|Year : 1977 | Volume
| Issue : 1 | Page : 28-32
Genetics studies in retinoblastoma
K Srinivasa Rao, G Radha Krishna, C Ramakrishna Rao
Andhra Medical College, Visakhapatnam-2, India
K Srinivasa Rao
Prof. of pathology, Kakatiya Medical College, Warangal 506 007
|How to cite this article:|
Rao K S, Krishna G R, Rao C R. Genetics studies in retinoblastoma. Indian J Ophthalmol 1977;25:28-32
Retinoblastoma is the most common intraocular tumour of childhood and it is second to malignant melanoma of the uvea among all intraocular. tumours. It is frequently observed at birth. It usually appears in children under five years of age and is less frequent after seven years. It has however,occasionally been reported in adults.
It is postulated that the development of a retinoblastoma is dependent upon the presence of a single dominant gene. The number of such genes in the population is constantly increasing as a result of mutations, and also diminishing because of deaths of affected persons.
Falls and Neel  have calculated this rate of mutatian to be 2.3x10 -5 per generation. Without therapy most retinoblastoma genes would be diminished because the affected persons would not live long enough to transmit their mutant genes. For the reasons not now understood, all persons who possess this paricular gene do not develop a retinoblastoma. This "failure of penetrance" probably accounts for those unusual kind reds exhibiting "horizontal" rather than "vertical" constellation (i.e., several affected siblings whose parents are normal). One explanation for failure of penetrance is that a cellular alteration to malignant change is required and that in certain cases such changes do not occur. This concept would also account for the occurrence of unilateral cases and explain the multicentric origin that commonly is observed.
A substantial number of pedigrees, mostly showing affected sibships, are now available. From the accumulated literature it appears that there is no high rate of parental consanguinity in affected sibships, that some of the affected sibs are now known to have themselves transmitted the disease, and that there are now, many pedigrees with transmission over two or three generations. The available material gives little support for recessive inheritance and suggests dominance with incomplete expressivitv and penetrance.
Vogel  holds that germinal mutations account for only a minority of the cases of retinoblastomas, most cases being genuinely sporadic. The risk of transmission by a member of a known retinoblastoma family, whether affected in one year or both, is rather less than 50 per cent characteristic of dominance, owing to incomplete penetrance and expression of the same.
From the statistical study of incidence of retinoblastoma it would appear, either genetically determined or by somatic mutation. Within the past five years a number of syndromes usually involving mutiple system associated with gross alteration in either structure or total number of chromosomes have been reported. Among these, the most common structurally described is a deletion of a long arm of the chromosome-named as 13 q-syndrome. This seems to be associated with high incidence of retinoblastoma. Multiple congenital malformations are also described in gross chromosomal abnormalities. The relatively high incidence of retinoblastoma in D-deletion syndrome adds great importance to their recognition. It suggests the possibility that the gene locus responsible for the familial forms of the tumour might eventually be found on chromosome-13. A genetic component involved in the normal development of the eye is apparently located on the long arm of the No.13 chromosome.
| Methods and Material|| |
Chromosome analysis was done by the modified method of Moorehead ct al. Karyotyping was done according to Denver typing. We used a modification of the Trypsin and Giemsa banding technique of Seabright. 
From the records of King George Hospital, Visakhapatnam, about 14,657 new patients attended the Ophthalmic department every year. Out of them about 5 to 7 are the retinoblastoma patients. The incidence of retinoblastoma in this institution is 0.03%.
The total cases that are seen in Ophthalmic department for 3 years, i.e., 1973 to 1975 are 13. Out of them three are bilateral.
From the family history and pedigrees analysed there are no similar complaints in the family for at least two or three generations except in one family where, there is evidence of transmission of the same complaint for three generations. This shows that if an abnormal gene once formed, will be transmitted to the affected individual's off-spring as an autosomal dominant gene with incomplete penetrance in two successive generations (71 out of 137 recorded families) and there are several authenticated examples of transmission for three or four successive generations, but if the penetrance of 80% as calculated by Vogel  is accep,ed its failure results in many apparently normal individuals, male or female, acting as carriers so that the incidence of neoplasm is lower than the expected 50% characteristic of Mendelian dominant transmission. Thus if the proband and his father or mother are affected. the off-spring will have a 40% chance of having a neoplasm. One or more generations are frequently missed so that the pedigrees often show a horizontal rather than a vertical alignment, reveal siblings of a normal (but carrier) parent being affected (10 affected) sibs. ,, There are 75% consanguineous histories among the parents in our series of studies.
| Genetic Studies - Results|| |
Ten cases had unilateral retinoblastoma and three cases had bilateral retinoblastomas with sporadic occurrence, the former with somatic mutation type and the latter with germinal mutation type. In one case there is transmission for three generations continuously in the sibs of histories in the pedigrees analysed where there is consanguinity.
But in all other 12 cases there is no transmission in any other sibs and there is neither horizontal nor vertical transmission history in the pedigrees analysed, though there are 75% histories of consanguinity in the parents. Vogel  and Smith and Sorsby  also have reported similarly in their cases involving 80-90% of all sporadic somatic mutation types.
It is a significant point of observation in our series of study that 75% of cases show parenteral consanguinity, the available material and pedigree studies and vertical transmission studies, do not indicate or give support for recessive inheritance and suggest dominance with incomplete penetrance and expressivity
Somatic anomalies of distinctive features like aplastic thumbs. microcephaly, protruding trigoncephaly, upper teeth, low set ears, cleft or high arched palate micrognathia, and mentally retarded growth and development have been reported by Wilson et al  but were not found in our series. Only one case showed polydactaly and one case showed mental retardation with microcephaly.
Karyotype analysis was done in seven cases (i.e., from 6th to 12th).
6th case -A 1 upper arm breaks.
7th case -Normal
8th case -D deletion syndrome.
9th case -D deletion syndrome.
tOth case -Normal
11th case --Normal
12th case -Triploidy. 69-chromosomes.
i 3th case -D deletion syndrome.
The pedigrees are analysed in 13 cases where in one case there is evidence of transmisson of this tumour in three generations successively. In this case the present family members that are available to our study are three brothers. The eldest brother married to uncle's niece where lie had two daughters and one son. Among the three children two daughters affectcd with this tumour expired in Kakinada General Hospital. The second brother affected bilaterally with this tumour aged 37 years now, got his left eye enucleated in Madras and the rightr eye was irradiated at the age of two years in Madras General Hospital. His right eye vision is 6/36 and is working as a public works inspector. There is evidence of old irridated retinoblastoma multiple foci on fundus examnation, He married his uncle's niece and had one male child and this child was brought to this Hospital in Stage III. We have exanterated the right orbit and blood transfusion was given but on third postoperative day the child expired. The third brother of this family married to a distant relation, i. e., no consanguinity, having two children and on examination no evidence of this tumour. The detailed pedigree analysis is shown. In other 12 cases there is no neither horizontal nor vertical transmission histories in pedigrees analysed, though there are 75% consanguineous histories among the parents.
In our study 10 cases are unilateral and three cases are bilateral. The important point to be stressed here is that in bilateral cases mental retardation development is a constant feature. A germinal mutation affecting every cell inherited affection. A somatic mutation occuring precursor retinal cells developing in one eye never to involve the other eye. A phenocepy which results in the tumour cells developing in retina.
The question of danger of further sibs being affected can be dismissed in all cases of sporadic retinoblastoma, bilateral not less than unilateral.
It needs to be stressed that in sporadic unilateral retinoblastoma it is essential to probe deeply in the family history, for rare irregular dominance with its serious implications can easily be overlooked.
In this connection, however it must be remembered that cases which are apparently sporadic may in fact be familial, thus Machlim  in a study of all retinoblastoma occuring in a 17 year period in Ohio, found that if the pedigrees of apparently sporadic cases were checked from every available source, some 10.5 % revealed the disease in collateral lines. Somatic mutation type probably involved 80 to 90 % of all sporadic cases ,,, this type is not transmitted. General mutation type are transmitted as an irregular dominant trait with incomplete penetrance, and the tragedy is that the majority of these cases tend to be bilateral. ,,
| Discussion|| |
From the accumulated literature it appears that there is no high rate of parental consanguinity in affected sibships, that some of the affected sibs are now known to have themselves transmitted the diseases, and that there are now many pedigrees with transmission over two or three generations. But it is an interesting point to note in our series of study that 75% of cases show parenteral consanguinity. The available material and pedigree studies and vertical transmission studies of the families, do not indicate or give support for recessive inheritance and suggest dominance with incomplete penetrance and expressivity.
Out of 13 cases 10 are unilateral and three are bilateral. This shows that most of the cases are sporadic (96%) and most frequently unilateral. The sporadic cases occur either as a sporadic mutation or a new germinal mutation.
Bilateral incidence is 23 % in our studies and in literature the incidence is 20 to 30 of cases. The second eye is affected independently and not by metastasis or continuity via the chiasma. The high incidence of bilateral affection is dominantly inherited retinoblastorna as recorded in the literature and in the offspring of survivors from sporadic bilateral retinoblastoma as a dominant disorder either in transmission or as a new mutation. This disorder, though fully or almost fully penetrant, is not always fully expressed.
The parents are consanguineous in all the three bilateral cases. The parents are consanguineous in seven unilateral cases and nonconsanguineous in three unilateral cases. Mental retardation is a eonstant feature in all the three bilateral cases. All the three bilateral cases have been reported histologically as undifferentiated or pseudorosette type.
The incidence of retinoblastoma is 0.03,0 in this institution. Two sexes are affected equally. The youngest patient was 1 month old and the oldest 14 years. Except in one case (where the pedigree is shown), in other cases there is neither horizontal nor vertical transmission history in pedigrees analysed, though there are 75 % consanguineous histories among the parents.
Except in one case all other cases are of sporadic occurrence with somatic mutation type in 10 cases and germinal mutation type in three cases.
The study of these cases do not indicate or give support to recessive inheritance and suggest dominance with incomplete penetrance and expressivity.
The most common structurally described disorder is a common of a long arm of the chromosome-13 named as 13-syndrome and this seems to be associated with high incidence of retinoblastoma.
Of the 13 cases studied there were three deaths.
| Summary|| |
Genetic studies in 13 cases of retinoblastomas were made. The pedigrees of 13 cases showed that 75 ,°o of cases show parenteral consanguinity. Somatic anomalies were not constant in our series. In 12 cases no other siblings were affected though 75% showed consanguinity. Only one case showed vertical and horizontal transmission in 3 generations. The available material gives little support for recessive inheritance and suggests dominance with incomplete expressivity and penetrance.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]