American Journal of Medical Genetics 40:290-293 (1991)
Oculocerebrocutaneous (Delleman) Syndrome: A Pleiotropic Disorder Affecting Ectodermal Tissues With Unilateral Predominance Joe J. Hoo, Kathleen Kapp-Simon, Beverly Rollnick, and Margaret Chao Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center (J.J.H.) and Center for Craniofacial Anomalies, University of Illinois (K.K.-S.,B.R.) and Department of Pediatrics, Cook County Hospital (M.C.), Chicago
We present a patient with oculocerebrocutaneous syndrome. The boy shows only mild psychomotor delay in spite of rather severe appearing anomalies of the central nervous system. A primarily unilateral involvement of this syndrome is emphasized. A postzygotic/ somatic mutation resulting in a mosaic state might account for the primarily ectodermal involvement, the unilateral predominance, and the sporadic nature of this syndrome. An alternative hypothesis of an environmental factor might also explain the clinical manifestations of the syndrome. KEY WORDS: oculocerebrocutaneous syndrome, Dellemen syndrome, orbital cyst, skin appendages, skin hypoplasia, somatic mutation, environmental factor INTRODUCTION Delleman and Oorthuys [19811 reported on 2 Dutch children with a syndrome of multiple congenital anomalies consisting of orbital cysts, micro-/anophthalmia, malformation of the central nervous system, focal dermal hypoplasia, and skin appendages. They suggested the term “oculocerebrocutaneous” syndrome. Three other cases [Delleman et al., 1984;Ferguson et al., 1984; Wilson et al., 19851 were reported subsequently. In 1988, Al-Gazali et al. reviewed the above 5 cases and their own 4, and coined the eponym “Delleman” syndrome. Giorgi et al. [19891, Clericuzio [19891 and Brodsky et al. [1990] each added another case. Most Received for publication June 7,1990; revision received November 2, 1990. Address reprint requests to Joe J . Hoo, M.D., Section ofGenetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center, 1750 W. Harrison St., Chicago, IL 60612. This work is dedicated to the memory of Dr. Beverly Rollnick.
0 1991 Wiley-Liss, Inc.
recently, Bleeker-Wagemakers et al. [19901reported another Dutch patient. They also identified 4 other cases [Ladenheim and Metrick, 1956; Braun-Vallon et al., 1958; Saraux and Offret, 1967; Dollfus et al., 19681 in the literature without the term “oculocerebrocutaneous syndrome.” Thus, at least 17 cases are known. Here we report on a boy of German descent with oculocerebrocutaneous syndrome and emphasize the mild degree of his developmental delay.
CLINICAL REPORT B.B. is the first child of young, healthy, and nonconsanguineous parents of German descent. The pregnancy with him was described as uneventful with no evidence of mutagenic or teratogenic exposure. It was a spontaneous vaginal delivery with a birth weight of 3,460 g. Multiple skin appendages were noted around his left eye and left face (Fig. 1).The left eyeball appeared small. Area of hypoplastic skin were noted on the left groin surrounding the base of the penis (Fig. 2) and on the left palm. A tiny spot of hairy skin was noted on his right chest. The CT scan and MRI of the brain showed severe microphthalmia of the left eye, underdevelopment of the left frontal lobe (Fig. 3), absence of corpus callosum and thickness of the tectum (Fig. 4). High-resolution chromosomes at 550-850 band stage did not show any microscopically discernible structural anomaly. The skin appendages were removed in early infancy. An enucleation of the rudimentary left eye followed by implantation of an eye prosthesis was performed at 8 months. Bilateral orchidopexy was done at 2 years. His gross psychomotor development was mildly delayed. He rolled over at 6 months, sat alone at 7% months, crawled at 15 months, and walked at 18 months. He was enrolled in a developmental therapy program with physical and occupational therapies beginning at age 9 months. Muscle strength was deemed normal but voluntary motor control and movement patterns were delayed. His mental development assessments via the Mental Scale of the Bayley Scales of Infant Development (BSID) indicated a steady but slower than normal rate of mental
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Fig. 4. Magnetic resonance imaging at age 5 months showing absence of corpus callosum and thickness of tectum (arrow). Fig. 1. Newborn patient before removal of the skin appendages on left half of the face.
growth with MDI’s over multiple BSID tests ranging from 60 to 75. Deficits were primarily in the sensorymotor area. He demonstrated a left-sided dominance with a reluctance to perform bilateral movements. Lack of bilateral vision also affected hand-eye coordination and visual perceptual development. Expressive and re ceptive language developmentprogressed normally dur ing the first 2112 years of life. At age 3 years he appeared alert and responsive to his environment. He was more irritable than average and did not respond well to handling by unfamiliar adults. In a structured situation he displayed below average concentration and persistence. No seizure activity has ever been observed. He is the only affected case in the family. Two younger twin brothers have recently been born and are not affected. Fig. 2. Thin and hypoplastic integument on the left groin with skin appendage on the medial margin.
Fig. 3. Hypoplasia of the left frontal lobe with dilatation of the left ventricle at age 5 months.
DISCUSSION In the review of 16 patients Bleeker-Wagemakers al. (1990)noted that orbital cysts, skin appendages, and skin hypoplasia were found in over 85%of patients; 75% had mental retardation; 60-70% had either seizures, microphthalmia, intracranial cyst or skull defect. About half did not have a corpus callosum. Eyelid coloboma, rib “dysplasia,” generalized asymmetry or cleft lip/palate were noted in 20-30% of the patients. Most anomalies are confined to the eye, the brain and the skin; thus, the term “oculocerebrocutaneous” syndrome does appear appropriate. As noted by Bleeker-Wagemakers et al. (1990), Ladenheim and Metrick 119561were apparently the first to describe this entity, but it was Delleman and Oorthuys [19811 who first raised the notion of a new syndromic entity. The acronym “Delleman syndrome” has been cited in the literature and it is easier to remember than the term “oculocerebrocutaneous.” The real incidence of the syndrome might be far higher than is estimated from the number Of published cases. Cases of orbital cysts [Renard et al., 19641 are
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likely incomplete forms of the same syndrome. Furthermore, as noted by Walbaum [1984], other cases have apparently been reported under other denominations such as “encephalo-oculo-cutaneous dysplasia” [Haberland and Perou, 1970; Fishman et al., 1984;Walbaum et al., 19791. The prognosis for mental development of our patient was initially considered to be guarded, as his early CT scan and MRI of the brain showed rather obvious anomalies. However, he has so far been functioning and developing much better than expected. The enrollment in infant stimulation program has certainly benefitted him. The patient of Wilson et al. [19841has also apparently done well. About 75% of the reported patients showed mental retardation and 25% appeared t o have functioned relatively well. Findings on the CT scan and MRI might not predict the severity of mental retardation. The major affected organsltissues-eye, brain, and skin-are of ectodermal origin. The orbital cysts displayed neuroepithelial hamartomatous structures and the skin appendages were essentially epithelial hamartomatous tissues [Al-Gazali et al., 19881.These hamartomatous structures and the hyperplastic tectum suggest an uncontrolled hyperplasia of those ectodermal tissues. On the other hand, the microphthalmia, the skin hypoplasia, the hypoplasia of cerebrum and the agenesis of corpus callosum indicate hypo-/aplasia of the same ectodermal tissues. It seem that a regulatory mechanism for a normal and balanced development of those ectodermal tissues has been disturbed. It is also interesting to note that the disorder usually affects only one side of the body. In our patient, the cerebral hypoplasia, the microphthalmia, the skin appendages, and the focal skin hypoplasia are found on the left side. In fact, most reported cases also show left involvement. The ratio of unilateral left involvement to unilateral right involvement is about 2 :1. Bilateral presence of orbital or intracranial cysts has been reported in some of the patients. Nonetheless, there is still a predominantly affected side or a unilateral predominance. Happle [1987] postulated that this disorder might be caused by a somatic mutation of an autosomal “dominant” lethal gene, which is only compatible with survival in the mosaic state. Thus, in our patient, a single mutated ectodermal cell multiplied and migrated to become parts of his left forebrain, the left side of his face, his left palm and his left groin. But it is more difficult to envision that a similar genetic defect can result in apparently opposite anomalies of the same tissues, for instance, the hamartomatous structure of skin appendages versus the hypoplastic skin lesions. Perhaps, these seemingly opposite anomalies could be explained as follows: If an uncontrolled cystic growth occurs in the eyeanlage, the rest of the eye-anlage would develop poorly and result in a micro-Ianophthalmia. As a matter of fact, skin appendages were noted at the medial margin of the hypoplastic skin area at the left groin of our patient. It is possible that in the course of further embryonal and fetal development, the hyperplastic lesions can regress and the hypoplastic lesions can be “healed.” This would
account for the absence of orbital cyst in our patient, the lack of skin appendages around punch-like lesions in most patients, as well as the lack of hypoplastic lesions surrounding most skin appendages. An alternative hypothesis of an external factor as the cause of this disorder might better explain the unilateral predominance in this disorder. Aside from the well-documented and widely cited lateral asymmetry of human brain [Corballis, 19831, it is known that in human fetuses, on average, right gonads tend to develop faster than left gonads, right gonads exceed left gonads in weight, protein, and DNA contents, and hence in numbers of cells [Mittwoch and Kirk, 1975; Mittwoch, 19761.Likewise, the upper limbs tend to develop earlier than the lower limbs, so as the right limbs in comparison to the left limbs (Judy Hall, personal communication).It can therefore be assumed that there might be a subtle right and left difference in the timing of embryonal ectodermal development, in which the right side might develop earlier than the left side. Thus, a “brief exposure’’ to an as yet unknown external factor at the most sensitive period of ectodermal development will likely cause an unilateral disturbance of development.An earlier exposure will result in a right-sided lateralization, whereas a later exposure will result in a left unilateral predominance. If the “short exposure” occurs at the moment the large portion of the right side has finished its development and the large portion of the left side has just started its own, bilateral involvement can be the result. A similar non-simultaneous developmental timing of ectodermal tissue within one side might explain the patchy skin lesions under this non-genetic hypothesis. Similar subtle right advancement in the limb development resulting in right predominance of limb anomaly following teratogenic exposure at certain period of embryonal development has also been observed in mouse embryos [Milaire, 19851.
ACKNOWLEDGMENTS We wish to thank Ms. Sandra Dunworth (Center for Craniofacial Anomalies, University of Illinois) for assistance in collecting the clinical data; Dr. Glen Dobbin (Department of Radiology, University of Illinois) for assistance in interpretation of the MRI and CT scan films; Dr. Judith Hall (Department of Medical Genetics, University of British Columbia) and Dr. Kathy Sulik (Department of Cell Biology and Anatomy, The University of North Carolina) for discussion on lateral asymmetry of embryonal development. REFERENCES Al-Gazali LI, Donnai D, Berry SA, Say B, Mueller RF (1988): The oculocerebrocutaneous (Delleman) syndrome. J Med Genet 25~773-778. Bleeker-Wagemakers LM, Hamel BC, Hennekam RCM, Beemer FA, Oorthuys HWN (1990): Oculocerebrocutaneous syndrome. J Med Genet 27:69, 70. Braun-Vallon S, Joseph R, Hezelof C, Ribierre M, Lagraulet J (1958): Un cas de teratome de I’orbite. Bull Mem SOCFr Ophtalmol 58:805-809. Brodsky MC, Harper RA, Keppen LD, Glasier CM (1990): Anophthalmia in Delleman syndrome. Am J Med Genet 37:157, 158. Clericuzio C (1989):Oculocerebrocutaneous syndrome and the family
Oculocerebrocutaneous Syndrome of neurodermal disorders: developmental consideration. Proceedings of the 10th David W. Smith workshop on malformation and morphogenesis. Madrid, Spain, 23-29 May, 1989:39. Corballis MC (1983):“Human Laterality.” New York: Academic Press. Delleman JW, Oorthuys JWE (1981): Orbital cyst in addition to congenital cerebral and focal dermal malformations: A new entity? Clin Genet 19:191-198. Delleman JW, Oorthuys JWE, Bleeker-Wagemakers EM, Ter Haar BGA, Ferguson JW (1984): Orbital cyst in addition to congenital cerebral and focal dermal malformations: A new entity! Clin Genet 25470-4’72. Dollfus MA, Marx P, Langlois J , Clement JC, Farthomme J (1968): Congenital cystic eyeball. Am J Ophthalmol 66504-509. Ferguson JW, Hutchison HT, Rouse BM (1984): Oculo, cerebral and cutaneous malformation: confirmation of a n association. Clin Genet 25:464-469. Fishman MA, Chang CSC, Miller J E (1984): Encephalocraniocutaneous lipomatosis. Pediatrics 61:580-582. Giorgi PL, Gabrielli 0, Catassi C, Coppa GV (1989): Oculocerebrocutaneous syndrome: description of a new case. Eur J Pediatr 148:325, 326. Haberland C, Perou M (1970):Encephalocraniocutaneous lipomatosis. A new example of ectomesodermal dysgenesis. Arch Neurol 22:144-155. Happle R (1987): Lethal genes surviving by mosaicism: a possible
293
explanation for sporadicbirth defects involving the skin. J Am Acad Dermatol 162399-906. Ladenheim J, Metrick S (1956):Congenital microphthalmos with cyst formation. Am J Ophthalmol 41:1059-1062. Milaire J (1985):Histological changes induced in developing limb buds of C57B1 mouse embryos submitted in utero to the combined influence of acetazolamide and cadmium sulphate. Teratology 32: 433-451. Mittwoch U (1976): Differential growth of human fetal gonads with respect to sex and body side. Ann Hum Genet 40:133-138. Mittwoch U, Kirk D (1975): Superior growth of the right gonad in human fetuses. Nature 257991, 792. Renard G, Fontaine M, Dhermy P, Caquet N (1964): Microphtalmie bilaterale avec kystes orbitaires associee a des appendices faciaux Fr Ophthalmol 77:297-316. surnumeraires. Bull Mem SOC Saraux H, Offret H (1967): Les choristomes corneo-conjunctivaux. J Genet Hum [Suppl] 24:ll-22. Walbaum R (1984):Encephalo-oculo-cutaneousdysplasia. Clin Genet 26:493, 494. Walbaum R, Van de Velde-Staquet MF, Bahon-le-Capon J, Bondiquet B, Dhellemmes P, Krivosic R, Fontaine G (1979):Neurolipomatose avec dysplasic encephalo-oculo-cutanee.Pediatrie 34:717-723. Wilson RD, Traverse L, Hall JG, Flodmark CO, Rootman J (1985): Oculocerebrocutaneous syndrome. Am J Ophthalmol99:142-148.
Oculocerebrocutaneous (Delleman) Syndrome: A Pleiotropic Disorder Affecting Ectodermal Tissues With Unilateral Predominance Joe J. Hoo, Kathleen Kapp-Simon, Beverly Rollnick, and Margaret Chao Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center (J.J.H.) and Center for Craniofacial Anomalies, University of Illinois (K.K.-S.,B.R.) and Department of Pediatrics, Cook County Hospital (M.C.), Chicago
We present a patient with oculocerebrocutaneous syndrome. The boy shows only mild psychomotor delay in spite of rather severe appearing anomalies of the central nervous system. A primarily unilateral involvement of this syndrome is emphasized. A postzygotic/ somatic mutation resulting in a mosaic state might account for the primarily ectodermal involvement, the unilateral predominance, and the sporadic nature of this syndrome. An alternative hypothesis of an environmental factor might also explain the clinical manifestations of the syndrome. KEY WORDS: oculocerebrocutaneous syndrome, Dellemen syndrome, orbital cyst, skin appendages, skin hypoplasia, somatic mutation, environmental factor INTRODUCTION Delleman and Oorthuys [19811 reported on 2 Dutch children with a syndrome of multiple congenital anomalies consisting of orbital cysts, micro-/anophthalmia, malformation of the central nervous system, focal dermal hypoplasia, and skin appendages. They suggested the term “oculocerebrocutaneous” syndrome. Three other cases [Delleman et al., 1984;Ferguson et al., 1984; Wilson et al., 19851 were reported subsequently. In 1988, Al-Gazali et al. reviewed the above 5 cases and their own 4, and coined the eponym “Delleman” syndrome. Giorgi et al. [19891, Clericuzio [19891 and Brodsky et al. [1990] each added another case. Most Received for publication June 7,1990; revision received November 2, 1990. Address reprint requests to Joe J . Hoo, M.D., Section ofGenetics, Department of Pediatrics, Rush-Presbyterian-St. Luke’s Medical Center, 1750 W. Harrison St., Chicago, IL 60612. This work is dedicated to the memory of Dr. Beverly Rollnick.
0 1991 Wiley-Liss, Inc.
recently, Bleeker-Wagemakers et al. [19901reported another Dutch patient. They also identified 4 other cases [Ladenheim and Metrick, 1956; Braun-Vallon et al., 1958; Saraux and Offret, 1967; Dollfus et al., 19681 in the literature without the term “oculocerebrocutaneous syndrome.” Thus, at least 17 cases are known. Here we report on a boy of German descent with oculocerebrocutaneous syndrome and emphasize the mild degree of his developmental delay.
CLINICAL REPORT B.B. is the first child of young, healthy, and nonconsanguineous parents of German descent. The pregnancy with him was described as uneventful with no evidence of mutagenic or teratogenic exposure. It was a spontaneous vaginal delivery with a birth weight of 3,460 g. Multiple skin appendages were noted around his left eye and left face (Fig. 1).The left eyeball appeared small. Area of hypoplastic skin were noted on the left groin surrounding the base of the penis (Fig. 2) and on the left palm. A tiny spot of hairy skin was noted on his right chest. The CT scan and MRI of the brain showed severe microphthalmia of the left eye, underdevelopment of the left frontal lobe (Fig. 3), absence of corpus callosum and thickness of the tectum (Fig. 4). High-resolution chromosomes at 550-850 band stage did not show any microscopically discernible structural anomaly. The skin appendages were removed in early infancy. An enucleation of the rudimentary left eye followed by implantation of an eye prosthesis was performed at 8 months. Bilateral orchidopexy was done at 2 years. His gross psychomotor development was mildly delayed. He rolled over at 6 months, sat alone at 7% months, crawled at 15 months, and walked at 18 months. He was enrolled in a developmental therapy program with physical and occupational therapies beginning at age 9 months. Muscle strength was deemed normal but voluntary motor control and movement patterns were delayed. His mental development assessments via the Mental Scale of the Bayley Scales of Infant Development (BSID) indicated a steady but slower than normal rate of mental
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291
Fig. 4. Magnetic resonance imaging at age 5 months showing absence of corpus callosum and thickness of tectum (arrow). Fig. 1. Newborn patient before removal of the skin appendages on left half of the face.
growth with MDI’s over multiple BSID tests ranging from 60 to 75. Deficits were primarily in the sensorymotor area. He demonstrated a left-sided dominance with a reluctance to perform bilateral movements. Lack of bilateral vision also affected hand-eye coordination and visual perceptual development. Expressive and re ceptive language developmentprogressed normally dur ing the first 2112 years of life. At age 3 years he appeared alert and responsive to his environment. He was more irritable than average and did not respond well to handling by unfamiliar adults. In a structured situation he displayed below average concentration and persistence. No seizure activity has ever been observed. He is the only affected case in the family. Two younger twin brothers have recently been born and are not affected. Fig. 2. Thin and hypoplastic integument on the left groin with skin appendage on the medial margin.
Fig. 3. Hypoplasia of the left frontal lobe with dilatation of the left ventricle at age 5 months.
DISCUSSION In the review of 16 patients Bleeker-Wagemakers al. (1990)noted that orbital cysts, skin appendages, and skin hypoplasia were found in over 85%of patients; 75% had mental retardation; 60-70% had either seizures, microphthalmia, intracranial cyst or skull defect. About half did not have a corpus callosum. Eyelid coloboma, rib “dysplasia,” generalized asymmetry or cleft lip/palate were noted in 20-30% of the patients. Most anomalies are confined to the eye, the brain and the skin; thus, the term “oculocerebrocutaneous” syndrome does appear appropriate. As noted by Bleeker-Wagemakers et al. (1990), Ladenheim and Metrick 119561were apparently the first to describe this entity, but it was Delleman and Oorthuys [19811 who first raised the notion of a new syndromic entity. The acronym “Delleman syndrome” has been cited in the literature and it is easier to remember than the term “oculocerebrocutaneous.” The real incidence of the syndrome might be far higher than is estimated from the number Of published cases. Cases of orbital cysts [Renard et al., 19641 are
292
Hoo et al.
likely incomplete forms of the same syndrome. Furthermore, as noted by Walbaum [1984], other cases have apparently been reported under other denominations such as “encephalo-oculo-cutaneous dysplasia” [Haberland and Perou, 1970; Fishman et al., 1984;Walbaum et al., 19791. The prognosis for mental development of our patient was initially considered to be guarded, as his early CT scan and MRI of the brain showed rather obvious anomalies. However, he has so far been functioning and developing much better than expected. The enrollment in infant stimulation program has certainly benefitted him. The patient of Wilson et al. [19841has also apparently done well. About 75% of the reported patients showed mental retardation and 25% appeared t o have functioned relatively well. Findings on the CT scan and MRI might not predict the severity of mental retardation. The major affected organsltissues-eye, brain, and skin-are of ectodermal origin. The orbital cysts displayed neuroepithelial hamartomatous structures and the skin appendages were essentially epithelial hamartomatous tissues [Al-Gazali et al., 19881.These hamartomatous structures and the hyperplastic tectum suggest an uncontrolled hyperplasia of those ectodermal tissues. On the other hand, the microphthalmia, the skin hypoplasia, the hypoplasia of cerebrum and the agenesis of corpus callosum indicate hypo-/aplasia of the same ectodermal tissues. It seem that a regulatory mechanism for a normal and balanced development of those ectodermal tissues has been disturbed. It is also interesting to note that the disorder usually affects only one side of the body. In our patient, the cerebral hypoplasia, the microphthalmia, the skin appendages, and the focal skin hypoplasia are found on the left side. In fact, most reported cases also show left involvement. The ratio of unilateral left involvement to unilateral right involvement is about 2 :1. Bilateral presence of orbital or intracranial cysts has been reported in some of the patients. Nonetheless, there is still a predominantly affected side or a unilateral predominance. Happle [1987] postulated that this disorder might be caused by a somatic mutation of an autosomal “dominant” lethal gene, which is only compatible with survival in the mosaic state. Thus, in our patient, a single mutated ectodermal cell multiplied and migrated to become parts of his left forebrain, the left side of his face, his left palm and his left groin. But it is more difficult to envision that a similar genetic defect can result in apparently opposite anomalies of the same tissues, for instance, the hamartomatous structure of skin appendages versus the hypoplastic skin lesions. Perhaps, these seemingly opposite anomalies could be explained as follows: If an uncontrolled cystic growth occurs in the eyeanlage, the rest of the eye-anlage would develop poorly and result in a micro-Ianophthalmia. As a matter of fact, skin appendages were noted at the medial margin of the hypoplastic skin area at the left groin of our patient. It is possible that in the course of further embryonal and fetal development, the hyperplastic lesions can regress and the hypoplastic lesions can be “healed.” This would
account for the absence of orbital cyst in our patient, the lack of skin appendages around punch-like lesions in most patients, as well as the lack of hypoplastic lesions surrounding most skin appendages. An alternative hypothesis of an external factor as the cause of this disorder might better explain the unilateral predominance in this disorder. Aside from the well-documented and widely cited lateral asymmetry of human brain [Corballis, 19831, it is known that in human fetuses, on average, right gonads tend to develop faster than left gonads, right gonads exceed left gonads in weight, protein, and DNA contents, and hence in numbers of cells [Mittwoch and Kirk, 1975; Mittwoch, 19761.Likewise, the upper limbs tend to develop earlier than the lower limbs, so as the right limbs in comparison to the left limbs (Judy Hall, personal communication).It can therefore be assumed that there might be a subtle right and left difference in the timing of embryonal ectodermal development, in which the right side might develop earlier than the left side. Thus, a “brief exposure’’ to an as yet unknown external factor at the most sensitive period of ectodermal development will likely cause an unilateral disturbance of development.An earlier exposure will result in a right-sided lateralization, whereas a later exposure will result in a left unilateral predominance. If the “short exposure” occurs at the moment the large portion of the right side has finished its development and the large portion of the left side has just started its own, bilateral involvement can be the result. A similar non-simultaneous developmental timing of ectodermal tissue within one side might explain the patchy skin lesions under this non-genetic hypothesis. Similar subtle right advancement in the limb development resulting in right predominance of limb anomaly following teratogenic exposure at certain period of embryonal development has also been observed in mouse embryos [Milaire, 19851.
ACKNOWLEDGMENTS We wish to thank Ms. Sandra Dunworth (Center for Craniofacial Anomalies, University of Illinois) for assistance in collecting the clinical data; Dr. Glen Dobbin (Department of Radiology, University of Illinois) for assistance in interpretation of the MRI and CT scan films; Dr. Judith Hall (Department of Medical Genetics, University of British Columbia) and Dr. Kathy Sulik (Department of Cell Biology and Anatomy, The University of North Carolina) for discussion on lateral asymmetry of embryonal development. REFERENCES Al-Gazali LI, Donnai D, Berry SA, Say B, Mueller RF (1988): The oculocerebrocutaneous (Delleman) syndrome. J Med Genet 25~773-778. Bleeker-Wagemakers LM, Hamel BC, Hennekam RCM, Beemer FA, Oorthuys HWN (1990): Oculocerebrocutaneous syndrome. J Med Genet 27:69, 70. Braun-Vallon S, Joseph R, Hezelof C, Ribierre M, Lagraulet J (1958): Un cas de teratome de I’orbite. Bull Mem SOCFr Ophtalmol 58:805-809. Brodsky MC, Harper RA, Keppen LD, Glasier CM (1990): Anophthalmia in Delleman syndrome. Am J Med Genet 37:157, 158. Clericuzio C (1989):Oculocerebrocutaneous syndrome and the family
Oculocerebrocutaneous Syndrome of neurodermal disorders: developmental consideration. Proceedings of the 10th David W. Smith workshop on malformation and morphogenesis. Madrid, Spain, 23-29 May, 1989:39. Corballis MC (1983):“Human Laterality.” New York: Academic Press. Delleman JW, Oorthuys JWE (1981): Orbital cyst in addition to congenital cerebral and focal dermal malformations: A new entity? Clin Genet 19:191-198. Delleman JW, Oorthuys JWE, Bleeker-Wagemakers EM, Ter Haar BGA, Ferguson JW (1984): Orbital cyst in addition to congenital cerebral and focal dermal malformations: A new entity! Clin Genet 25470-4’72. Dollfus MA, Marx P, Langlois J , Clement JC, Farthomme J (1968): Congenital cystic eyeball. Am J Ophthalmol 66504-509. Ferguson JW, Hutchison HT, Rouse BM (1984): Oculo, cerebral and cutaneous malformation: confirmation of a n association. Clin Genet 25:464-469. Fishman MA, Chang CSC, Miller J E (1984): Encephalocraniocutaneous lipomatosis. Pediatrics 61:580-582. Giorgi PL, Gabrielli 0, Catassi C, Coppa GV (1989): Oculocerebrocutaneous syndrome: description of a new case. Eur J Pediatr 148:325, 326. Haberland C, Perou M (1970):Encephalocraniocutaneous lipomatosis. A new example of ectomesodermal dysgenesis. Arch Neurol 22:144-155. Happle R (1987): Lethal genes surviving by mosaicism: a possible
293
explanation for sporadicbirth defects involving the skin. J Am Acad Dermatol 162399-906. Ladenheim J, Metrick S (1956):Congenital microphthalmos with cyst formation. Am J Ophthalmol 41:1059-1062. Milaire J (1985):Histological changes induced in developing limb buds of C57B1 mouse embryos submitted in utero to the combined influence of acetazolamide and cadmium sulphate. Teratology 32: 433-451. Mittwoch U (1976): Differential growth of human fetal gonads with respect to sex and body side. Ann Hum Genet 40:133-138. Mittwoch U, Kirk D (1975): Superior growth of the right gonad in human fetuses. Nature 257991, 792. Renard G, Fontaine M, Dhermy P, Caquet N (1964): Microphtalmie bilaterale avec kystes orbitaires associee a des appendices faciaux Fr Ophthalmol 77:297-316. surnumeraires. Bull Mem SOC Saraux H, Offret H (1967): Les choristomes corneo-conjunctivaux. J Genet Hum [Suppl] 24:ll-22. Walbaum R (1984):Encephalo-oculo-cutaneousdysplasia. Clin Genet 26:493, 494. Walbaum R, Van de Velde-Staquet MF, Bahon-le-Capon J, Bondiquet B, Dhellemmes P, Krivosic R, Fontaine G (1979):Neurolipomatose avec dysplasic encephalo-oculo-cutanee.Pediatrie 34:717-723. Wilson RD, Traverse L, Hall JG, Flodmark CO, Rootman J (1985): Oculocerebrocutaneous syndrome. Am J Ophthalmol99:142-148.
