Thalidomide Embryopathy Research Articles

7055 Metabolic Disorders In Thalidomide Embryopathy

Abstract Disclosure: A. Tanabe: None. Thalidomide embryopathy (TE) is a congenital limb defect that occurs in neonates born to pregnant women who have taken thalidomide. Typical abnormalities of the TE are upper limb hypoplasia and and/or auditory dysfunction. In Japan, thalidomide was marketed as an agent for sleep-induce and digestive ulcers from 1958 to 1962. Up to now, approximately 290 cases have been certified and are supported by the government as drug-induced disease. Currently, many of the victims are in their late 50s, and in addition to congenital disabilities, various health issues such as lifestyle-related diseases can be developed. We investigated their metabolic condition using data of medical health checkup between 2017 and 2018. Fifty-one Japanese cases of TE (28 men and 23 women) were included in this study. The mean age was 56.4±1.6 years in men and 55.9±1.2 years in women. The prevalence of upper limb deformities was 64% in men and 74% in women; the remaining patients had only hearing impairment. The mean body mass index (BMI) was 22.7±2.1 in men and 22.5±4.0 in women. Eleven percent of men and 17% of women had a BMI between 25-30, while 9% of women and no men had a BMI of 30 or greater. Liver dysfunction was seen in 32% of men and 9% of women. The mean high-density lipoprotein cholesterol level was 60±17 mg/dL in men and 68±18 mg/dL in women. The mean low-density lipoprotein (LDL) cholesterol level was 120±28 mg/dL in men and 136±35 mg/dL in women, with 25% of men and 48% of women had LDL level of 140 mg/dL or greater. The mean triglyceride (TG) level was 144±85 mg/dL in men and 116±61 mg/dL in women, with 43% of men and 17% of women had a level of 150 mg/dL or greater. The mean HbA1c level was 6.0±1.0% in men and 5.9±0.4% in women. The prevalence of impaired glucose tolerance was 25% in men and 13% in women. Fatty liver (FL) evaluated by ultrasonography or CT scan was 61% in men and 39% in women. The patients with FL showed significantly high body fat percentage and TG level in men, high alanine aminotransferase, γ-glutamyl transpeptidase and TG levels in women, respectively, compared to the patients without FL. The prevalence of hypertriglyceridemia was significantly higher in men with FL compared with men without FL. There was no significant difference in with or without the upper limb abnormalities in both groups. Although without obvious overweight, more than 40 % of the patients had dyslipidemia and 50% of the patients had FL. The limb abnormalities can result in movement limitations however other factors may be involved in the development of metabolic disorders in TE. The results of this study provide valuable information for future health management in thalidomide embryopathy. (This study was conducted by a research grant from the National Center for Global Health and Medicine, Japan: 21A1015 and a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Japan: 20KC2005, 23KC2017). Presentation: 6/2/2024

9342 Managing Osteoporosis In Patients With Phocomelia: Challenges And Strategies

Abstract Disclosure: M. Renzu: None. C. Hubers: None. V. Mehta: None. A.M. Qazi: None. A.M. Satei: None. D.K. Yerasuri: None. Introduction: Phocomelia, a rare congenital limb malformation, often results from disruptions in limb bud formation during embryonic stage, due to genetic mutations, teratogens, or environmental factors like thalidomide embryopathy. These disruptions pose unique challenges in bone health management, including an increased risk of osteoporosis.We present a case report of a 52-year-old patient with phocomelia who developed an early onset severe osteoporosis. This case stresses the need for specific measures and care to tackle bone health in individuals with congenital limb anomalies. Case Presentation: A 52-year-old white female with phocomelia, had absence of the left forearm and hand, as well as a transverse tibial deficiency with a prosthetic left lower leg since the age of 1. Osteoporosis was diagnosed after follow-up, with initial osteopenia noted at age 49. DEXA scan showed lumbar osteopenia, radial osteoporosis, and bilateral femoral neck osteopenia. FRAX score showed an 11.9% risk of osteoporotic fracture and 3.1% risk of a hip fracture.Risk factors to her osteoporosis included late menarche, early menopause due to hysterectomy, and a history of hormone replacement therapy without pregnancies. Also, chronic colitis and diarrhea caused malabsorption issues. Her left hip bone mineral density was disproportionately low due to chronic prosthesis use, necessitating close monitoring and treatment initiation with Denosumab, along with vitamin D3 and calcium supplementation.As of the latest follow-up, the patient is closely monitored, and improvement is noted in her condition. She has incorporated daily gym sessions into her routine, indicating proactive engagement in her well-being. Discussion: Managing osteoporosis in patients with phocomelia needs a personalized approach, considering the patient's unique anatomical challenges and the limitations of traditional osteoporosis management strategies. Bone tissue adapts its structure based on mechanical loading, with reduced loading in deformed limbs leading to increased resorption and elevated osteoporosis risk. Tailored treatment plans, including Denosumab, which is known as an effective pharmacological option for managing osteoporosis, complemented by dietary adjustments to enhance vitamin D and calcium intake. Physical therapy programs play a vital role in muscle strengthening and balance improvement, reducing fracture risk.Another challenge that patients with phocomelia face is barriers to accessing healthcare services, like limited specialized care providers, financial constraints, and transportation difficulties, leading to increased morbidity. Hence early screening and intervention are essential to prevent osteoporotic complications. Overall, a comprehensive approach to osteoporosis management in phocomelia patients is crucial for optimizing outcomes and enhancing quality of life. Presentation: 6/3/2024

Skeletal computed tomography findings of upper extremities in middle-aged persons with thalidomide embryopathy.

Individuals with thalidomide embryopathy are now approximately 60 years old. For years, they have been compensating for their hypoplastic limbs in various aspects of daily living, and they face secondary problems such as limb and back pain. Imaging analysis is beneficial for understanding the pathogenesis of these problems. However, previous studies on skeletal imaging were mainly radiographic studies conducted at young ages, and there are few studies on skeletal imaging after aging, with most of them being case reports. In this study, detailed analyses of the skeletons of the upper extremities were performed using three-dimensional computed tomography and multiplanar reconstruction images in five individuals with thalidomide embryopathy aged approximately 60 years. Each individual frequently complained of neck, shoulder, and/or back pain. Dislocation, subluxation, and osteoarthritis were observed in the shoulder joints in some individuals. Hypoplasia of the trochlea and/or capitulum of the humerus, coronoid fossa, olecranon, and coronoid processes was observed in the elbow joints. Fusion and hypoplasia of the carpal bones were frequently observed in wrist joints. Radiocarpal and ulnocarpal synostoses were also observed. The joint instability and osteoarthritis found in this study may have contribute to upper limb pain in individuals with thalidomide embryopathy.

Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption

Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

The impact of ageing on the health and wellbeing of people with thalidomide embryopathy: a comparison of the health impact with the general population

Purpose As people living with thalidomide embryopathy (TE) are now entering their seventh decade, we examine the impact of ageing and the prevalence of comorbid health conditions reported in holistic needs assessments (HNAs) by individuals with TE, compare it with an age-matched sample of the general population, and explore the relationship between comorbidities and TE pattern of impairment. Materials and methods The HNA categories were mapped and compared to those of the Health Survey for England (HSE) and analysed across four impairment groups (A–D). Results 94% (392/415) of individuals with TE residing in the UK participated in the HNA and consented to a secondary analysis of the data. Less than 2% (5/392) reported no comorbidities; 94% reported nervous system problems; including pain, pins and needles and numbness. Individuals with TE reported a significantly greater number of health comorbidities, including musculoskeletal problems, than the age-matched HSE population. Conclusions Individuals with TE report significantly more health and well-being concerns than the general population of a similar age. Long-term monitoring is needed to ensure that support and rehabilitation services can meet their evolving needs.

SAT678 Metabolic Disorders In Thalidomide Embryopathy

Abstract Disclosure: A. Tanabe: None. Thalidomide embryopathy (TE) is a disease that develops in neonates born from women who have taken thalidomide during early pregnancy. Most cases of TE are characterized by developmental abnormalities of the limbs and/or auditory organs. In Japan, thalidomide was marketed as an agent for sleep-induce and digestive ulcers from 1958 to 1962. Up to now, 309 patients have been certified and are supported by the government as drug-induced disease. Currently, many of the victims are in their late 50s, and in addition to congenital disabilities, various health issues such as lifestyle-related diseases can be developed. We investigated their metabolic condition using data of medical health checkup between 2017 and 2019. Sixty-five Japanese cases of TE (33 men and 32 women) were included in this study. The mean age was 56.3±1.5 years in men and 56.1±1.2 years in women. The prevalence of upper limb deformities was 70% in men and 72% in women. The mean body mass index (BMI) was 22.7±2.1 in men and 22.5±4.0 in women. Twelve percent of men and 9% of women had a BMI between 25-30, while 9% of women and no men had a BMI of 30 or greater. Liver dysfunction was seen in 67% of men and 19% of women. The mean low-density lipoprotein cholesterol level was 61±19 mg/dL in men and 69±22 mg/dL in women. The mean high-density lipoprotein (LDL) cholesterol level was 116±29 mg/dL in men and 142±35 mg/dL in women, with 21% of men and 56% of women had LDL level of 140 mg/dL or greater. The mean triglyceride (TG) level was 137±82 mg/dL in men and 121±70 mg/dL in women, with 39% of men and 22% of women had a level of 150 mg/dL or greater. The mean fasting blood glucose level was 114±31 mg/dL in men and 102±17 mg/dL in women. The mean HbA1c level was 5.9±0.9% in men and 5.9±0.4% in women. The prevalence of impaired glucose tolerance was 19% in men and 9% in women. Fatty liver evaluated by ultrasonography or CT scan was 56% in men and 41% in women. The patients with fatty liver showed significantly high BMI, body fat percentage and TGs in men, high alanine aminotransferase and TGs in women, respectively, compared to the patients without fatty liver. There was no significant difference in with or without the upper limb abnormalities in both groups. This is the second report of metabolic disorders in TE, following one from our research group in 2015. Although without obvious overweight, thirty percent of the patients had dyslipidemia and 50% of the patients had the fatty liver. Because there was no association between limb abnormalities and metabolic disorders, other factors could be involved in the development of metabolic disorders. The results of this study provide valuable information for future health management in thalidomide embryopathy. (This study was conducted by a research grant from the National Center for Global Health and Medicine, Japan: 21A1015 and a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Japan: 20KC2005, 23KC2017). Presentation: Saturday, June 17, 2023

A New Strategy for the Old Challenge of Thalidomide: Systems Biology Prioritization of Potential Immunomodulatory Drug (IMiD)-Targeted Transcription Factors.

Several molecular mechanisms of thalidomide embryopathy (TE) have been investigated, from anti-angiogenesis to oxidative stress to cereblon binding. Recently, it was discovered that thalidomide and its analogs, named immunomodulatory drugs (IMiDs), induced the degradation of C2H2 transcription factors (TFs). This mechanism might impact the strict transcriptional regulation of the developing embryo. Hence, this study aims to evaluate the TFs altered by IMiDs, prioritizing the ones associated with embryogenesis through transcriptome and systems biology-allied analyses. This study comprises only the experimental data accessed through bioinformatics databases. First, proteins and genes reported in the literature as altered/affected by the IMiDs were annotated. A protein systems biology network was evaluated. TFs beta-catenin (CTNNB1) and SP1 play more central roles: beta-catenin is an essential protein in the network, while SP1 is a putative C2H2 candidate for IMiD-induced degradation. Separately, the differential expressions of the annotated genes were analyzed through 23 publicly available transcriptomes, presenting 8624 differentially expressed genes (2947 in two or more datasets). Seventeen C2H2 TFs were identified as related to embryonic development but not studied for IMiD exposure; these TFs are potential IMiDs degradation neosubstrates. This is the first study to suggest an integration of IMiD molecular mechanisms through C2H2 TF degradation.

Commentary on Markiewicz etal. Age-related changes in patients with upper limb thalidomide embryopathy in the United Kingdom.

Commentary on Markiewicz etal. Age-related changes in patients with upper limb thalidomide embryopathy in the United Kingdom.

Age-related changes in patients with upper limb thalidomide embryopathy in the United Kingdom.

We report the long-term upper limb disability, health-related quality of life (HRQoL), functional impairment, self-perception of appearance and prevalence of neuropathic pain in patients with upper limb thalidomide embryopathy in the United Kingdom. One-hundred and twenty-seven patients responded to our electronic questionnaire. Mean Quick Version of the Disabilities of Arm, Shoulder, and Hand score was 54.3 (SD 22.6). Median EuroQoL 5-Dimension 5-Likert index, Work and Social Adjustment Scale, Derriford Appearance Scale 24 and Neuropathic Pain Scale were 0.6 (IQR 0.4 to 0.7), 15.5 (IQR 8.0 to 23.5), 35.5 (IQR 28.0 to 50.5), and -0.8 (IQR -1.4 to 0.8), respectively. Thirty-three patients (26%) reported neuropathic pain. Finger changes associated with radial longitudinal deficiency were an independent predictor of more severe upper limb disability. Eighty-nine patients (70%) reported deteriorating HRQoL with increasing age. Patients with upper limb thalidomide embryopathy experience age-related worsening of symptoms and function, highlighting the need for ongoing specialist care and support.Level of evidence: IV.

Autologous breast reconstruction in a patient with thalidomide embryopathy: case report

Autologous breast reconstruction in a patient with thalidomide embryopathy: case report

Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy.

HAND2 is a transcription factor important for embryonic development, required for limbs and cardiovascular development. Thalidomide is a drug responsible to a spectrum of congenital anomalies known as Thalidomide Embryopathy (TE), which includes mainly limb and heart defects. It is known that HAND2 interaction with TBX5, an important protein for limbs and heart development, is inhibited by Thalidomide. The aim of this study was to evaluate and characterize HAND2 in the context of TE, and to evaluate its variability in TE individuals. DNA from 35 TE subjects was extracted from saliva samples and PCR was performed for amplification and Sanger sequencing of HAND2 coding sequence. The analysis showed only one variant; a synonymous variant p.P51 (rs59621536) in exon 1 found in three individuals. Further in silico evaluation confirmed highly HAND2 conservation, being the 3'UTR the most polymorphic region of the gene. Additional computational analyses classified the variant as neutral, without alteration in splicing and miRNA sites. In silico predictions pointed to alteration of two CpG islands adjacent to the variant; however, we did not observe any alterations on the methylation pattern of HAND2 gene in our sample. Moreover, alteration of the binding site of MeCP2, a nuclear protein involved in DNA methylation, was predicted along with alteration in HAND2 mRNA structure. Considering HAND2 being a well conserved gene, further studies with a larger sample should be performed to evaluate the role this gene on genetic susceptibility to TE.

National Competence Network Contergan - Ensuring medical care for people with thalidomide embryopathy

In 2021, a national network of multidisciplinary medical competence-centers has established itself in Germany that is committed to ensuring the care of people with thalidomide embryopathy. This article would like to draw attention to this competence network and give an overview of the most important medical care needs of aging people with thalidomide-induced body and sensory impairments. Here, the available scientific evidence and clinical peculiarities in medical care from a general medical-internal, orthopedic-paintherapeutic, sociomedical and psychosomatic-psychotherapeutic perspective will be presented and necessary tasks for the future will be discussed.

Health-related quality of life after 50 years in individuals with thalidomide embryopathy: Evidence from a German cross-sectional survey.

As individuals with thalidomide embryopathy now reaching their 60's they undergo long-term sequelae of their prenatal damage and experience a wide range of secondary health problems, in particular chronic musculoskeletal pain, movement restrictions, and mental disorders. These health problems are having a negative impact on their life circumstances and their health-related quality of life (HRQOL). The aim of this study was to determine the HRQOL in individuals with thalidomide embryopathy in comparison to individuals of the age-adjusted general population in Germany with and without chronic disease conditions (primary outcome). And, further explore the influence of impairment patterns, pain stage, and mental disorders on physical and mental dimensions of HRQOL (secondary outcome). A cross-sectional survey of 202 individuals with thalidomide embryopathy from North Rhine-Westphalia/Germany was conducted, which gathered information about physical examinations including a standardized determination of the pain stage, a structured psychological interview, and the HRQOL. The final dataset was 186 cases for primary outcome. Individuals with thalidomide embryopathy (50.6 years, 55.9% females) show a significantly reduced physical HRQOL comparison to the age-adjusted German population with chronic diseases (physical component score; pcs: 33.4 vs. 45.3, p< .001). In addition, male individuals with thalidomide embryopathy show a significantly reduced mental HRQOL to their male counterparts in this comparison (mental component score; mcs: 45.0 vs. 50.0, p= .005). The subgroup analyses show that individuals with thalidomide embryopathy with quadruple impairment have a significantly lower physical HRQOL than those with hearing loss (pcs: 25.0 vs. 38.5; ci's not overlapping). Second, individuals with thalidomide embryopathy with severe compared to mild stages of pain have significantly poorer levels of physical and mental HRQOL (pcs: 25.8 vs. 37.7, ci not overlapping; mcs: 40.4 vs. 51.8, ci's not overlapping). And, individuals with thalidomide embryopathy without a mental disorder show a high mental HRQOL (mcs: 53.2), while in comparison to the total sample those with somatoform and personality disorders have a significantly reduced physical HRQOL (pcs: 27.5 and 24.8; both ci's not overlapping), and those with depressive disorders have a significant reduced mental HRQOL (mcs: 38.0 vs. 45.8, ci's not overlapping). A longitudinal decreasing HRQOL in individuals with thalidomide embryopathy is known, as well as high prevalence of mental disorders and chronic pain syndromes. This study shows a strong association between these two influencing factors and a poor HRQOL.

Implementation of a Pregnancy Prevention Programme (PPP) with a Controlled Distribution System (CDS) for the Generic Teratogenic Phthalimides Thalidomide, Lenalidomide and Pomalidomide.

Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in some countries as an over-the-counter medicine. Publications reporting profound teratogenic effects with thalidomide brought about major revisions to the monitoring of the safety of medicines. As a consequence of previously unrecognised teratogenic effects, it has been estimated that over 12,000 children were born with a range of defects and disabilities, including severe congenital anomalies. Notably, it has been hypothesised that around 40% of babies with thalidomide-induced malformations born during the 1950s and 1960s died in the neonatal period. The commonest causes of death were atresia of the small bowel, cardiac or renal malformations. Nevertheless, phocomelia (as a typical manifestation of thalidomide´s teratogenic effects) has been reported once again after thalidomide was approved for use in areas where leprosy is endemic. As a result, thalidomide embryopathy remains an important topic in countries such as Brazil. Nowadays thalidomide is approved around the world for the treatment of a wide range of conditions, including leprosy, Crohn's disease, multiple myeloma, and certain malignant solid tumours. Second-generation immunmodulatory drugs including lenalidomide and pomalidomide have received approval for use in the management of various forms of neoplastic disease. Based on clinical experience with thalidomide and its derivatives, learnings have been transferred to further research on a subset of substituted phthalimides each of which has a high risk of causing teratogenic effects. This group of phthalimides is classified within regulatory science as human teratogens. In order to gain approval, a Pregnancy Prevention Programme (PPP), along with a Controlled Distribution System (CDS) is required. The challenges of PPPs in particular for a generic manufacturer have been described, including Raising of awareness, and education; Special aspects of data collection and evaluation; Ethically and socially relevant aspects, and Utilising existing information technology and infrastructure. This paper highlights the risks of unplanned pregnancies, provides information on the regulatory background, and regulatory expectations. Our aim is to provide insights and practical learnings that have impacted operational risk management with the teratogenic phthalimides. Opportunities are presented that may support the implementation of harmonised approaches for PPP and CDS using existing IT-systems across countries and companies.

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

The identification of thalidomide–Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of NOS3, which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, Crbn was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as Tbx5, Esco2, Recql4, and Sall4; Crbn and Sall4 were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide–Cereblon.

Vigilância e farmacovigilância da talidomida no Brasil - uma visão geral

Introduction:The thalidomide is probably the best-known teratogenic drug and still results in cases of severe physical deformities in children born in Brazil. Objective:To present the overall context of surveillance and pharmacovigilance of thalidomide in Brazil. Method:This article presents a narrative review of current literature concerning thalidomide regulation, policies, and pharmacovigilance in Brazil. Results:New cases of congenital abnormalities whose phenotype is compatible with thalidomide embryopathy were identified in the last ten years, while the approval of thalidomide for new indications was recently updated. The mechanisms of diagnosing thalidomide embryopathy are complex, remaining the challenge in distinguishing this condition from other congenital abnormalities. The increasing number of thalidomide users in Brazil is correlated with the occurrence of embryopathy and the real extension of the rationality of its use is largely unknown. Additionally, our pharmacovigilance and surveillance systems are predominantly based on voluntary reports, issues that remains over the years. Conclusions:The policies have improved over the years to prevent the fetus from being exposed to thalidomide, and current regulation establishes rules for controlling its distribution, prescription, dispensation, and use. Brazilian surveillance system is manual and pharmacovigilance is supported by voluntary reports. The failure of the system to properly control the thalidomide use and its effects might lead to serious consequences to the community; therefore, this subject deserves constant attention.

Chronic Pain in People Impaired by Thalidomide Embryopathy: An Explorative Analysis of Prevalence, Pain Parameters and Biopsychosocial Factors

The aim of the study was to show the frequency, localisation, intensity, quality and degree of chronic pain in people with thalidomide-induced congenital defects (thalidomide embryopathy) and to investigate the association with biopsychosocial factors more closely. A group of 202 people from North Rhine-Westphalia with thalidomide embryopathy were studied for the first time both physically for the pattern of the original damage and also psychiatrically in a structured diagnostic interview (SCID I & SCID II). The results were combined with a standardized pain interview (MPSS) and questionnaires on further pain-related (SF-36, painDETECT) and sociodemographic variables and analysed. In the analysis 167 completed datasets were included. The prevalence of pain in the sample population was 94%. The majority (107, 54.0%) already showed an advanced stage of chronicity in the MPSS: 63 subjects with Stage II (37.7%) and 44 with Stage III (26.3%). In 74 subjects (44.3%) the PainDetect score showed a possible or neuropathic pain component. The factors that most reliably influenced the chronicity of pain proved to be hip pain (p<0.001) and also mental health disorders (p=0.001), above major depression (p<0.001) and also somatic symptom disorders and substance-related disorders (p=0.001 in each case). Social variables proved non-significant here (p=0.094 for living alone, p=0.122 for unemployment, p=0.167 for lack of college education), as did the care situation (p=0.191 for care dependency) and the underlying pattern of organ damage (p=0.229 for damage to hearing, p=0.764 for dysmelia). People with thalidomide defects frequently suffer from a separate pain disorder which can be seen as secondary thalidomide-induced damage and which requires specialized and personalized multimodal pain management.

Cereblon-Based Small-Molecule Compounds to Control Neural Stem Cell Proliferation in Regenerative Medicine.

Thalidomide, a sedative drug that was once excluded from the market owing to its teratogenic properties, was later found to be effective in treating multiple myeloma. We had previously demonstrated that cereblon (CRBN) is the target of thalidomide embryopathy and acts as a substrate receptor for the E3 ubiquitin ligase complex, Cullin-Ring ligase 4 (CRL4CRBN) in zebrafish and chicks. CRBN was originally identified as a gene responsible for mild intellectual disability in humans. Fetuses exposed to thalidomide in early pregnancy were at risk of neurodevelopmental disorders such as autism, suggesting that CRBN is involved in prenatal brain development. Recently, we found that CRBN controls the proliferation of neural stem cells in the developing zebrafish brain, leading to changes in brain size. Our findings imply that CRBN is involved in neural stem cell growth in humans. Accumulating evidence shows that CRBN is essential not only for the teratogenic effects but also for the therapeutic effects of thalidomide. This review summarizes recent progress in thalidomide and CRBN research, focusing on the teratogenic and therapeutic effects. Investigation of the molecular mechanisms underlying the therapeutic effects of thalidomide and its derivatives, CRBN E3 ligase modulators (CELMoDs), reveals that these modulators provide CRBN the ability to recognize neosubstrates depending on their structure. Understanding the therapeutic effects leads to the development of a novel technology called CRBN-based proteolysis-targeting chimeras (PROTACs) for target protein knockdown. These studies raise the possibility that CRBN-based small-molecule compounds regulating the proliferation of neural stem cells may be developed for application in regenerative medicine.

Thalidomide and unilateral limb defects: the Italian chapter of a neverending story

Fifty years after the event, Italy introduced legislation to compensate malformations in children - now in their sixties - born to mothers who had been prescribed the antiemetic drug thalidomide for morning sickness. However, compensation has been denied to people 'only' damaged in one half of their body as opposed to those with bilateral malformations. The present study reviews the papers describing case series of children born with 'thalidomide embryopathy' in the UK, Germany, and other countries around 1960. Most clinical series were not organized on the basis of inclusion/exclusion criteria, thus allowing for probable selection and information biases on maternal use of thalidomide. In any case, they included a sizable number of children with a unilateral limb defect born from mothers certainly exposed to thalidomide during the relevant pregnancy. In many of these children, limb defects were associated with visceral malformations, as frequently observed following exposure to thalidomide in utero. Similarly, later literature reviews were not bias-free in their choice of articles, as is the case of a recently proposed 'diagnostic algorithm' for thalidomide-caused specific malformations and of the advice by the Italian National Institute of Health ruling out the possibility of thalidomide producing unilateral limb defects. Overall, the scientific evidence suggests that thalidomide can cause unilateral limb defects.

Quality of life and pain in patients with thalidomide embryopathy in Japan.

BackgroundThe aim of this study was to assess psychological/psychiatric problems and quality of life (QOL) in patients with thalidomide embryopathy (TE), with a specific focus on pain, including pain severity and the effects of coping strategies for pain.MethodsA questionnaire survey was conducted to evaluate the severity of pain experienced by patients with TE, pain management strategies, time perspective, mental health status, and QOL. Of 67 patients with TE who underwent a health checkup, 51 respondents who gave valid responses were included in analysis.ResultsGHQ‐28 suggested that 41.2% of respondents appeared to potentially have psychiatric disorders. The mean scores of QOL were still within a normal range. There is no significant differences were found between limb disability group and hearing impairment group in QOL or mental health status. About 82.4% of respondents reported that they experience physical pain, and the use of the cognitive coping strategy “catastrophizing” to cope with pain was significantly associated with mental health status and QOL.ConclusionThis study demonstrate that although some patients with TE have some form of mental health problem, they still maintain a normal range QOL despite their disabilities. In addition, pain was not as strongly associated with mental health problems and QOL as would be expected, and variables such as “catastrophizing” to cope with pain appear to potentially be associated with reduced mental health and QOL.