Letters to the Editor

Indian Pediatrics 2000;37: 691

Cornelia de Lange Syndrome

This is with reference to the article on Cornelia de Lange Syndrome(1) and the subsequent correspondence(2). As Dr. Matthew points out, the occurrence of Cornelia de Lange syndrome in one of two dizygotic twins (in this case a boy and a girl), is indeed what one would expect. However, I would like to address his two subsequent observations.

The occurrence of a genetic, autosomal dominant disorder, in two siblings (not monozygotic twins), with both parents being normal, is not necessarily an argument for an environmental cause. Indeed, since the mid 1980s, geneticists have been aware of the phenomenon of gonadal mosaicism in humans. This refers to the presence of more than one germ cell carrying a mutation in the gonad of the individual, when the rest of body (somatic cells, as well as other germ cells) carry normal copies of the gene. This can give rise to exactly the scenario described, with no need to invoke an environmental cause for the syndrome.

The converse, monozygotic twins dis-cordant for a disorder, once again may not point to an environmental cause. In the case of a presumed autosomal dominant disorder, such as Cornelia de Lange syndrome(3), this situation has in fact been reported(4,5). A post-zygotic mutation event in one of the twins, very early in gestation, can explain it. This can also be seen in the case of female monozygotic twins with an X-linked disorder, if the X-inactivation pattern is skewed in one of them. In addition, monozygotic twinning- related multiple malformation cases are actually more often discordant than concordant.

The classic rules of genetics and genotype-phenotype correlations have been stood on their head by some recent observations in molecular genetics. While this causes some confusion, it is also an exciting time where previously ill-defined mechanisms of biology slowly yield their secrets to new techniques and under-standing.

Marthand S. Eswara,
President, Neurogene,
572 Alberta Avenue,
Sunnyvale CA 94087,
USA.

1. Sheela SR. Cornelia de Lange syndrome: Discordance in twins. Indian Pediatr 1999; 36: 1267-1270.

2. Matthew A. Cornelia de Lange Syndrome: Discordance in twins. Indian Pediatr 2000; 37: 458.

3. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. OMIM Entry 122470. Updated Feb 1, 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/

4. Carakushannsky G, Berthier C. The de Lange syndrome in one of twins. J Med Genet 1976; 13: 404-406.

5. Carakushannsky G, Aguair MB, Goncalves MR, Berthier CO, Kahn E, Carakushannsky M, et al. Identical twin discordance for the Brachmann-de Lange syndrome revisited. Am J Med Genet 1996; 63: 458-460.