J. ment. Defic. Res. (1976) 20, 89
89
A CASE OF CLINICAL ANOPHTHALMIA WITH AN ABNORMAL KARYOTYPE WENDY M. DONOGHUE Pleasant Creek Training Centre, Stawell, Victoria, Australia and JILL HARVEY St. J^icholas Hospital^ Carllon, Victoria, Australia CASE REPORT The patient, R.W., a female, was born on 'l^i.'l.ij'l, lollovving a normal pregnancy and labour. Presentation was by vertex at forty weeks and birth was normal, the baby weighing 71b. 8oz. Blindness was noted forty-eight hours after birth. The mother was unable to recall any abnormal features of the pregnancy except that hydramnios was suspected at five months but never confirmed. She had had no contact with any toxic agents, infectious diseases or sick animals. Iron was the only tablet taken during pregnancy. There arc two other children of the marriage, a male and a female, both oi whom are intellectually normal and physically healthy. One maternal and one paternal grandfathei' had diabetes, and a maternal uncle has been admitted to a mental hospital, but no other physica! or mental abnormalities are known on either side of the family. Initially the child presented a marked feeding problem. She was gavage-fed for seven week.s in hospital and for a further month at home. During infancy there were two admissions to hospital with failure to thrive and in childhood tlie patient contracted morbilli and rubella, mumps and chickenpox, from all of which she made a satisfactory recovery. Motor milestones were all greatly delayed. Tho child held her head up at one year, sat alone at eighteen months and could walk with support at eight years. Her first word was said at seven years, but neither speech nor walking made much progress and remain at a very low level of competence. The child repetitively shakes her head, sucks her fingers and regurgitates her food, especially when attention normally foctissed on her is withdrawn. She can sing a few tunes and likes music. General health is good, apart from a tendency to diarrhoea. The child is now aged thirteen years and six months, is microcepTialic and has marked retardation of growth. Cranial circunitcrence is 49 cm., weight 21 kg. and height 120 cm. There is a port-wine stain in the occipital region about 4 cm. across and mitd kyphoscoliosis of the thoracic spine. Hands are small and fxjorly developed with wasting of thcnar and hypothenar eminences. The feet are also small with the great toes disproportionately larger than the otiier toes and a gap between the first and second toes. There is a valgtis deformity of both ankles. A few pubic hairs are present but there are no other signs of sexual development. (Fig. 2.) The palpebral fissures are small, about 1.5 cm in length and fringed with eyelashes. Lacrimation is normal. The orbits are small and shallow and are apparently hned with conjunctiva and contain some fatty tissue. Clinically no optic apparatus is recognisable. (Fig. 3.) X-rays ofthe chest and skull show no abnormality, apart from a small calvarium. Bone age is approximately equal to chronological age. Received 2nd October, 1975
90
ANOPHTHALMIA
Fig. 1 (left) Subject compared to a girl of the same age with normal growth pattern. Fig. 2 (above) Feet of subject, showing large greal toes, gap between fu-st and second toes, and vagus deformities of ankles. Fig. 3 (below) Full face of subject, showing small palpebral fissures. The chromosomes of this palient were first studied when she was admitted lo a residential hospital for the mentally retarded. Chromosomes were cultured and stained by standard techniqites. In the majority of metaphascs analysed iliere was a marker chromosome jiresent, giving the karutype 46,XX/47,XX, -j mar. The marker chromosome was sumll, approximately three-quarters the size of chromosome number 22, almost nu-tacentric and did nol cari-y satellites. (Fig. 4a.) Family studies were negative. The father had a Tioruial karyotype and the mother, brother and sister displayed prominent Dp -|- in otherwise normal karyotypes. This was considered to be a normal variant. Repeat chromosome studies of the patient confirmed mosaicism. The marker chromosome was present in seventy per cent of 150 metaphases analysed. Ciienisa banding, tising a modified method of Seabright (1971). did not enable the marker chromosome to be identified. Using this technique, the marker chromosome had a pale staining centromeric area and darker staining areas on the distal segments of both arms (Fig. 4b). The marker chromosome lacked a distinctive banding pattern and as a result its origin remains unknown. Finger, palm and sole prints did not deviate from normal. The primary palmar creases were unremarkable and ihe only remarkable feattire in the derniatoglyphics of this patient was the unusually high number of secondary creases and grooves on the fingers and palms. DISCUSSION
Clinical anophthalmos is an uncommon condition atid has been reported in connection with a number of different aetiological factors. In 1959 Sarma described a case which he atttibuted to severe Vitamin A deficiency.
WENDY M. DONOGHUE and JILL HARVEY
A A
91
A A
A A
21
22
mar
Fig. 4(a) Partial karyotypes of G group chromosomes and marker chromosome from three metaphases.
0 )( n )> u it n II II
•*
if.
«•
1% ti
!6
'9
30
mar
•
r
17
2/
Fig. 4(b) Giemsa banded karyotype of patient.
XX
92
ANOPHIHALMIA
Thalidomide has caused microphthalmia and unilateral anophthalmia. In some cases an X-linkcd recessive mode of inheritance has been postulated. Pearce, Nigam and Rootrnan in 1974 described fhe case of a native Indian woman v\ho was twice married. The ten children of her first marriage were normal but there were five children of fhe second marriage, of whom three, two females and a male, had anophthalmia, associated with renal and cardiac defects, and died in early infancy. Bennett in 1973 also reported a case of anophthalmia, possibly ofthe X-linked type, in which the subject was the only affected member of a sibship of eight, the parents being blood relations. Unlike the majority of other subjects described this one was of normal intelligence. Anophthalnios is also included in certain rare syndromes. GoU.Z Syndrome (focal dermal hypoplasia) consists of congenital skin defects, i.e. streaks of thin skin with herniated nodules of subcutaneous fat, patches of altered pigmentation and angiofibromas, microcephaly and anomalies of teeth and digits. A case of unilateral anophthalmos has been reported with this. Goldenhaar's Syndrome (oculo-auriculo-vertebral dysplasia). Epibulbar dermoids, preauricular appendages, vertebral anomalies and occasional mental defect have been associated with anophthalmia and microphthalmia. MeckeVs Syndrome. Severe microcephaly with occipital encephalocoele, hexa- or hepfadactyly, cleft palate and lip and polycystic kidneys has been associated with microphthalmia and anophthalmia. However, all these syndromes are physically distinctive and are not associated with chromosomal anomalies. The chromosomal anomaly most often assoeiated with anophthalmia is Trisomy D (Patau's Syndrome). Here, microcephaly, with a keel-shaped forehead, various facial anomalies including cleft lip and palate, hypertelorism and Cyclops, inguinal and umbilical herniae and abnormalities of hands and feet ean be associated with anophthalmia, which is however mo.st commonly unilateral. Pyne in 1969 described a baby with bilateral anophthalmos and other abnormalities with this chromosomal pattern who died soon after birth. In 1974 Welter, Lewis, Scharff and Smith described a case of KHnefeltcr's Syndiome associated with bilateral anophthalmia. This unfortunate was thought by them to have X-linked anophthalmos, with the necessary gene carried on the extra chromosome. Masket, Galioto and Best in 1970 described a case of anophthalmos associated with digital anomalies, spina bifida, congenitally dislocated hips and renal anomalies. In this case ten per cent of cells were polyploid with chromosomal numbers of sixty. A syndrome has also been reported in which a small extra acrocentric chromosome is consistently present. Its features are hypertelorism, with a downward palpebral slant, pre-auricular fistulas and skin-tags and a high incidence of imperforate anus and anal atresia. Microphthalmia has been reported in this connection but not anophthalmia.
WENDY M. DONOGHUE and JILL HARVEY
93
The subject of this study is therefore in a separate category and does nof appear to fit into any of fhe groups in which anophthalmia is known to occur. The reduced growth and retarded pttberty .shown by this child may be due to the action of her abnormal chromosome but could be secondary effects of her congenital blindness. Blind human subjects do not show the nonnal slow-wave, N.R.E.M. sleepinduced secretion of growth hormone. Blinded rats, or those kept in darkness, show both reduced body weight and retarded puberty. Smythe and Lazartis (197.'i) produced evidence to show that the pineal gland, in conditions of reduced lighting, produces inereased amounts ofthe hormone melatonin. This substance, they claim, by blocking the release and/or metabolism of serotonin, causes a redtiction in growth hormone release. SUMMARY Bilateral clinical anophthalmia in a thirteen-year-old mentally retarded girl was described. Abnormalities of feet and a port-wine stain on the neck were associated with this, and an extra marker chromosome, which was metacentric and had a definite centromere but no distinctive banding pattern, was present in seventy per cent of cells. ACKNOWLEDGEMENTS The assistance of Miss May Hail and Miss Helena Huba is gratefully acknowledged.
BENNETT, M . E.
REFERENCE.S (1973) A study in a case of congenital anophthainiia. Arrwr. J. Psychoiiterapy.
27, 529. and BEST, M . (1970) Anophlhalmia, multiple abnormalities and unusual karyotype. Amer. J. Ophlhal.. 70, 381. PEARCE, W . G., NIGAM, S. and ROOTMAN, J. (1974) Primary anophlhaiinos. Histological and genetic features. Canad. J. OpkthaL, 9, 141. pYNE, R. J. (1969) Report on fotir babies with bilateral anophthalmos and extreme MASKET. S., GALIOTO, F. M .
microphthalmia. Trans. Au.st. Coll. Ophthal. 1, 147. SEABRIGHT, M . (1971) A rapid banding technique for human chromosomes. Lancet ii, 971. SsTYTHE, G. A. and LAZARUS, L . (1973) Growth hormone r("gulation by melatonin and serotonin. Nature 244, 230. WELTER, D . A. LEWIS, L . W . SCM.A.RFF, L . and SMITH, W. S. (1974) Klinefelter's syndrome v\'ith
anophthalmia. Amer. J. Ophthal. 77. 89.^). SARMA, V. (1959) Maternal Vitamin A deficiency, fetal mirmccphaly and anoplillialmia. Obstet. Gynaec. 13, 299.
89
A CASE OF CLINICAL ANOPHTHALMIA WITH AN ABNORMAL KARYOTYPE WENDY M. DONOGHUE Pleasant Creek Training Centre, Stawell, Victoria, Australia and JILL HARVEY St. J^icholas Hospital^ Carllon, Victoria, Australia CASE REPORT The patient, R.W., a female, was born on 'l^i.'l.ij'l, lollovving a normal pregnancy and labour. Presentation was by vertex at forty weeks and birth was normal, the baby weighing 71b. 8oz. Blindness was noted forty-eight hours after birth. The mother was unable to recall any abnormal features of the pregnancy except that hydramnios was suspected at five months but never confirmed. She had had no contact with any toxic agents, infectious diseases or sick animals. Iron was the only tablet taken during pregnancy. There arc two other children of the marriage, a male and a female, both oi whom are intellectually normal and physically healthy. One maternal and one paternal grandfathei' had diabetes, and a maternal uncle has been admitted to a mental hospital, but no other physica! or mental abnormalities are known on either side of the family. Initially the child presented a marked feeding problem. She was gavage-fed for seven week.s in hospital and for a further month at home. During infancy there were two admissions to hospital with failure to thrive and in childhood tlie patient contracted morbilli and rubella, mumps and chickenpox, from all of which she made a satisfactory recovery. Motor milestones were all greatly delayed. Tho child held her head up at one year, sat alone at eighteen months and could walk with support at eight years. Her first word was said at seven years, but neither speech nor walking made much progress and remain at a very low level of competence. The child repetitively shakes her head, sucks her fingers and regurgitates her food, especially when attention normally foctissed on her is withdrawn. She can sing a few tunes and likes music. General health is good, apart from a tendency to diarrhoea. The child is now aged thirteen years and six months, is microcepTialic and has marked retardation of growth. Cranial circunitcrence is 49 cm., weight 21 kg. and height 120 cm. There is a port-wine stain in the occipital region about 4 cm. across and mitd kyphoscoliosis of the thoracic spine. Hands are small and fxjorly developed with wasting of thcnar and hypothenar eminences. The feet are also small with the great toes disproportionately larger than the otiier toes and a gap between the first and second toes. There is a valgtis deformity of both ankles. A few pubic hairs are present but there are no other signs of sexual development. (Fig. 2.) The palpebral fissures are small, about 1.5 cm in length and fringed with eyelashes. Lacrimation is normal. The orbits are small and shallow and are apparently hned with conjunctiva and contain some fatty tissue. Clinically no optic apparatus is recognisable. (Fig. 3.) X-rays ofthe chest and skull show no abnormality, apart from a small calvarium. Bone age is approximately equal to chronological age. Received 2nd October, 1975
90
ANOPHTHALMIA
Fig. 1 (left) Subject compared to a girl of the same age with normal growth pattern. Fig. 2 (above) Feet of subject, showing large greal toes, gap between fu-st and second toes, and vagus deformities of ankles. Fig. 3 (below) Full face of subject, showing small palpebral fissures. The chromosomes of this palient were first studied when she was admitted lo a residential hospital for the mentally retarded. Chromosomes were cultured and stained by standard techniqites. In the majority of metaphascs analysed iliere was a marker chromosome jiresent, giving the karutype 46,XX/47,XX, -j mar. The marker chromosome was sumll, approximately three-quarters the size of chromosome number 22, almost nu-tacentric and did nol cari-y satellites. (Fig. 4a.) Family studies were negative. The father had a Tioruial karyotype and the mother, brother and sister displayed prominent Dp -|- in otherwise normal karyotypes. This was considered to be a normal variant. Repeat chromosome studies of the patient confirmed mosaicism. The marker chromosome was present in seventy per cent of 150 metaphases analysed. Ciienisa banding, tising a modified method of Seabright (1971). did not enable the marker chromosome to be identified. Using this technique, the marker chromosome had a pale staining centromeric area and darker staining areas on the distal segments of both arms (Fig. 4b). The marker chromosome lacked a distinctive banding pattern and as a result its origin remains unknown. Finger, palm and sole prints did not deviate from normal. The primary palmar creases were unremarkable and ihe only remarkable feattire in the derniatoglyphics of this patient was the unusually high number of secondary creases and grooves on the fingers and palms. DISCUSSION
Clinical anophthalmos is an uncommon condition atid has been reported in connection with a number of different aetiological factors. In 1959 Sarma described a case which he atttibuted to severe Vitamin A deficiency.
WENDY M. DONOGHUE and JILL HARVEY
A A
91
A A
A A
21
22
mar
Fig. 4(a) Partial karyotypes of G group chromosomes and marker chromosome from three metaphases.
0 )( n )> u it n II II
•*
if.
«•
1% ti
!6
'9
30
mar
•
r
17
2/
Fig. 4(b) Giemsa banded karyotype of patient.
XX
92
ANOPHIHALMIA
Thalidomide has caused microphthalmia and unilateral anophthalmia. In some cases an X-linkcd recessive mode of inheritance has been postulated. Pearce, Nigam and Rootrnan in 1974 described fhe case of a native Indian woman v\ho was twice married. The ten children of her first marriage were normal but there were five children of fhe second marriage, of whom three, two females and a male, had anophthalmia, associated with renal and cardiac defects, and died in early infancy. Bennett in 1973 also reported a case of anophthalmia, possibly ofthe X-linked type, in which the subject was the only affected member of a sibship of eight, the parents being blood relations. Unlike the majority of other subjects described this one was of normal intelligence. Anophthalnios is also included in certain rare syndromes. GoU.Z Syndrome (focal dermal hypoplasia) consists of congenital skin defects, i.e. streaks of thin skin with herniated nodules of subcutaneous fat, patches of altered pigmentation and angiofibromas, microcephaly and anomalies of teeth and digits. A case of unilateral anophthalmos has been reported with this. Goldenhaar's Syndrome (oculo-auriculo-vertebral dysplasia). Epibulbar dermoids, preauricular appendages, vertebral anomalies and occasional mental defect have been associated with anophthalmia and microphthalmia. MeckeVs Syndrome. Severe microcephaly with occipital encephalocoele, hexa- or hepfadactyly, cleft palate and lip and polycystic kidneys has been associated with microphthalmia and anophthalmia. However, all these syndromes are physically distinctive and are not associated with chromosomal anomalies. The chromosomal anomaly most often assoeiated with anophthalmia is Trisomy D (Patau's Syndrome). Here, microcephaly, with a keel-shaped forehead, various facial anomalies including cleft lip and palate, hypertelorism and Cyclops, inguinal and umbilical herniae and abnormalities of hands and feet ean be associated with anophthalmia, which is however mo.st commonly unilateral. Pyne in 1969 described a baby with bilateral anophthalmos and other abnormalities with this chromosomal pattern who died soon after birth. In 1974 Welter, Lewis, Scharff and Smith described a case of KHnefeltcr's Syndiome associated with bilateral anophthalmia. This unfortunate was thought by them to have X-linked anophthalmos, with the necessary gene carried on the extra chromosome. Masket, Galioto and Best in 1970 described a case of anophthalmos associated with digital anomalies, spina bifida, congenitally dislocated hips and renal anomalies. In this case ten per cent of cells were polyploid with chromosomal numbers of sixty. A syndrome has also been reported in which a small extra acrocentric chromosome is consistently present. Its features are hypertelorism, with a downward palpebral slant, pre-auricular fistulas and skin-tags and a high incidence of imperforate anus and anal atresia. Microphthalmia has been reported in this connection but not anophthalmia.
WENDY M. DONOGHUE and JILL HARVEY
93
The subject of this study is therefore in a separate category and does nof appear to fit into any of fhe groups in which anophthalmia is known to occur. The reduced growth and retarded pttberty .shown by this child may be due to the action of her abnormal chromosome but could be secondary effects of her congenital blindness. Blind human subjects do not show the nonnal slow-wave, N.R.E.M. sleepinduced secretion of growth hormone. Blinded rats, or those kept in darkness, show both reduced body weight and retarded puberty. Smythe and Lazartis (197.'i) produced evidence to show that the pineal gland, in conditions of reduced lighting, produces inereased amounts ofthe hormone melatonin. This substance, they claim, by blocking the release and/or metabolism of serotonin, causes a redtiction in growth hormone release. SUMMARY Bilateral clinical anophthalmia in a thirteen-year-old mentally retarded girl was described. Abnormalities of feet and a port-wine stain on the neck were associated with this, and an extra marker chromosome, which was metacentric and had a definite centromere but no distinctive banding pattern, was present in seventy per cent of cells. ACKNOWLEDGEMENTS The assistance of Miss May Hail and Miss Helena Huba is gratefully acknowledged.
BENNETT, M . E.
REFERENCE.S (1973) A study in a case of congenital anophthainiia. Arrwr. J. Psychoiiterapy.
27, 529. and BEST, M . (1970) Anophlhalmia, multiple abnormalities and unusual karyotype. Amer. J. Ophlhal.. 70, 381. PEARCE, W . G., NIGAM, S. and ROOTMAN, J. (1974) Primary anophlhaiinos. Histological and genetic features. Canad. J. OpkthaL, 9, 141. pYNE, R. J. (1969) Report on fotir babies with bilateral anophthalmos and extreme MASKET. S., GALIOTO, F. M .
microphthalmia. Trans. Au.st. Coll. Ophthal. 1, 147. SEABRIGHT, M . (1971) A rapid banding technique for human chromosomes. Lancet ii, 971. SsTYTHE, G. A. and LAZARUS, L . (1973) Growth hormone r("gulation by melatonin and serotonin. Nature 244, 230. WELTER, D . A. LEWIS, L . W . SCM.A.RFF, L . and SMITH, W. S. (1974) Klinefelter's syndrome v\'ith
anophthalmia. Amer. J. Ophthal. 77. 89.^). SARMA, V. (1959) Maternal Vitamin A deficiency, fetal mirmccphaly and anoplillialmia. Obstet. Gynaec. 13, 299.
