Mutations in SALL4 in malformed Father and Daughter postulated previously due to reflect mutagenesis by thalidomide
✍ Scribed by Jurgen Kohlhase; Lewis B. Holmes
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 58 KB
- Volume
- 70
- Category
- Article
- ISSN
- 1542-0752
No coin nor oath required. For personal study only.
✦ Synopsis
W.G. McBride wrote a letter to the Editor entitled "Thalidomide may be a mutagen" (McBride, 1994). We write to bring important developments related to this hypothesis to the attention of the readers of Birth Defects Research (Part A): Clinical and Molecular Teratology. Kohlhase et al. (2003) have identified and reported mutations in the SALL4 gene in Case 2 and her father, who were described in Dr. McBride's letter (McBride, 1994). We will review the original hypothesis, this new information, and other related suggestions for clinicians.
To put this finding in perspective, McBride (1994) described two families in which the affected parent had been exposed during gestation to thalidomide. A child of each thalidomide-exposed parent had been born with the same pattern of limb malformations that the parent had. In Case 1, the child had, ". . . no thumbs and only two digits on both hands. She has severe malformations of both legs, and the left leg is much shorter than the right. Both feet taper to one toe, neither of which has nails. Her father was born in 1960 with malformations of both hands and both legs . . . . His mother . . . said that she had taken six to eight thalidomide tablets. Her father had no thumbs or digits on the right hand but has a thumb and one digit on the left hand and has normal forearms."
In Case 2, ". . . the father has bilateral malformations of the forearm and hand and also suffers from left-sided deafness. His daughter also has malformations of both forearms and hands." Dr. McBride suggested that "The birth of these children raises the possibility of thalidomide being a human mutagen" (McBride, 1994) The editors of the journal (British Medical Journal) asked Dr. Andrew Read, a medical geneticist at St. Mary's Hospital at the University of Manchester, to comment on these two cases presented by Dr. McBride. He noted, ". . . if thalidomide . . . had a second, independent activity as a mutagen there would be no reason why it should specifically produce mutations leading to limb malformations. Mutagens attack genes at random . . . . I think . . . the two affected children have genetic syndromes . . . . Case 1 seems to have split hand deformity . . . . Case 2 has a different condition, involving reduction of the whole arm and shoulders, probably the Holt-Oram syndrome . . . . The grandparents are reported as unaffected, which suggests that a new mutation has occurred at some point in each pedigree . . . . Since each father was exposed to thalidomide in utero, it is quite possible that the father's malformations were caused by thalidomide-or maybe a combination of a genetic predisposition and the teratogen" (Read, 1994).
Three aspects of the original hypothesis and these new findings should be noted and are reviewed here: 1) absence