American Journal of Medical Genetics 37:244-249 (1990)
Holoprosencephaly: Examples of Clinical Variability and Etiologic Heterogeneity Giovanni Corsello, Piera Buttitta, Marina Cammarata, Alfio Lo Presti, Emiliano Maresi, Luigi Zumpani, and Liborio Giuffre Patologia Neonatale Universita di Palermo (G.C., M.C., L.G.); Ospedale dei Bambini “G. Di Cristina”, U S L 58, Palermo (P.B.); Divisione di Ostetricia e Ginecologia, Ospedale Aiuto Materno U S L 60 (A.L.P., L.Z.); and Anatomia Patologica Universita di Palermo (E.M.).Palermo, Italy Clinical variability and causal heterogeneity of holoprosencephalyis discussed in relation to several newborn infants with cyclopia (cases 4,5,6), cebocephaly (cases 2,3),and premaxillary agenesis (case 1). In subjects with holoprosencephaly,the presence of multiple malformations is an indicator of concomitant chromosome aberrations, as in present case 1 (Down syndrome) and case 3 (trisomy 13). Cases 5 and 6 are two monozygotictwins with the same type of cyclopia and alobar holoprosencephaly recognized by prenatal ultrasonography. The diagnostic importance of ultrasonographic, cytogenetic, and pathological studies is pointed out in view of etiologic evaluation, genetic counseling, and prevention of holoprosencephaly. KEY WORDS: craniofacial malformations, chromosome aberrations
holoprosencephaly; if incomplete, holoprosencephaly can be semilobar or lobar (Table I). A close embryological relationship seems to exist between cerebral and craniofacial abnormalities. In fact, the primordial defect of the sequence is probably located within the prechordal mesenchyme, a n area that develops into the median facial structures and is also supposed to induce the differentiation process of prosencephalon [Cohen et al., 19711. Although a close relationship between facial and cerebral malformations is usually accepted, about 30% of cases with alobar holoprosencephaly show only mild facial malformations [De Myer et al., 19641. The clinical classification of holoprosencephaly depends on the type and severity of facial midline hypoplasia. The main clinical variants of holoprosencephaly are premaxillary agenesis, cebocephaly, ethmocephaly, and cyclopia. Etiologic evaluation of holoprosencephaly is often a complex problem for pediatricians and geneticists. Chromosome aberrations, mendelian mutations, and exogenous agents can, in fact, cause identical forms of holoprosencephaly [Munke, 19891. Among chromosome aberrations, trisomy 13 is frequently associated with holoprosencephaly, whereas various manifestations of the sequence are present in cases of the following:
INTRODUCTION Holoprosencephaly is a midline developmental field defect of prosencephalon and craniofacial structures that presents with great clinical variability and eti1. deletion of the short arm of chromosome 2 [Munke ologic heterogeneity. Its incidence has been variously et al., 1988a; Wilson et al., 1989; Grundy et al., 19891; estimated between 15,200 and 1:53,395 births [Myr2. duplication of the short arm of chromosome 3 ianthopoulos and Chung, 1974;Roach et al., 1975; Saun- [Kurtzman et al., 1987; Martin and Steinberg, 19831; ders et al., 19841.Moreover, a very high incidence (0.4%) 3. duplications of the long arm of chromosome 6 [Neu has been noted in spontaneous abortions [Matsunaga et al., 19811; and Shiota, 19771.Holoprosencephaly is a malformation 4. deletion of the long arm of chromosome 7 [McMorsequence of the brain with anomalies occurring during row et al., 1987; Schinzel, 19841; cleavage of the prosencephalic vescicle into two hemi5. duplication or deletion of the long arm of chromospheres. If this defect is complete, the result is alobar some 13 [Wilson et al.. 19861: 6. deletion of the short armof chromosome 18 [Munke et al., 1988bI; 7. deletion of the long arm of chromosome 18 [Yanoff Received for publication May 5,1989 revision received March 1, e t al., 19701; 1990. 8. 21 trisomy [Epstein et al., 1988; Pi et al., 1980; Address reprint requests to Giovanni Corsello, Cattedra di Patologia Neonatale Istituto Materno Infantile Universita di Pa- Urioste et al., 1988; present case l]; 9. triploidy [Harris et al., 1981; Lambert et al., 1984; lermo (Dir. Prof. Liborio Giuffre), Via CardinaleRampolla 1,90142 Zergollern et al., 19721. Palermo, Italy. 0 1990 Wiley-Liss, Inc.
Heterogeneity of Holoproseneephaly TABLE I. Anatomic Variants of HoloDrosenceDhah Alobar Semilobar Lobar
Absence of interhemispheric cleavage. Single ventricle Posterior interhemispheric fissure with rudimental cerebral hemispheres. Single ventricle Clear interhemispheric fissure. Two lateral ventricles
When holoprosencephaly is inherited as a mendelian trait, transmission can be recessive, dominant, or X-linked. An environmental etiology also must be suspected in some cases [Mollica et al., 19793. Gestational diabetes [Barr et al., 19831, maternal intake of salicylates [Benawra et al., 19801 or steroids [Stabile et al., 19851 during pregnancy, and intrauterine cytomegalovirus infection [Byrne et al., 19871 have been involved as possible causal agents. The etiologic complexity of holoprosencephaly is illustrated by the cases described in the present report.
CLINICAL REPORTS Patient 1 This male patient was born after a n uneventful pregnancy, the fifth, to healthy and nonconsanguineous parents (mother’s age 39 years, father’s age 42 years). At birth he had microcephaly, flat occiput, hypotelorism, flat nose, midface hypoplasia, bilateral cleft of lip and palate, micrognathia, short neck, bilateral simian crease, clinodactyly of both 5th fingers, diastema between 1st and 2nd toe bilaterally, hyperlaxity of joints, and generalized hypotonia (Fig. 1).He had a good clinical course during the neonatal period. Chromosome studies obtained from peripheral blood demonstrated trisomy 21, leading to a diagnosis of holoprosencephaly (premaxillary agenesis) in a n infant with Down syndrome.
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Patient 2 This boy was born after a n uneventful pregnancy, the third, to healthy, young, nonconsanguineous parents (mother’s age 26 years, father’s age 29 years). At birth (spontaneous term delivery): weight 2,750 g, length 47 cm, cranial circumference 26 cm, severe microcephaly, hypotelorism, bilateral microphthalmia, midfacial hypoplasia, nasal hypoplasia with single nostril, and cleft of lip and palate (Fig. 2). There was no clinical evidence of other malformations, and chromosomes were normal. Death occurred soon after birth. Postmortem examination demonstrated the presence of alobar holoprosencephaly (cebocephaly) with single ventricle (Fig. 3) without associated malformations.
Patient 3 This male patient was born after the first pregnancy of healthy, young, and nonconsanguineous parents (mother’s age 21 years, father’s age 24 years). During pregnancy a n ultrasound scan showed intrauterine growth retardation and enlargement of the cerebral ventricles. At birth weight was 2,140 g, length 45 cm, cranial circumference 25 cm; severe microcephaly, extreme hypotelorism, anophthalmia OS, severe microphthalmia OD, long and irregular nose (proboscis-like) with single nostril, cleft of palate, midface hypoplasia more consistent on the left side, abnormal and asymmetric auricles with left auricle atresia (Fig. 4) all were present. Chest, abdomen, and limbs were apparently normal. Death occurred 6 hours after birth. Chromosomes obtained from peripheral blood were normal. Blood analysis for TORCH complex was negative. Postmortem examinations demonstrated the presence of a n alobar holoprosencephaly (cebocephaly) with enlarged single ventricle, hypoplasia of left craniofacial bones, and pulmonic stenosis.
Fig. 1. Case 1:Premaxillary agenesis in infant with Down syndrome. Note flat, hypoplastic nose with bilateral cleft of lip and palate. Fig. 2. Case 2: Newborn infant with cebocephaly. Note severe nasal hypoplasia with single nostril and cleft of lip.
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Patient 4 This female patient was born after a n uneventful pregnancy, the fourth, to healthy and nonconsanguineous parents (mother’s age 35 years, father’s age 37 years). At birth (spontaneous term delivery) weight was 2,750 g, length 50 cm, cranial circumference 26.5 cm; microturricephaly, arrhinia with dystopic proboscis, single quadrangular orbit with complete fusion of the eyes, flat face, severe midface hypoplasia, cleft of palate, small and abnormal auricles, short neck, bilateral simian crease, and rockerbottom deformity of the feet bilaterally all were present (Fig. 5). Death occurred 5 hours after birth. Chromosome examination showed trisomy 13. Autopsy showed alobar holoprosencephaly with single ventricle, hypoplasia of facial bones, tricuspid stenosis, severe bilateral hydronephrosis with pyeloureteral obstructions.
Patients 5, 6
Fig. 3. Case 2: Anatomic view oftypical alobar holoprosencephaly. a: Frontal view with absence of interhemispheric fissure; b: Same view without the frontal cortex to show a single ventricle.
These two male monozygotic twins were born after the first pregnancy to young, nonconsanguineous parents (mother’s age 22 years, father’s age 27 years). During pregnancy (32nd week) a n ultrasound scan demonstrated the presence of two fetuses with single amniotic sac, single ventricle, pseudohydrocephalus, proboscis, and cyclopia (Fig. 6). At birth (cesarean section a t 38 weeks) the twins weighed 1,720g and 2,110 g; the length of twin 1was 43 cm and 48 cm of twin 2, cranial circumference was 31 cm in twin 1 and 37 cm of twin 2. Both had identical findings of holoprosencephaly with cyclopia, dystopic proboscis, flat face, midface hypoplasia, pseudohydrocephalus (more severe in fetus 21, and asymmetric atresia of apparently low-set ears (Fig. 7). There was no clinical evidence of other malformations. Death occurred soon after birth. Chromosomes. obtained from peripheral blood, were normal in both. Normal results of TORCH complex analysis.
DISCUSSION Holoprosencephaly is a developmental field defect with variable severity. All components of this field defect arise during the first 4 postovulatory weeks. Inter-
Fig. 4. Case 3: Newborn infant withcebocephaly. Note proboscis-like nose with single nostril and left facial hypoplasia. Fig. 5. Case 4: Newborn infant with cyclopia and trisomy 13. Note arrhinia, forehead proboscis, and anophthalmia.
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Fig. 7. Cases 5 and 6 : Monozygotic twins at birth with cyclopia and alobar holoprosencephaly. Note identical proboscis and abnormal external ears. Twin 2 on the right has a single orbit with two corneae and a pseudohydrocephalic head; twin 1 on the left has a single orbit with single eye.
Fig. 6 . Prenatal ultrasonography of monozygotic twins with holoprosencephaly at 32 weeks of gestation. a: Left: proboscis on the facial profile in one fetus (twin 2). Right: large single ventricle (alobar holoprosencephaly) with absence of midline structures and severe cerebral hypoplasia in the same fetus (twin 2). b:Left: evident single orbit in the other fetus (twin 1).Right: alobar oloprosencephaly with single ventricle and absence of midline structures in the same fetus (twin 1).
ferences with induction by the prechordal plate at or before stage 8 (18 days) would be expected to affect the future mediobasal part of the neural plate and the future optic primordium. Disturbances of stage 9 (20 days) would result in anophthalmia. Defective distribution of the cephalic neural crest causes incomplete formation of the chondrocranium and a reduction in the size of the ganglia and of the cranial nerves. Failure of bilateral cleavage of the telencephalon occurs at or before 4 weeks (stages 13 and 14) [Muller and O’Rahilly, 19891. Holoprosencephaly is, by definition, causally heterogeneous and is frequently found in aneuploidy and polyploidy (as in our cases 1 and 41, where it represents a disturbance of genetic homeostasis [Shapiro, 19831.
There is disagreement on the occurrence of holoprosencephaly in Down syndrome, with Urioste et al. [19891 suggesting causal and Epstein et al. [19881suggesting a chance association. True multiple congenital anomalies (MCA) syndromes with holoprosencephaly more likely represent aneuploidy than nonsyndromal holoprosencephaly, which may be due to environmental causes in some cases [Cohen, 1982, 19891. Holoprosencephaly may be recognized prenatally by ultrasonography, especially the alobar variant, because of single ventricle and “pseudohydrocephalus,” cyclopia, and proboscis or cleft without premaxillary agenesis [Blackwell et al., 1982; Hill et al., 1982; Mazzone et al., 19881. Absence of rotation, which prosencephalon normally undergoes after cleavage, simulates hydrocephalus, a s in twin cases 5 and 6; if rotation is incomplete, a typical “cup” shape of the encephalon results. If rotation occurs normally, the cerebral cortex uniformly covers the single ventricle as in our cases 2, 3, and 4. Prenatal diagnosis of facial defects is reported less frequently than cerebral malformations [Lev-Gur et al., 1983; Romero et al., 19881. The observation of the same kind of holoprosencephaly in monozygotic (MZ)twins (present cases 5 and 6 ) is quite exceptional; however, it makes sense because of the association of holoprosencephaly and twinning as midline defects occurring during blastogenesis. Early structural defects in MZ twins are, in fact, nonconcordant in about 80% of cases [Suslak et al., 19871. In the concordant cases, mendelian inheritance may be presumed if chromosome abnormalities and environmental causes can be excluded. Most holoprosencephaly is sporadic; however, in all nonaneuploid or teratogenic cases, eval-
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Hattori H, Okuno T, Momoi M, Kataoka K, Mikawa H, Shiota K (1987): Single central maxillary incisor and holoprosencephaly. Am J Med Genet 28:483-487. Hill LM, Breckle R, Bonebrake CR (1982): Ultrasonic findings with holoprosencephaly. J Reprod Med 27:172-175. Johnson VP (1989): Holoprosencephaly: A developmental field defect. Am J Med Genet 34:258-264. Kurtzman DN, Van Dyke DL, Rich CA, Weiss L (1987): Duplication 3p2143pter and cyclopia. Am J Med Genet 27:33-37. Lambert JC, Philip P, Charpenter G, Ferrari M, Donzeau M, Ayraud N (1984): Triploidy with cyclopia and identical HLA alleles in the parents. J Med Genet 21:63-66. Lev-Gur M, Maklad NF, Pate1 S (1983): Ultrasonic findings in fetal cyclopia. J Reprod Med 28:554-557. Martin NJ, Steinberg BG (1983):The dup (3) ( p 2 b p t e r ) syndrome: a case with holoprosencephaly. Am J Med Genet 14:767-772. Matsunaga E, Shiota K (1977):Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology 16:261-272. Mazzone D, Milana A, Scollo P (1988):Diagnosi prenatale di un caso di oloprosencefalia. Riv Ital Pediatr 14:130-132. McMorrow LE, Toth IR, Gluckson MM, Leff A, Wolman SR (1987): A lethal presentation of de novo deletion 7q. J Med Genet 24:629-631. Mollica F, Pavone L, Nuciforo G, Sorge G (1979):A case of cyclopia. Role of environmental factors. Clin Genet 16:69-71. Miiller F, O’Rahilly R (1989): Mediobasal prosencephalic defects, inREFERENCES cluding holoprosencephaly and cyclopia, in relation to the development of the human forebrain. Am J Anat 185391-414, Barr M Jr, Hanson JW, Currey K, Sharp S, Torriello H, Scmickel RD, Wilson G (1983): Holoprosencephaly in infants of diabetic mothers. Miinke M (1989): Clinical, cytogenetic molecular approach to the geJ Pediatr 102565468. netic heterogeneity of holoprosencephaly (Invited Editorial). Am J Med Genet 34:237-245. Benawra R, Mangurten HH, Duffel1 DR (1980): Cyclopia and other anomalies following ingestion of salicylates. J Pediatr 96: Miinke M, Emanuel BS, Zackai EH (1988a):Holoprosencephaly: Asso1069-1071. ciation with interstitial deletion of 2p and review of cytogenetic literature. Am J Med Genet 30:929-938. Blackwell DE, Spinnato JA, Hirsch G, Giles HR, Sackler J (1982): Antenatal ultrasound diagnosis of holoprosencephaly: a case reMunke M, Page GC, Brown LG, Armson BA, Zackai EH, Mennuti MT, port. Am J Obstet Gynecol 145848-849. Emanuel BS (198813): Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male. Hum Genet 80:219-223. Byrne PJ, Silver MM, Gilbert JM, Cadera W, Tanswell AK (1987): Cyclopia and congenital cytomegalovirus infection. Am J Med Ge- Myrianthopoulos NC, Chung CS (1974):Congenital malformations in net 28:61-65. singletons: Epidemiologic survey. Birth Defects Orig Art Ser X( 11):1-58. Cervenak FA, Isaacson G., Hobbins JC, Chitkara U, Tortora M, Berkowitz RL (1985): Diagnosis and management of fetal holoprosenNeu RL, Gallien J U , Steinberg-Warren N, Wynn RJ, Bannerman RM cephaly. Obstet Gynecol 66:322-326. (1981): An infant with trisomy 6q21-tqter. Ann Genet 24:167-169. Cohen MM Jr (1982):An update on the holoprosencephalic disorders. J Pediat 101:865-869. Pi SY, Finemann RM, Wing SD, Grunnet M, Chan G (1980):Holoprosencephaly in a Down syndrome child. Am J Med Genet 5201-206. Cohen MM Jr (1989): Perspectives on holoprosencephaly: Part 111: Spectra, distinctions, continuities, and discontinuities. Am J Med Roach E, DeMyer W, Palmer K, Conneally M, Merritt A (1975):HoloGenet 34:271-288. prosencephaly: birth data, genetic and demographic analysis of 30 families. Birth Defects Orig Art Ser XI(2):294-313. Cohen MM Jr, Jirasek J E , Guzman RT, Gorlin RJ (1971):Holoprosencephaly and facial dysmorphia: Nosology, etiology and pathoRomero R, Pilu G, Jeanty P, Ghidini A, Hobbins J C (1988):“Prenatal genesis. In Bergsma D, McKusick V, Jorgenson R, Hussels I (eds): Diagnosis of Congenital Anomalies.” Newfolk, Appleton & Lange, “Clinical Delineation of Birth Defects: Part XI, Orofacial Strucpp 59-65. tures,’’New York: Alan R. Liss Inc., for the National FoundationSaunders ES, Shortland D, Dunn PM (1984):What is the incidence of March of Dimes. BD:OAS VII (7):125-135. holoprosencephaly? J Med Genet 21:21-26. DeMyer W, Zeman W, Palmer CG (1964): The face predicts the brain: Schinzel A (1984): Cyclopia and cebocephaly in two newborn infants diagnostic significance of median facial anomalies for holoprosenwith unbalanced segregation of a familial translocation rep (1;7) cephaly (arhinencephaly). Pediatrics 34:256-263. (q32;Q34). Am J Med Genet 18:153-161. Epstein CJ, Set0 S, Golabi M (1988):Chance vs causality in the association of Down syndrome and holoprosencephaly. Am J Med Genet Shapiro B (1983): Down syndrome-A disruption of homeostasis. Am J Med Genet 14241-270. 30:939-942. k y n s JP, Van Den Berghe H (1988): Single central maxillary incisor Stabile M, Bianco A, Iannuzzi S, Buonocori MC, Ventruto V (1985): A case of suspected teratogenic holoprosencephaly. J Med Genet and holoprosencephaly. Am J Med Genet 30:943-944. 22:147-149. Gilbert EF, Opitz J M (1976):The pathology of some malformations and hereditary diseases of the respiratory tract. In Bergsma D, Schimke Suslak L, Mimms GM, Desposito F (1987):Monozygosity and holoprosencephaly: cleavage disorders of the “midline field.” Am J Med RN (eds): “Growth Problems and Clinical Advances.” New York: Genet 28:99-102. Alan Liss, Inc., for the National Foundation-March of Dimes. Birth Defects:OAS XII(6):239-270 Taylor A1 (1968):Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Grundy HO, Niemeyer P, Rupani MK, Ward VF, Wassman ER (1989): Med Genet 5:227-252. Prenatal detection of cyclopia associated with interstitial deletion of 2p. Am J Med Genet 34:268-270. Urioste M, Valcarcel E, Gomez MA, Pine1 I, Garcia de Leon R, Diaz de Bustamante A, Tebar R, Martinez-Frias ML (1988): HoloprosenHarris MJ, Poland BJ, Dill FJ (1981): Triploidy in 40 human spontacephaly and trisomy 21 in a child born to a nondiabetic mother. Am neous abortuses: assessment of phenotype in embryos. Obstet GyJ Med Genet 30:925-928. necol 57:600-606.
uation of first-degree relatives is indicated. In the autosoma1 dominant form, mild malformations can be observed in the relatives, i.e., hypotelorism, submucous cleft of palate, or single central upper maxillary incisor. Indeed, recent studies have shown that single upper central maxillary incisor in otherwise apparently perfectly normal persons is a risk factor for holoprosencephaly in offspring [Gilbert and Opitz, 1976; F’ryns and Van Den Berghe, 1988; Hattori et al., 1987;Johnson, 19891. In view of extreme causal heterogeneity, it is important to attempt chromosome analysis in all stillborn fetuses, whether obviously syndromal or not. A pathological study is indicated not only to determine if the defect is alobar or not, but also to recognize possible associated malformations, as in present cases 3 and 4. In nonsyndromal cases without clear indication of cause, the recurrence risk has been empirically estimated at 6%[Cervenak et al., 19851.Proper etiologic and prognostic evaluation requires a multidisciplinary approach, including at a minimum ultrasonographic, clinical, pathologic, and cytogenetic expertise.
Heterogeneity of Holoprosencephaly Wilson GN, Dasouki M, Barr M (1986): Occurrence of holoprosencephaly in chromosome 13 disorders cannot be explained by duplication/ deficiency of a single locus. Am J Med Genet [Supp1]2:65-72. Wilson WG, Shanks DE, Sudduth KW, Couper KA, McIlhenny J (1989): Holoprosencephaly and interstitial deletion of 2(p2101p2109). Am J Med Genet 34252-254.
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Yanoff M, Rorke LB, Niederer BS (1970): Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am J Ophthalmol 70:391-402. Zergollern L, Drazancic A, Damianov I, Hitrec V, Gorecan V (1972):A liveborn infant with triploidy (69,XXX). Z Kinderheilk 112:293-300.
Holoprosencephaly: Examples of Clinical Variability and Etiologic Heterogeneity Giovanni Corsello, Piera Buttitta, Marina Cammarata, Alfio Lo Presti, Emiliano Maresi, Luigi Zumpani, and Liborio Giuffre Patologia Neonatale Universita di Palermo (G.C., M.C., L.G.); Ospedale dei Bambini “G. Di Cristina”, U S L 58, Palermo (P.B.); Divisione di Ostetricia e Ginecologia, Ospedale Aiuto Materno U S L 60 (A.L.P., L.Z.); and Anatomia Patologica Universita di Palermo (E.M.).Palermo, Italy Clinical variability and causal heterogeneity of holoprosencephalyis discussed in relation to several newborn infants with cyclopia (cases 4,5,6), cebocephaly (cases 2,3),and premaxillary agenesis (case 1). In subjects with holoprosencephaly,the presence of multiple malformations is an indicator of concomitant chromosome aberrations, as in present case 1 (Down syndrome) and case 3 (trisomy 13). Cases 5 and 6 are two monozygotictwins with the same type of cyclopia and alobar holoprosencephaly recognized by prenatal ultrasonography. The diagnostic importance of ultrasonographic, cytogenetic, and pathological studies is pointed out in view of etiologic evaluation, genetic counseling, and prevention of holoprosencephaly. KEY WORDS: craniofacial malformations, chromosome aberrations
holoprosencephaly; if incomplete, holoprosencephaly can be semilobar or lobar (Table I). A close embryological relationship seems to exist between cerebral and craniofacial abnormalities. In fact, the primordial defect of the sequence is probably located within the prechordal mesenchyme, a n area that develops into the median facial structures and is also supposed to induce the differentiation process of prosencephalon [Cohen et al., 19711. Although a close relationship between facial and cerebral malformations is usually accepted, about 30% of cases with alobar holoprosencephaly show only mild facial malformations [De Myer et al., 19641. The clinical classification of holoprosencephaly depends on the type and severity of facial midline hypoplasia. The main clinical variants of holoprosencephaly are premaxillary agenesis, cebocephaly, ethmocephaly, and cyclopia. Etiologic evaluation of holoprosencephaly is often a complex problem for pediatricians and geneticists. Chromosome aberrations, mendelian mutations, and exogenous agents can, in fact, cause identical forms of holoprosencephaly [Munke, 19891. Among chromosome aberrations, trisomy 13 is frequently associated with holoprosencephaly, whereas various manifestations of the sequence are present in cases of the following:
INTRODUCTION Holoprosencephaly is a midline developmental field defect of prosencephalon and craniofacial structures that presents with great clinical variability and eti1. deletion of the short arm of chromosome 2 [Munke ologic heterogeneity. Its incidence has been variously et al., 1988a; Wilson et al., 1989; Grundy et al., 19891; estimated between 15,200 and 1:53,395 births [Myr2. duplication of the short arm of chromosome 3 ianthopoulos and Chung, 1974;Roach et al., 1975; Saun- [Kurtzman et al., 1987; Martin and Steinberg, 19831; ders et al., 19841.Moreover, a very high incidence (0.4%) 3. duplications of the long arm of chromosome 6 [Neu has been noted in spontaneous abortions [Matsunaga et al., 19811; and Shiota, 19771.Holoprosencephaly is a malformation 4. deletion of the long arm of chromosome 7 [McMorsequence of the brain with anomalies occurring during row et al., 1987; Schinzel, 19841; cleavage of the prosencephalic vescicle into two hemi5. duplication or deletion of the long arm of chromospheres. If this defect is complete, the result is alobar some 13 [Wilson et al.. 19861: 6. deletion of the short armof chromosome 18 [Munke et al., 1988bI; 7. deletion of the long arm of chromosome 18 [Yanoff Received for publication May 5,1989 revision received March 1, e t al., 19701; 1990. 8. 21 trisomy [Epstein et al., 1988; Pi et al., 1980; Address reprint requests to Giovanni Corsello, Cattedra di Patologia Neonatale Istituto Materno Infantile Universita di Pa- Urioste et al., 1988; present case l]; 9. triploidy [Harris et al., 1981; Lambert et al., 1984; lermo (Dir. Prof. Liborio Giuffre), Via CardinaleRampolla 1,90142 Zergollern et al., 19721. Palermo, Italy. 0 1990 Wiley-Liss, Inc.
Heterogeneity of Holoproseneephaly TABLE I. Anatomic Variants of HoloDrosenceDhah Alobar Semilobar Lobar
Absence of interhemispheric cleavage. Single ventricle Posterior interhemispheric fissure with rudimental cerebral hemispheres. Single ventricle Clear interhemispheric fissure. Two lateral ventricles
When holoprosencephaly is inherited as a mendelian trait, transmission can be recessive, dominant, or X-linked. An environmental etiology also must be suspected in some cases [Mollica et al., 19793. Gestational diabetes [Barr et al., 19831, maternal intake of salicylates [Benawra et al., 19801 or steroids [Stabile et al., 19851 during pregnancy, and intrauterine cytomegalovirus infection [Byrne et al., 19871 have been involved as possible causal agents. The etiologic complexity of holoprosencephaly is illustrated by the cases described in the present report.
CLINICAL REPORTS Patient 1 This male patient was born after a n uneventful pregnancy, the fifth, to healthy and nonconsanguineous parents (mother’s age 39 years, father’s age 42 years). At birth he had microcephaly, flat occiput, hypotelorism, flat nose, midface hypoplasia, bilateral cleft of lip and palate, micrognathia, short neck, bilateral simian crease, clinodactyly of both 5th fingers, diastema between 1st and 2nd toe bilaterally, hyperlaxity of joints, and generalized hypotonia (Fig. 1).He had a good clinical course during the neonatal period. Chromosome studies obtained from peripheral blood demonstrated trisomy 21, leading to a diagnosis of holoprosencephaly (premaxillary agenesis) in a n infant with Down syndrome.
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Patient 2 This boy was born after a n uneventful pregnancy, the third, to healthy, young, nonconsanguineous parents (mother’s age 26 years, father’s age 29 years). At birth (spontaneous term delivery): weight 2,750 g, length 47 cm, cranial circumference 26 cm, severe microcephaly, hypotelorism, bilateral microphthalmia, midfacial hypoplasia, nasal hypoplasia with single nostril, and cleft of lip and palate (Fig. 2). There was no clinical evidence of other malformations, and chromosomes were normal. Death occurred soon after birth. Postmortem examination demonstrated the presence of alobar holoprosencephaly (cebocephaly) with single ventricle (Fig. 3) without associated malformations.
Patient 3 This male patient was born after the first pregnancy of healthy, young, and nonconsanguineous parents (mother’s age 21 years, father’s age 24 years). During pregnancy a n ultrasound scan showed intrauterine growth retardation and enlargement of the cerebral ventricles. At birth weight was 2,140 g, length 45 cm, cranial circumference 25 cm; severe microcephaly, extreme hypotelorism, anophthalmia OS, severe microphthalmia OD, long and irregular nose (proboscis-like) with single nostril, cleft of palate, midface hypoplasia more consistent on the left side, abnormal and asymmetric auricles with left auricle atresia (Fig. 4) all were present. Chest, abdomen, and limbs were apparently normal. Death occurred 6 hours after birth. Chromosomes obtained from peripheral blood were normal. Blood analysis for TORCH complex was negative. Postmortem examinations demonstrated the presence of a n alobar holoprosencephaly (cebocephaly) with enlarged single ventricle, hypoplasia of left craniofacial bones, and pulmonic stenosis.
Fig. 1. Case 1:Premaxillary agenesis in infant with Down syndrome. Note flat, hypoplastic nose with bilateral cleft of lip and palate. Fig. 2. Case 2: Newborn infant with cebocephaly. Note severe nasal hypoplasia with single nostril and cleft of lip.
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Patient 4 This female patient was born after a n uneventful pregnancy, the fourth, to healthy and nonconsanguineous parents (mother’s age 35 years, father’s age 37 years). At birth (spontaneous term delivery) weight was 2,750 g, length 50 cm, cranial circumference 26.5 cm; microturricephaly, arrhinia with dystopic proboscis, single quadrangular orbit with complete fusion of the eyes, flat face, severe midface hypoplasia, cleft of palate, small and abnormal auricles, short neck, bilateral simian crease, and rockerbottom deformity of the feet bilaterally all were present (Fig. 5). Death occurred 5 hours after birth. Chromosome examination showed trisomy 13. Autopsy showed alobar holoprosencephaly with single ventricle, hypoplasia of facial bones, tricuspid stenosis, severe bilateral hydronephrosis with pyeloureteral obstructions.
Patients 5, 6
Fig. 3. Case 2: Anatomic view oftypical alobar holoprosencephaly. a: Frontal view with absence of interhemispheric fissure; b: Same view without the frontal cortex to show a single ventricle.
These two male monozygotic twins were born after the first pregnancy to young, nonconsanguineous parents (mother’s age 22 years, father’s age 27 years). During pregnancy (32nd week) a n ultrasound scan demonstrated the presence of two fetuses with single amniotic sac, single ventricle, pseudohydrocephalus, proboscis, and cyclopia (Fig. 6). At birth (cesarean section a t 38 weeks) the twins weighed 1,720g and 2,110 g; the length of twin 1was 43 cm and 48 cm of twin 2, cranial circumference was 31 cm in twin 1 and 37 cm of twin 2. Both had identical findings of holoprosencephaly with cyclopia, dystopic proboscis, flat face, midface hypoplasia, pseudohydrocephalus (more severe in fetus 21, and asymmetric atresia of apparently low-set ears (Fig. 7). There was no clinical evidence of other malformations. Death occurred soon after birth. Chromosomes. obtained from peripheral blood, were normal in both. Normal results of TORCH complex analysis.
DISCUSSION Holoprosencephaly is a developmental field defect with variable severity. All components of this field defect arise during the first 4 postovulatory weeks. Inter-
Fig. 4. Case 3: Newborn infant withcebocephaly. Note proboscis-like nose with single nostril and left facial hypoplasia. Fig. 5. Case 4: Newborn infant with cyclopia and trisomy 13. Note arrhinia, forehead proboscis, and anophthalmia.
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Fig. 7. Cases 5 and 6 : Monozygotic twins at birth with cyclopia and alobar holoprosencephaly. Note identical proboscis and abnormal external ears. Twin 2 on the right has a single orbit with two corneae and a pseudohydrocephalic head; twin 1 on the left has a single orbit with single eye.
Fig. 6 . Prenatal ultrasonography of monozygotic twins with holoprosencephaly at 32 weeks of gestation. a: Left: proboscis on the facial profile in one fetus (twin 2). Right: large single ventricle (alobar holoprosencephaly) with absence of midline structures and severe cerebral hypoplasia in the same fetus (twin 2). b:Left: evident single orbit in the other fetus (twin 1).Right: alobar oloprosencephaly with single ventricle and absence of midline structures in the same fetus (twin 1).
ferences with induction by the prechordal plate at or before stage 8 (18 days) would be expected to affect the future mediobasal part of the neural plate and the future optic primordium. Disturbances of stage 9 (20 days) would result in anophthalmia. Defective distribution of the cephalic neural crest causes incomplete formation of the chondrocranium and a reduction in the size of the ganglia and of the cranial nerves. Failure of bilateral cleavage of the telencephalon occurs at or before 4 weeks (stages 13 and 14) [Muller and O’Rahilly, 19891. Holoprosencephaly is, by definition, causally heterogeneous and is frequently found in aneuploidy and polyploidy (as in our cases 1 and 41, where it represents a disturbance of genetic homeostasis [Shapiro, 19831.
There is disagreement on the occurrence of holoprosencephaly in Down syndrome, with Urioste et al. [19891 suggesting causal and Epstein et al. [19881suggesting a chance association. True multiple congenital anomalies (MCA) syndromes with holoprosencephaly more likely represent aneuploidy than nonsyndromal holoprosencephaly, which may be due to environmental causes in some cases [Cohen, 1982, 19891. Holoprosencephaly may be recognized prenatally by ultrasonography, especially the alobar variant, because of single ventricle and “pseudohydrocephalus,” cyclopia, and proboscis or cleft without premaxillary agenesis [Blackwell et al., 1982; Hill et al., 1982; Mazzone et al., 19881. Absence of rotation, which prosencephalon normally undergoes after cleavage, simulates hydrocephalus, a s in twin cases 5 and 6; if rotation is incomplete, a typical “cup” shape of the encephalon results. If rotation occurs normally, the cerebral cortex uniformly covers the single ventricle as in our cases 2, 3, and 4. Prenatal diagnosis of facial defects is reported less frequently than cerebral malformations [Lev-Gur et al., 1983; Romero et al., 19881. The observation of the same kind of holoprosencephaly in monozygotic (MZ)twins (present cases 5 and 6 ) is quite exceptional; however, it makes sense because of the association of holoprosencephaly and twinning as midline defects occurring during blastogenesis. Early structural defects in MZ twins are, in fact, nonconcordant in about 80% of cases [Suslak et al., 19871. In the concordant cases, mendelian inheritance may be presumed if chromosome abnormalities and environmental causes can be excluded. Most holoprosencephaly is sporadic; however, in all nonaneuploid or teratogenic cases, eval-
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Mazzone D, Milana A, Scollo P (1988):Diagnosi prenatale di un caso di oloprosencefalia. Riv Ital Pediatr 14:130-132. McMorrow LE, Toth IR, Gluckson MM, Leff A, Wolman SR (1987): A lethal presentation of de novo deletion 7q. J Med Genet 24:629-631. Mollica F, Pavone L, Nuciforo G, Sorge G (1979):A case of cyclopia. Role of environmental factors. Clin Genet 16:69-71. Miiller F, O’Rahilly R (1989): Mediobasal prosencephalic defects, inREFERENCES cluding holoprosencephaly and cyclopia, in relation to the development of the human forebrain. Am J Anat 185391-414, Barr M Jr, Hanson JW, Currey K, Sharp S, Torriello H, Scmickel RD, Wilson G (1983): Holoprosencephaly in infants of diabetic mothers. Miinke M (1989): Clinical, cytogenetic molecular approach to the geJ Pediatr 102565468. netic heterogeneity of holoprosencephaly (Invited Editorial). Am J Med Genet 34:237-245. Benawra R, Mangurten HH, Duffel1 DR (1980): Cyclopia and other anomalies following ingestion of salicylates. J Pediatr 96: Miinke M, Emanuel BS, Zackai EH (1988a):Holoprosencephaly: Asso1069-1071. ciation with interstitial deletion of 2p and review of cytogenetic literature. Am J Med Genet 30:929-938. Blackwell DE, Spinnato JA, Hirsch G, Giles HR, Sackler J (1982): Antenatal ultrasound diagnosis of holoprosencephaly: a case reMunke M, Page GC, Brown LG, Armson BA, Zackai EH, Mennuti MT, port. Am J Obstet Gynecol 145848-849. Emanuel BS (198813): Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male. Hum Genet 80:219-223. Byrne PJ, Silver MM, Gilbert JM, Cadera W, Tanswell AK (1987): Cyclopia and congenital cytomegalovirus infection. Am J Med Ge- Myrianthopoulos NC, Chung CS (1974):Congenital malformations in net 28:61-65. singletons: Epidemiologic survey. Birth Defects Orig Art Ser X( 11):1-58. Cervenak FA, Isaacson G., Hobbins JC, Chitkara U, Tortora M, Berkowitz RL (1985): Diagnosis and management of fetal holoprosenNeu RL, Gallien J U , Steinberg-Warren N, Wynn RJ, Bannerman RM cephaly. Obstet Gynecol 66:322-326. (1981): An infant with trisomy 6q21-tqter. Ann Genet 24:167-169. Cohen MM Jr (1982):An update on the holoprosencephalic disorders. J Pediat 101:865-869. Pi SY, Finemann RM, Wing SD, Grunnet M, Chan G (1980):Holoprosencephaly in a Down syndrome child. Am J Med Genet 5201-206. Cohen MM Jr (1989): Perspectives on holoprosencephaly: Part 111: Spectra, distinctions, continuities, and discontinuities. Am J Med Roach E, DeMyer W, Palmer K, Conneally M, Merritt A (1975):HoloGenet 34:271-288. prosencephaly: birth data, genetic and demographic analysis of 30 families. Birth Defects Orig Art Ser XI(2):294-313. Cohen MM Jr, Jirasek J E , Guzman RT, Gorlin RJ (1971):Holoprosencephaly and facial dysmorphia: Nosology, etiology and pathoRomero R, Pilu G, Jeanty P, Ghidini A, Hobbins J C (1988):“Prenatal genesis. In Bergsma D, McKusick V, Jorgenson R, Hussels I (eds): Diagnosis of Congenital Anomalies.” Newfolk, Appleton & Lange, “Clinical Delineation of Birth Defects: Part XI, Orofacial Strucpp 59-65. tures,’’New York: Alan R. Liss Inc., for the National FoundationSaunders ES, Shortland D, Dunn PM (1984):What is the incidence of March of Dimes. BD:OAS VII (7):125-135. holoprosencephaly? J Med Genet 21:21-26. DeMyer W, Zeman W, Palmer CG (1964): The face predicts the brain: Schinzel A (1984): Cyclopia and cebocephaly in two newborn infants diagnostic significance of median facial anomalies for holoprosenwith unbalanced segregation of a familial translocation rep (1;7) cephaly (arhinencephaly). Pediatrics 34:256-263. (q32;Q34). Am J Med Genet 18:153-161. Epstein CJ, Set0 S, Golabi M (1988):Chance vs causality in the association of Down syndrome and holoprosencephaly. Am J Med Genet Shapiro B (1983): Down syndrome-A disruption of homeostasis. Am J Med Genet 14241-270. 30:939-942. k y n s JP, Van Den Berghe H (1988): Single central maxillary incisor Stabile M, Bianco A, Iannuzzi S, Buonocori MC, Ventruto V (1985): A case of suspected teratogenic holoprosencephaly. J Med Genet and holoprosencephaly. Am J Med Genet 30:943-944. 22:147-149. Gilbert EF, Opitz J M (1976):The pathology of some malformations and hereditary diseases of the respiratory tract. In Bergsma D, Schimke Suslak L, Mimms GM, Desposito F (1987):Monozygosity and holoprosencephaly: cleavage disorders of the “midline field.” Am J Med RN (eds): “Growth Problems and Clinical Advances.” New York: Genet 28:99-102. Alan Liss, Inc., for the National Foundation-March of Dimes. Birth Defects:OAS XII(6):239-270 Taylor A1 (1968):Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. J Grundy HO, Niemeyer P, Rupani MK, Ward VF, Wassman ER (1989): Med Genet 5:227-252. Prenatal detection of cyclopia associated with interstitial deletion of 2p. Am J Med Genet 34:268-270. Urioste M, Valcarcel E, Gomez MA, Pine1 I, Garcia de Leon R, Diaz de Bustamante A, Tebar R, Martinez-Frias ML (1988): HoloprosenHarris MJ, Poland BJ, Dill FJ (1981): Triploidy in 40 human spontacephaly and trisomy 21 in a child born to a nondiabetic mother. Am neous abortuses: assessment of phenotype in embryos. Obstet GyJ Med Genet 30:925-928. necol 57:600-606.
uation of first-degree relatives is indicated. In the autosoma1 dominant form, mild malformations can be observed in the relatives, i.e., hypotelorism, submucous cleft of palate, or single central upper maxillary incisor. Indeed, recent studies have shown that single upper central maxillary incisor in otherwise apparently perfectly normal persons is a risk factor for holoprosencephaly in offspring [Gilbert and Opitz, 1976; F’ryns and Van Den Berghe, 1988; Hattori et al., 1987;Johnson, 19891. In view of extreme causal heterogeneity, it is important to attempt chromosome analysis in all stillborn fetuses, whether obviously syndromal or not. A pathological study is indicated not only to determine if the defect is alobar or not, but also to recognize possible associated malformations, as in present cases 3 and 4. In nonsyndromal cases without clear indication of cause, the recurrence risk has been empirically estimated at 6%[Cervenak et al., 19851.Proper etiologic and prognostic evaluation requires a multidisciplinary approach, including at a minimum ultrasonographic, clinical, pathologic, and cytogenetic expertise.
Heterogeneity of Holoprosencephaly Wilson GN, Dasouki M, Barr M (1986): Occurrence of holoprosencephaly in chromosome 13 disorders cannot be explained by duplication/ deficiency of a single locus. Am J Med Genet [Supp1]2:65-72. Wilson WG, Shanks DE, Sudduth KW, Couper KA, McIlhenny J (1989): Holoprosencephaly and interstitial deletion of 2(p2101p2109). Am J Med Genet 34252-254.
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Yanoff M, Rorke LB, Niederer BS (1970): Ocular and cerebral abnormalities in chromosome 18 deletion defect. Am J Ophthalmol 70:391-402. Zergollern L, Drazancic A, Damianov I, Hitrec V, Gorecan V (1972):A liveborn infant with triploidy (69,XXX). Z Kinderheilk 112:293-300.
