1. This serieshas confirmed the previous case reportssuggesting that polydactyly,' craniosynostosis,'9and anal anomalies20 occur with this deletion,these being present in 1 to 2% of patients.The parent group had less severe cardiac and

developmental problems than the group as awhole. One interpretation of this is that theyrepresent the phenotypic spectrum associatedwith the deletion better than the overall groupand that there are many people in the commu-nity who have not come to medical attention ormay be receiving some medical care, yet arenot recognised as having a deletion withinchromosome band 22ql 1. An alternativeinterpretation is that the milder end of thespectrum is more likely to reproduce. Perhapsthe true spectrum lies somewhere between thetwo groups. In this series heart defects werealways more severe in the children than in theparents. However, there has been one report ofa child with a heart defect less severe than heraffected mother.2' Developmental status wasbetter in one, similar in seven, and worse innine of the 17 cases. The palatal abnormalitieswere less severe in 10 of the children and simi-lar to their parents in 12. The cardiac and pala-tal status, and development of these childrenare similar to the whole group. We suspect thatthe child-parent differences observed are be-cause people with more representative heartdefects and with moderate and severe mentalhandicap are less likely to have children of theirown. Considerable variability was observedbetween sibs.Most of the clinical findings in this study

reflect previous reports. However, from previ-

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ous descriptions one would have expectedimmunological problems to be common butthis was not the case. In contrast, renalproblems were common, being present in 36%of those who had had abdominal ultrasound.This investigation should clearly be a routineinvestigation in these patients. Constitutionalshort stature has not been emphasised beforebut is part of the phenotype associated with thisdeletion. This study highlights the need forfurther investigation in some areas, especiallythat of behavioural and psychiatric complica-tions. Twenty-eight percent of patients haveinherited deletions, emphasising the need forstudying both parents when a child is found tohave a deletion.

We would like to thank Tina Buchholz (Miunchen), the manyclinicians and scientists who are not coauthors but haveprovided patient information, and the subjects and familiesincluded in this study for their help and cooperation. This workhas been supported by the Hemizygosity of Chromosome22ql 1 and Human Birth Defects grant, GENE-CT93 0053, theDanish Medical Research Council, and Italian Telethon,contract NE.399 to BD.

1 Lipson AH, Yuille D, Angel M, et al. Velocardiofacial(Shprintzen) syndrome: an important syndrome for thedysmorphologist to recognise. _7 Med Genet 1991;28:596-604.

2 Demczuk S, Aurias A. DiGeorge syndrome and related syn-dromes associated with 22ql 1.2 deletions. A review. AnnGenet (Paris) 1995;38:59-76.

3 Wilson DI, Burn J, Scambler P, Goodship J. DiGeorgesyndrome: part of CATCH 22. 7 Med Genet 1993;30:852-6.

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