Journal of Medical Genetics, 1985, 22, 39-45

Trigonocephaly and the Opitz C syndromeC SARGENT, J BURN, M BARAITSER, AND M E PEMBREY

From the Mothercare Paediatric Genetics Unit, Institute of Child Health, and The Hospitalfor Sick Children,Great Ormond Street, London.

SUMMARY We present 12 cases of trigonocephaly of which six were associated with othermalformations. On the basis of this experience we examine the diagnostic criteria for thepresumed autosomal recessive trigonocephaly C syndrome.

The term trigonocephaly was coined by Welcker in18621 on the basis of seven cases. It describes acongenital cranial anomaly in which a narrowpointed forehead, often associated with somebiparietal widening, results in a skull which istriangular in shape when viewed from above. Partialor complete obliteration of the metopic suture is acharacteristic feature. In their reviews Currarinoand Silverman2 in 1960 and Anderson et a13 in 1962noted that a number of early European authors hadmade reference to associated malformations, parti-cularly of the forebrain. Their own cases, and thosein published reports, could be divided broadly into amajor group in which metopic synostosis was anisolated defect associated with only cosmetic prob-lems, and a second group where major malforma-tions and mental retardation were evident. Subse-quent advances in cytogenetics have shown thataneuploidy can account for some of the cases in thelatter group; trigonocephaly has been reported as afeature in 3q-, 7p-, 9p-, llq-, and trisomy13q.4 5

In 1969 Opitz et a16 reported a brother and sisterboth of whom died in infancy from the effects of amultiple malformation syndrome which includedtrigonocephaly. The chromosomes appeared nor-mal. Given the eponym C syndrome after the familyname, it was reported as a new syndrome, possiblywith recessive inheritance. Three further cases werereported in 1975.7 8 In 1981 Antley et a19 reviewedthe experience of eight centres and found six furthercases. In one of these the parents were secondcousins, and in another the fetus in a subsequentpregnancy was considered to be affected and wasterminated. These observations, and the equal sexratio, led the authors to conclude that an autosomalrecessive gene defect is the likely basis for thissyndrome.Received for publication 16 March 1984.Accepted for publication 22 May 1984.

We review twelve children with trigonocephalyseen at The Hospital for Sick Children, GreatOrmond Street, six with multiple malformations ofwhom two have reached adulthood, and six with anisolated metopic craniostenosis. On this basis weexamine the diagnostic criteria, prognosis, and risksof recurrence.

Methods of ascertainment

Cases 3, 4, 5, and 6 were identified among patientsreferred to the Genetics Clinic after the report in1981 by Antley et al.9Case 2 was ascertained as part of a research study

of twins and triplets with heart defects. Examinationof the notes made when this girl was an infantrevealed that she had trigonocephaly with multiplemalformations. It was also noted that the clinicalfeatures were very similar to another child who hadrecently been a patient at the hospital, case 1. Cases1 and 2 were visited at home in order to assess theircurrent clinical state.

Since 1959 patients referred to the NeurosurgicalUnit with craniosynostosis have been recorded in adiscrete index. Review of this revealed six cases oftrigonocephaly among the 300 records, all of whichwere isolated anomalies.

Case reports (table 1)

CASE 1

Case 1, a boy, was born on 30.4.63 at 39 weeks'gestation, weighing 2-835 kg. Pregnancy and de-livery were uneventful. The parents were unrelatedand there was one healthy sib. A small headcircumference with a pointed forehead and leftoccipital prominence and a deep sacral dimple werenoted at birth. There were no neonatal problemsand he was referred to this hospital at 12 days forreview of his cranial malformations (fig la).

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At 4 weeks the child developed cyanotic episodesassociated with stiffness and twitching which re-sponded to anticonvulsive therapy. This was mod-ified following recurrent fits at 6 months. Headcircumference was noted to be progressing along the

3rd centile but development was clearly delayed.There was an internal strabismus. He had a grosslyabnormal EEG and an air encephalogram indicatedcerebral atrophy with deformity of the anteriorhorns of the lateral ventricle.

TABLE 1 Clinical manifestations offive patients with trigonocephaly and multiple malformations compared on a similarformat to those summarised by Antley et al.9 (Italicised features have been added.)

Case nio Summary

I 2 3 4 5 Previous Presentt

Sex M F F F M 6F 5M 3F 2MTrigonocephaly + + + + +Neonatal OFC (centile) 3rd 3rd 3rd 5/9 3/3Postnatal microcephaly - + + + + 4/5 4/5Cowlick - - - - - 6/9 (1/5Apparently short neck + + + - + 9/1() 4/5Hypoplastic nose with broad root + + + + + 11/11 5/5and epicanthus

Anteverted nares + + + - + 4/5Characteristic palate + + - + 9/9 3/4Long simple philtrum + + + + + 9/1() 5/5Attached frenulum + - 4/5 1/2Neonatal micrognathia + + + + 9/1( 4/4Ear: reduced cartilage + + + 6/8 3/3Ear: abnormal shape + + + - + 8/1() 4/5Ear: low set and/or posteriorly - + - + + 1()/1() 3/5

rotatedUpward slanting palpebral + + + + + 9/1() 5/5

fissuresHspotelorism - + + + + 4/5Strabismus + + + + - 8/11 4/5Polysyndactyly - - - - - 4/11 ()/5Bridged palmar or simian crease + + - - - 6/9 2/5Ulnar deviation of fingers - - - - - 4/10 ()/5Clinodactvlv + + + + - 4/5Short limbs - + + + 4/1(0 3/4Varus or equinovalgus + - + + + 4/11) 4/5

deformitiesContractures - + -y + - 5/6 1/5Dislocated/dysplastic joints - + + - - 6/7 2/5Cryptorchidism/prominent clitoris + - - 8/I1 1/3Haemangiomas/naevi - + + - - X/9 2/5Sacral dimple + - - - - 4/4 1/5Pectus - + + + - 5/11) 3/5Cardiovascular defect - ?+ + - - 8/11 2/5Survival Alive Alive Died Died Alive Died at early age

21) y 19 y 7 mth 2 /½ y 1() mth 5/11 2/5

FIG 1 Facial appearance ofcase I (a) ininfancy and (b) at 19 years.

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Review at the age of 19 years revealed a severelyretarded boy in residential care. His height was 134cm (below the 3rd centile) and his head circum-ference had reached 51 cm. It was reported thatfollowing correction of bilateral equinovarus de-formity at the age of 8 years he had become able towalk but continued to prefer bottom shuffling. Hevocalised but had no speech. He helped with his owndressing and was able to feed himself. His trigo-nocephaly was still evident (fig lb), as was aprominent nuchal ridge with a small bony lump 1-5cm in diameter on the left side of the occiput. Therewas mild synophrys and upward slanting palpabralfissures, but relatively normal eye placement with anouter canthal distance of 8 cm, interpupillarydistance of 6-5 cm, and inner canthal distance of 3cm. The nasal bridge had developed well causing theepicanthic folds to disappear. The philtrum was welldefined but short (1-5 cm) with a nose length of 4-5cm. His ears were long, normally inserted, andprobably of simple form but were grossly swollenowing to head banging. The mouth was wide and thepalate was highly arched. His neck was short and hisnipples widely spaced. His hands were short withbilateral single palmar creases together with taper-ing fingers and clinodactyly of both fifth fingers. Thebig toes were short and the other toes werecrowded. Puberty was delayed with only one testispalpable, a prepubertal penis and scrotum, andsparse pubic and facial hair. He was judged to beseverely mentally retarded. Chromosome analysiswith G banding gave a normal karyotype.

CASE 2Case 2, a girl, was born at 34 weeks' gestation, thesecond of triplets. Birth weight was 1-332 kg and hermale co-triplets weighed 2-239 kg and 2-041 kg. Herparents are of European origin and unrelated. Theco-triplets and the paternal half sister have remainedhealthy. The abnormal skull shape was evident frombirth. Early weight gain was poor mainly due to

feeding difficulty. At 5 months her weight hadrisen to only 2-353 kg. On referral striking trigo-nocephaly, a small anterior fontanelle, increasedbiparietal diameter, and prominent occiput werenoted (fig 2a, b). She had clinical features of aventricular septal defect. At 6 months she was ableto smile but unable to hold up her head. An EEGshowed definite abnormality with asymmetrybetween the two hemispheres most marked in thefrontal and temporal regions. There was relativepoverty of activity over the left side. She began towalk at 2 years 3 months, 9 months later than hersibs, and began to feed herself at the age of 3 years.At this stage, in addition to global retardation, shewas noted to have persistence of the metopic ridge,yellow teeth, and a high palate.Review at the age of 19 years revealed a mod-

erately to severely retarded girl unable to dressherself and having very little recognisable speech.She continued to live with her parents with whomshe had good social interaction and who reportedher to be able to understand simple instructions.Her head circumference remained small at 46-5 cmbut the trigonocephaly was much less striking. Therewas mild synophrys and somewhat close set eyes(inner canthal distance 3*2 cm, interpupillary dis-tance 6 cm, outer canthal distance 8-75 cm). She hada long nose of 5*65 cm and a short philtrum of 1-6 cm(fig 2c). She was able to hear normally but hadminor anomalies of helix folding. A broad anterioralveolar ridge was noted with crowded and rathercarous teeth. She was 125 cm tall (below the 3rdcentile) with a stooping posture. She had lax fingerjoints but limited extension of the elbows. Shortbroad thumbs, long big toes, and poor circulation inthe extremities were noted. The strawberry naevihad faded and she had apparently normal pubertaldevelopment with good breast development. Hercardiac murmur had become insignificant. Chromo-some analysis with G banding revealed a normal46,XX karyotype.

FIG 2 Case 2. (a) Facial-appearance at 5 months.(b) Skull shape at 5 months.(c) Facial appearance at 19 years.

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CASE 3This female child was born to healthy non-consanguineous parents. Amniocentesis had beencarried out following the finding of a raised serumalphafetoprotein. Amniotic fluid alphafetoproteinand chromosome analysis were normal, though areduced biparietal diameter was noted. Birth weightwas 3-325 kg with a head circumference of 31-5 cmand length of 46-5 cm. An abnormal facies, atrigonocephalic skull, and a large pigmented hairynaevus over the left forearm were noted at birth (fig3a). Comment was made on the prominent metopicsuture on referral at 3 weeks (fig 3b). There weremajor feeding problems due to a poor suck reflexand little evidence of developmental progress.Seizures were suspected but an EEG was normal.At 3 weeks heart failure with cardiomegaly led tothe discovery of a severe congenital mitral stenosis,which caused her death at 7 months of age.At necropsy her weight had reached 5-45 kg with

a crown-heel length of 63 cm and crown-rump lengthof 42 cm. Head circumference was 38-5 cm with abiparietal diameter of 9 3 cm. The brain weighed570 g and was normal on external examination. Themitral valve cusps were noted to be thickened andnodular with very short chordae tendinae extendingto the tips of grossly hypertrophied papillary mus-cles. The other valves were normal. The foramenovale was patent and the right coronary ostium wasectopic, arising 1 cm above the aortic cusps.

CASE 4This female was the first born of unrelated parents.The family history was negative. The pregnancy hadbeen uneventful and the birth in February 1980followed a normal labour and delivery. Trigo-nocephaly with a prominent metopic suture and an

I,~~~~0

FIG 3 Facial appearance of case 3 at (a) 3 weeks and (b) at6 months. Note the prominent metopic ridge.

impalpable anterior fontanelle were noted. Anunusual clenched hand posture prompted chromo-some analysis, but this was normal. When followedup at 2 months, the child was noted to have difficultyswallowing though sucking reflex was normal. Thehead circumference was 36 cm and her generalawareness was noted to be poor. There were flexiondeformities of the fingers, limited abduction of thehips, and limited extension of the elbows, withmetatarsus varus deformity at the left ankle.She was referred for diagnosis at 21 months of age

at which time a marked delay in psychomotordevelopment was evident. She was unable to sit andpaid little attention to her surroundings. There wasstill obvious trigonocephaly (fig 4), large softpinnae, and broad alveolar ridges. Necropsy follow-ing death at 2½/2 years revealed a brain withpolymicrogyria, absent corpus callosum, olivarydysplasia, cerebellar heterotopias, and paucity ofcentral white matter and descending tracts.The mother's second pregnancy resulted, in

February 1981, in the birth of a male child followinga normal delivery. He was noted to have multiplecongenital abnormalities with arthrogryposis,rocker-bottom feet, and single palmar creases. Hisfacial appearance was noted to be very similar tothat of his sister. He died at the age of 2 days fromrespiratory distress syndrome. A limited necropsyrevealed a poorly formed gyral pattern.The mother gave birth to two healthy daughters in

1982 and 1983.

CASE 5Case 5, a male, was the first child of first cousinMuslim parents. The pregnancy was uneventful andthe child was born at term following a normaldelivery weighing 2-7 kg. When seen at 10 months,

.lff ,.L.. ,a11s .rv_

FIG 4 Facial appearance of case 4 at 21 months.

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developmental delay and multiple congenital ano-malies were evident. His weight and length wereboth just below the 3rd centile. The trigonocephalicskull was asymmetrical and the fontanelles appearedto be closed (fig 5). Despite lack of gross motordevelopment he would grasp objects and smile at hismother. Chromosome analysis revealed a normalmale karyotype. Ultrasound examination at 7months had revealed a small brain.

Trigonocephaly with multiple malformations andchromosome anomaly

CASE 6

This male child was born in August 1980 at 37weeks' gestation by lower segment Caesarian sec-

tion and weighed 3*17 kg. Subsequent developmentwas slow and there were major feeding difficultiesdue to poor sucking. He had two febrile convulsionsduring the first year. He smiled at 10 months but was

unable to sit at 16 months when referred for furtherassessment. At this stage his head circumferencewas 44-7 cm and weight was 7-8 kg, both well belowthe 3rd centile, but his length was 77-5 cm which was

on the 10th centile. He was noted to have severaldysmorphic features (fig 6).

Skeletal survey revealed very retarded carpalcentres and a generalised osteoporosis with under-modelling of the long bones. CT scan showeddilation of the lateral and third ventricles, absenceof the cerebellar vermis, and a large fluid containingcavity in the posterior fossa. The basal cislerns wereenlarged and there was prominence of the sylvianfissures, interhemispheric fissure, and corticalsulci. The picture was interpreted as being a variantof Dandy-Walker syndrome with cerebral atrophy.The chromosomes had been examined in a regional

FIG 5 Appearance ofcase 5 at 10 months.

FIG 6 Facial appearance ofcase 6 at 16 months.

unit and had been reported to be normal. Adiagnosis of trigonocephaly C syndrome was sug-gested. However, a second chromosome sample hadbeen sent to our own laboratory where the prepara-tion revealed a terminal deletion from the long armof chromosome 3, with a breakpoint at 3q27(46,XY,del(3)(pter-sq27:)).The child died at the age of 26 months and

necropsy revealed a brain weight of 880 g with smallcerebellar hemispheres and dilated ventricles. Therewas an acute pericarditis which had contributed todeath.

Isolated trigonocephaly

With the exception of one case of congenitaldeafness and one child of normal intellect with

TABLE 2 Clinicalfeatures ofsix cases ofsimpletrigonocephaly referred to the Neurosuirgical Unitforassessment.

Case No

7 8 9 /10 1 12

Sex M M F M M FBirth weight 23(0 3-75 3 25 32(2 2X()

(kg)Early N N N N N Ndevelopment

Late N N Bdevelopment

Operation - - + - + +

Dysmorphic features

Hypotelorism - + + + + +Hypoplastic + - +nose

Other features - - D

N=normal milestones. B=behavioural problems, normal intcllcct.D=severe congenital deafness.

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behaviour problems, the medical records revealedthat the six children referred to the neurosurgicalunit for assessment of trigonocephaly were healthyand of normal development. Table 2 summarises theclinical features in this group.

Discussion

Clinical details of twelve children with trigo-nocephaly are presented, six with multiple mal-formations and six with an isolated skull anomaly.Based as it is on the experience of a referralpaediatric hospital, the distribution almost certainlybears little relationship to the true incidence of thetwo types. A prominent metopic ridge in an other-wise normal child may not be brought to medicalattention and the child is unlikely to be referredunless there is concern about the cosmetic aspects.Of those seen at our hospital with uncomplicatedtrigonocephaly, the outcome seemed satisfactorywhether or not surgery was employed. There wasevidence of the deformity improving with agethough surgery should not be ruled out. Smith"' hasemphasised that even in cases of deformity due tointrauterine compression improvement with age isnot invariable, while bone resection at an early stagehas a very low morbidity in good hands and can

permit normal skull growth. Parents whose child istrigonocephalic but doveloping normally should bereassured. In our cases and other published cases

intellect was normal. It is probable that the con-

genital deafness in case 9 was coincidental.The cases of simple trigonocephaly had dysmor-

phic features similar to those of the complex cases.

In particular, orbital hypotelorism, telecanthus, andupward slanting palpebral fissures should be re-

garded as being consequent upon the malformationof and around the lower part of the metopic suture.It might be best to regard these as a 'trigonocephalysequence' rather than multiple features of a specificsyndrome.

Antley et at9 have discussed the full spectrum offeatures of the C syndrome. Table 1 shows that thefeatures in the first five children reported here fitclosely with those described previously. However,the 'characteristic palate' is not invariable. Never-theless, broad alveolar ridges are useful in diagnosisas is the striking softness of the ears in some cases.Case 3 was distinguished by a large hairy naevus

on the forearm. Also, the child had severe congenit-al mitral stenosis which led to an early death. This isa rare malformation which is difficult to diagnoseclinically though is recognised readily by echocar-diography. It is possible that this anomaly contri-buted to death in other reported cases.

Survival is poor in the presence of complex

trigonocephaly, but parents should not be advised toanticipate early death in view of the survival toadulthood of cases 1 and 2. These two are the oldestsufferers to be described in detail. Features of noteare the profound retardation and short stature. Case1 also had delayed puberty of uncertain cause, whilecase 2 adopted a stooped posture in part due to adegree of joint limitation.

Parental consanguinity in one case, albeit in afamily from an inbred population, and an affectedsib pair add further weight to earlier suggestions ofautosomal recessive inheritance. However, cautionis necessary. Trigonocephaly with its attendantdysmorphic features and mental retardation mayresult from a variety of chromosome disorders whichdraws attention to the relative non-specificity of this'syndrome'. Case 6 is of particular interest in thisrespect. The karyotype was reported normal by areputable cytogeneticist, whereupon the clinicalfeatures were accepted as being typical of Opitz Csyndrome. It was by chance that the chromosomeswere examined by a second laboratory and the smallde novo deletion indentified.

In the light of this experience, we suggest thatcases of trigonocephaly be divided into isolatedtrigonocephaly, a usually trivial and sporadic de-formity, and complex trigonocephaly. A proportionof the latter appear to result from an autosomalrecessive gene defect which should be called Opitz Csyndrome. Even after the exclusion of chromosomeanomaly, it is probable that this syndrome isheterogeneous and that the risk of recurrence willfall substantially below 1 in 4. A recurrence risk ofthe order of 10% would be reasonable advice untilan empirical risk is established.

We thank the colleagues who referred thesechildren, and the members of the Department ofNeurosurgery for allowing reference to their cra-niosynostosis index. We also thank Melanie Barhamand Carol Reeves for their preparation of the textand illustrations, respectively. JB is supported byMRC grant number G8203878.References

Welcker H. Untersuchungen uber wachstum und bau desmenschlichen schadels. Leipzig: Engelmann, 1862:120-4.

2 Currarino G, Silverman FN. Orbital hypotelorism.arhinencephaly and trigonocephaly. Radiology 1960;74:206-17.Anderson FM, Gwinn JL, Todt JC. Trigonocephaly: identityand surgical treatment. J Neurosurg 1962;19:723-30.

4 de Grouchy J, Turleau C. Atlas des maladies chromosomiques.2nd ed. Paris: Expansion Scientifique Frangaise, 1982.Borgaonkar DS. Chromosomal variation in man. A catalog ofchromosomal variants and anomalies. 3rd ed. New York: Liss,1980.

6 Opitz JM, Johnson RC, McCreadie SR, Smith DW. The Csyndrome of multiple congenital anomalies. Birth Defects1969;V(2):161-6.

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7 Preus M, Alexander WJ, Fraser FC. The 'C' syndrome. BirthDefects 1975;XI(2):58-62.

8 Oberklaid F, Danks DM. The Opitz trigonocephaly syndrome:a case report. Am J Dis Child 1975;129:1348-9.

9 Antley RH, Do Sung Hwang, Theopold W, et al. Furtherdelineation of the C (trigonocephaly) syndrome. Am J MedGenet 1981;9:147-63.

" Smith DW. Recognizable patterns of hluman malformation.Philadelphia: Saunders, 1981.

Correspondence and requests for reprints to Dr MBaraitser, Clinical Genetics Unit, Institute of ChildHealth, 30 Guilford Street, London WC1N 1EH.

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