Opitz C Trigonocephaly Syndrome and MidlineBrain Anomalies

Giuseppe Zampino,1 Concezio Di Rocco,2 Gianfranco Butera,1 Francesca Balducci,1Cesare Colosimo,3 Maria Giulia Torrioli,4 and Pierpaolo Mastroiacovo1*1Istituto di Pediatria, Facolta di Medicina ‘‘A. Gemelli,’’ Universita Cattolica, Rome, Italy2Sezione di Neurochirurgia Pediatrica, Facolta di Medicina ‘‘A. Gemelli,’’ Universita Cattolica, Rome, Italy3Istituto di Radiologia, Facolta di Medicina ‘‘A. Gemelli,’’ Universita Cattolica, Rome, Italy4Istituto di Neuropsichiatria Infantile, Facolta di Medicina ‘‘A. Gemelli,’’ Universita Cattolica, Rome, Italy

We describe a child with trigonocephaly,strabismus, upslanting palpebral fissures,nasal bridge hypoplasia, hypertrophic al-veolar ridges and large gingivo-labialfrenula, short neck, hip ‘‘dysplasia,’’ equino-varus deformities, cryptorchidism, atrialseptal defect ostium secundum, and severemental retardation, findings consistentwith C syndrome. The patient also had aDandy-Walker malformation, complete cal-losal agenesis, and occipital meningocele.These structural defects are independent ofthe premature closure of the metopic su-ture, and confirm that midline brain anoma-lies are part of C syndrome.

The hypothesis that the basic develop-mental defect in this syndrome primarily af-fects the midline field is supported by theconcomitance of other anomalies, such asconotruncal heart defects, omphalocele,and genital anomalies. Am. J. Med. Genet.73:484–488, 1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: C syndrome; trigonocephaly;mental retardation; corpuscallosum agenesis; Dandy-Walker malformation; mid-line developmental field; cra-niosynostosis

INTRODUCTION

The Opitz trigonocephaly or C syndrome, a multiplecongenital anomalies/mental retardation syndrome,probably due to an autosomal-recessive gene, is char-

acterized by mental retardation, trigonocephaly, typi-cal facial appearance, broad dental alveolar ridges,large gingivo-labial frenula, short neck, cutis laxa, jointanomalies, polydactyly, and visceral malformations in-cluding defects of the kidney, lung, genitalia, and heart[Opitz et al., 1969; Oberklaid and Danks, 1975; Antleyet al., 1981; Flatz et al., 1984; Sargent et al., 1985;Lalatta et al., 1990; Camera et al., 1990; Stratton et al.,1990; Haaf et al., 1991; Glickstein et al., 1995].

We report on a child with Opitz trigonocephaly syn-drome and midline brain anomalies to highlight theimportance of these defects in the diagnosis and treat-ment of patients with this condition.

CLINICAL REPORT

The male patient was born at term by spontaneousvaginal delivery after a pregnancy complicated by oli-gohydramnios. His parents are healthy and noncon-sanguineous and do not resemble the baby. Family his-tory was unremarkable with respect to congenitalanomalies and psychomotor retardation. Birth weightwas 2,550 g (−2 SD); length 44 cm (−3 SD); and OFC29.5 cm (−4 SD); Apgar score was 8 and 9 at 1 and 5min, respectively. The newborn infant presented withmedian occipital meningocele which was treated surgi-cally at age 1 month, and bilateral pes equinovarussupinatus which was corrected with casts.

During the second day of life he had episodes of bra-dycardia, apnea, and convulsions with cyanosis,treated with phenobarbital. His clinical course wascharacterized by slow neurologic development. At age10 months he was hypotonic and only partially capableof holding up his head. At 2 years he could partiallycontrol his trunk but was unable to hold a sitting po-sition. He could move his arms to his mouth but couldnot grab objects. He was able to interact with hismother by smiling and cooing. EEG had always showna poor organization of background rhythm, with sharpwaves and spikes.

Clinical examination at 28 months showed a weightof 12.050 g (−1 SD), length of 82.7 cm (−2 SD), and OFCof 44.5 cm (−3.5 SD). Examination also showed trigo-nocephaly, mild craniofacial asymmetry, upslanting

Contract grant sponsor: Associazione Italiana per lo Studiodelle Malformazioni.

*Correspondence to: Pierpaolo Mastroiacovo, M.D., Istituto diPediatria, Universita Cattolica S. Cuore, Largo A. Gemelli 8,00168 Rome, Italy. E-mail: mc8682mclink@it

Received 18 April 1997; Accepted 8 July 1997

American Journal of Medical Genetics 73:484–488 (1997)

© 1997 Wiley-Liss, Inc.

palpebral fissures, bilateral epicanthic folds, ptosis,strabismus due to hypofunction of lateral recti muscles,a small nose with broad and flat bridge, bulbous tipwith anteverted nares, long philtrum, a thin upper lip,a narrow and high-arched palate, hypertrophic centralfrenulum directly attached to the upper lip, a wide dia-stema between the upper medial incisors, and enlarged

Fig. 1. Frontal view of patient’s face. Note frontal prominence, epican-thus, strabismus, and hypoplastic and short nose.

Fig. 2. Hypertrophic and abnormally attached gingivo-labial frenula.

Fig. 3. Full view of patient. Note short neck, small penis, and asym-metric lower limbs.

Fig. 4. Three-dimensional bony surface reconstructed CT scan. Frontalcaudocranial view. Note frontal beaking of calvaria.

Fig. 5. MRI of brain. A, B: Axial T1-weighted images of the posterior fossa. C: Sagittal T1-weighted image. D: Coronal T1-weighted image. Notetrigonocephalic head with mild asymmetry of the frontal bone, anterior beaking, and extreme reduction of the ethmoidal width; large cyst in the posteriorfossa; markedly hypoplastic cerebellar vermis; tract of the excised meningocele (arrow) in the occipital bone; and agenesis of corpus callosum withhypoplasia of the left cingulate gyrus.

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alveolar ridges (Figs. 1, 2). Other abnormalities in-cluded a short neck, pilonidal sinus, clinodactyly of thefifth fingers, cryptorchidism and a small penis, andasymmetric lower limbs with the right leg 2 cm longerthan the left (Fig. 3). There was a 2/6 systolic murmur,and on ultrasound there was an ostium secundumatrial defect.

The auditory brain stem response (ABR) recordingevaluation showed a mild left conductive hypoacusis.

Cystography at 5 months documented both an activeand passive vescico-ureteral reflux of grade II to theleft. Kidney ultrasonography showed mild ectasis ofthe left calyceal cavity. Neuroradiological evaluation,including CT with three-dimensional reformation andMRI of the brain, showed a trigonocephalic head withasymmetry of the frontal bone, anterior beaking andextreme reduction of the ethmoidal width, and a largecerebrospinal fluid cyst in the posterior fossa, consis-tent with Dandy-Walker malformation with vermianagenesis and hemispheric cerebellar and brain stemhypoplasia. Moreover, a lacuna was seen in the occipi-tal bone, representing the residue of the meningocele.The corpus callosum was completely absent and theleft cingulate gyrus was hypoplastic. The ventricularsystem was asymmetrically enlarged (Figs. 4, 5). Pro-methafase chromosome analysis on peripheral lympho-cytes was normal: 46,XY.

DISCUSSION

Trigonocephaly describes a triangular-shaped headwith a prominent metopic crest and lateral frontal de-pression. This is usually the result of the prematureclosure of the metopic suture, accounting for 7% of cra-niosynostoses [Genitori et al., 1991]. Trigonocephalyhas been described either as an isolated anomaly or aspart of the clinical spectrum of some syndromes.

Isolated metopic synostosis commonly representsonly an aesthetic anomaly, rarely associated with in-tracranial pathology and mental retardation [Di Roccoet al., 1996]. Among the craniosynostoses, trigono-cephaly causes the fewest complications. Intracranialhypertension, secondary papillary edema, and optic at-rophy are exceptional findings [Denis et al., 1994]. Sig-nificantly impaired cognitive development and behav-ioral abnormalities are rare, occurring in about 5–7% ofcases [Sidoti et al., 1996]. A pilot study to investigatethe development of children with metopic synostosisshowed that only 15% of these children have expressivelanguage delay of more than 6 months, which is relatedto a selective drop in the auditory short-term memory,and poorer naming vocabulary compared to more ab-stract verbal reasoning [Czorny et al., 1994; Hearst etal., 1995].

Severe mental retardation, which may occur in somepatients with trigonocephaly, is not due to isolated cra-niostenosis, but rather to associated developmental de-fects of the brain [Schaap et al., 1992].

In addition to trigonocephaly and those relatedanomalies that can be regarded as part of a trigonoce-phalic ‘‘sequence’’ (hypothelorism, strabismus, upslant-ing palpebral fissures), our patient also presents withhypoplasia of the nasal root, buccal anomalies, in par-

ticular wide alveolar ridges and hypertrophic frenula,abnormally shaped ears, short neck, hip ‘‘dysplasia,’’equinovarus deformities, cryptorchidism, heart defect,and severe mental retardation. These are all consistentwith the diagnosis of Opitz trigonocephaly syndrome.

Our patient was noted to have a range of brainanomalies including a true Dandy-Walker cyst, agen-esis of cerebellar vermis, hypoplasia of the brain stemand cerebellar hemispheres, and occipital meningocele,all fitting into the spectrum of midline brain anoma-lies.

Previously reported brain abnormalities in Opitztrigonocephaly syndrome include agenesis of the cor-pus callosum [Sargent et al., 1985; Chu et al., 1994;Glickstein et al., 1995; Addor et al., 1995], cerebellarvermis hypoplasia [De Koster et al., 1990], cerebral at-rophy/ventricolomegaly [Antley et al., 1981; Sargent etal., 1985], megacysterna magna [De Koster et al., 1990;Lalatta et al., 1990], and a generalized reduction inwhite matter [Opitz et al., 1969; Lalatta et al., 1990].

All these anomalies, with the exception of corticalatrophy, point to a possible developmental defect of thecerebral midline in this syndrome.

A more generalized involvement of the midline fieldis supported by body anomalies such as conotruncalcardiac defects [Antley et al., 1981; Flatz et al., 1984;Glickstein et al., 1995], omphalocele [Lalatta et al.,1990; Cabral de Almeida et al., 1992], diaphragmatichernia [Addor et al., 1995], and genital abnormalities,occasionally reported in Opitz trigonocephaly syn-drome.

Further studies will need to determine the role ofcentral nervous system anomalies in the clinical mani-festations of the syndrome and what these anomalies’value will be in predicting clinical outcome.

Thus, the comprehensive evaluation of this conditionmust include a detailed neurological evaluation, usingboth MRI and CT scan.

ACKNOWLEDGMENTS

We thank J.L. Mente for editorial assistance in pre-paring the English text, and the Associazione Italianaper lo Studio delle Malformazioni for its support.

REFERENCES

Addor MC, Stefanutti D, Farron F, Meinecke P, Lacombe D, Sarlangue J,Prescia G, Schorderet DF (1995): ‘‘C’’ trigonocephaly syndrome withdiaphragmatic hernia. Genet Counsel 6:113–120.

Antley RM, Hwang DS, Theopold W, Gorlin RJ, Steeper T, Pitt D, DanksDM, McPherson E, Bartels H, Wiedeman H-R, Opitz JM (1981): Fur-ther delineation of the C (trigonocephaly) syndrome. Am J Med Genet9:147–163.

Cabral de Almeida JCC, Llerena JC, Vargas FR, Alonso MR (1992): Csyndrome and omphalocele: Another example (Letter). Am J MedGenet 43:385.

Camera G, Serra G, Selicorni A (1990): ‘‘C’’ trigonocephaly syndrome: Twoadditional cases (Letter). Am J Med Genet 37:463–464.

Chu WT, Teebi AS, Gibson L, Breg WR, Yang-Feng TL (1994): FISH diag-nosis of partial trisomy 13 and tetrasomy 13 in a patient with severetrigonocephaly (C) phenotype. Am J Med Genet 52:92–96.

Czorny A, Forlodou P, Stricker M, Ricbourg B (1994): Triangular skull.Apropos of trigonocephaly. Neurochirurgie 40:209–221.

De Koster J, Legius E, de Zegher F, Devlieger H, Fryns JP, Eggermont E

C Syndrome and Brain Anomalies 487

(1990): Opitz C syndrome and pseudohypoaldosteronism. Am J MedGenet 37:457–459.

Denis D, Genitori L, Bardot J, Saracco JB, Choux M, Maumenee IH (1994):Ocular findings in trigonocephaly. Graefes Arch Clin Exp Ophthalmol232:728–733.

Di Rocco C, Velardi F, Ferrario A, Marchese E (1996): Metopic synostosis:In favour of a ‘‘simplified’’ surgical treatment. Childs Nerv Syst 12:654–663.

Flatz SD, Schinzel A, Doehring E, Kamran D, Eilers E (1984): Opitz trigo-nocephaly syndrome: Report of two cases. Eur J Pediatr 141:183–185.

Genitori L, Cavalheiro S, Lena G, Dollo C, Choux M (1991): Skull base intrigonocephaly. Pediatr Neurosurg 17:175–181.

Glickstein J, Karasik J, Garcia Caride D, Marion RW (1995): ‘‘C’’ trigono-cephaly syndrome: Report of a child with agenesis of the corpus callo-sum and tetralogy of Fallot, and review. Am J Med Genet 56:215–218.

Haaf T, Hofmann R, Schmid M (1991): Opitz trigonocephaly syndrome. AmJ Med Genet 40:444–446.

Hearst D, Jones B, Hayward R (1995): Craniosynostosis and cognitive de-velopment: A retrospective pilot study of children with metopic synos-

tosis. Abstracts of Consensus Conference on Paediatric Neurosurgery,Craniosynostoses, Rome, May 1995, p 84.

Lalatta F, Clerici Bagozzi D, Salmoiraghi MG, Tagliabue P, Tischer C,Zollino M, Di Rocco C, Neri G, Opitz JM (1990): ‘‘C’’ trigonocephalysyndrome: Clinical variability and possibility of surgical treatment. AmJ Med Genet 37:451–456.

Oberklaid F, Danks DM (1975): The Opitz trigonocephaly syndrome. Am JDis Child 129:1348–139.

Opitz JM, Johnson RC, McCreadie SR, Smith DW (1969): The C Syndromeof Multiple Congenital Anomalies. BD:OAS V (2):161–166.

Sargent C, Burn J, Baraitser M, Pembrey ME (1985): Trigonocephaly andthe Opitz C syndrome. J Med Genet 22:39–45.

Schaap C, Schrander-Stumpel CTRM, Fryns JP (1992): Opitz-C syndrome:On the nosology of mental retardation and trigonocephaly. GenetCounsel 3:209–215.

Sidoti EJ, Marsh JL, Marty Grames L, Noetzel MJ (1996): Long-term stud-ies of metopic synostosis: Frequency of cognitive impairment and be-havioral disturbances. Plast Reconstr Surg 97:276–281.

Stratton RF, Sykes NJ, Hassler TW (1990): C syndrome with apparentlynormal development. Am J Med Genet 37:460–462.

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