Poor balance, bilateral upper limb phocomelia, no previous exercise: a challenging combination for fall prevention in a middle-aged thalidomide survivor.

Poor balance and falls pose substantial risks to health and well-being. Thalidomide survivors with arm defects have an additional risk being unable to protect themselves in a fall. Generic exercise information to improve strength and balance is increasingly available to the elderly. However, disability can carry a lifetime risk. Identifying and correcting underlying musculoskeletal issues, correction of gait abnormalities together with establishing an appropriate exercise routine that is affordable, convenient and fun should improve outcomes at any stage of adult life. This can be challenging, not least in those who have never previously exercised and who are now middle aged or older. The Thalidomide Trust piloted focused support for a middle-aged thalidomide survivor with bilateral radial club hands and increasing balance issues who had never previously exercised. This met with great success improving his strength, balance, gait and posture together with ensuring an established exercise routine to maintain the improvement.

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.

Developmental toxicity of flucytosine following administration to pregnant rats at a specific time point of organogenesis.

To investigate the abnormalities that are specific to administration of flucytosine at one time point during embryonic organogenesis, flucytosine was administered orally to pregnant Sprague Dawley (SD) rats in a single dose on day 11 of pregnancy at 25 or 35 mg/kg. Fetuses on day 20 of pregnancy were externally, viscerally, and skeletally examined. Maternal body weight gain and food consumption were suppressed the day after administration of a 35 mg/kg. Fetal examinations revealed various alterations in both dose groups: externally preaxial polydactyly in the hind limb; skeletally fused lumbar centrum, absent sacral centrum, supernumerary sacral vertebra, and absent ribs. Our findings indicated that specific types of external and skeletal anomalies were induced following flucytosine administration on day 11 of pregnancy.

Robotic assisted radical prostatectomy for localised prostate cancer in thalidomide generation.

Thalidomide was used in the late 1950s and early 1960s as a sedative for morning sickness in pregnant women. It resulted in thousands of babies being born with various congenital anomalies, such as phocomelia. Subsequently, the drug was banned for this indication. Most of the survivors have become thalidomide adults and now they are in their fifties. We report the first case of a robot-assisted radical prostatectomy in a 54-year-old male with prostate cancer and phocomelia as a result of thalidomide embryopathy. He presented with a PSA of 3.3 and was diagnosed with Gleason 3 + 4 prostate cancer. An extra peritoneal approach was chosen due to his body habitus and to avoid extreme Trendelenburg tilt. Side docking with the da Vinci robot was employed and the prostatectomy was carried out in the standard extra peritoneal fashion. At 6 months' follow-up his PSA is unrecordable and he is voiding well with minimal urinary incontinence, requiring 1 pad/day. We aim to outline our approach and highlight the technical modifications in this rare physically disabling condition.

Real-time measurement of blood pressure with Nexfin in a patient with thalidomide-related phocomelia.

We report the novel application of photoplethysmographic technology with the Nexfin HD monitor for real-time measurement of blood pressure (BP) in a patient with tetraamelia. The patient was a 58-year-old man with tetraamelia secondary to thalidomide exposure in utero, who presented for surgical excision of a maxillary schwannoma. Because difficulty of cuff use on rudimentary limbs and failure to gain invasive arterial access due to abnormalities of limb vasculature, this population is known to pose some unique challenges for BP measurement. Nexfin may offer an alternative noninvasive method to detect BP in patients with phocomelia during the perioperative period.

Exposure to methylergonovine maleate as a cause of sirenomelia.

BACKGROUND: Sirenomelia is a rare, but deadly condition characterized by fusion of the lower limbs, lower spinal column defects, severe malformations of the urogenital and lower gastrointestinal tract, and an aberrant abdominal umbilical artery. METHODS: The two main hypotheses, not mutually exclusive, that have been advanced to explain the pathogenesis of sirenomelia are the blastogenetic theory and the vascular disruption theory. RESULTS: We describe a case of sirenomelia, probably associated with the use of methylergonovine maleate, an ergot alkaloid, during the first weeks of pregnancy. CONCLUSION: On the basis of the mechanisms of vascular disruption and early administration of methylergonovine maleate at a critical stage of organogenesis, we conclude that exposure to methylergonovine maleate could be the cause of the development of sirenomelia. Birth Defects Research (Part A) 106:643-647, 2016. © 2016 Wiley Periodicals, Inc.

Foetal fibular hemimelia with focal femoral deficiency following prenatal misoprostol use: A case report.

Misoprostol is a well known abortifacient. It can cause teratogenicity like Mobius sequence and terminal transverse limb defects. We report a rare case of proximal focal femoral deficiency with fibular hemimelia in a woman who had attempted abortion with self-administered misoprostol and later continued the pregnancy. Though the absolute risk of congenital malformations with its use is low ∼1%, this should be clearly communicated to the women requesting abortion to help them make fully informed reproductive health decisions.

Sirenomelia: two cases in Cali, Colombia.

We report two cases of sirenomelia, a rare congenital defect with a prevalence rate of 1:100 000 births; both cases were observed in Cali, Colombia. Both pregnant women were referred from Buenaventura, Colombia. The expecting mothers shared multiple adverse sociodemographic factors. Their homes were located in a city where the entire population is of low socioeconomic status living under conditions of extreme poverty. They were uneducated, with nutritional deficiencies and no access to drinking water most of the time. Both were exposed to water and fish from a nearby river contaminated with leachate from a poorly managed landfill. A similar relation was previously reported in Cali in 2005 between environmental factors and sirenomelia. We suggest that there is a common aetiological factor of environmental origin between these two sirenomelia cases and propose that exposure to derivatives from landfills should be included among the factors for this rare defect of multifactorial aetiological origin.

Sirenomelia after phenobarbital and carbamazepine therapy in pregnancy.

BACKGROUND: Epilepsy still remains a serious challenge for any obstetrician due to the potential teratogenicity of all antiepileptics. However, without appropriate maternal therapy the seizures can reappear, with direct negative impact on fetus. Currently, sirenomelia is the most severe caudal pole dysgenesis, consequent to an abnormal vascular supply development in the fetal lower body. CASE REPORT: We report a stillborn, GA/LMP = 37 weeks, delivered by an epileptic woman, who received in the first four months of pregnancy phenobarbital (PH) 0.1 g/day and carbamazepine (CMZ) 0.4 g/day, followed only by PH 0.1 g/day, until delivery. The stillborn, weighing 2200 g, presented sirenomelia type II, with some of its "classic" features: oligohydramnios, absence of kidneys, bladder, rectum, uterus, and a single umbilical artery. Some other "particularities" included: no Potter's facies and no significant cardio-pulmonary abnormalities. DISCUSSION: Since PH and CMZ alone are responsible, commonly, for mild abnormalities, we hypothesized that combined therapy with PH and CMZ (both strong enzyme-inductors, especially PH) potentiated their teratogenicity, by producing supplementary quantities of epoxides and/or other oxides, which accumulated in the fetal tissues. Except for sirenomelia, all other mild abnormalities, theoretically associated with "fetal CMZ and/or PH syndrome," are rarely observed, fact which demonstrates the drug-drug interactions between the two antiepileptics. CONCLUSION: This report highlights the possibility that PH/CBZ therapy during fetal organogenesis can induce sirenomelia, by a synergistic teratogenic effect and support the recommendation to use only one drug in pregnant epileptic women. A careful ultrasound monitoring of these patients is mandatory due to the teratogenic risk of both seizures and therapy.

Talidomida: 50 años después / The thalidomide experience: review of its effects 50 years later

Este año es el 50° aniversario del descubrimiento del efecto teratogénico de la talidomida, y aunque se conocen otros fármacos teratogénicos, la talidomida sigue preocupando a profesionales sanitarios y población general. Sin embargo, y junto con la tragedia humana que causó, ese descubrimiento supuso también el inicio de la investigación sobre las malformaciones congénitas y sus causas. Los objetivos son exponer lo que fue el efecto real de la talidomida y los momentos del embarazo en los que supone un riesgo, así como las consecuencias que tuvo su descubrimiento. Además, se realiza por primera vez un análisis para determinar los tipos de malformaciones que realmente produjo la talidomida. Para ello, se comparan las proporciones de 13 grupos de malformaciones de extremidades observadas en las series de niños expuestos prenatalmente a talidomida de la literatura médica, frente a las de esos mismos 13 grupos en los 1.491 niños recién nacidos con malformaciones de extremidades del registro del ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas) no expuestos al fármaco. Los resultados muestran que los defectos, y su forma de presentación más característica de la talidomida (focomelia, ausencia/hipoplasia del pulgar), son significativamente más frecuentes entre los casos de niños expuestos de la literatura médica que entre los del ECEMC. Por el contrario, la afectación sólo de los miembros inferiores es 3 veces menos frecuente en los niños expuestos a talidomida que en no expuestos del ECEMC. Otros grupos de defectos muestran la misma frecuencia en todas las series comparadas, lo que documenta que, como para todos los teratógenos que hoy se conocen, no en todos los niños con malformaciones expuestos a talidomida, estas fueron debidas al efecto del fármaco. Por tanto, si una mujer embarazada utiliza un fármaco de riesgo para el desarrollo embrionario, no necesariamente el hijo tendrá malformaciones. Finalmente, se muestra la gran paradoja de este «temido» fármaco, que causó un drama humano produciendo malformaciones en casi 10.000 niños y que, por otra parte, ha supuesto una formidable contribución al desarrollo del conocimiento científico y terapéutico (AU)

Sirenomelia apus after trimethoprim exposure: first-trimester ultrasound diagnosis-a case report.

We report the early prenatal ultrasound diagnosis of sirenomelia apus at 12+4 weeks in a patient with trimethoprim exposure in the vulnerable period. First-trimester scan revealed a malformed fetus with one femur, one small tibia, no feet, intraabdominal unilocular cystic structure, and two-vessel umbilical cord with allantoic cyst. Ultrasound visualization with two/three/four-dimensions was helpful in the process of parental counseling.

[The thalidomide experience: review of its effects 50 years later]. / Talidomida: 50 años después.

This year is the 50(th) anniversary of the discovery that the drug thalidomide causes birth defects and should therefore be considered as a teratogen. However, despite the existence of several other drugs that are also human teratogens, thalidomide continues to cause concern among health professionals as well as the general population. The objectives of this article are to make a short historical review of the discovery that this drug severely alters the embryo development, the critical period of gestation and the identification of the real effect of thalidomide. For the first time an analysis is provided to identify the type of malformations for which thalidomide really increases the risk. The proportions of the different types of malformations groups from the series of patients considered to be affected by thalidomide from the literature were compared with the proportions of the same malformations groups in non-exposed infants from the Spanish Collaborative Study of Congenital Malformation (ECEMC). The aim of the analysis was to calculate the relative frequencies of 13 groups of malformations observed in series of patients exposed to thalidomide, by comparison with the same groups of defects in 1,491 patients with limb malformations from the ECEMC consecutive newborn infants, non-exposed to thalidomide. The results showed that the groups with the most classical limb malformations attributed to thalidomide (phocomelia, thumb absence/hypoplasia) had a significantly very higher frequency in exposed cases than in the ECEMC's cases. However, cases presenting with only lower limb malformations were 3 times less frequent in thalidomide cases than in those of ECEMC. Finally, other groups presented the same frequency as those observed in the ECEMC's cases. The results of the 2 last groups, strongly suggests that they were not due to the effect of thalidomide. In addition to the short historical review of the teratogenicity risk of thalidomide, and their new therapeutic properties, it is documented that, as it happens with all other currently known human teratogens, not all malformations observed in infants prenatally exposed to thalidomide were caused by this drug. Finally, it is discussed the paradox that the «feared¼ thalidomide drug causing a great human drama affecting about 10,000 infants has led to a formidable contribution to the scientific knowledge, and large range of therapeutic applications.

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.