The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis.

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.

Thalidomide: the tragedy of birth defects and the effective treatment of disease.

Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women. It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for leprosy and later, multiple myeloma. In rural areas of the world that lack extensive medical surveillance initiatives, thalidomide treatment of pregnant women with leprosy has continued to cause malformations. Research on thalidomide mechanisms of action is leading to a better understanding of molecular targets. With an improved understanding of these molecular targets, safer drugs may be designed. The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in the biochemical pathways of limb development. In celebration of the Society of Toxicology's 50th Anniversary, which coincides with the 50th anniversary of the withdrawal of thalidomide from the market, it is appropriate to revisit the lessons learned from the thalidomide tragedy of the 1960s.

[New pharmacological availability of thalidomide based on experience in patients with multiple myeloma].

Thalidomide was developed in the 1950s as a sedative having only a low toxicity. However, McBride and Lenz reported in 1961 a close correlation between oral administration of thalidomide by pregnant women and a particular deformity (phocomelia) of their babies. In the 1990s, the biological activities of thalidomide were determined to include the control of tumor necrosis factor-alpha production and inhibition of angiogenesis. In 1994, Folkman et al. reported that thalidomide exhibited a strong inhibition of angiogenesis in their experiments with rabbits and that this effect had a significant relationship to phocomelia. They suggested a utility of thalidomide as a therapeutic agent for diseases that involve angiogenesis, particularly tumorous diseases. Furthermore, in 1994, Vacca et al. reported that the bone marrow of multiple myeloma (MM) patients was rich in blood vessels and that there is a causal relationship between the activity of MM and marrow angiogenesis. According to these data, thalidomide was tested in many countries as a new therapeutic agent for MM. In this review, new pharmacological availability of thalidomide is described on the basis of our experiences.

Thalidomide: current and potential clinical applications.

More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behçet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.

Prenatal diagnosis of thalidomide syndrome.

A case of thalidomide syndrome diagnosed by ultrasound in the 17th week of pregnancy is presented. The pregnant woman had leprosy and received adjuvant treatment with thalidomide. The affected fetus was exposed to the drug until the 35th day of pregnancy and presented absent external ears, upper limb phocomelia and absent tibiae and fibulae. No internal organ abnormalities were noticed at autopsy.