Thalidomide embryopathy: Follow‐up of cases born between 1959 and 2010

Kowalski, Thayne Woycinck; Sanseverino, Maria Teresa Vieira; Schüler‐Faccini, Lavínia; Vianna, Fernanda Sales Luiz

doi:10.1002/bdra.23376

Cited by 27 publications

(28 citation statements)

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“…Thalidomide and its derivatives, lenalidomide and pomalidomide, are potent immunomodulatory (IMiDs), antiangiogenic and anti-inflammatory drugs 1 . Identified in 1961, Thalidomide Embryopathy (TE) is the consequence of embryonic exposure to thalidomide and is mainly characterized as limb reduction defects, although it can affect almost every organ and system 2,3 .…”

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CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

Kowalski

Gomes

Caldas-Garcia

et al. 2020

Sci Rep

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The Cereblon-CRL4 complex has been studied predominantly with regards to thalidomide treatment of multiple myeloma. Nevertheless, the role of Cereblon-CRL4 in Thalidomide Embryopathy (TE) is still not understood. Not all embryos exposed to thalidomide develop TE, hence here we evaluate the role of the CRL4-Cereblon complex in TE variability and susceptibility. We sequenced CRBN, DDB1, CUL4A, IKZF1, and IKZF3 in individuals with TE. To better interpret the variants, we suggested a score and a heatmap comprising their regulatory effect. Differential gene expression after thalidomide exposure and conservation of the CRL4-Cereblon protein complex were accessed from public repositories. Results suggest a summation effect of Cereblon variants on pre-axial longitudinal limb anomalies, and heatmap scores identify the CUL4A variant rs138961957 as potentially having an effect on TE susceptibility. CRL4-Cereblon gene expression after thalidomide exposure and CLR4-Cereblon protein conservation does not explain the difference in Thalidomide sensitivity between species. In conclusion, we suggest that CRL4-Cereblon variants act through several regulatory mechanisms, which may influence CRL4-Cereblon complex assembly and its ability to bind thalidomide. Human genetic variability must be addressed not only to further understand the susceptibility to TE, but as a crucial element in therapeutics, including in the development of pharmacogenomics strategies.

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confidence: 99%

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

Kowalski

Gomes

Caldas-Garcia

et al. 2020

Sci Rep

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“…9-12 Now, CRBN is known to significantly play a role in ubiquitin-mediated protein degradation as proportions and the prescription is difficult to robustly control, new TE babies are still potentially born. 4,5 It is widely believed that the antiangiogenic action of thalidomide is responsible for the majority of TE phenotypes, including phocolemia. 1,6 This action might cause as-yet-unknown congenital vascular anomalies.…”

Section: Article P 2364mentioning

confidence: 99%

A Lesson From the Thalidomide Tragedy　― <i>The Past Is Never Dead. It’s Not Even Past.</i> William Faulkner, From “<i>Requiem for a Nun</i>” ―

Yashiro

Miyagawa

Sawa

2018

Circ J

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antiangiogenic, immunomodulatory, and antineoplastic (Figure 1). These pharmacological actions are beneficial for treating erythema nodosum leprosum and multiple myeloma, 1 and it is now used to treat them. In industrialized countries, its use is carefully monitored under strict guidelines such as "THALOMID Risk Evaluation and Mitigation Strategy" in USA (http://www.thalomidrems. com/about.html) and "Thalidomide Education and Risk Management System" in Japan (http://www.fujimoto-pharm. co.jp/jp/iyakuhin/thalido/pdf/TERMS-5.pdf). However, we already know that TE is not a past problem. 1,3 In 1996, it was reported that TE had still been occurring in South America since the early 1960s. That report revealed that a total of 34 patients with TE were confirmed to be born between 1969 and the 1990 s. All of them, 33 cases in Brazil and 1 in Argentina, were related to leprosy treatment. In developing countries, where leprosy is at endemic

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“…Therefore, the current health statuses of thalidomiders, even in countries with hundreds of thalidomiders, such as Germany, the United Kingdom (UK), and Japan, have seldom been reported, and never fully understood, possibly resulting in inefficient treatments (Newbronner, Glendnning, Atkin, et al, ; Peters et al, ). However, several surveys focusing on the physical or orthopedic situations of thalidomiders have recently been conducted (Ghassemi Jahani et al, ; Ghassemi Jahani et al, ; Ghassemi Jahani, Danielson, Karlsson, & Danielsson, ; Ghassemi Jahani, Danielsson, Karlsson, & Brisby, ; Kowalski, Sanseverino, Schuler‐Faccini, et al, ). For example, one recent study focused mainly on lifestyle‐related diseases among middle‐aged thalidomiders (Shiga, Shimbo, & Yoshizawa, ), while a few others investigated internal organ and vascular anomalies using imaging screening (Tajima, Wada, & Yoshizawa, ; Weinrich et al, ).…”

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confidence: 99%

A nationwide survey regarding the life situations of patients with thalidomide embryopathy in Japan, 2018: First report

Hinoshita

Beppu

Shioji

et al. 2019

Birth Defects Research

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Background: Clinical studies on the effects of thalidomide-induced damage on thalidomide victims as they age have only recently started to be conducted, but no studies have examined socioeconomic differences in terms of healthcare and social status between thalidomiders and the age-matched general population in Japan. Therefore, we carried out a nationwide survey focusing on the life situations of thalidomiders. Method: Questionnaires were sent to 274 thalidomiders in Japan. The questionnaire items basically matched those of the Comprehensive Survey of Living Conditions (CSLC) in the general population conducted by the Japanese Government. The results were compared with those of the CSLC for individuals aged 55-59 years, which was the cohort most similar in age to the average thalidomider living in Japan. Results: More thalidomiders rated their health condition as relatively bad or bad compared with the general population (20.2% vs. 13.3%, respectively). A much higher percentage of thalidomiders reported having some health or physical problem caused by a disease or injury (68.8% vs. 32.6%, respectively), and thalidomiders reported visiting medical and healthcare-related facilities more frequently. A higher proportion of thalidomiders (9.2%) were unemployed, and thalidomiders tended to feel higher levels of worry and stress, especially in terms of the future. Conclusions: The results of this nationwide survey of the life situations of thalidomiders in Japan clarified their health conditions and the related associations with socioeconomic status. These findings could be expected to help improve the provision of medical and healthcare, welfare measures, and financial support for thalidomiders in the near future. K E Y W O R D Shealth, life situations, nationwide survey, questionnaire, thalidomide embryopathy

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Thalidomide embryopathy: Follow‐up of cases born between 1959 and 2010

Abstract: Although there is no sufficient evidence that thalidomide exposure caused or worsened the described events, this approach helps to better understand the TE phenotype, improves the clinical diagnosis, and can lead to adequate health support for these individuals.

Cited by 27 publications

References 40 publications

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

A Lesson From the Thalidomide Tragedy　― <i>The Past Is Never Dead. It’s Not Even Past.</i> William Faulkner, From “<i>Requiem for a Nun</i>” ―

A nationwide survey regarding the life situations of patients with thalidomide embryopathy in Japan, 2018: First report

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Thalidomide embryopathy: Follow‐up of cases born between 1959 and 2010

Abstract: Although there is no sufficient evidence that thalidomide exposure caused or worsened the described events, this approach helps to better understand the TE phenotype, improves the clinical diagnosis, and can lead to adequate health support for these individuals.

Cited by 27 publications

References 40 publications

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation

A Lesson From the Thalidomide Tragedy ― <i>The Past Is Never Dead. It’s Not Even Past.</i> William Faulkner, From “<i>Requiem for a Nun</i>” ―

A nationwide survey regarding the life situations of patients with thalidomide embryopathy in Japan, 2018: First report

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A Lesson From the Thalidomide Tragedy　― <i>The Past Is Never Dead. It’s Not Even Past.</i> William Faulkner, From “<i>Requiem for a Nun</i>” ―