American Journal of Medical Genetics 43:946-948 ( 1992)
Ophthalmological, Skeletal, and Cardiac Abnormalities in Sibs Born to Consanguineous Parents: A New Syndrome? Rita de Cassia Stocco dos Santos, Nelson H.C. Castro, Oilita Pereira Ferraz, Janete Walter-Moura, Zan Mustachi, Nina A.B. Pagnan, and Thomaz R. Gollop Seruiqo de Genktica, Instituto Butantan (R.C.S.S., N.H.C.C., OP.F., J . W.M.), Hospital Infantil Darcy Vargas (Z.M.), and Instituto de Medicina Fetal e Gene‘tica Humana (N.A.B.?’., T.R.G.), Scio Paulo, Brazil We report on a sibship from a consanguineous couple consisting of one boy with anophthalmia, one boy with buphthalmos and multiple congenital skeletal, muscle, and cardiac abnormalities, and a stillborn girl with anophthalmia and cardiac and skeletal abnormalities.A possible new syndromeof autosoma1 recessive inheritance and variable expressivity is discussed, comparing this report with others. o 1992 Wiley-Liss, Inc.
KEY WORDS: Anophthalmia,megalocornea, buphthalmos, consanguinity INTRODUCTION Some congenital anomalies present such wide variability that diagnosis and estimates of recurrence risk are difficult. One of these disorders is anophthalmia, which has been reported to occur in two general forms: 1)primary or true when there are no optic renmants and 2) secondary, when an extreme form of microphthalmia is present [Richieri-Costa et al., 19831. In some cases, it may be difficult to distinguish between the two types and some authors prefer the term “clinical anophthalmia” to designate the apparent absence of the ocular globes [Aughton, 19901. Here, we report on the presence of anophthalmia in a sibship from a consaguineous couple. One of the children had only anophthalmia and coloboma; another had megalocornea, aniridia, lens luxation, and cardiac, skeletal, and muscle abnormalities; the third (a stillborn girl) was described as having anophthalmia and limb and heart malformations.
Received for publication May 30,1991; revision received October 6, 1991. Address reprint requests to Rita de Cassia Stocco dos Santos, ServiCo de Genetica-Instituto Butantan, P.O. Box 65, S8o Paulo, Brazil.
0 1992 Wiley-Liss, Inc.
CLINICAL REPORTS The consaguineous couple (M.P.S., a 41-year-old woman and J.A.S., a 37-year-oldman) are black second cousins (Fig. 1)(III-lO,III-9).She had had 4 pregnancies which resulted in 2 boys, a stillborn girl, and an induced abortion. R.P.S. (a 10-year-oldboy), 1st child of the couple (Figs. 1, 2a), was born at term after a normal pregnancy and delivery. We have no information about birthweight or neonatal events. When the parents were seen for genetic counseling, the boy was 10 years old and the only clinical abnormalities detected involved the eyes: left anophthalmia with blepharophymosis and right partial coloboma. Computerized tomography (Fig. 3a) showed absence of the left globe and optic nerve. All other physical parameters were normal for age and his intelligence was normal. R.S. (a 6-year-old boy), 3rd child of the couple, (Fig. 1, 2b,c) was born at term for normal delivery. He was not evaluated at birth and the mother reported that he could walk at age 2 years. At age 6 years his height was 106 cm (10th centile) and he showed remarkable muscle hypoplasia and growth retardation. He also had dolichocephaly, skull asymmetry with right occipital depression, dysplastic ears with normal implantation, left supraorbital depression, and bilateral buphthalmos. Optical analysis showed bilateral megalocornea (14 mm), (Fig. 3b), multiple corneal endothelial defects, right aniridia, bilaterally detached retina, fibrous proliferation, and a very hight level of myopia. He also had prognathia, hypoplastic maxilla, high-arched palate, and long philtrum. His thorax was bell-shaped with a “pectus cavus.” Echo-dopplercardiography showed prolapse of the atrioventricular valves, moderate mitral insufficiency, and mild tricuspid insufficiency. He had a large umbilical hernia, a right inguinal hernia, bilateral cryptorchidism, severe scoliosis, and bilateral camptodactyly (second to fifth digit and second to fifth toe), plus ulnar deviation of all digits (Fig. 4). A muscle biopsy showed type I1 fiber atrophy. He has normal intelligence. The parents reported that the fourth child was a still-
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Fig. 1. Pedigree.
born girl with left anophthalmia, bilateral camptodactyly, clubfoot, and heart defect that we could verify through clinical report and that caused her death. The parents had normal eyes and there were no reports of ocular anomalies in the pedigree. M.P.S.,the mother of the sibs, had fifth finger clinodactyly. Chromosomes of the parents and patients were normal.
DISCUSSION We conclude that the sibs reported here have a genetic disorder distinct from those already described due to the unique combination of anophthalmia, coloboma, aniridia, buphthalmos, megalocornea, and cardiac, muscular, and skeletal anormalities with normal intelligence. Waardenburg [19611, Richieri-Costa et al. [19831, and
Fig. 2. a: PatientR.P.S., age 10 years. b,c:Patient R.S., age 6 years.
Fig. 3. Computerized tomography (a): Patient R.P.S.-left ophthalmia: (b):Patient R.S.-bilateral megalocornea.
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Stocco dos Santos et al. The eye defects detected in the present sibship (anophthalmia, coloboma, aniridia, and megalocornea) may be argued to be different expressions of a defective embryonic process. Considering that the parents of our patients are consanguineous, we propose that this may be an autosomal recessive trait.
ACKNOWLEDGMENTS We are indebted to Dr. Isaac Neustein for ophthalmological examination, Roseli da Silva for careful edition and typing, and Luiz Antonio Tadeu Dias for photographic documentation. This work was supported by CNPq. REFERENCES Fig. 4. Radiological aspects of patient R.S ulnar deviation of digits.
Merrer et al. [19881 reported anophthalmia associated with camptodactyly. Klein and F’ranceschetti [19661described secondary anophthalmia and mental retardation. Pearce et al. [19741reported anophthalmia associated with visceral anomalities, while Gorlin et al. [19631 described the association of microphthalmia, iris changes, syndactyly, camptodactyly, hypoplastic dental enamel, and speech anomalies. Brunquell et al. C19841 described true anophthalmia in a patient with seizures, mental retardation, and scoliosis.Atkin and PatilL19841 described true anophthalmia in a patient with seizures, mental retardation, and scoliosis,Atkin and Patil[19841 described microphthalmos, visceral malformations, and ectrodactyly. Donnenfeld et al. [19901reported microphthalmia and chorioretinal lesions, and Aughton [19901 reported bilateral clinical anophthalmia and a small mandible. Keppen et al. [19901reported mental retardation, microphthalmia, and hypogonadotropic hypogonadism. These reports show the variability of anomalies associated with anophthalmia or microphthalmia and other eye defects such as coloboma and chrorioretinal anomalies. As to the pattern of inheritance, the presence of consanguineous parents in some reports suggests autosomal recessive traits, while in other cases, an X-linked pattern was verified [Atkin and Patil, 19841.
Atkin JF, Patil S (1984): Apparently new oculo-cerebro-acral syndrome. Am J Med Genet 19:585-587. Aughton DJ (1990): Clinical anophthalmia, dextrocardia and skeletal anomalies in an infant born to consanguineous parents. Am J Med Genet 37:178-181. Brunquell PJ, Papale JH, Horton JC, Williams RS,Zgrabik MJ, Albert DM, Hedley-Whyte ET (1984): Sex-linked hereditary bilateral anophthalmos, pathologic and radiologic correlation. Arch Ophthalmol 102:108-113. Donnenfeld AE,Graham Jr JM, Packer RJ, Aquino R, Berg SZ, Emanuel BS (1990):Microphthalmia and chorioretinal lesions in a girl with a n Xp22.2-pter deletion and partial 3p trisomy: Clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 37:182-186. Gorlin RJ,Meskin LH, Gene JW St (1963): Oculodentodigital dysplasia. J Pediatr 6359-75. Keppen LD, Brodsky MC, Michael JM, Poindexter AR (1990): Hypogonadotropic hypogonadism in mentally retarded adults with microphthalmia and clinical anophthalmia. Am J Med Genet 36:285287. Klein D, Franceschetti A (1966): Missbildungen und Krankheiten des Auges. In Becker PE (ed): “Humangenetik.” Stuttgart George Thieme Verlag, Vol 4. Merrer ML, Nessmann C, Briard ML, Maroteaux P (1988): Ophthalmoacromelic syndrome. Ann Genet 31:226-229. Pearce WG, Nigam S, Rootman J (1974):Primary anophthalmos, histological and genetic features. Can J Ophthalmol 9:141-145. Richieri-Costa A, Gollop TR, Otto PG (1983): Autosomal recessive anophthalmia with multiple congenital abnormalities, Type Waardenburg. Am J Med Genet 14507-615. Waardenburg P J (1961): Autosomally-recessive anophthalmia with malformations of the hands and feet. In Waardenburg PJ, Franceschetti A, Klein D (eds): “Genetics and Ophthalmology,” Vol 1. Assen: Royal Van Gorcum.
Ophthalmological, Skeletal, and Cardiac Abnormalities in Sibs Born to Consanguineous Parents: A New Syndrome? Rita de Cassia Stocco dos Santos, Nelson H.C. Castro, Oilita Pereira Ferraz, Janete Walter-Moura, Zan Mustachi, Nina A.B. Pagnan, and Thomaz R. Gollop Seruiqo de Genktica, Instituto Butantan (R.C.S.S., N.H.C.C., OP.F., J . W.M.), Hospital Infantil Darcy Vargas (Z.M.), and Instituto de Medicina Fetal e Gene‘tica Humana (N.A.B.?’., T.R.G.), Scio Paulo, Brazil We report on a sibship from a consanguineous couple consisting of one boy with anophthalmia, one boy with buphthalmos and multiple congenital skeletal, muscle, and cardiac abnormalities, and a stillborn girl with anophthalmia and cardiac and skeletal abnormalities.A possible new syndromeof autosoma1 recessive inheritance and variable expressivity is discussed, comparing this report with others. o 1992 Wiley-Liss, Inc.
KEY WORDS: Anophthalmia,megalocornea, buphthalmos, consanguinity INTRODUCTION Some congenital anomalies present such wide variability that diagnosis and estimates of recurrence risk are difficult. One of these disorders is anophthalmia, which has been reported to occur in two general forms: 1)primary or true when there are no optic renmants and 2) secondary, when an extreme form of microphthalmia is present [Richieri-Costa et al., 19831. In some cases, it may be difficult to distinguish between the two types and some authors prefer the term “clinical anophthalmia” to designate the apparent absence of the ocular globes [Aughton, 19901. Here, we report on the presence of anophthalmia in a sibship from a consaguineous couple. One of the children had only anophthalmia and coloboma; another had megalocornea, aniridia, lens luxation, and cardiac, skeletal, and muscle abnormalities; the third (a stillborn girl) was described as having anophthalmia and limb and heart malformations.
Received for publication May 30,1991; revision received October 6, 1991. Address reprint requests to Rita de Cassia Stocco dos Santos, ServiCo de Genetica-Instituto Butantan, P.O. Box 65, S8o Paulo, Brazil.
0 1992 Wiley-Liss, Inc.
CLINICAL REPORTS The consaguineous couple (M.P.S., a 41-year-old woman and J.A.S., a 37-year-oldman) are black second cousins (Fig. 1)(III-lO,III-9).She had had 4 pregnancies which resulted in 2 boys, a stillborn girl, and an induced abortion. R.P.S. (a 10-year-oldboy), 1st child of the couple (Figs. 1, 2a), was born at term after a normal pregnancy and delivery. We have no information about birthweight or neonatal events. When the parents were seen for genetic counseling, the boy was 10 years old and the only clinical abnormalities detected involved the eyes: left anophthalmia with blepharophymosis and right partial coloboma. Computerized tomography (Fig. 3a) showed absence of the left globe and optic nerve. All other physical parameters were normal for age and his intelligence was normal. R.S. (a 6-year-old boy), 3rd child of the couple, (Fig. 1, 2b,c) was born at term for normal delivery. He was not evaluated at birth and the mother reported that he could walk at age 2 years. At age 6 years his height was 106 cm (10th centile) and he showed remarkable muscle hypoplasia and growth retardation. He also had dolichocephaly, skull asymmetry with right occipital depression, dysplastic ears with normal implantation, left supraorbital depression, and bilateral buphthalmos. Optical analysis showed bilateral megalocornea (14 mm), (Fig. 3b), multiple corneal endothelial defects, right aniridia, bilaterally detached retina, fibrous proliferation, and a very hight level of myopia. He also had prognathia, hypoplastic maxilla, high-arched palate, and long philtrum. His thorax was bell-shaped with a “pectus cavus.” Echo-dopplercardiography showed prolapse of the atrioventricular valves, moderate mitral insufficiency, and mild tricuspid insufficiency. He had a large umbilical hernia, a right inguinal hernia, bilateral cryptorchidism, severe scoliosis, and bilateral camptodactyly (second to fifth digit and second to fifth toe), plus ulnar deviation of all digits (Fig. 4). A muscle biopsy showed type I1 fiber atrophy. He has normal intelligence. The parents reported that the fourth child was a still-
Megalocornea and Anophthalmia
947
I
I1
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Fig. 1. Pedigree.
born girl with left anophthalmia, bilateral camptodactyly, clubfoot, and heart defect that we could verify through clinical report and that caused her death. The parents had normal eyes and there were no reports of ocular anomalies in the pedigree. M.P.S.,the mother of the sibs, had fifth finger clinodactyly. Chromosomes of the parents and patients were normal.
DISCUSSION We conclude that the sibs reported here have a genetic disorder distinct from those already described due to the unique combination of anophthalmia, coloboma, aniridia, buphthalmos, megalocornea, and cardiac, muscular, and skeletal anormalities with normal intelligence. Waardenburg [19611, Richieri-Costa et al. [19831, and
Fig. 2. a: PatientR.P.S., age 10 years. b,c:Patient R.S., age 6 years.
Fig. 3. Computerized tomography (a): Patient R.P.S.-left ophthalmia: (b):Patient R.S.-bilateral megalocornea.
an-
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Stocco dos Santos et al. The eye defects detected in the present sibship (anophthalmia, coloboma, aniridia, and megalocornea) may be argued to be different expressions of a defective embryonic process. Considering that the parents of our patients are consanguineous, we propose that this may be an autosomal recessive trait.
ACKNOWLEDGMENTS We are indebted to Dr. Isaac Neustein for ophthalmological examination, Roseli da Silva for careful edition and typing, and Luiz Antonio Tadeu Dias for photographic documentation. This work was supported by CNPq. REFERENCES Fig. 4. Radiological aspects of patient R.S ulnar deviation of digits.
Merrer et al. [19881 reported anophthalmia associated with camptodactyly. Klein and F’ranceschetti [19661described secondary anophthalmia and mental retardation. Pearce et al. [19741reported anophthalmia associated with visceral anomalities, while Gorlin et al. [19631 described the association of microphthalmia, iris changes, syndactyly, camptodactyly, hypoplastic dental enamel, and speech anomalies. Brunquell et al. C19841 described true anophthalmia in a patient with seizures, mental retardation, and scoliosis.Atkin and PatilL19841 described true anophthalmia in a patient with seizures, mental retardation, and scoliosis,Atkin and Patil[19841 described microphthalmos, visceral malformations, and ectrodactyly. Donnenfeld et al. [19901reported microphthalmia and chorioretinal lesions, and Aughton [19901 reported bilateral clinical anophthalmia and a small mandible. Keppen et al. [19901reported mental retardation, microphthalmia, and hypogonadotropic hypogonadism. These reports show the variability of anomalies associated with anophthalmia or microphthalmia and other eye defects such as coloboma and chrorioretinal anomalies. As to the pattern of inheritance, the presence of consanguineous parents in some reports suggests autosomal recessive traits, while in other cases, an X-linked pattern was verified [Atkin and Patil, 19841.
Atkin JF, Patil S (1984): Apparently new oculo-cerebro-acral syndrome. Am J Med Genet 19:585-587. Aughton DJ (1990): Clinical anophthalmia, dextrocardia and skeletal anomalies in an infant born to consanguineous parents. Am J Med Genet 37:178-181. Brunquell PJ, Papale JH, Horton JC, Williams RS,Zgrabik MJ, Albert DM, Hedley-Whyte ET (1984): Sex-linked hereditary bilateral anophthalmos, pathologic and radiologic correlation. Arch Ophthalmol 102:108-113. Donnenfeld AE,Graham Jr JM, Packer RJ, Aquino R, Berg SZ, Emanuel BS (1990):Microphthalmia and chorioretinal lesions in a girl with a n Xp22.2-pter deletion and partial 3p trisomy: Clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 37:182-186. Gorlin RJ,Meskin LH, Gene JW St (1963): Oculodentodigital dysplasia. J Pediatr 6359-75. Keppen LD, Brodsky MC, Michael JM, Poindexter AR (1990): Hypogonadotropic hypogonadism in mentally retarded adults with microphthalmia and clinical anophthalmia. Am J Med Genet 36:285287. Klein D, Franceschetti A (1966): Missbildungen und Krankheiten des Auges. In Becker PE (ed): “Humangenetik.” Stuttgart George Thieme Verlag, Vol 4. Merrer ML, Nessmann C, Briard ML, Maroteaux P (1988): Ophthalmoacromelic syndrome. Ann Genet 31:226-229. Pearce WG, Nigam S, Rootman J (1974):Primary anophthalmos, histological and genetic features. Can J Ophthalmol 9:141-145. Richieri-Costa A, Gollop TR, Otto PG (1983): Autosomal recessive anophthalmia with multiple congenital abnormalities, Type Waardenburg. Am J Med Genet 14507-615. Waardenburg P J (1961): Autosomally-recessive anophthalmia with malformations of the hands and feet. In Waardenburg PJ, Franceschetti A, Klein D (eds): “Genetics and Ophthalmology,” Vol 1. Assen: Royal Van Gorcum.
