Dear Editor,

We would like to thank the authors Hornby and Gilbert for their interesting letter referring to our case report of bilateral colobomatous microphthalmos with orbital cyst.[1] Their remarks and view are relevant and demand further clarification.

Because our intention was to investigate more in depth the origin of the cyst fluid and wall and because of space limitations, we were not able to provide additional data about the documented vitamin A deficiency (VAD) during pregnancy in our histopathologic case report.[2] We will provide these here. The mother had a history of a biliopancreatic diversion (Scopinaro procedure) which resulted in a diminished absorption in order to induce weight loss. However, this operation is associated with a risk to develop nutritional deficiencies, especially of fat-soluble vitamins (A,D,E,K), and this in up to 6 percent of cases.[3] In our case, from the 16th week of gestation onwards, the vitamin A status of the mother had been monitored along with other nutritional parameters (Table 1).

Subsequently, she had been hospitalized for intravenous administration of a multivitamin preparation, extra vitamin B12 and iron, together with oral suppletion of folic acid and multivitamins. Despite such maximal repletion there had been a documented hypovitaminosis A at least from week 16 until the 24th week of gestation. From week 28 of gestation she had been hospitalized for parenteral nutrition to further support her vitamin status. The father was healthy, and no consanguinity was present. History of any eye abnormalities in the family was negative. It is very likely that a depletion of vitamin A during conception and the first weeks of pregnancy was present because vitamin A has a depot within the liver, as such preventing an acute drop in its plasma level. Futhermore plasma vitamin A level do not decrease during pregnancy under normal physiologic conditions. Therefore, ocular development probably occurred in the context of a vitamin A deficiency. Previous research done by Hornby et al. pointed out a possible link between VAD during pregnancy and an increased incidence of microphthalmos in newborns, in particular in cases with a genetic recessive predisposition to the teratogenic effects of varying degrees of VAD during pregnancy.[4] Cools et al. reported the presence of bilateral congenital microphthalmos in two newborns in a series of nine cases of biliopancreatic diversion–related adverse neonatal outcome.[3] In one of them, VAD occurred during pregnancy. Excess as shortage of vitamin A during gestation may result in an anomalous development of the organism (e.g. teratogenicity of vitamin A analogues such as isotretinoin), especially of the eyes.[5] Accumulating data are providing further evidence to support a possible link between VAD and congenital microphthalmos and consider vitamin A level as a possible nutritional risk factor for abnormal development such as folic acid in the prevention of neural tube defects. This may have implications in preconceptional evaluation, especially for women with a history of bypass surgery. Parenteral nutrition as preconceptional treatment may be sufficient to replete vitamin and nutrient stores in these cases.

References

1. Hornby SJ, Gilbert C. Vitamin A deficiency and possible link with colobomatous malformations. Br J Ophthalmol July 2007 eLetter

2. Decock, C. E., Breusegem, C. M., Van Aken, E. H, and Leroy, B. P. High beta-trace protein concentration in the fluid of an orbital cyst associated with bilateral colobomatous microphthalmos. Br.J Ophthalmol. 91(6), 836-837. 2007.

3. Cools M, Duval ELIM, Jespers A. Adverse neonatal outcome after maternal biliopancreatic diversion operation: report of 9 cases. Eur J Pediatr 2006;165:199-202

4. Hornby SJ, Ward SJ, Gilbert CE. Eye birth defects in humans may be caused by a recessively-inherited genetic predisposition to the effects of maternal vitamin A deficiency during pregnancy. Med Sci Monit. 2003;9(11):HY23-6.

5. Dickman ED, Thaller C, Smith SM. Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects. Development 1997;124:3111-21.

Dear Editor

We read with interest the letter by Decock et al regarding the rare congenital ocular malformation (orbital cyst and bilateral colobomatous microphthalmos). [1]

The female child reported was the product of a mother with documented vitamin A deficiency (VAD) during the second trimester of pregnancy after previous gastric bypass surgery for morbid obesity. The authors do not report the symptoms or biochemical evidence of VAD in this particular mother nor the treatment she received but presumably it is likely that she had subclinical VAD during the first trimester when the foetal fissure may be disturbed causing coloboma.

This has striking parallels with a cases series of children with ocular coloboma from South India reported previously by our group. In that study maternal night blindess presumable from VAD was reported in 16% of mothers of children with coloboma compared with 5% rate for the normal local population of mothers. Studies by the Indian Institute of Nutrition of the same population showed that 50% of mothers have biochemical evidence of VAD during pregnancy mostly asymptomatic and subclinical. [2]

We have previously reported epidemiological and laboratory evidence to support a hypothesis that there may be a genetic (recessive) predisposition to the teratogenic effect of mild to moderate maternal vitamin A deficiency in pregnancy. This may explain the higher prevalence of colobomatous malformations in certain Asian countries where maternal vitamin A deficiency is common and consanguineous marriages popular, the low risk to siblings, and birth-order effect with increased frequency of colobomas in higher birth-orders. Mutations in a gene involved in cellular access to vitamin A that normally protects the mother or the embryo from natural variation in dietary vitamin A intake could render that individual intolerant of conditions of vitamin A deficiency. [3]

If such a gene-environment interaction is shown to be true there are public health implications for the prevention of blindness from anomalies akin to the research showing benefits of folic acid supplementation in prevention of neural tube defects. However, this form of intervention would be much more difficult with vitamin A which is itself a powerful teratogen if present in excess.

References

1. Decock, C. E., Breusegem, C. M., Van Aken, E. H, and Leroy, B. P. High beta-trace protein concentration in the fluid of an orbital cyst associated with bilateral colobomatous microphthalmos. Br.J Ophthalmol. 91(6), 836-837. 2007.

2. Hornby SJ, Ward SJ, Gilbert CE, Dandona L, Foster A, Jones RB. Environmental risk factors in the aetiology of congenital malformations of the eye in children in South India. Arch.Trop.Paed. 2002;22:67-77.

3. Hornby, S. J., Gilbert, C. E., and Ward, S. J. Eye birth defects in humans may be caused by a recessively-inherited genetic predisposition to the effects of maternal vitamin A deficiency during pregnancy. Med Sci Monit 9(11), HY23-26. 2003.