58Med Genet 1996;33:578-584

Holoprosencephaly in the west of Scotland1975-1994

M L Whiteford, J L Tolmie

AbstractCases of holoprosencephaly which oc-curred in the west ofScotland over the past20 years were ascertained from genetics,paediatric, and pathology department re-cords. Fifty cases were identified ofwhich17 had an underlying cytogenetic ab-normality. Of the remaining 33 cases, 26were delivered after 28 weeks' gestationgiving a birth prevalence of 1 in 26 730.Twenty-one babies were liveborn and ninechildren are currently alive. All survivorsare profoundly mentally retarded andmost have seizures. Twenty-eight patientswith non-chromosomal holoprosen-cephaly had a total of 23 sibs and threefamilies were identified where there waseither recurrence of holoprosencephaly(one family), a related cerebral mal-formation (one family), or mental han-dicap (one family) giving an overallrecurrence risk for serious neurologicaldisability of 12% (standard error 7%). Weconclude that holoprosencephaly does notnecessarily breed true and this observationshould be taken into account when givinggenetic counselling and attempting ultra-sound prenatal diagnosis after the birth ofan affected child(JMed Genet 1996;33:578-584)

Key words: holoprosencephaly; frequency; recurrencerisk.

Duncan GuthrieInstitute of MedicalGenetics,Yorkhill NHS Trust,Glasgow G3 8SJ, UKM L WhitefordJ L Tolmie

Correspondence to:Dr Whiteford.

Received 26 October 1995Revised version accepted forpublication 1 March 1996

Holoprosencephaly is a congenital mal-formation which encompasses a spectrum ofabnormalities affecting the forebrain and mid-face. Its mildest form comprises orbitalhypotelorism, a single central incisor, andarrhinencephaly (absence of the olfactory bulbsand tracts), whereas its most severe mani-festation is the cyclops phenotype with com-

plete failure of division of the embryonicforebrain into right and left cerebral hemi-spheres.' Estimates of the birth incidence ofholoprosencephaly lie between 1:16002 and1:53 3943 and a study from south-west Eng-land found incidences of 1:14 520 and 1:5200in two consecutive three year periods.4 Mostcases of holoprosencephaly occur sporadicallyand published reviews have suggested that ap-proximately 50% of cases are associated withchromosome abnormalities, trisomy 13 beingthe commonest chromosomal cause. Never-theless, sparse data are available on the fre-quency of holoprosencephaly associated withcytogenetic abnormalities compared with thefrequency of non-chromosomal holoprosen-

cephaly and a detailed population based, clin-ical genetic study of this cerebral malformationhas not previously been reported.6

Genetic counselling advice given to coupleswho have had one child affected by holo-prosencephaly is complicated by the mal-formation's heterogeneity. Both autosomal re-cessive and autosomal dominant gene defectsare reported but X linked holoprosencephalyis especially rare.7'-0 Dominantly inheritedholoprosencephaly has variable expression andcan be difficult to diagnose since only subtlesigns, such as reduced head circumference ora single central incisor, may indicate the mildlyaffected parent of a severely affected child.Teratogenic factors or maternal illness, espe-cially maternal insulin dependent diabetesmellitus, may also predispose to holoprosen-cephaly.1" Usually, genetic advice is empiricaland often refers to an American study of 30families with livebom, cytogenetically normalchildren affected by holoprosencephaly, whowere assessed at the Indiana University MedicalCenter between 1957 and 1970. In this study,Roach et al2 derived a recurrence risk forholoprosencephaly of 6%, the figure which isquoted today by many clinical geneticists.The present study aimed to identify all cases

of holoprosencephaly which have occurred inthe west of Scotland over a 20 year period, toassess the circumstances of the malformation'sdiagnosis, its frequency, and its clinical as-sociations. We also sought to discover whetherclose relatives of an affected person were affec-ted by cerebral malformation or neurologicaldisability to help clarify genetic counsellingimplications following the birth of an affectedfetus or infant.

Setting and methodsThe west of Scotland has an estimated popu-lation ofjust under 3 million. The area includedin this study is that served by five regionalhealth boards: Argyll and Clyde, Ayrshire andArran, Forth Valley, Greater Glasgow, and Lan-arkshire. Over 90% of paediatric deaths arereferred to the Royal Hospital for Sick Childrenin Glasgow for necropsy; a small number ofpaediatric necropsies are also carried out in twoof the other health board areas. The Glasgowpathology department currently obtains con-sent for necropsy for approximately 80% of allchildhood deaths and fetal losses.

Patients (fetuses, infants, and children) wereascertained through examination of day booksand records from local pathology departmentsand paediatric departments as well as the filesofthe regional paediatric neurology and genetic

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Table 1 Number of cases of holoprosencephaly1975-1994 and karyotype abnormalities

Karyotype No ofpatients

Normal 26Trisomy 13 1313ql2-ql4 deletion 113q22 or 31 deletioh* 17q34 or 35-qter deletion* 17q36-qter deletion IFailed culture 4Not available 3

* Precise breakpoints could not be determined.

Table 2 Frequency of non-chromosomal holoprosencephaly throughout the west ofScotland. Note the apparent low frequency in Forth Valley may be real or simply reflectmisdiagnosis of one or two cases in a less populous area where no cases ofholoprosencephaly were recorded in local pathology department files and the solitary caseidentified was a livebomn child diagnosed at the regional referral hospitalHealth board No of births* Cases ofHPE Frequency ofHPE

Argyll and Clyde 117891 8 1:14736Ayrshire and Arran 97 090 5 1:19 415Forth Valley 68 545 1 1:68 545Greater Glasgow 256 554 12 1:21 380Lanarkshire 154870 7 1:22 124Total west of Scotland 694 950 33 1:21 059

* Total births (livebirths and stillbirths) supplied by Vital Statistics Branch, General RegisterOffice for Scotland, Edinburgh.

departments. The patients selected for thisstudy were those diagnosed as having holo-prosencephaly/arrhinecephaly on CT scan orat necropsy or both and who were born betweenyears 1975 and 1994. The obstetric case notesof the mothers were studied to obtain detailsof the pregnancy and delivery, and probands'paediatric case notes were reviewed. Generalpractitioners of the mothers were contacted byletter in order to obtain information about thehealth of other members of the family and toconfirm the number of sibs of each index case.Eleven surviving patients (two of whom sub-sequently died) were personally examined bythe authors.

ResultsCASES AND CYTOGENETIC ANALYSISThroughout the 20 year period, 50 cases ofholoprosencephaly occurred giving an overallfrequency of 1:14 000. Eighteen patients were

ascertained from the genetic department data-base, 16 from pathology department records,and 12 from the paediatric neurology de-partment database. One patient's name was

found from all three sources and 15 patients'names were found in two of the three sources.

Cytogenetic results were available for 43patients (table 1).The first of two cases with 1 3q deletions was

detected after amniocentesis was performedbecause of increased Down syndrome risk (1in 34) from maternal serum screening; thepregnancy was subsequently terminated. Theother patient was a liveborn child who survivedfor 14 days. Two patients had 7q deletionswhich included band 7q36, the location of thedesignated HPE3 gene.'2 These cases were alsodiagnosed by amniocentesis following ab-normal maternal serum screening results andthe observation of abnormalities on ultrasoundscanning. Both pregnancies were subsequentlyterminated at 22 weeks' gestation. One fetushad a cyclops phenotype while the other hadlobar holoprosencephaly.

Patients known to have chromosomal ab-normalities were excluded from further analysisof the results and the following refers to theremaining 33 patients, 26 ofwhom had provennormal karyotypes and seven in whom culturesfailed or cytogenetic analysis was not at-tempted.

FREQUENCYTable 2 shows the frequency of non-chro-mosomal holoprosencephaly for each health

Table 3 Pregnancy outcome

Pregnancy Gestation Birth Weight Maternal Paternal PrenatalCase Year outcome (wk) weight (g) centile age (y) age (y) diagnosis

1 1975 Livebirth 40 3680 50th 26 26 No2 1977 Livebirth 35 1020 25-50th 33 27 No3 1978 TOP 36 1130 <3rd N/A N/A Yes (36 wk)4 1979 TOP 18 80 N/A N/A N/A Yes (18 wk)5 1980 Stillbirth 32 1200 3rd 20 N/A No6 1981 TOP 20 175 N/A 31 N/A Yes (20wk)7 1982 Livebirth 31 1030 3rd 23 35 No8 1984 TOP 17 77 N/A 28 N/A Yes (17 wk)9 1985 Livebirth 39 3374 75th 26 27 No10 1986 Livebirth 41 3100 25th 25 27 No11 1986 Livebirth 34 2200 50th 24 26 No12 1987 Livebirth 35 2070 10-25th 19 N/A No13 1987 Missed abortion 16 144 N/A 24 N/A No14 1987 Stillbirth 31 800 <3rd 27 29 No15 1987 Livebirth 38 2800 25-50th 24 N/A No16 1987 Livebirth 40 3040 25-50th 38 N/A No17 1988 Livebirth 40 2920 25th 22 25 No18 1988 Livebirth 31 1700 97th 26 N/A No19 1989 Livebirth 41 3120 25th 27 N/A No20 1990 Livebirth 38 2080 <3rd 23 27 Yes (28 wk)

(Twin) (Dizygotic)21 1991 Livebirth 40 2760 3rd 34 N/A No22 1991 Stillbirth 33 1320 <3rd 34 36 No23 1991 Livebirth 40 3660 50-75th 20 N/A No24 1991 Livebirth 34 2620 75-90th 36 36 No25 1991 Livebirth 35 1960 25th 25 25 No26* 1992 TOP 19 328 N/A 26 25 Yes (19 wk)27 1993 Livebirth 36 3400 97th 27 28 Yes (30 wk)28 1993 Livebirth 38 2640 25-50th 20 20 No29 1993 Livebirth 40 4320 >97th 22 23 No30 1993 TOP 22 335 N/A 39 N/A Yes (22 wk)31* 1993 Livebirth 38 2560 25-50th 27 26 No32 1994 TOP 34 1490 50th 24 26 Yes (32 wk)33 1994 TOP 25 660 10th 27 26 Yes (25 wk)* Sib-pair. N/A=information not available.

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board area and for the whole region. Twenty-six infants were delivered after 28 weeks'gestation giving a birth prevalence of 1 in26 730.

PREGNANCY OUTCOMEObstetric case notes for 30 of the 32 motherswere examined. One mother was identified ashaving two children with holoprosencephaly

and in two cases there was insufficient in-formation available from necropsy reports forthe obstetric case notes to be traced. In-formation regarding the parents, pregnancies,and birth details is summarised in table 3.

CLINICAL FEATURESThe clinical features of the affected childrenand fetuses are summarised in table 4. This

Table 4 Clinicalfeatures, classification, survival, and sibs

Severity of Age at Age now Position in LaterCase Karyotype Sex Clinical features HPE

1 46, XY M Microcephaly, epicanthic folds, oblique Semilobarpalpebral fissures, malformed ears,micrognathia, midface hypoplasia, high archedpalate, talipes, pectus excavatum, hypoplasticgenitalia, seizures

2 46, XY M Microcephaly, arrhinencephaly, cerebellar Alobarhypoplasia, absent nose, bilateral cleft lip andpalate, bilateral simian creases, absent digit 1foot

3 46, XY M Encephalocele, absent pituitary gland, single Alobar/cyclopsorbit, NTD, complex congenital heart defect,absent ribs, adrenal hypoplasia, absent kidneyand ureter, 2 cord vessels

4 Unknown M Arrhinencephaly, single orbit, NTD, Alobar/cyclopsexomphalos

5 Failed culture F Microcephaly, midline cleft lip and palate Alobar6 Unknown F Single orbit with fused globes, proboscis, Alobar/cyclops

anencephaly, NTD, adrenal hypoplasia7 46, XX F Hydrocephalus, midline cleft lip and palate, Alobar

hypotelorism, absent nose, low set ears, neckwebbing, posterior fossa cyst, 2 accessoryspleens

8 46, XX F Cyclops, proboscis, anencephaly, unilateral Alobar/cyclopsabsent adrenal gland and kidney

9 46, XX F Microcephaly, sloping forehead, mental Semilobarretardation, spastic diplegia

10 46, XX F Non-dysmorphic, colpocephaly, mental Semilobarretardation, seizures

11* 46, XY M Median cleft lip and palate, arrhinencephaly, Semilobarabnormal cerebellar vermis, diabetes insipidus,adrenal hypoplasia

12 Unknown F Median cleft lip, absent nasal septum, Alobararrhinencephaly

13 Failed culture M Median cleft lip and palate, absence of crista Alobargalli and ethmoid plates

14t 46, XY M Microcephaly, cebocephaly, hypotelorism, Alobarsingle nostril, choanal atresia, microstomia,2 cord vessels, single hypogastric artery

15 46, XX F Central cleft lip and palate, single nostril, Alobarseizures, diabetes insipidus, abnormaltemperature control

16 46, XX F Microcephaly, iris coloboma, mental Semilobarretardation, spastic quadriplegia

17 46, XX F Microcephaly, cerebellar hypoplasia, sloping Alobarforehead, low set ears, bilateral cleft lip andpalate, complex congenital heart disease

18 Failed culture F Hydrocephalus, arrhinencephaly, cebocephaly, Alobar/cyclopssingle orbit, central proboscis, supernumerarydigit on 1 hand (so did older sib)

19 46, XY M Microcephaly, plagiocephaly, mental Semilobarretardation, spastic quadriplegia

20 46, XY M Microcephaly, hypotelorism, central cleft lip Alobarand palate, flat nose, VSD, seizures

21 46, XX F Hypotelorism, partly occluded nostril, Semilobarunilateral cleft lip, microcephaly, cerebellarhypoplasia

22 Failed culture Hydrocephalus, posterior fossa cyst, Alobarmicrophthalmia, absent optic bulbs, absentnose, bilateral cleft lip and palate, malformedlow set ears, complex congenital heart defect,abnormal liver lobation

23 46, XX F Microcephaly, frontal encephalocele Alobar24 46, XY M Frontal encephalocele, hypertelorism, Alobar

exophthalmos, iris, choroid, and optic nerve

colobomata, bilateral cleft lip and palate,hypoplastic cerebellum, seizures, talipes

25 46, XY M Microcephaly, iris coloboma, single nostril, Semilobarbilateral cleft lip, seizures

26t 46, XX F Hydrocephalus, 11 pairs of ribs, 2 cord vessels Alobar27 46, XX F Posterior encephalocele, cleft palate Semilobar28 46, XX F Microcephaly, sloping forehead, optic nerve Semilobar

hypoplasia, lissencephaly, seizures29 46, XY M Hydrocephalus, flat forehead, hypotelorism Alobar30 46, XY M Hydrocephalus, arrhinencephaly, midline cleft Lobar

lip and palate, extremely low set, malformedears, micrognathia, 2 cord vessels

31it 46, XX F Microcephaly, hypotelorism, seizures, diabetes Semilobarinsipidus, hypoplastic nails

32 46, XY M Extreme hypotelorism, central proboscis, Alobaraccessory auricles, facial skin tag

33 46, XX F Microcephaly, arrhinencephaly Alobar

* Sib had cerebral malformation. t Sib has single central incisor and mental retardation. t Sib pair.

death (y) family sibs

3 y 2nd 0

13 h

TOP

TOP

StillbornTOP

1 h

TOP

3 d

6 d

Spont abortion

Stillborn

3-6 y

2nd

N/A

N/A

N/A3rd

1st

N/A

9.5 2nd

8-0 1st

1st

N/A

N/A

N/A0

3

N/A

3

1st 1

2nd 2

3rd 4

2nd 0

4*5 3rd

1st3 h

1 h

5 m

9 m

Stillborn

1-3 y

TOP5 d

0

2nd

5 8 3rd 0

2nd twin 0

1st 1

2nd 1

3-0 3rd 03-5 2nd 0

1st

3rd1st

1 *8 2nd

1-5 1st2ndTOP

TOP

TOP

1-8 4th

1st

2nd

0I

0

0

0

0

0

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table also shows the severity of the lesion, theposition of the affected child in the family, andthe number of sibs born after the proband.Note that cases 2, 3, 7, 14, 17, 20, and 24,had abnormalities which would have been inkeeping with a diagnosis of trisomy 13 but hadnormal karyotypes; for this reason we did notexclude patients with multiple abnormalitiesfrom the non-chromosomal group if karyotypedata were not available.

SURVIVAL AND PROGNOSISNine of the 21 liveborn babies are still alive(table 4). The oldest survivor is currently aged9-5 years. Three surviving children have alobarholoprosencephaly and all the survivors areprofoundly mentally retarded. Twelve childrendied and approximately 60% of these deathsoccurred within the first week of life (table 4).

SEX RATIOThe overall sex ratio for non-chromosomalholoprosencephaly was 18 females: 15 malesand within the alobar subtype of holo-prosencephaly the ratio was 11 females:10males. For cyclopia, the ratio was three females:two males.

PARENTSThe mean maternal age of 26-7 years (range19-39 years) and mean paternal age of 27-4years (range 20-36 years) were not significantlydifferent from expected. Two sets of parentswere Pakistani and first cousins, but no otherparents were known to be consanguineous.One mother was a poorly controlled, insulin

Figure 1 Case 11. (All photographs of childrenreproduced with parental consent.)

dependent diabetic and another took an oralcontraceptive pill during the first 12 weeks ofpregnancy. No other possible teratogens wereidentified.

PREGNANCY OUTCOME AND PRENATALDIAGNOSISTwenty-one babies (64%) with non-chro-mosomal holoprosencephaly were liveborn atan average gestation of 37 weeks, one preg-nancy was diagnosed as a missed abortion at16 weeks' gestation, and a further three babieswere stillborn at an average gestation of 32weeks.A total of eight pregnancies were prenatally

diagnosed by ultrasound examination and nonerepresented a sib recurrence. All eight preg-nancies were terminated. Four of these caseshad an associated neural tube defect and it wasthe latter malformation rather than holo-prosencephaly which was detected by ultra-sound scanning. Two cases were terminatedbecause of the antenatal detection of hydro-cephalus and in these cases holoprosencephalywas only diagnosed at necropsy. In the re-maining two cases, holoprosencephaly wasdiagnosed prenatally at the Regional FetalMedicine Centre, one case having been referredfrom another obstetric unit at 25 weeks' gest-ation on account of ultrasonographically diag-nosed growth retardation, the second casebeing diagnosed at 32 weeks' gestation whenthe mother presented with abdominal pain.One liveborn male infant, who had an un-affected female co-twin, was also diagnosed at28 weeks' gestation and this pregnancy con-tinued to term. A further liveborn child wasnoted to have a posterior fossa malformation

Figure 2 Sib of case 11.

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Figure 3 Case 14.

Figure 4 Sib of case 14 showing single central incisor on right.

at 30 weeks' gestation and postnatal cranialultrasound examination showed semilobarholoprosencephaly in addition. Thus, accurateultrasound prenatal diagnosis of the cerebralmalformation was accomplished in only threeof 33 cases (9%) with holoprosencephaly.

AFFECTED SIB PAIRS AND RECURRENCE RISK

Information regarding sibs was available for 28families. In one family two sibs had holo-prosencephaly and in two families one sib hadholoprosencephaly while a second sib had an-

other cerebral malformation. These three famil-ies are discussed in more detail.The parents of case 11 (fig 1) are both

Scottish and non-consanguineous. The firstborn affected child died at the age of 3 daysand necropsy showed an abnormality of thecerebellar vermis in addition to holopro-sencephaly. His parents subsequently had a

healthy daughter but their third child, also a

male, was noted from birth to have episodic

tachypnoea without other clinical features ofJoubert syndrome. Neuroimaging studies in-dicated that he had cerebellar hypoplasia anda neuronal migration disorder. On clinical ex-amination there was an impression of mildhypotelorism (not confirmed by measurement)and midface hypoplasia (fig 2). He died atthe age of 10 months and necropsy confirmeddisturbed neuronal migration and cerebellarhypoplasia with underdevelopment of the ce-rebellar vermis. There was no abnormalityof the forebrain. The proband with ho-loprosencephaly also had a structurally ab-normal cerebellum and these male sibs werepresumed to have genetically related cerebralmalformations.

Case 14 (fig 3), identified through pathologydepartment records, was the stillborn son of aPakistani couple who were also first cousins.When the mother's obstetric case notes wereexamined, we realised that his older sister hadpreviously been referred to the genetic clinicbecause of her dysmorphic appearance andmild-moderate mental retardation. No diag-nosis was made and cranial CT scan was nor-mal. Clinical review of the older sister revealedhypotelorism, midface hypoplasia, a broadnose, and a single central incisor with an intactsense of smell (fig 4). Both parents have normalteeth, head circumferences, and normal facialappearances. Although we cannot be certain,the facial appearance of the handicapped sibsuggests she has microscopic cerebral dys-genesis that is genetically related to holo-prosencephaly which affected her stillbornbrother.

Case 31 (fig 5) is the child of Scottish, non-consanguineous parents. At the age of 3 monthsshe was referred to our clinic with microcephalyand holoprosencephaly. Her mother told usthat her previous pregnancy had been ter-minated at 25 weeks' gestation after diagnosisof hydrocephalus by ultrasound scanning. Weobtained a copy of the necropsy report for thisfetus (case 26, fig 6) which stated clearly thatthe pathological diagnosis was alobar holo-prosencephaly in addition to hydrocephalus.

In summary, 23 children were born afterthe affected fetus or child and recurrence ofholoprosencephaly was identified in one family.In two families another cerebral malformationwas present in one sib. This gives an overallrecurrence risk of 12% (standard error 7%) forholoprosencephaly or mental handicap or both.

DiscussionFREQUENCY OF HOLOPROSENCEPHALYPrevious studies which noted the frequency ofholoprosencephaly did not identify proportionsofchromosomal and non-chromosomal cases,'3or considered only non-chromosomal holo-prosencephaly.2 In this study, we discoveredthat 34% of all cases of holoprosencephaly hada cytogenetic abnormality. Thirteen patients,or three quarters of all cytogenetically abnormalpatients, had trisomy 13. We identified a furtherseven cases oftrisomy 13 from necropsy recordsand since these cases did not have holo-prosencephaly, during our study some 65% of

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Figure 5 Case 31.

Figure 6 Case 26 (sib of case 31).

patients with trisomy 13 had holo-prosencephaly. However, not all cases of tri-somy 13 will have been ascertained fromnecropsy records. Therefore, we also examinedthe regional cytogenetic register and discovereda total of 78 cases of trisomy 13 during thestudy period, giving a frequency of trisomy 13of 1:9000. Assuming that 65% of all cases oftrisomy 13 have holoprosencephaly, a figure in

agreement with 70% quoted by Taylor,'4 thetotal frequency of holoprosencephaly in fetusesand infants who were born within the west ofScotland is 1:8000, and the frequency of non-chromosomal holoprosencephaly is 1:21 000.Considering cases born after 28 weeks' gest-ation and using total births as the denominator,the birth prevalence estimate is 1 in 26 730.Certainly, this is a minimum estimate becauseof incomplete ascertainment of cases, for ex-ample, cases of semilobar and lobar holo-prosencephaly may have been missed becausefacial signs were lacking and neuroimaging in-vestigations were not routinely performed onchildren with mental retardation. Nevertheless,we regard our local population frequency andprevalence estimates as being good ap-proximations to the true figures.

CLINICAL FEATURES AND SEVERITY OF LESIONThe clinical features of the children and fetuseswith holoprosencephaly were extremely vari-able with all manifestations of the cerebrallesion being represented. We found that 21patients had alobar holoprosencephaly, 11 hadsemilobar holoprosencephaly, and one hadlobar holoprosencephaly (table 3). Five of thepatients with alobar holoprosencephaly had acyclops phenotype. The majority of patientshad multiple abnormalities, with cleft lip/palateand neural tube defects being present mostfrequently. One important practical pointwhich emerged is that even severely affectedchildren with premaxillary agenesis may haveprolonged survival for several years and thiswas not always appreciated at the time of theirbirth. Only three children had normal facialfeatures (cases 2, 9, and 17). These three chil-dren are still alive and in each case holo-prosencephaly was diagnosed by neuro-imaging when investigating mental retardationand seizures. Therefore, as in previous studies,we found the "face predicts the brain" in mostbut not all children with holoprosencephalyand the majority of patients with the facialfeatures ofholoprosencephaly have alobar holo-prosencephaly.

GENETIC COUNSELLING AND PRENATALDIAGNOSISWe found that 28 cases had a total of 23subsequent sibs and three sib pairs were iden-tified. In two families the proband was thesecond affected child because the first child/fetus was not diagnosed as affected by holo-prosencephaly. Only one sib had holo-prosencephaly but, on clinical grounds, therewas evidence that the affected sibs had a relatedcerebral malformation. Thus, in this smallstudy the "recurrence risk" for non-chro-mosomal holoprosencephaly and related ce-rebral malformations is 12% (standard error7%). Although this is greater than the 6% re-currence risk figure calculated by Roach et al,'in our study, the recurrence risk will decreaseif more unaffected sibs are born, and as only10 mothers had their last pregnancy more than

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five years ago, there is a possibility that somefamilies are not yet complete.

In 1985 Chervenak et al'5 reported ultra-sound prenatal diagnosis of alobar holo-prosencephaly and in our series, whichextended from 1975 to 1994, only three caseswith alobar holoprosencephaly were diagnosedby prenatal scans at Regional Fetal MedicineCentres. Unfortunately we could not establishthe number of times an affected fetus wassubject to detailed ultrasound examination andholoprosencephaly was missed. Certainly, inthe three families where there was recurrenceof holoprosencephaly or a related cerebral mal-formation, each fetus underwent detailed ultra-sound examination at the local hospital.However, there were reasons for missing therecurrence in each case: in the first the affectedsib had cerebellar vermis aplasia, which is prob-ably more difficult to detect; in the secondfamily, although the ultrasonographer wasaware that there was a sib with mental handicapand malar hypoplasia, it was not recognisedthat this could be related to holoprosencephaly;in the third family, recurrence of holo-prosencephaly was missed, but perhaps thecontributory factor was mistaken diagnosis ofhydrocephalus in the proband. Finally, in re-spect of prenatal diagnosis, it is notable thatsix cases (20%) with non-chromosomal holo-prosencephaly had a posterior fossa ab-normality, and also that cerebellar vermisaplasia was the major intracranial sign of re-currence in one family. We therefore suggestthat when detailed ultrasonographic evaluationofthe fetus is indicated on account ofa previousfamily history of holoprosencephaly, special at-tention is paid to the fetal posterior fossa and

the significance of any abnormality therein iscarefully considered, even in the presence ofnormal hemispheric division. We would alsosuggest that the ultrasonographic evaluation iscarried out at the most experienced centreavailable.We would like to thank the staff of the Department of Pathologyat the Royal Hospital for Sick Children, Glasgow, particularlythe consultant pathologists Dr Alan Howatson and Dr AinsleyPatrick who performed the necropsies and Mrs Robert Toddfor her help in collecting the data.

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2 Roach E, De Myer W, Conneally PM, et al. Holo-prosencephaly: birth data, genetic and demographic ana-lyses of 30 families. Birth Defects 1975;11:294-313.

3 Myrianthopoulos NC, Chung CS. Congenital mal-formations in singletons: epidemiological survey. BirthDefects 1974;X(11): 1-58.

4 Saunders ES, Shortland D, Dunn PM. What is the incidenceof holoprosencephaly? Jf Med Genet 1984;21:21-6.

5 Ming PM, Goodner DM, Park TS. Cytogenetic variants inholoprosencephaly. Report of a case and review of theliterature. Am J Dis Child 1976;130:864-7.

6 Muenke M. Holoprosencephaly as a genetic model forcraniofacial development. Dev Biol 1994;5:293-301.

7 Muenke M. Clinical, cytogenetic and molecular approachesto the genetic heterogeneity of holoprosencephaly. Am JfMed Genet 1989;34:237-45.

8 Cohen MM Jr. Perspectives on holoprosencephaly. PartI. Epidemiology, genetics and syndromology. Teratology1989;40:211-35.

9 Muenke M, Gurriere F, Bay C, et al. Linkage of a humanbrain malformation, familial holoprosencephaly, to chro-mosome 7 and evidence for genetic heterogeneity. ProcNatl Acad Sci USA 1994;91:8102-6.

10 Hockey A, Crowhurst J, Culity G. Microcephaly, holo-prosencephaly, hypokinesia: a second report of a newsyndrome. Prenat Diagn 1988;8:683-6.

11 Barr M Jr, Hanson JW, Currey K, et al. Holoprosencephalyin infants of diabetic mothers. J Pediatr 1983;102:565-8.

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