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Anophthalmia, Multiple Abnormalities, and Unusual Karyotype
ANOPHTHALMIA, MULTIPLE ABNORMALITIES, AND UNUSUAL KARYOTYPE SAMUEL MASKET, M.D.,
FRANK M.
MILTON BEST,
GALIOTO, JR., M.D.,
AND
M.D.
New York, New York Anophthalmia is a rare clinical entity, about 100 cases having been reported since 1900. 1 E x t r e m e microphthalmos can be dif ferentiated from absolute anophthalmos only by careful histologie study of the orbital tis sues on postmortem examination. I n all, there have been only 10 such cases where mi croscopic study of the orbit has revealed no evidence of ocular structure. 2 Because such differentiation is difficult, the term clinical anophthalmia is appropriate when it appears that no ocular tissue is grossly present in the orbit. T h e following case report describes a child with bilateral clinical anophthalmia as sociated with an unusual combination of congenital abnormalities and an abnormal karyotype. C A S E REPORT
A boy, two years and nine months of age, was admitted to the hospital for evaluation of multiple congenital defects. He was born to a 23-year-old Puerto Rican mother by normal spontaneous deliv ery after a nine-month gestation. The exact birth weight is unknown. At birth it was noted the child had a normal cry, but that he was flaccid and had bilateral anophthalmia as well as absence of one toe on each foot. Careful discussion of family history revealed no abnormalities in either parent or in four siblings of the propositus. It was learned, however, that in the fifteenth week of the mother's pregnancy she in jured her lower back and underwent radiographie study of the lumbosacral region which revealed a nondisplaced fracture of the proximal coccygeal From the Department of Ophthalmology, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospital, Welfare Island, New York (Drs. Masket and Best), and the Department of Pediatrics, New York Medical College, Flower and Fifth Avenue Hospitals, New York, New York (Dr. Galioto). This study was aided in part by Grant 69-869 from the American Heart Association and USPHS Grant NB07162-04. Reprint requests to Dr. Milton Best, Department of Ophthalmology, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospi tal, Welfare Island New York, New York 10017. 381
segment. She received propoxyphene (Darvon) for pain. The growth and development of the propositus has been generally retarded. He cannot sit, stand, walk, or talk. He eats only baby foods and requires a bottle with nipple in order to drink. Physical ex amination revealed a small child (height 31 inches, weight 19J^ pounds) in no distress. Slight frontal bossing was evident, as well as patchy incomplete alopecia on the back of the head. The eyelids appeared normal and lacrimal puncta were present but the palpebral apertures were diminished bi laterally. Eyelid function was intact and when the child cried, lacrimation was noted. The orbits were 10-12 mm deep and lined by beefy colored, papillated conjunctiva. At the apex of each orbit there was a flat piece of yellow-gray tissue 3 mm in di ameter (Fig. 1). The ears, auditory canals and tympanic membranes were normal. Dentition was normal for age. The neck was flaccid and the child had poor head control. The chest and abdomen were unremarkable. The testes were descended bilaterally but small. Both hands had shortened fifth digits and hyperextensible small joints (Fig. 2), while the feet had four toes bilaterally and minor club-foot de formities (Fig. 3). Neurologic examination was nor mal except for general hypotonia of skeletal muscle. Laboratory results were the following: hemo globin electrophoretic pattern type AA ; urine nega tive for amino acids, phenylketones, and mucopolysaccharides ; VDRL negative ; rubella and toxoplasmosis antibody titers negative. The electrocardio gram and electroencephalogram were normal for
Fig. 1 (Masket, Galioto, and Best). The eyelids appear normal, but the orbit is shallow and no ocular structure is present.
382
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 2 (Masket, Galioto, and Best). Little finger of each hand is shortened. age. Chest x-ray films were normal, and radiographic study of the skull showed no evidence of fracture or intracranial calcification. The facial bones were slightly underdeveloped the orbits were small and the optic foramina were minute but pres ent bilaterally. Skeletal studies revealed spina bifida and bilateral congenital dislocation of the hips with pseudo-acetabular formation. Radiographic studies of the hands and wrists revealed that the bone age was six months. The shortening of the fifth digits on both hands was due to symmetrically shortened second phalanges. Studies of the feet showed ab sence of the lateral digits and fusion of the lateral metatarsals bilaterally. An intravenous pyelogram revealed crossed fused renal ectopia with no renal tissue present on the right side of the abdomen. The right ureter, however, passed across the midline, from the left side, to enter the bladder in a normal position. A renal scan confirmed the findings of crossed fused renal ectopia. Karyotyping, performed on the circulating white blood cells, showed that 90% of the cells were nor mal, but that 10% of the cells were polyploid, with chromosome numbers of approximately 60. Ocular examination of the parents and two of the siblings revealed no abnormalities.
SEPTEMBER, 1970
tion, and an abnormal karyotype consisting of 1 0 % polyploid cells. T o our knowledge this combination of anomalies has not been previously reported. T h e etiology of these congenital defects is obscure. It seems unlikely that all the anoma lies present could be the result of the moth er's injury or the radiologie study of the mother's lower back at 15 weeks' gestation. Anophthalmia has been described with tri somy of the large acrocentric chromosomes, numbers 13 to 15. Patau and co-authors 3 re ported a case wherein anophthalmia was as sociated with cleft lip and palate, cardiac malformations, mental retardation, and polydactyly. Ellis and Marwood 4 described a similar syndrome, but the eyes were present and had colobomata bilaterally. F o r the pres ent case trisomy 13-15 was not present but polyploidy was detected in the circulating white blood cells. Although polyploidy has
DISCUSSION
W e have described a child with bilateral clinical anophthalmos, shortened fifth digits of both hands, absent lateral toes on both feet, hyperextensible small joints, spina bi fida, bilateral congenital dislocated hips, crossed fused renal ectopia, mental retarda
Fig. 3 (Masket, Galioto, and Best). The foot has four toes.
383
ANOPHTHALMIA
VOL. 70, NO. 3
been associated with malignancies of the soft tissues and hematopoeitic system," it has not been previously described in association with congenital ocular defects. Book and Santessene did present a case of triploidy (chromo some number 69), but there were no ocular abnormalities. Apparently, the present case report is the first to associate anophthalmia, multiple anomalies, and mental retardation with polyploidy. ACKNOWLEDGMENT
The karyotype was prepared and interpreted by Dr. Nesrin Bingol. Dr. M. Felipe Montoya supplied clinical information regarding the patient.
REFERENCES
1. Duke-Elder, S. : System of Ophthalmology, vol. Ill, part 2. St. Louis, C. V. Mosby, 1963, p. 417. 2. Duke-Elder, S.: System of Ophthalmology, vol. Ill, part 2. St. Louis, C. V. Mosby, 1963, p. 421. 3. Patau, K., Therman, E., Smith, D. W., and Inhorn, S. L. : Multiple congenital anomaly caused by an extra autosome. Lancet 1:70, 1960. 4. Ellis, J. R., and Marwood, J. C: Autosomal trisomy syndromes. Lancet 2:263, 1961. 5. Bauke, J., and Schooling, K.: Polyploidy in human malignancy. Cancer 22:686, 1968. 6. Book, J. A., and Santesson, B. : Malformation syndrome in man associated with triploidy (69 chromosomes). Lancet 1:858, 1960.
OCULAR PATHOLOGY OF PATAU'S SYNDROME WITH AN UNBALANCED D/D TRANSLOCATION DAVID J. APPLE, M.D.,
JACK D. HOLDEN,
M.D.,
AND BEVERLY STALLWORTH, B.S.M.T.
New Orleans, Louisiana Trisomy 13-15 (Trisomy D, Patau's syn drome 1 ) is the chromosomal aberration which is most closely associated with ocular abnormalities. Several histopathologic re ports of this condition have appeared in the ophthalmic literature during the past decade and the characteristic ocular features are well documented. Zimmerman and Font 2 have emphasized that these characteristic ocular pathologic features could be very use ful in the diagnosis of the disease in cases in which karyotypes were not obtained or when the interpretation of the karyotype is diffi cult. The diagnostic usefulness of these pathologic features is well demonstrated in this report which describes, with special em phasis on the ocular findings, an unusual form of Patau's syndrome consisting of an unbalanced D / D translocation in which the From the Department of Pathology, Louisiana State University Medical Center and Charity Hos pital, New Orleans, Louisiana. This study was sup ported in part by a National Foundation Grant CE39 and by a USPHS Grant GM-01202. Reprint requests to David J. Apple, M.D., Oph thalmic Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. 20305.
affected individual has a total of 46 chromo somes (pseudodiploid) rather than the usual 47 (aneuploid) noted in most cases. Because the chromosome pattern was atypical, a care ful examination of the eyes was helpful in establishing a complete clinical, pathologic, and cytogenetic correlation which rendered an unequivocal final diagnosis. The usual form of D trisomy arises dur ing meiosis when a pair of homologous chro mosomes of the D group fails to separate and move into two separate gametes (nondisjunction). A gamete is produced which contains an extra D chromosome and a chro mosome count of 24. Fertilization of this ab normal gamete with a normal haploid gamete (23 chromosomes) produces an aneuplodic zygote containing 47 chromosomes. Chromosomal translocation produces a structural alteration. A D / D translocation is formed when simultaneous breakage of the short arms of two D chromosomes is fol lowed by reciprocal fusion of the long arms of their centromeres. The insignificant short arms are lost in the subsequent stages of di vision. If these alterations occur during
FRANK M.
MILTON BEST,
GALIOTO, JR., M.D.,
AND
M.D.
New York, New York Anophthalmia is a rare clinical entity, about 100 cases having been reported since 1900. 1 E x t r e m e microphthalmos can be dif ferentiated from absolute anophthalmos only by careful histologie study of the orbital tis sues on postmortem examination. I n all, there have been only 10 such cases where mi croscopic study of the orbit has revealed no evidence of ocular structure. 2 Because such differentiation is difficult, the term clinical anophthalmia is appropriate when it appears that no ocular tissue is grossly present in the orbit. T h e following case report describes a child with bilateral clinical anophthalmia as sociated with an unusual combination of congenital abnormalities and an abnormal karyotype. C A S E REPORT
A boy, two years and nine months of age, was admitted to the hospital for evaluation of multiple congenital defects. He was born to a 23-year-old Puerto Rican mother by normal spontaneous deliv ery after a nine-month gestation. The exact birth weight is unknown. At birth it was noted the child had a normal cry, but that he was flaccid and had bilateral anophthalmia as well as absence of one toe on each foot. Careful discussion of family history revealed no abnormalities in either parent or in four siblings of the propositus. It was learned, however, that in the fifteenth week of the mother's pregnancy she in jured her lower back and underwent radiographie study of the lumbosacral region which revealed a nondisplaced fracture of the proximal coccygeal From the Department of Ophthalmology, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospital, Welfare Island, New York (Drs. Masket and Best), and the Department of Pediatrics, New York Medical College, Flower and Fifth Avenue Hospitals, New York, New York (Dr. Galioto). This study was aided in part by Grant 69-869 from the American Heart Association and USPHS Grant NB07162-04. Reprint requests to Dr. Milton Best, Department of Ophthalmology, New York Medical College, Center for Chronic Disease, Bird S. Coler Hospi tal, Welfare Island New York, New York 10017. 381
segment. She received propoxyphene (Darvon) for pain. The growth and development of the propositus has been generally retarded. He cannot sit, stand, walk, or talk. He eats only baby foods and requires a bottle with nipple in order to drink. Physical ex amination revealed a small child (height 31 inches, weight 19J^ pounds) in no distress. Slight frontal bossing was evident, as well as patchy incomplete alopecia on the back of the head. The eyelids appeared normal and lacrimal puncta were present but the palpebral apertures were diminished bi laterally. Eyelid function was intact and when the child cried, lacrimation was noted. The orbits were 10-12 mm deep and lined by beefy colored, papillated conjunctiva. At the apex of each orbit there was a flat piece of yellow-gray tissue 3 mm in di ameter (Fig. 1). The ears, auditory canals and tympanic membranes were normal. Dentition was normal for age. The neck was flaccid and the child had poor head control. The chest and abdomen were unremarkable. The testes were descended bilaterally but small. Both hands had shortened fifth digits and hyperextensible small joints (Fig. 2), while the feet had four toes bilaterally and minor club-foot de formities (Fig. 3). Neurologic examination was nor mal except for general hypotonia of skeletal muscle. Laboratory results were the following: hemo globin electrophoretic pattern type AA ; urine nega tive for amino acids, phenylketones, and mucopolysaccharides ; VDRL negative ; rubella and toxoplasmosis antibody titers negative. The electrocardio gram and electroencephalogram were normal for
Fig. 1 (Masket, Galioto, and Best). The eyelids appear normal, but the orbit is shallow and no ocular structure is present.
382
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 2 (Masket, Galioto, and Best). Little finger of each hand is shortened. age. Chest x-ray films were normal, and radiographic study of the skull showed no evidence of fracture or intracranial calcification. The facial bones were slightly underdeveloped the orbits were small and the optic foramina were minute but pres ent bilaterally. Skeletal studies revealed spina bifida and bilateral congenital dislocation of the hips with pseudo-acetabular formation. Radiographic studies of the hands and wrists revealed that the bone age was six months. The shortening of the fifth digits on both hands was due to symmetrically shortened second phalanges. Studies of the feet showed ab sence of the lateral digits and fusion of the lateral metatarsals bilaterally. An intravenous pyelogram revealed crossed fused renal ectopia with no renal tissue present on the right side of the abdomen. The right ureter, however, passed across the midline, from the left side, to enter the bladder in a normal position. A renal scan confirmed the findings of crossed fused renal ectopia. Karyotyping, performed on the circulating white blood cells, showed that 90% of the cells were nor mal, but that 10% of the cells were polyploid, with chromosome numbers of approximately 60. Ocular examination of the parents and two of the siblings revealed no abnormalities.
SEPTEMBER, 1970
tion, and an abnormal karyotype consisting of 1 0 % polyploid cells. T o our knowledge this combination of anomalies has not been previously reported. T h e etiology of these congenital defects is obscure. It seems unlikely that all the anoma lies present could be the result of the moth er's injury or the radiologie study of the mother's lower back at 15 weeks' gestation. Anophthalmia has been described with tri somy of the large acrocentric chromosomes, numbers 13 to 15. Patau and co-authors 3 re ported a case wherein anophthalmia was as sociated with cleft lip and palate, cardiac malformations, mental retardation, and polydactyly. Ellis and Marwood 4 described a similar syndrome, but the eyes were present and had colobomata bilaterally. F o r the pres ent case trisomy 13-15 was not present but polyploidy was detected in the circulating white blood cells. Although polyploidy has
DISCUSSION
W e have described a child with bilateral clinical anophthalmos, shortened fifth digits of both hands, absent lateral toes on both feet, hyperextensible small joints, spina bi fida, bilateral congenital dislocated hips, crossed fused renal ectopia, mental retarda
Fig. 3 (Masket, Galioto, and Best). The foot has four toes.
383
ANOPHTHALMIA
VOL. 70, NO. 3
been associated with malignancies of the soft tissues and hematopoeitic system," it has not been previously described in association with congenital ocular defects. Book and Santessene did present a case of triploidy (chromo some number 69), but there were no ocular abnormalities. Apparently, the present case report is the first to associate anophthalmia, multiple anomalies, and mental retardation with polyploidy. ACKNOWLEDGMENT
The karyotype was prepared and interpreted by Dr. Nesrin Bingol. Dr. M. Felipe Montoya supplied clinical information regarding the patient.
REFERENCES
1. Duke-Elder, S. : System of Ophthalmology, vol. Ill, part 2. St. Louis, C. V. Mosby, 1963, p. 417. 2. Duke-Elder, S.: System of Ophthalmology, vol. Ill, part 2. St. Louis, C. V. Mosby, 1963, p. 421. 3. Patau, K., Therman, E., Smith, D. W., and Inhorn, S. L. : Multiple congenital anomaly caused by an extra autosome. Lancet 1:70, 1960. 4. Ellis, J. R., and Marwood, J. C: Autosomal trisomy syndromes. Lancet 2:263, 1961. 5. Bauke, J., and Schooling, K.: Polyploidy in human malignancy. Cancer 22:686, 1968. 6. Book, J. A., and Santesson, B. : Malformation syndrome in man associated with triploidy (69 chromosomes). Lancet 1:858, 1960.
OCULAR PATHOLOGY OF PATAU'S SYNDROME WITH AN UNBALANCED D/D TRANSLOCATION DAVID J. APPLE, M.D.,
JACK D. HOLDEN,
M.D.,
AND BEVERLY STALLWORTH, B.S.M.T.
New Orleans, Louisiana Trisomy 13-15 (Trisomy D, Patau's syn drome 1 ) is the chromosomal aberration which is most closely associated with ocular abnormalities. Several histopathologic re ports of this condition have appeared in the ophthalmic literature during the past decade and the characteristic ocular features are well documented. Zimmerman and Font 2 have emphasized that these characteristic ocular pathologic features could be very use ful in the diagnosis of the disease in cases in which karyotypes were not obtained or when the interpretation of the karyotype is diffi cult. The diagnostic usefulness of these pathologic features is well demonstrated in this report which describes, with special em phasis on the ocular findings, an unusual form of Patau's syndrome consisting of an unbalanced D / D translocation in which the From the Department of Pathology, Louisiana State University Medical Center and Charity Hos pital, New Orleans, Louisiana. This study was sup ported in part by a National Foundation Grant CE39 and by a USPHS Grant GM-01202. Reprint requests to David J. Apple, M.D., Oph thalmic Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. 20305.
affected individual has a total of 46 chromo somes (pseudodiploid) rather than the usual 47 (aneuploid) noted in most cases. Because the chromosome pattern was atypical, a care ful examination of the eyes was helpful in establishing a complete clinical, pathologic, and cytogenetic correlation which rendered an unequivocal final diagnosis. The usual form of D trisomy arises dur ing meiosis when a pair of homologous chro mosomes of the D group fails to separate and move into two separate gametes (nondisjunction). A gamete is produced which contains an extra D chromosome and a chro mosome count of 24. Fertilization of this ab normal gamete with a normal haploid gamete (23 chromosomes) produces an aneuplodic zygote containing 47 chromosomes. Chromosomal translocation produces a structural alteration. A D / D translocation is formed when simultaneous breakage of the short arms of two D chromosomes is fol lowed by reciprocal fusion of the long arms of their centromeres. The insignificant short arms are lost in the subsequent stages of di vision. If these alterations occur during