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Year : 1969  |  Volume : 17  |  Issue : 1  |  Page : 1-7

Von hippel-lindau disease - a chromosomal study

Department of Ophthalmology and Haematology, Postgraduates Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication4-Jan-2008

Correspondence Address:
I S Jain
Department of Ophthalmology and Haematology, Postgraduates Institute of Medical Education and Research, Chandigarh
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Jain I S, Das K C, Mahajan B C. Von hippel-lindau disease - a chromosomal study. Indian J Ophthalmol 1969;17:1-7

How to cite this URL:
Jain I S, Das K C, Mahajan B C. Von hippel-lindau disease - a chromosomal study. Indian J Ophthalmol [serial online] 1969 [cited 2020 Nov 28];17:1-7. Available from: https://www.ijo.in/text.asp?1969/17/1/1/37571

Table 1

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Table 1

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  Introduction Top

In 1904, von HIPPEL[8] published a clinical description of a vascular tumour of the retina, but it was LINDAU[11] who in 1926 published his monograph which correlated the occurrence of vascular tumours of the retina with similar tumours of the cerebellum, associated with cysts and tumours of other organs.

Various family studies of this disease are available in the literature, which show an autosomal dominant type of inheritance with varying degrees of penetrance. However, few reports on chromosome studies are available.

KOBAYASHI AND SHIMADA[10] reported chromosomal abnormalities in two unrelated Japanese patients, who were found to have morphologic abnormalities including chromatid breakages and numerical changes such as aneuploidy with 45, 47 and 49 chromosomes and polyploidy with 92 and 115 chromosomes.

The present communication describes chromosomal abnormalities in a mother and her child who were both affected with the disease.

  Case Reports Top

Case No. 1.

V. L. 11/2 years old female Hindu child reported in the eye out patient department on 4th June, 1965 with a white pupillary reflex in her right eye.

She was born after full term and was delivered normal. There was no history of fever or any other illness.

General physical examination was essentially normal.

Eye Examination

Corneal diameter measured 12 mm in both the eyes in both horizontal and vertical meridians. The pupil in the right eye looked black, but on throwing light from the nasal side a vascularised yellowish area in the retina was noticed.

Fundus Examination in the above eye revealed hyperemic optic disc. There was a solid detachment of the retina in the supero-temporal quadrant with dense white exudates scattered over the detached portion. In addition two deeply pigmented masses were seen over this area. Similar areas with greyish white exudates were seen in the inferonasal and inferotemporal quadrants.

In the left eye, the optic disc was normal. There was a small reddish white lentil sized mass with well defined margins in the superotemporal region. The blood vessels, in this segment were found dilated and tortuous, especially the veins which at the point of exit from the mass presented a hose pipe appearance. Similar globular masses though of much smaller size were seen in the upper nasal lower nasal and lower temporal quadrants. There was in addition evidence of retinal oedema and soft exudates more so on the nasal side. The patient was put on oral steroids. Retinal oedema subsided but there was no change in the size of these masses.

Case No. 2.

K. D. 32 years old female, mother of the first patient, presented in the eye O.P.D. on 12th April, 1966 with gradual deterioration of vision, occasional double vision and muscae in the right eye for the last 2-3 months. On examination, the vision in the right eye was only perception of light, the eye was divergent by -15'.

Fundus examination in the right eye revealed a normal optic disc, with dilated and tortuous superior temporal veins. About three disc diameters away in the supero-temporal segment there were yellowish grey tumor like masses raised above the surface with shining white and dark spots scattered below these masses. Along the course of the veins especially on the nasal side, there was dispersal of pigment in blotches. The left eye visual acuity was 6/9. In the fundus a tuberous mass about one disc diameter in size was detected in the superonasal quadrant. The vessels around this mass were dilated and tortuous. No blood vessel was seen running over this mass.

Examination of other members of the family.

No other siblings were available, as this was her only and the first child.

Parents of the mother were already dead. Only one brother was alive who was clinically examined and was found to be normal.

However, no cytogenetic studies could be undertaken on him, as he was not available for further studies.

  Method And Materials Top

Chromosomal studies have been undertaken in the affected mother and her child, from 72 hours culture of peripheral leucocytes; the method used is that of DAS. ABDULLA ROHATGI AND CHATTERJEE.[5] Varying numbers of metaphase plates have been analysed for the study of karyotype and structural abnormalities.

  Results Top

The chromosomal abnormalities encountered in the affected mother are recorded in [Table - 1]. It may be noted that out of 37 metaphase counted, 33 plates had 46 chromosomes, 3 had 45 chromosomes and one had 44 chromosomes. Thirty metaphase plates have been analysed for the study of karyotype which includes three cells with 45 chromosomes and one with 44 chromosomes. All the three metaphase plates with 45 chromosomes showed a consistent abnormality of loss of one chromosome in G-Group (G-21, or 22 monosomy) [Figure - 1]. The plate with 44 chromosomes showed loss of one chromosome in G group and one in E group. Five metaphase plates showed chromatid breaks involving chromosomes in B and C series [Figure - 1]. Two of these plates had 45 chromosomes, whereas three had 46 chromosomes. Child: 43 metaphase plates have been counted. The distribution of chromosome number is shown in [Table - 1], thirty metaphase plates showed 46 chromosomes, 6 showed 45 chromosomes and 7 showed multiple chromatid breaks, and chromosome number could not be reliably counted. Thirty metaphase plates have been analysed for karyotype. This included 6 plates with 45 chromosomes and 24 plates with 46 chromosomes. Five metaphase plates with 45 chromosomes showed consistent loss of one chromosome in the G group (G 21 or 22 monosomy). One plate with 45 chromosomes showed loss of one chromosome in the C group (monosomy C group).

Structural chromosomal abnormalities were observed in large number of metaphase plates. Chromatid breaks involving chromosomes of B, C and D series were present in seven metaphase plates,-5 having 46 chromosomes and 2 having 45 chromosomes [Figure - 2]. Six metaphase plates revealed multiple chromosomal breaks of severe degree as a result of which chromosome count and karyotype analysis were not possible in these plates [Figure - 3].

  Discussion Top

Numerous reports are available on the clinical and pathological features of von Hippel Lindau disease, yet very little information is available on its pathogenesis. Multiple haemangioblastic lesions involving retina, central nervous system and many other viscera, is a very striking phenomenon and makes this very closely related to Sturge-Weber syndrome. and syndrome of ataxia telangiectasia. The fact that considerable overlapping of clinical manifestations occur between these syndromes strengthens the possibility that an aetiological relationship exists amongst these diseases (MELMON and ROZEN)[12]

In the present report the case described involve a mother and her female child. The intensity of lesions were severer in the child than the mother.

Cytogenetic studies carried out in the affected child and the mother revealed almost similar chromosomal changes. These were characterised by chromatid breaks involving chromosomes in B, C and D series in a good number of metaphase plates. There were multiple chromatid breaks in about 12 per cent of metaphase plates in the child. Although the total number of chromosomes was 46, hypodiploidy was present in 10 to 14 per cent of the cells in both the subjects. The chromosomal abnormalities described in the present report are distinct from G 12 trisomy reported by HAYWARD AND BOWER[7] in a case of Sturge Weber Syndrome.

MELMON AND ROSEN[12] carried out cytogenetic studies in one of their 12 cases and reported normal findings. KOBAYASHI AND SHIMADA[10] described chromatid breaks in a significant number of metaphase plates, in two cases of this syndrome. Numerical abnormalities were found only in a few cells studied. Chromosomal abnormalities reported in the present series are striking, and the findings in the mother as well as the affected child are remarkably similar. Of particular interest are the chromatid breaks involving one or multiple chromosomes in a plate. [Figure - 1],[Figure - 2],[Figure - 3] Chromatid breaks have been consistently observed in patients following exposure to benzene (TOUGH, COURT-BROWN, BAIKIE, BUCKTON, HARNDEN, JACOBS, KING AND McBRIDE[15]) ionizing radiation (COURT-BROWN).

BUCKION AND McLEAN[4]) and in those with nutritional megaloblastic anemia (DAS AND AIKAT[6]).

Recently chromatid breaks of varying degrees have been reported in three apparently unrelated disorders such as Fanconi's anemia,[3],[14] Bloom's syndrome[1],[2] and Ataxia telangiectasia[1],[2],[13]. All these three disorders are known to be inherited as autosomal recessive. An increased incidence of leukaemia and lymphoreticular neoplasia have been observed in association with these three genetic disorders.[15] In Bloom's syndrome and ataxia telangiectasia vascular anomalies of the face are frequently observed. In yon Hippel Lindau's disease unlike those in Bloom's syndrome and ataxia telangiectasia, variety of angioblastic lesions involving several organs constitute the most important pathological feature. The chromosomal changes in this disease characterised by chromatid breaks appear to be comparable findings to those of Bloom's syndrome and ataxia telangiectasia. It is, however. uncertain if these chromosomal anomalies are in any way linked with the occurrence of angioblastic lesions involving various organs in von Hippel Lindau disease.

It will be useful to know whether chromosomal changes of similar nature also appear in apparently healthy family members of the case of this disease. Further studies on Cytogenetics, in similar cases will be most useful to ascertain the relevance of chromosal changes in the pathogenesis of this syndrome.

  Summary Top

Few reports are available regarding chromosomal changes in von Hippel Lindau disease. Chromosal abnormalities in the form of multiple chromatid breaks, and G. Group monosomy are described in a mother and her child suffering from this disease. The relevance of these chromosomal changes to the pathogenesis of this disease is discussed.

  References Top

BLOOM, D.: Congenial Telangiectasis Erythema resembling Lupus erythematosus in Dwarfs. Am. J. of Dis. child, 88, 754, (1954).  Back to cited text no. 1
BLOOM, D.: The syndrome of congenital Telangiectasis Erythema and stunted growth. J. of Pediat. 68, 103. (1966).  Back to cited text no. 2
BLOOM, G. E., WARNER, S., GERALD, P. S. and DIAMOND, L. K.: Chromosome abnormalities in Constitutional Aplastic Anemia. New Eng. J. of Med. 274, 8-14, (1966).  Back to cited text no. 3
COURT BROWN, W. M., BUCKTON, K. E. AND McLEAN, A. S.: Quantitative studies of chromosome aberration in man following acute and chronic Exposure to X-ray and Gamma ray. Lancet i, 1239-1241, (1965).  Back to cited text no. 4
DAS, G. C. ABDULLAH, S. ROHATGI, S., AND CHATTERJEE, J.: A simplified method for the study of human chromosomes by leucocyte culture from peripheral blood. Naturwiss 52, 137-138, (1965).  Back to cited text no. 5
DAS, K. C. AND AIKAT, B. K.: Chromosomal abnormalities in nutritional anemia. Abstract Proc. of IV congress of Asian and Pacific society. Hematology, 1967, New Delhi  Back to cited text no. 6
HAYWARD, M. D. AND BOWER. B. D.: Chromosomal Trisomy associated with Sturge Weber Syndrome. Lancet ii. 844, (1960).  Back to cited text no. 7
HIPPEL, E. von: On a very vare melody of the retina. (In German). von Graefe Arch. Ophth. 59, 83, (1904).  Back to cited text no. 8
JOSEP, E., FRANMENI JR., MILLER R. W.: Epidemiology of human leukaemia (Recent observation). J. of National Institute of Cancer. 38, 593-606(1967).  Back to cited text no. 9
KOBAYASHI, M., SHIMADAK K.: Chromosomal aberration in von Hippel Lindau disease (Report of two cases), Jap. J. of Ophth., 10. 38 (1966).  Back to cited text no. 10
LINDAU, A.: Studies on the small cysts of the brain. Pathogenesis and Relationship to angiomatosis Retinae. Acta Path. ed. Microbiol Scandinav. Supp. 1 Pl, 1926.  Back to cited text no. 11
MELMON, K. L. AND ROSEN, S. W.: von Hippel Lindau disease. Amer. J. of Med. 36, 595, (1964).  Back to cited text no. 12
SAWITSKY, A., BLOOM, D., and GERMAN; 1.: Chromosomal Breakage and acute leukemia in congenital telangiectasis Erythema and stunted growth. Ann. Int. Med. 65, 487-495, (1966).  Back to cited text no. 13
SWIFT, M. R. and HIRSCHHORN, K.: Fanconi's anaemia. Inherited susceptibility to chromosome breakage in various tissues Ann. Int. Med. 65. 496-503, (1966).  Back to cited text no. 14
TOUGH, I. M., COURT BROWN, W. M., BAIKIE, A. G. BUCKTON, K. E., HARNDEN, D. G., JACOBS, P. A. KING, AND MACBRIDE, J. A.: Chromosome aberration and exposure to ambient benzene. Lancet i. 411. (1961).  Back to cited text no. 15


  [Figure - 1], [Figure - 2], [Figure - 3]

  [Table - 1]


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