Thalidomide Embryopathy

Thalidomide syndrome: embryonic exposure, phenotype, genetic phenocopies and prevention

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of the entity

Thalidomide embryopathy is the set of congenital malformations resulting from exposure of the human embryo to thalidomide during a narrow window of organogenesis, between days 20 and 36 after fertilisation, corresponding to days 34 to 50 counted from the first day of the last menstrual period [1, 23]. Orphanet classifies it as a malformation syndrome under the code ORPHA:3312 and describes it by the association of phocomelia, amelia and anomalies of the proximal limb segment and of the hand plate, with auricular, ocular, cardiac, renal, digestive and genital anomalies, and with infant mortality estimated at up to 40% [1]. There is no phenotype entry of its own in OMIM, because the condition is not genetic: what is transmitted between generations is not the defect but the possibility of repeated exposure, and for that reason this article addresses simultaneously the historical entity, the cases that continue to occur and the genetic phenocopies that require a formal differential diagnosis [9, 36].

The alternative designation thalidomide syndrome is used in the clinical literature and in Brazilian health regulations, and Orphanet records the expression fetal thalidomide syndrome as a synonym [1, 2]. The term embryopathy is preferable because it places the injury in the embryonic period and distinguishes it from fetopathies, in which late exposure produces mainly growth restriction or dysfunction of organs already formed [23].

1.2. Historical overview and founding papers

Thalidomide was synthesised in 1954 in what was then West Germany and introduced to the market in 1956 by the company Chemie-Grünenthal as a non-barbiturate, non-addictive sedative, presented as safe even in overdose [23, 25]. The discovery of an antiemetic action rapidly extended its use to the treatment of vomiting in pregnancy, and the drug was marketed in 46 countries under different names, among them Distaval in the United Kingdom and Australia, Softenon in several European countries and Contergan in Germany; in some markets it was available without prescription and free samples were distributed to doctors to give to women with nausea [23, 24]. The number of women exposed will never be known [23].

The first warning signs were reports of peripheral neuropathy in treated adults, followed by communications of severe congenital defects that were initially not attributed to the drug [23]. In 1961, two clinicians working independently, Widukind Lenz in Germany and William McBride in Australia, established the association between taking the drug in early pregnancy and the malformations, publishing it in 1961 and 1962 [23, 25]. Thalidomide was withdrawn from the British market at the end of November 1961 and from most other countries between 1961 and 1962, and the incidence of these defects subsequently fell [23].

In the United States, thalidomide was not authorised between 1957 and 1962. Frances Kelsey, the Food and Drug Administration physician responsible for evaluating the application, refused to approve it because of the reports of peripheral neuropathy and the doubts about effects in pregnancy, and for this received the President's Award for Distinguished Federal Civilian Service, conferred by President John F. Kennedy [23]. The episode transformed drug regulation: toxicity testing came to require several species and complementary in vitro tests, after it was realised that the rodents habitually used in screening are far less sensitive to thalidomide than non-human primates or rabbits [23, 37].

Legal accountability was uneven. Neither any individual nor the manufacturing company was ever convicted; Grünenthal issued an apology only in 2012, without admitting liability, and distributors in some countries, such as Distillers in the United Kingdom and Australia, paid compensation after litigation, to which was added state support of widely varying amounts between countries [23].

1.3. A teratogen that returned to clinical practice

The story did not end with withdrawal from the market. In 1965, Jacob Sheskin described the efficacy of thalidomide in erythema nodosum leprosum, an inflammatory reaction of leprosy, after prescribing it as a sedative to a patient and observing resolution of the symptoms and skin lesions within three days [25]. There followed recognition of its anti-inflammatory properties, mediated by inhibition of tumour necrosis factor alpha production, and of its immunomodulatory and antiangiogenic properties, and the drug came to be used in multiple myeloma and other neoplasms, in Crohn's disease, in Behçet's disease, in lupus, in manifestations associated with human immunodeficiency virus infection and in vascular malformations, including hereditary haemorrhagic telangiectasia [23, 31, 38].

The return of the drug created the problem that dominates the contemporary approach: a potent and clinically useful human teratogen, available in countries where leprosy is endemic. In Brazil, use for erythema nodosum leprosum was approved in 1965 and has never been interrupted; new cases of embryopathy occurred between the 1970s and the 1990s, and were identified again after 2005, despite restrictive legislation [25, 39, 40]. This second generation of affected people, described by Brazilian groups from the Teratogen Information Service of Porto Alegre and from the network of the Latin American Collaborative Study of Congenital Malformations, is the reason the entity still requires active clinical recognition and not merely historical memory [25, 40].

1.4. Milestones in the elucidation of the mechanism

For five decades more than thirty models were proposed to explain the teratogenesis, from deoxyribonucleic acid mutagenesis to effects on chondrogenesis, the neural crest and cell adhesion molecules [23]. Two milestones reorganised the field. In 1994, Robert D'Amato and colleagues showed that thalidomide inhibits fibroblast growth factor-induced vascularisation in the rodent cornea, which supported the antiangiogenic hypothesis [23]. In 2010, Takumi Ito and colleagues identified cereblon as the thalidomide-binding protein and showed that the drug initiates its teratogenic effects by binding to that protein and disrupting the activity of the associated ubiquitin ligase, with loss of Fgf8 expression and altered limb outgrowth in zebrafish and chick [3].

The third phase, already in this decade, identified the neosubstrates: proteins that the cereblon complex degrades only in the presence of the drug. SALL4 was demonstrated independently by two groups in 2018, with the decisive observation that germline variants of SALL4 cause, in humans, syndromes that phenocopy the embryopathy [4, 41]. The p63 isoforms followed in 2019 and the factor PLZF in 2021, the latter degraded both by thalidomide and by its metabolite 5-hydroxythalidomide [5, 6].

1.5. Conventions used in this article

The anatomical designations of the reduction defects follow the European classification described in the clinical genetics literature: terminal transverse defects, proximal intercalary defects, longitudinal lateral or medial absence and split hand or foot [28]. Phocomelia is an intercalary defect, with reduction or absence of the proximal elements and a relatively preserved hand or foot plate, although radiographic reassessment of the historical series has shown that most limbs labelled as phocomelic in fact corresponded to extreme forms of longitudinal defect [23, 31]. Phenocopy designates a genetic condition whose phenotype mimics that of an environmental exposure; here it applies mainly to the disorders related to SALL4, TBX5 and ESCO2 [23, 36]. The entities of the differential diagnosis are described here mainly in the features that distinguish them from the embryopathy.

2. Molecular Genetics and Pathophysiology

2.1. Why a genetics section exists for an embryopathy

The entity has no causal gene, no pattern of inheritance and is not transmitted. Thalidomide was neither mutagenic nor genotoxic in the Ames assay in Salmonella typhimurium and Escherichia coli, in the forward mutation assay in Chinese hamster ovary cells or in the mouse micronucleus test, results that appear in the United States label itself [8]. The genetic relevance of the topic is threefold: the mechanism of action of the drug operates through a ubiquitin ligase encoded by a human gene; the products degraded under the effect of the drug are developmental transcription factors whose germline variants cause recognised malformation syndromes; and the variability of the damage between equally exposed individuals suggests genetic modifiers of susceptibility [3, 4, 42].

2.2. Chemistry and disposition of the drug

Thalidomide is a synthetic derivative of glutamic acid consisting of two linked rings, one glutarimide and one phthalimide [23]. It has an unstable chiral carbon, so that two enantiomers coexist and interconvert rapidly in body fluids and in water; the S enantiomer is the teratogenic one, but racemisation prevents the production of a stable form free of that risk, and the drug was and is marketed as a racemic mixture [23]. The active half-life of the parent molecule is about eight to twelve hours, with spontaneous hydrolysis in fluids and hepatic metabolism by the cytochrome P450 system, with participation of the CYP2C19 and CYP3A isoforms; at least eighteen degradation products have been identified, some teratogenic in embryo culture, which indicates that teratogenesis results from the parent molecule and from metabolites [23, 31].

The relevance of metabolism has been reinforced by recent work: zebrafish embryos expressing the human CYP3A enzyme sustain more pronounced damage, and the metabolite 5-hydroxythalidomide binds cereblon and forms a complex that degrades SALL4, whereas the unchanged molecule induces mainly a complex with Ikaros, responsible for the immunomodulatory actions [31]. Metabolic activation thus appears to be necessary for the antiangiogenic and teratogenic action [31].

2.3. Cereblon and the CRL4 ubiquitin ligase

Cereblon is encoded by CRBN, at cytoband 3p26.2, with reference transcript NM_016302 and UniProt protein Q96SW2 [7]. It functions as the substrate recognition subunit of a cullin-RING type E3 ubiquitin ligase, formed with DDB1 and CUL4A, which selects proteins for ubiquitination and proteasomal degradation; recognised physiological substrates include MEIS2, IKZF1, CSNK1A1, ILF2 and GLUL [3, 7]. In neurones, cereblon restrains large-conductance calcium-activated potassium channels through KCNT1, sustaining presynaptic glutamate release [7].

The demonstration that cereblon is the primary target came from the observation that zebrafish and chick embryos expressing a modified form of the protein, unable to bind thalidomide, are protected from the damage, including maintenance of Fgf8 expression [3, 31]. Binding of the drug does not simply block the ligase: it alters substrate specificity, so that proteins that were not targets come to be degraded, which is the molecular basis of the therapeutic class of protein degraders [4, 31]. The crystal structures of the DDB1-cereblon complex bound to thalidomide, lenalidomide and pomalidomide, published in 2014, established that cereblon is the substrate receptor within the complex and that it binds these drugs enantioselectively, the same work having identified by unbiased screening the transcription factor MEIS2 as an endogenous substrate displaced by the drug [17]. This duality explains why binding to cereblon is not in itself sufficient to cause malformations: transgenic mice expressing human cereblon do not develop embryopathy with thalidomide [41].

Biallelic germline variants of CRBN cause a distinct condition with no phenotypic relation to the embryopathy: autosomal recessive intellectual disability type 2, OMIM 607417, described in a consanguineous North American family with the homozygous variant NM_016302.4(CRBN):c.1255C>T p.(Arg419Ter) and in few additional families, with a gene-disease relationship graded as moderate by the ClinGen consortium [7, 43]. The existence of this entity does not imply increased susceptibility to thalidomide and should not be confused with the teratogenic mechanism [7].

2.4. Neosubstrates: SALL4, p63 and PLZF

The characterisation of the neosubstrates gave the phenotype an indirect genetic explanation. In a proteomic analysis of human embryonic stem cells and tumour lines, eleven new targets were identified, eight of them C2H2-type zinc finger proteins, including SALL4, ZNF827, ZBTB39, RNF166, ZNF653, ZNF692, ZNF98 and GZF1 [4]. Specificity differs between drugs of the class: thalidomide robustly degrades ZNF692, SALL4 and RNF166; lenalidomide adds ZNF827, FAM83F, RAB28 and its own substrate CSNK1A1; pomalidomide shows the greatest expansion, with ZBTB39, ZFP91, DTWD1 and ZNF653 [4]. Since a causal target of teratogenicity would have to be degraded by every drug of the class, and since IKZF1 and IKZF3 were demonstrably not causal for congenital defects, SALL4 stood out because it is degraded by all three [4].

The SALL4 degron lies in the second zinc finger domain, and glycine 416 is the critical residue: the substitutions p.Gly416Ala and p.Gly416Asn (NP_065169.1, residue of the MANE transcript NM_020436.5; substitutions introduced experimentally and not germline alleles described in patients) abolish drug-dependent binding to cereblon and prevent degradation, while preserving the folding of the domain [4]. Binding to cereblon-thalidomide was characterised by time-resolved fluorescence resonance energy transfer and by in vitro ubiquitination [4]. The clinical importance is direct: heterozygous loss of function of SALL4 causes, in humans, Duane-radial ray syndrome, acro-renal-ocular syndrome and IVIC syndrome, whose manifestations overlap with those of the embryopathy, including absent thumbs, phocomelia, defects of the auricle and the eye and congenital heart disease [4, 11, 41].

The p63 isoforms constitute the second demonstrated neosubstrate. The ΔNp63α isoform is essential to limb development and the TAp63α isoform to cochlear development and hearing; in zebrafish, thalidomide affects the pectoral fins and the otic vesicles precisely by inducing the degradation of one and the other, respectively, which offers a molecular explanation for the characteristic association between limb and ear defects [5].

The third is the promyelocytic leukaemia zinc finger factor, PLZF, encoded by ZBTB16. Degradation depends on the first and third zinc finger domains and is induced by thalidomide, by its derivatives and by 5-hydroxythalidomide; in chick embryos, thalidomide and the metabolite degrade PLZF but not SALL4, cause teratogenic phenotypes, and experimental knockdown of Plzf produces short limb bones, whereas PLZF overexpression partially rescues the phenotype [6]. Taken together, these findings support the view that the drug and its metabolites form different complexes with cereblon, with substrate repertoires that vary between species and tissues, and that the pleiotropy of the damage reflects that multiplicity [6, 31].

2.5. Species specificity and the toxicological lesson

The resistance of rodents, which concealed the teratogenicity in the preclinical tests of the 1950s, now has a molecular explanation at two levels. Mouse and rat cereblon has isoleucine at position 391, corresponding to valine 388 of the human protein (NP_057386.2), and that difference prevents the binding and degradation of zinc finger substrates; in addition, mouse and zebrafish SALL4 itself has substitutions in the second zinc finger domain that prevent binding to human cereblon in vitro [4]. The experimental consequence is instructive: mice carrying the murine knock-in allele designated in the publication as Crbn I391V degrade IKZF1, IKZF3, ZFP91 and CSNK1A1 and show more fetal losses on exposure to drugs of the class, but do not develop an embryopathy resembling the human one; and humanisation of the zinc finger domain of murine SALL4, with five amino acid substitutions, is sufficient to allow its thalidomide-dependent degradation in a human cell line [4]. The most accessible sensitive species is the rabbit, in which SALL4 is degraded, which explains its historical usefulness as a model [4, 41].

2.6. Antiangiogenesis, reactive species and cell death

The cereblon mechanism does not replace the earlier hypotheses: the three explanatory lines coexist and probably operate in cascade [23, 31]. The most detailed antiangiogenic evidence comes from a stable analogue derived from 5-hydroxythalidomide, designated CPS49, applied to chick embryos at the moment the limbs are forming. The vessels are destroyed within the first hour after exposure, several hours before any change in the expression of limb signalling genes; limb area is reduced by six hours; at twenty-four hours truncated limbs are observed, with increased cell death and loss of fibroblast growth factor signalling, both in the apical ectodermal ridge and in the mesenchyme, and of Sonic hedgehog signalling; and seven days after a single exposure limbs with a phocomelic appearance emerge [23].

Vascular selectivity explains the time dependence. Vessels undergoing active angiogenesis lose their smooth muscle covering to allow endothelial cell proliferation and migration, and it is these that the compound destroys, whereas quiescent vessels, with smooth muscle coverage, are protected [23]. In the developing limb the vasculature acquires muscular coverage only late, which coincides with the observation that early exposure causes amelia or severe truncation and late exposure is confined to the digits [23, 31]. Analogues without antiangiogenic activity and inactive hydrolysis products were not teratogenic in the same assays, and later work showed that the antiangiogenic action can occur independently of cereblon, suggesting a direct effect on the endothelium in addition to the effect mediated by the neosubstrates [23, 31].

The second line is the induction of reactive oxygen species and of cell death. Exposure to thalidomide generates oxidative stress, and administration of a scavenger of oxidative intermediates, alpha-phenyl-N-tert-butylnitrone, prevented limb anomalies in rabbit embryos and prevented the formation of the teratogenic hydrolysis products in culture [23]. The loss of Fgf8 and Fgf10 expression in treated rabbit embryos is reversed by the same scavenger, and thalidomide increases the expression of bone morphogenetic proteins and of Dickkopf-1, an antagonist of the Wnt pathway, with a role in cell death [23].

2.7. From the molecular lesion to the malformation pattern

Limb development depends on two signalling centres: the apical ectodermal ridge, which expresses Fgf8 and induces Fgf10 in the mesenchyme, and the zone of polarising activity, which maintains Sonic hedgehog expression, in a feedback loop that sustains proliferation and establishes the pattern along the proximodistal axis, with the humerus and femur forming before the radius, ulna, tibia and fibula, and these before the hand and foot [23]. The proposed explanation for phocomelia fits this scheme: destruction of the vessels causes cell death and loss of signalling in the proximal regions, whose tissue cannot be replaced because the molecular environment that patterned it no longer exists; if signalling recovers, only the distal structures, close to the apical ridge, are formed; if the loss is total, amelia results [23]. Dysregulation of these same signals has been proposed to explain the paradoxical polydactyly observed in reduced limbs of affected people [23].

Other documented targets and pathways include tubulin binding by a thalidomide analogue, with altered cytoskeletal dynamics and blockade of cell division; inhibition of the nitric oxide pathway and of soluble guanylate cyclase, with reduced cyclic guanosine monophosphate and failure of angiogenesis, reversible by increasing that mediator; and depletion of the vascular endothelial growth factor receptor in zebrafish [23]. Studies in monkey fetuses and in human and murine stem cells have documented expression changes in about two thousand genes, concentrated in vascular and cytoskeletal pathways [23]. There is further evidence of a transition from the embryonic vascular pattern to an adult-type pattern in the human limb at around day 45 after conception, equivalent to about 59 days after the last menstrual period, whose disruption has been proposed to explain lower limb anomalies such as short femur, associated with the embryopathy [23].

2.8. Individual genetic susceptibility

Not all embryos exposed within the critical window are affected in the same way, and in non-human primate models the damage varies between littermates [23]. This variability has prompted the study of human modifiers. A Brazilian group sequenced CRBN, DDB1, CUL4A, IKZF1 and IKZF3 in people with embryopathy and proposed an additive effect of CRBN variants on preaxial longitudinal limb anomalies, identifying the CUL4A variant rs138961957 as a candidate to influence susceptibility; the authors present these results as a hypothesis, supported by regulatory effect scores and not by functional validation [42]. In an earlier study by the same group, comparison of seven polymorphisms in FGF8, FGF10, BMP4, SHH, TP53, TP63 and TP73 between 36 people with embryopathy and 135 people without malformations showed no allelic or genotypic differences [44]. Taken together, the sources consulted identify no genetic marker of clinical utility for predicting the individual risk of embryopathy after exposure, and prevention cannot therefore be stratified by genotype [42, 44].

3. Clinical Spectrum and Manifestations by System

3.1. Nature and limits of the available data

Knowledge of the phenotype rests on three bodies of information of differing quality. The first consists of the German, British and Australian clinical series of the 1960s and 1970s and a 1964 British government report, which documented the possibility that almost every tissue and organ may be affected [23]. The second comprises the descriptions of the recent Brazilian cases, obtained with photography, radiography and a structured questionnaire [25, 40]. The third comprises the cohort studies in adult survivors, which describe the late phenotype [31, 35, 45].

Two limitations run through the whole body of evidence. The diagnostic criteria were established from the most severely affected children, usually with bilateral limb damage, which excluded less severe forms and makes it likely that the true extent of the damage was underestimated [23]. And the exact incidence of internal malformations is unknown, because many were not apparent at birth and were identified only late, through imaging performed decades afterwards [23, 35].

3.2. Upper limbs

Congenital differences of the upper limb occurred in up to 87% of affected people, according to the hand surgery review citing the series of Mansour and colleagues [31]. The spectrum ranges from thumb hypoplasia of Blauth grades II and III to radial dysplasia of Bayne grade IV, with complete absence of the thumb, and, in the most severe forms, to phocomelia and amelia [31].

The order of vulnerability of the bones is one of the most characteristic features: the thumb is the first structure affected, followed by the radius, the humerus and, last, the ulna; in severe forms the radius, ulna and humerus are absent, and the hand plate articulates directly with the shoulder region [12, 23]. Radial dysplasia, with loss of the radius and the thumb, is the other frequent presentation [23].

The pattern is typically bilateral and more severe on the left, for reasons that remain unclear, and the symmetry of the reduction defects is regarded as a diagnostic hallmark [23, 31]. The rule admits documented exceptions: several studies describe unilateral defects and differences in severity between the two sides, so that asymmetry does not exclude the embryopathy nor does symmetry confirm it on its own [23].

Radiographic reassessment of the limbs historically labelled as phocomelic corrected their anatomical characterisation: almost none corresponded to the classical intercalary defects described before the tragedy, and most represented extreme forms of longitudinal defect [31]. In that configuration, the clavicle is present and usually normal, a scapula exists, but the shoulder joint is always absent, which leaves the hand without stability over the trunk [31]. Polydactyly was also observed in the hands of reduced limbs, at times in combination with phocomelia [23].

3.3. Lower limbs, shoulder and hip

The lower limbs may show phocomelia, amelia and reduced length of the long bones, but are affected less frequently and less severely than the upper limbs, and isolated involvement of the lower limbs is very rare [23]. The femur is the bone most frequently affected and the fibula the last to remain normal, in an order parallel to that of the upper limb [23]. The proposed explanation combines the fact that the lower limbs form slightly after the upper limbs with the short half-life of the drug: a single early dose might affect only the upper limbs, repeated doses over several days being required to damage the lower limbs [23].

The proximal joints have characteristic changes of their own. The acromioclavicular joint is more prominent and sharply contoured when the shoulder has been damaged, and the hip joint may be hypoplastic or completely absent, as may the pubic bone [2, 23].

3.4. Eyes and ears

The eyes and ears develop between the fourth or fifth and the eighth or ninth weeks, a period that overlaps with rapid limb growth, and their involvement is another diagnostic hallmark [23]. Ocular anomalies include microphthalmia, anophthalmia, poor vision, coloboma, strabismus and aberrant or absent lacrimation [23]. Ocular defects may be unilateral, but acuity may also be reduced in the apparently spared eye [23]. Disturbances of ocular motility are usually associated with auricular defects and with weakness of the facial muscles [23]. The strabismus of the embryopathy is described as resembling Duane anomaly, in which limitation of abduction is accompanied by globe retraction and narrowing of the palpebral fissure on adduction, and there are reports of aberrant cranial innervation with lacrimation triggered by chewing [11, 46].

Auricular anomalies are generally symmetrical and range from absence of the auricle to its reduction, with accessory auricular appendages; they are accompanied by hearing loss or deafness and by cranial nerve palsies [12, 23]. The United States label describes, to the same effect, anotia, micropinna and small or absent external auditory canals [8]. The European summary of product characteristics refers to microtia with anomaly of the external auditory meatus, blind-ending or absent, and less frequent lesions of the middle and inner ear [26].

3.5. Face and oral cavity

The most frequently cited facial finding is an extensive naevus or haemangioma present at birth, usually in the centre of the forehead, which may extend over the nose as far as the upper lip; it is a transient capillary haemangioma, which disappears over the first two to three years of life, and its regression explains why it is undervalued in the assessment of adults [23]. Facial palsy and asymmetry are associated, attributed to weakness of the facial muscles and to facial nerve damage, as well as irregular number and spacing of the teeth, small jaws, cleft lip and palate and a small nose [2, 23].

3.6. Spine and stature

Irregular vertebral spacing, vertebral fusion especially in the lower segment of the spine and progressive kyphosis have been described, the latter in some cases requiring surgical intervention over the course of life [2, 23]. Stature is frequently below average, through shortening of the lower limb bones and independently of the vertebral defects [23].

3.7. Internal malformations

All internal organs may be affected, with malformations of the heart, kidneys, genitalia and digestive tract [23]. Cardiac defects are probably the cause of many of the intrauterine and postnatal deaths [23]. Urinary tract anomalies include horseshoe kidney, hypoplasia, malrotation and ectopia [2, 23]. In the genitalia, absence of the testes, testicular anomalies and hypospadias have been described in males, and malformations of the uterus and reproductive tract in females [23]. In the digestive tract, anorectal stenosis, intestinal atresia, pyloric stenosis and inguinal hernia are reported [2, 23].

3.8. Nervous system

In addition to facial palsies and cranial nerve conduction problems, an increased incidence of autism and of epilepsy has been described, both usually diagnosed later in life [2, 23]. The pathophysiological hypothesis advanced is disruption of the developing neural pathways, possibly through inhibition of cerebral angiogenesis, with cell death and tissue loss; in an animal model, this type of damage may occur as late as the fetal period [23].

3.9. Quantification of risk and mortality

The quantitative information available refers to the risk after exposure and not to population prevalence, a distinction worth maintaining. Reports cited in the reference review indicate that a single 50 mg tablet taken within the sensitive window is sufficient to cause defects in up to 50% of pregnancies, and some authors considered it surprising that an embryo exposed in that period should escape unharmed, although the 1964 British report recorded some children without external damage despite confirmed exposure [23]. The European summary of product characteristics quantifies the frequency of severe and potentially fatal defects at about 30% [26]. The Brazilian textbook of genetic syndromes gives a range of 10% to 50% affected children among women taking the drug in the antenatal period, a figure that should be read as a risk conditional on exposure and not as a prevalence [2]. The United States label is categorical as to the minimum dose: a single capsule, of any strength, taken by a pregnant woman can cause severe birth defects [8].

Early mortality is concordant across independent sources: about 40% of affected infants died at birth or shortly afterwards, a proportion that appears in the United States label, in the Orphanet description and in the reference review, and that is attributed to the internal malformations [1, 8, 23]. A regulatory review adds that the most frequent causes of death were probably small bowel atresia and cardiac or renal malformations, presenting this as a hypothesis [24]. Besides neonatal mortality, many embryos with these malformations will have died in utero, so that the true number of affected pregnancies will never be known; there were, indeed, reports of an increased spontaneous abortion rate in that period [23].

4. Clinical Recognition and Warning Signs

4.1. When to suspect in the newborn

Suspicion arises from the malformation pattern and is confirmed, or not, by the history of exposure. Thalidomide embryopathy should be considered in a newborn with a bilateral and symmetrical limb reduction defect, predominantly of the upper limbs and with preaxial involvement, that is, of the thumb and radius, especially when anomalies of the auricle, eye, heart, kidney or digestive tract coexist [23, 25]. The combination of a reduction defect with auricular and ocular anomaly is more informative than any isolated finding, because those structures form in the same period [23].

The pre-test probability depends on the geographical and social context. In countries where leprosy is endemic and thalidomide is distributed for erythema nodosum leprosum, suspicion must be active: in Brazil, where about 24,000 cases of multibacillary leprosy are diagnosed each year, of which 30% to 50% develop erythema nodosum leprosum, the number of potential users of the drug has been estimated at about 10,000, and approximately four million tablets are distributed per year [25]. A figure published subsequently indicates 40,000 new cases of leprosy per year in the country [40]. The prevalence of the disease is not homogeneous: it was about 5 per 10,000 inhabitants for the country as a whole, with fewer than 1 per 10,000 in the South and 7 per 10,000 in the North and North-East [25].

4.2. Taking the exposure history

The history of exposure is the decisive diagnostic element and, at the same time, the most fragile. The critical window requires the intake to be dated precisely: what matters is the interval between days 20 and 36 after fertilisation, that is, between days 34 and 50 counted from the first day of the last menstrual period, a period that coincides with the peak of vomiting in pregnancy and with the phase in which many women do not yet know they are pregnant [23]. The window itself was determined through interviews with parents and doctors in the 1960s, correlating dates of intake with the damage observed [23].

In contemporary practice, denial of exposure is frequent and does not exclude the diagnosis. In Brazilian proactive surveillance, the two newborns with a suggestive phenotype were born to mothers who denied taking the drug when specifically questioned, and in three clinically characteristic cases described earlier the maternal interview was likewise negative [25]. The authors cite as explanations maternal recall, fear of stigma for having used a contraindicated medicine and self-medication, besides sharing of the medicine between relatives and neighbours unaware of the risk [23, 25]. The history should therefore seek indirect risk factors: a diagnosis of leprosy, multiple myeloma, lupus, human immunodeficiency virus infection or graft-versus-host disease in the woman herself or in a close relative, which were the criteria used in population surveillance [25].

The assessment of any limb reduction defect includes, beyond thalidomide, a systematic search for other exposures and events of pregnancy between five and eleven weeks of gestation: vaginal bleeding, use of misoprostol, of vitamin A or other retinoids, of cocaine or of valproate, twinning and invasive procedures, such as chorionic villus sampling or an attempted termination of pregnancy; and the existence of fibrous bands identified at delivery or of amniotic bands in the placenta [28].

4.3. Targeted physical examination

The examination should cover all four limbs, even when the defect appears confined to one, and be documented with photography, a diagram and a written description, besides seeking nail hypoplasia and constriction bands [28]. Inspection of the scalp seeks aplasia cutis, which suggests Adams-Oliver syndrome; of the tongue and mandible, micrognathia and hypoglossia, which suggest the oromandibular-limb hypogenesis sequence; of the chest, absence of the pectoralis major, which suggests Poland anomaly [28]. Assessment of the eyes and face should look specifically for sixth and seventh cranial nerve palsy, easily missed in the infant, and the heart should be examined in every case [28]. When the severe defect involves the lower limbs, the anus and external genitalia are examined [28]. In the parents, examination of the hands and feet, and of the heart when Holt-Oram syndrome is suspected, guides the genetic differential diagnosis [28].

In the specific context of the embryopathy, it is important to seek the signs that tend to go unnoticed: the midline facial capillary haemangioma at birth, transient and therefore absent in the assessment of older children; the sharp prominence of the acromioclavicular joint; hypoplasia or absence of the hip joint; strabismus with globe retraction; and absence of lacrimation [23].

4.4. Warning signs and emergency situations

The priorities of the neonatal period arise from the internal malformations, not from the limb defects. Immediate assessment is required for signs of congenital heart disease, including cyanosis, murmur, tachypnoea and poor weight gain; for signs of digestive obstruction, because intestinal atresia and pyloric stenosis present early and are cited among the causes of neonatal death; and for signs of renal compromise, given the spectrum of urinary malformations described [8, 23, 24]. Congenital heart disease accompanies 15% of children with limb reduction defects in general, so echocardiography and electrocardiography are indicated in every infant with these defects, whatever the presumed aetiology [28].

A second category of alert concerns hearing and vision: the hearing loss associated with the auricular anomalies and the visual deficit associated with microphthalmia and coloboma condition language development and learning, and justify early formal assessment and not merely routine screening [2, 23].

4.5. Prenatal detection

Obstetric ultrasound can detect external anomalies before birth, and there is a Brazilian report of prenatal diagnosis of the syndrome, cited by the Brazilian textbook of genetic syndromes [2]. The radius and ulna are identifiable from the beginning of the second trimester, but thumb hypoplasia is not detectable if there is no bone absence [47]. An ultrasound suspicion of a limb reduction defect in a context of possible exposure should lead to targeted morphological assessment of the heart, kidneys and digestive tract and to specialist counselling, not to an immediate aetiological attribution [27, 28].

4.6. Absence of newborn screening

There is no biochemical or genetic newborn screening for this entity, nor would it be conceivable, since the marker is the exposure and not an analyte [2]. The functional equivalent of screening is epidemiological surveillance of sentinel phenotypes, described in the sections on diagnosis and epidemiology, which detects increases in the frequency of compatible defects in populations with access to the drug [25].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Nature of the diagnosis

The diagnosis of thalidomide embryopathy is clinical and history-based, by exclusion of genetic causes. No test determines the aetiology: the Brazilian textbook of genetic syndromes states this explicitly and adds that the available investigations serve to characterise the manifestations listed in the phenotype, not to prove the cause [2]. This absence of laboratory confirmation is the central problem of the entity, because proof of ingestion is frequently insufficient, phenotypic variation is marked and there is always the possibility of an alternative genetic condition [27].

5.2. Recognition criteria and their revision

The criteria in use derive from the work of Smithells and Newman, published in 1992 in the Journal of Medical Genetics, which established the consistent features from examination of the most severely affected children, and they are still cited as the basis of diagnosis [23, 30]. The elements that the secondary literature identifies as hallmarks of those criteria are symmetry of the limb reduction defects, upper limb predominance with preaxial involvement in the order thumb, radius, humerus and ulna, symmetrical auricular anomalies, ocular and ocular motility anomalies, the midline facial capillary haemangioma at birth and the set of internal malformations [23]. The full text of the original 1992 paper was not accessible during the preparation of this article, so the description of the criteria rests on the review by Vargesson, which cites them directly [23].

The delimitation built from the extreme cases has an important methodological consequence: people with less severe damage or without bilateral limb involvement fell outside the definition and may not have been recognised [23]. For this reason, and also because of the resurgence of cases in Brazil and the growing use of the drug worldwide, the World Health Organization convened in 2014 an expert panel that re-examined the criteria and proposed a broader diagnostic system, with the aim of identifying more affected people and facilitating their access to treatment and support [23]. The document of that panel was not obtained, and its content is referred to here only through the description in the review that cites it [23].

5.3. The DATE algorithm

The most structured attempt to formalise the reasoning is the computerised algorithm described by Mansour, Baple and Hall in 2019, designated DATE, for diagnostic algorithm for thalidomide embryopathy [27]. The program assigns a numerical score to the probability that a person's congenital defects result from thalidomide exposure and returns, from the malformation pattern, a differential diagnosis [27]. The authors justify it by the three difficulties already mentioned, inadequate proof of ingestion, phenotypic variation and genetic alternatives, and place it in the context of new cases that continue to arise from both historical and current exposure [27]. The paper was consulted only in its abstract and reference list, because the full text is under restricted access; the specific scoring rules and the weights assigned to each finding could not therefore be reproduced [27].

5.4. Sentinel phenotype for population surveillance

For surveillance purposes, and not for individual diagnosis, a sentinel phenotype was defined in Brazil, designated the thalidomide embryopathy phenotype, which includes three categories of reduction defect, irrespective of laterality, since that information is frequently lost in registries: amelia, that is, complete absence of one or more limbs; intercalary transverse reduction defect, defined as absence or severe hypoplasia of the proximal parts of the limb, covering humerus, femur, radius, ulna, tibia and fibula, alone or in combination, with normal or approximately normal hands and feet, a category that includes phocomelia; and preaxial longitudinal reduction defect, that is, total or partial absence of the thumbs, of the first metacarpal or of the radius, or of the hallux, the first metatarsal and the tibia [25]. Defects that do not fall into these categories are excluded from the analysis [25].

Whenever the phenotype is identified, photographs and radiographs are requested and a detailed maternal interview is conducted [25]. Compatibility with the embryopathy is then assessed by three criteria: presence or absence of the congenital defects described in the literature for the entity; presence or absence of another aetiologically known syndrome presenting the same defects; and a maternal history of thalidomide use or of another associated risk factor, namely the patient herself or a close relative with leprosy, multiple myeloma, human immunodeficiency virus infection, lupus or graft-versus-host disease [25].

The system has high sensitivity and low specificity, by design: it includes all the reduction defects described in the syndrome, but groups together types of defect unrelated to the drug, a bias the authors controlled by direct assessment of every notified case [25]. Cumulative sum analysis, known as CUSUM, was preferred to the Poisson distribution for detecting increases in frequency, because it signals changes in prevalence more rapidly [25]. A study cited by the authors had concluded that surveillance of all reduction defects is insufficient to detect the embryopathy when the exposure rate is very low, even when monitoring only bilateral intercalary and preaxial defects; the Brazilian system is feasible precisely because local accessibility to the drug is high [25].

5.5. Investigations to perform

The work-up has two aims: to characterise the extent of the damage and to exclude the genetic phenocopies. The sequence of investigations applicable to any limb reduction defect, and therefore also to this entity, is established in the clinical genetics literature [28, 29].

5.6. Limits of the tests and wording of the report

The absence of an aetiological test has a consequence that must be made explicit in the clinical report: a negative genomic study does not confirm thalidomide embryopathy, it only reduces the probability of the phenocopies tested. Sequencing does not reliably detect structural variants, deep intronic variants or low-level mosaicism, and the proportion of detectable variants in a gene is not equivalent to the clinical sensitivity of the test. For Holt-Oram syndrome, for example, sequencing of TBX5 identifies variants in about 25% of sporadic cases and in 53% of familial cases, which means that a negative result in no way excludes that diagnosis when the phenotype is suggestive [47]. In the ESCO2 spectrum, the diagnosis may be established by biallelic variants or by the cytogenetic finding, which makes the karyotype indispensable even with normal sequencing [12].

The laboratory report should identify the gene, the transcript with its version, the nomenclature of the variant according to the recommendations of the Human Genome Variation Society in nucleotide and protein terms, the zygosity and the pathogenicity classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Variants of uncertain significance do not support a diagnosis and require family segregation studies and periodic reassessment, a principle that is especially relevant here, because the erroneous attribution of a genetic cause to an exposed person, or the converse, has distinct legal, compensatory and reproductive consequences [27, 36].

5.7. Prenatal and preimplantation diagnosis

For the embryopathy there is no aetiological prenatal test; prenatal assessment is morphological, by ultrasound, and has the limitations already described regarding the detection of thumb hypoplasia [2, 47]. Molecular prenatal diagnosis and preimplantation genetic testing apply exclusively to the genetic phenocopies, when the causal family variant is known: it is possible in SALL4-related disorders, with autosomal dominant inheritance, and in the ESCO2 spectrum and thrombocytopenia-absent radius syndrome, with autosomal recessive inheritance [11, 12]. For thrombocytopenia-absent radius syndrome, prenatal testing can be performed by chorionic villus sampling or amniocentesis when ultrasound detects radial ray defects [47].

5.8. Documented diagnostic errors

The literature records errors in both directions, and they illustrate why genetic testing is part of the diagnosis of this embryopathy. Several individuals with Okihiro syndrome, that is, with SALL4-related disorder, had received the diagnosis of thalidomide embryopathy, including a family described by McBride as proof that the drug was mutagenic; molecular reanalysis identified SALL4 variants in those people [36, 48, 49]. The case is instructive: a father considered a victim of the embryopathy had a daughter with a similar phenotype, and the correct explanation was an inherited dominant variant, not a transgenerational effect of the drug [36]. The practical rule derived from this series is that, if a person with a diagnosis of embryopathy has a child with similar radial ray malformations, with or without Duane anomaly and renal anomalies, a SALL4 variant is more likely to be found than a TBX5 variant [11]. Conversely, the limb and cardiac defects caused by TBX5 variants may be clinically indistinguishable from those caused by thalidomide [28].

6. Differential Diagnosis

6.1. Logic of the differential diagnosis

The differential diagnosis is organised into three groups. The first comprises the genetic phenocopies, that is, monogenic syndromes with preaxial and cardiac defects that reproduce the phenotype of the embryopathy, headed by SALL4-related disorders, Holt-Oram syndrome and the ESCO2 spectrum. The second comprises other genetic causes of limb reduction defect with distinctive features of their own, such as Fanconi anaemia, thrombocytopenia-absent radius syndrome, Cornelia de Lange syndrome and the dysplasias with long bone deficiency. The third comprises disruptive causes and other exposures, in which the limb formed normally and was subsequently damaged, such as amniotic bands and misoprostol [12, 23, 28].

The most useful clinical clue is the pattern: the embryopathy produces reduction defects that are typically bilateral and symmetrical, with preaxial involvement in the order thumb, radius, humerus and ulna, associated with auricular and ocular anomalies; vascular and amniotic disruptions produce asymmetrical defects; genetic syndromes tend to be bilateral with less variability between sides and bring with them their own findings, such as thrombocytopenia, marrow failure, a characteristic facies or premature centromere separation [23, 29, 50].

6.2. Comparative table

6.3. The three phenocopies that require testing in every case

SALL4-related disorders constitute the most important differential diagnosis, for three converging reasons: the phenotypic overlap is extensive, including amelia, phocomelia, radial hypoplasia, anomalies of the auricle, facial palsy, ocular anomalies with Duane anomaly and aberrant cranial innervation, congenital heart disease and digestive, urinary and genital malformations; misattribution has already occurred in documented form; and the reproductive implication is opposite, since this is a dominant condition with a 50% risk to offspring and penetrance of about 95% [11, 36]. Okihiro syndrome, grouped with hereditary nystagmus and strabismus and the congenital cranial dysinnervation disorders, should be retained as the mandatory test before establishing the diagnosis of embryopathy [48].

Holt-Oram syndrome is the second mandatory differential diagnosis, and the clinical genetics literature states explicitly that TBX5 variants and thalidomide exposure can cause clinically indistinguishable limb and cardiac defects [28]. The distinction rests on the restriction of the skeletal defects to the upper limb and on the absence of auricular, ocular, renal, vertebral or anal anomalies, which, when present, exclude the syndrome according to the criterion stated in the GeneReviews chapter on the ESCO2 spectrum [12, 47]. For counselling, the difference is decisive: the offspring of an affected person who inherits the TBX5 variant has a risk of about one in three of a severe upper limb reduction defect and of 5% of phocomelia [47].

The ESCO2 spectrum, historically designated pseudothalidomide syndrome, resembles the embryopathy through symmetrical phocomelia of all four limbs, midfacial haemangioma and internal malformations, and is distinguished by severe prenatal growth restriction, with birth weight of 1.5 to 2.2 kg in 88% of term cases and length frequently below 40 cm, by microcephaly in 95%, by cleft lip and palate in 57% and by the cytogenetic finding of premature centromere separation [12, 52, 53]. The association of cleft lip and palate with absence of the radius points to the ESCO2 spectrum and not to thrombocytopenia-absent radius syndrome [12]. This entity is described here in greater detail.

6.4. Second-line differential diagnoses and the value of negative findings

The presence of the thumbs with bilateral absence of the radii points decisively to thrombocytopenia-absent radius syndrome, because, unlike most conditions with radial hypoplasia, in that entity the thumb is always present [29, 54]. The thrombocytopenia tends to improve with age and may not be evident after the neonatal period, so that a normal full blood count in an older child does not exclude it [55]. In Fanconi anaemia, café-au-lait macules develop over time and may be absent in the infant, which is why chromosome breakage testing is reserved for cases with other signs, but remains on the diagnostic horizon during follow-up [29].

Two additional groups figure in the differential diagnosis of the severe forms according to the GeneReviews chapter on the ESCO2 spectrum: splenogonadal fusion with limb defects and micrognathia, whose molecular basis is not confirmed, and DK phocomelia syndrome, characterised by phocomelia, thrombocytopenia, encephalocele and urogenital anomalies, likewise without a confirmed molecular basis [12]. Mosaic variegated aneuploidy syndrome, caused by variants of BUB1B, CENATAC, CEP57, MAD1L1 or TRIP13, enters the cytogenetic differential diagnosis, because the premature centromere division that characterises it involves the sister chromatids in their entirety and not only the centromeric regions, unlike what occurs in the ESCO2 spectrum [12]. Chronic atrial and intestinal dysrhythmia, caused by SGOL1 variants, shows premature centromere separation without the railroad track appearance [12].

Finally, Brazilian surveillance itself identified as the main differential diagnoses of the phenotypes considered suggestive Roberts syndrome, Holt-Oram syndrome, Fanconi pancytopenia, thrombocytopenia-absent radius syndrome and the femur-fibula-ulna complex, besides unspecified developmental conditions, which confirms that the operational exclusion list is relatively short and stable [25].

7. Treatments and Risk Management Strategies

7.1. General principle and absence of targeted therapy

There is no treatment that corrects the embryopathy, nor any drug directed at the condition. The damage is structural, established before the ninth week of gestation, and clinical intervention has three axes: rehabilitation and functional surgery, treatment of the organ malformations according to the usual practice of each specialty, and management of the secondary complications that arise over the course of life. The fourth axis, prevention of further exposures, is the only one that alters the incidence of the disorder and is addressed in a subsection of its own [2, 31].

7.2. Team and therapeutic aims

The structure of care described in the Brazilian textbook of genetic syndromes assigns defined roles: to the family doctor and the paediatrician, assessment of the complications arising from the syndrome; to orthopaedics, the indication for prostheses and surgery of severely deformed limbs, including the decision on amputation; to speech and language therapy, improvement of functional hearing, oral language and articulation; to psychology, continuing support; to ophthalmology, prevention of visual complications; and to medical genetics, counselling [2]. The British historical experience showed that the effective model was the single multidisciplinary centre, bringing together surgery, prosthetic bioengineering, occupational therapy and physiotherapy and allowing joint admission of the child and the parents during assessment, precisely because many families came from far away and the process required time [31].

7.3. Rehabilitation, orthoses and prostheses

The most consistent lesson from the paediatric experience of the 1960s and 1970s is that the upper limb prostheses then available, cable-driven or gas-powered, scarcely improved function: they were too bulky, and children with good lower limb function rapidly learned to use their feet with great dexterity for tasks normally performed with the hands [31]. The role of passive prostheses remained restricted to cosmetic purposes in people with complete absence of the upper limb, and a vestigial digit could be used to operate a switch on a powered prosthesis [31]. The work of therapists, in teaching adaptations and simple orthoses for self-care activities, such as dressing and perineal hygiene, and in the use of the mouth to hold and manipulate objects, proved more decisive than the prosthetic technology of the time [31].

7.4. Upper limb surgery in the child

No procedure applies to an absent limb or to a vestigial digit attached to the trunk [31]. In the phocomelic configuration, in which the shoulder joint is absent and the hand is unstable, stabilisation with lengthening was attempted by mobilising the clavicle from its sternal insertion and fixing it to the hand, creating a rudimentary shoulder with some growth potential; the initial results were described as encouraging by the authors of the procedure, but the technique did not become widespread, and the non-surgical alternatives of therapeutic training proved probably more effective [31].

The field in which surgery had the greatest role was radial dysplasia. Experience accumulated in the correction of the radially deviated hand, by centralisation and by radialisation, and in the treatment of absent thumb by pollicisation of the index finger [31]. The usefulness of wrist realignment procedures was later questioned, but long-term follow-up of adults operated in childhood by centralisation, most with associated pollicisation, showed overall good function, with short forearms and some recurrence of the radial deviation [31]. The same follow-up documented that many of these people became well-adapted adults, married in their thirties and forties, had children and were in paid employment [31]. The techniques developed in that era remain in use in the treatment of congenital hand differences in general, whatever the aetiology [31].

7.5. Approach in the adult

The survivors of the historical exposure are now between 59 and 64 years old or more, and their clinical presentation has shifted from the malformation to its consequences: pain, progressive restriction in activities of daily living and symptoms of nerve origin, above all carpal tunnel syndrome [31]. Assessment should be holistic and conducted with specialists experienced in this population, including neurology, dermatology and the therapies; national organisations with extensive networks, such as the Thalidomide Trust in the United Kingdom, support patients and clinicians [31].

The history must establish the level of independence, the activities of daily living and the support network, because it determines which therapeutic options are practicable, and it must include the surgical history, given that most adults have been operated on, almost always in childhood [31]. Examination covers the whole upper limb and considers lower limb pathology, using up-to-date nomenclature and classification of the congenital differences to allow communication between specialists and the collection of comparable data; active and passive ranges are recorded and a detailed neurological examination is performed, all the more so because generalised sensory changes are common and cervical root entrapment may be present [31]. Functional assessment by physiotherapy or occupational therapy and the systematic use of patient-reported outcome questionnaires should form part of practice [31]. In imaging, radiographs should cover the affected joint and possibly the whole limb; orthogonal views may be difficult to obtain because of fixed flexion deformities, and computed tomography is particularly useful for characterising the pattern of deformity and planning surgery [31].

For symptoms of nerve origin, conduction studies should be performed, preferably by a neurophysiologist experienced in this population, because a mixed picture of compression and polyneuropathy is frequent and because the altered anatomy of the wrist makes the electrophysiological changes typical of carpal tunnel syndrome of little use [31]. Ultrasound assists surgical planning by identifying variations in the course of the nerve [31]. Carpal tunnel decompression is the upper limb procedure most frequently performed in adults with this embryopathy and reliably improves sensory symptoms, an extended median nerve release being worth considering, since the usual anatomical landmarks are unreliable [31]. The pathophysiology of the neuropathy in this population combines the mechanical effect of the deformity, namely the extreme wrist flexion of longitudinal radial deficiency, with a possible direct axonal toxicity of the drug, suggested by reports of late-onset neuropathy in adults treated with thalidomide for myeloma or Behçet's disease, successfully treated by decompression; the proposed mechanisms include inhibition of tumour necrosis factor alpha and of nuclear factor kappa B, required for the survival of sensory neurones, and capillary damage from prolonged exposure [31].

In wrist osteoarthritis secondary to dysplasia and repeated overload, once conservative treatment has been exhausted, the salvage options are denervation, partial arthrodesis, proximal row carpectomy, when feasible, and total arthrodesis; the position of total arthrodesis requires extreme care, because the apparently abnormal posture of the wrist may be essential for the performance of daily tasks, and the altered anatomy with smaller bones makes the operation technically more difficult, possibly requiring non-conventional implants [31]. There is no role for wrist arthroplasty, given the long-standing joint imbalance [31]. At the shoulder, the mainstay of treatment is physiotherapy and intra-articular injection; arthroplasty is very rarely performed, without robust long-term data, with more complications expected than in the general population and with observed cases of early revision and a worse outcome than before surgery, so that any major joint surgery of the upper limb, arthroplasty or arthrodesis, should be decided in a multidisciplinary meeting and with an explicit warning to the patient [31]. There is one known case of elbow arthroplasty in this population, with a poor outcome [31].

7.6. Perioperative and anaesthetic considerations

Early preoperative assessment by an experienced anaesthetist reduces delays and cancellations [31]. Venepuncture may be very difficult, because of limb shortening and anomalous vasculature, and the same problem explains the difficulty in palpating pulses and measuring blood pressure in the arms of some affected people, whose vascular pattern is altered [31]. Intubation may be difficult because of limited cervical extension, associated with cervical spine anomalies or skull dysplasia, and anatomical variations should be anticipated in brachial plexus block [31]. Postoperative planning must take account of the pre-existing limitations, with prior involvement of physiotherapy and occupational therapy, and prolonged use of bulky external immobilisation, such as plaster casts or rigid orthoses, which are highly limiting in these patients, should be avoided [31].

7.7. Doses of the drugs of the class and divergences between jurisdictions

The doses that follow refer to the treatment of the adult diseases for which thalidomide and its analogues are authorised, and appear here because they define the exposures that may give rise to new cases of embryopathy; none is intended for the treatment of the embryopathy. The sources consulted contain no clinical guideline with doses for this entity, so the reference is the official label of each jurisdiction, as indicated in each row.

The divergences between jurisdictions are material and should be known by those who prescribe or counsel. The United States label covers multiple myeloma and erythema nodosum leprosum; the European label covers only multiple myeloma and in a different combination, with melphalan and prednisone rather than dexamethasone alone [8, 26]. The daily dose of 200 mg in myeloma is identical in the two jurisdictions [8, 26]. By contrast, the prevention requirements diverge: the United States requires two simultaneous contraceptive methods and a male condom until 28 days after the last dose, whereas the European Union requires one effective method from the list in the summary of product characteristics and a male condom until at least seven days after withdrawal [8, 26]. The quantification of risk also differs in wording: the European text gives a frequency of about 30% for severe defects, and the United States text emphasises mortality of about 40% and the sufficiency of a single capsule [8, 26].

7.8. Data from the drug trials and their limits

The available trials concern the efficacy of thalidomide in its adult indications, not the treatment of the embryopathy. They are presented because they justify keeping the drug on the market and therefore the permanent need for the prevention programmes.

Reading these data requires three caveats. The erythema nodosum leprosum trials are old, with seven-day courses and heterogeneous comparators, and the label itself states that the principal data come from the published literature and from a retrospective study of 102 patients treated by the United States public health service, which does not allow them to be treated as contemporary high-level evidence [8]. Response rates are not comparable between trials conducted in different populations and eras, and the hazard ratio of 0.43 for time to progression should be read together with the absolute rates that support it, 31% versus 54% [8]. And the benefit in time to progression did not translate into a statistically demonstrated difference in overall survival in that trial, whose hazard ratio confidence interval includes unity [8].

7.9. Agents to avoid, pregnancy and breastfeeding

For the person with thalidomide embryopathy, the sources consulted describe no drugs specifically contraindicated by reason of the embryopathy; the relevant precautions are those arising from the organ malformations, namely renal function in urinary anomalies and the anaesthetic risk already described [2, 31]. For the woman of childbearing potential who requires thalidomide or an analogue, the contraindication is absolute in pregnancy, and management is codified in the prevention programmes described in the following subsection [8, 26]. Breastfeeding must be discontinued during treatment with thalidomide: there is no information on the presence of the drug in human milk, but it is excreted in the milk of lactating rabbits, with mean concentrations of 22 to 36 micrograms per millilitre at an oral dose of 150 mg/kg/day and values between 1.16 and 3.63 times those in plasma depending on the dose, the behaviour expected of a lipophilic compound [8]. The same principle appears in the European text, which recommends discontinuing breastfeeding [26].

As to pregnancy in women with the embryopathy, the Swedish study of offspring documented a caesarean section rate of 39% in affected mothers versus 14% in unaffected mothers, partly because of pelvic and uterine malformations, a finding that should guide obstetric planning [10].

7.10. Prevention: the exposure control programmes

The only intervention that reduces the incidence of the embryopathy is strict control of exposure in women of childbearing potential and in the partners of treated men. Three systems coexist, with different architectures.

In the United States, thalidomide is approved for marketing only through a restricted distribution programme, now designated Thalidomide REMS, for risk evaluation and mitigation strategy, whose mandatory components are certification of prescribers, signature by the patient of an agreement form with the physician, with compliance with the pregnancy testing and contraception requirements, and certification of pharmacies, which may dispense only to authorised patients [8]. The pregnancy testing schedule is the most demanding of the three systems: two negative tests before starting, the first within the preceding ten to fourteen days and the second within the twenty-four hours before prescription; thereafter weekly during the first four weeks and, subsequently, every four weeks in women with regular cycles or every two weeks in those with irregular cycles; any missed period or abnormal bleeding requires a further test and counselling, with suspension of the drug during assessment [8]. Contraception requires continuous heterosexual abstinence or two simultaneous methods, one of high efficacy, such as tubal ligation, intrauterine device, hormonal contraception in any of its forms or partner vasectomy, and an additional method, such as a latex or synthetic male condom, diaphragm or cervical cap, from four weeks before until four weeks after treatment, including dose interruptions, and even with a history of infertility, except after hysterectomy [8]. Men must use a condom in any sexual contact with a woman of reproductive potential during treatment, during interruptions and until twenty-eight days after the last dose, even after successful vasectomy, and may not donate sperm; blood donation is prohibited during treatment and for the following four weeks, because the blood could be transfused to a pregnant woman [8]. There is a pregnancy exposure registry that follows outcomes in exposed women and in partners of male patients and that also serves to identify the cause of each pregnancy [8].

In the European Union, including Portugal, prescribing and dispensing follow the Pregnancy Prevention Programme described in the summary of product characteristics itself, and thalidomide is contraindicated in women of childbearing potential who do not meet all the conditions of the programme and in men unable to comply with the contraceptive measures [26]. The programme begins by defining who is not of childbearing potential, applying the same criteria to the patient and to the patient's partner: age 50 years or over with natural amenorrhoea for at least one year, with the explicit note that amenorrhoea following cancer therapy or breastfeeding does not exclude potential; premature ovarian insufficiency confirmed by a gynaecologist; previous bilateral salpingo-oophorectomy or hysterectomy; and XY genotype, Turner syndrome or uterine agenesis [26]. Contraception requires an effective method, and the text lists as examples the implant, the levonorgestrel intrauterine system, depot medroxyprogesterone acetate, tubal sterilisation, intercourse only with a vasectomised partner, with vasectomy confirmed by two negative semen analyses, and ovulation-inhibiting progestogen-only preparations, such as desogestrel; as an alternative, absolute and continuous abstinence confirmed monthly is accepted [26]. Combined oral contraceptives are not recommended, because of the increased risk of venous thromboembolism in multiple myeloma, and a patient using them should change to one of the listed methods, bearing in mind that the thrombotic risk persists for four to six weeks after discontinuation of the combined preparation [26]. Pregnancy tests are performed under medical supervision with a minimum sensitivity of 25 mIU/ml, including in women practising abstinence, before starting, at the prescribing consultation or in the preceding three days and after at least four weeks of effective contraception, and are repeated every four weeks, including four weeks after the end of treatment, except with confirmed tubal sterilisation [26]. For men, a condom is required during treatment, during interruptions and for at least seven days after discontinuation, if the partner is pregnant or of childbearing potential without effective contraception, even after vasectomy, and semen donation is prohibited during that same period [26]. Handling precautions are added: do not give the medicine to anyone else, return unused capsules to the pharmacy at the end of treatment, do not donate blood during treatment and for the following seven days, wear disposable gloves when handling the blister or the capsule and avoid handling by women who are pregnant or suspected to be pregnant [26]. If pregnancy occurs, treatment is discontinued immediately and the woman is referred to a physician experienced in teratology; the same applies to the partner of a male patient [26].

In Brazil, the framework is simultaneously legal and regulatory and rests on Law No. 10,651 of 16 April 2003 and on Collegiate Board Resolution No. 11 of 22 March 2011 of the National Health Surveillance Agency, whose annex of indications was subsequently amended [34]. The architecture is that of a public monopoly: supply and trade in the substance and the medicine are prohibited, except to authorised pharmochemical manufacturers, official manufacturing laboratories and accredited public dispensing units; manufacture is restricted to official laboratories, according to Ministry of Health planning; sale by the dispensing units is barred and compounding in pharmacies is prohibited [34]. Dispensing units are accredited with a one-year validity, prescribers are registered on the basis of their professional council registration and users are entered in a national register [34]. Prescription may be issued only by a doctor registered with the regional medical council, for the indications set out in the annex to the resolution and in the approved package insert, through a Thalidomide Prescription Notification accompanied by a term of responsibility and information; the notification is valid for twenty days and the quantity per prescription may not exceed that needed for thirty days of treatment [34]. The contraceptive requirement differs from the European one and is close to the United States one: because of the severe teratogenic effects, the medicine may be prescribed to women of childbearing age only after medical assessment excluding pregnancy by a sensitive method and with evidence of the use of at least two effective contraceptive methods, at least one of them a barrier method, except in sterilised women; all patients between menarche and menopause are considered to be of childbearing age; the Unified Health System is responsible for supplying the contraceptive methods throughout treatment and until thirty days after its end, and male patients are instructed to use a condom throughout treatment and for the following thirty days [34]. Dispensing is carried out exclusively by a pharmacist, who completes the notification, returns the first copy to the patient and may dispense only if every field of the notification and of the term is completed; breaking the secondary packaging for split dispensing is prohibited [34]. For indications outside the annex, as a last therapeutic resort, prior authorisation from the agency is required, with a justification form, a copy of the notification and published literature demonstrating efficacy and safety, and a case progress report at each renewal [34]. The secondary packaging is white and bears, in red letters, the sentence stating that thalidomide causes the birth of children without arms and without legs, an unidentifiable image of an affected child, a black band with the prohibition for pregnant women or women who may become pregnant, with reference to the law and the resolution, and a red band indicating that it is subject to medical prescription and retention of the prescription [34]. The rule further regulates the return of unused medicine, disposal exclusively by incineration after a certificate from the health authority, the prohibition of donations outside the exceptions provided, permanent education campaigns under public authority, periodic training of professionals and the classification of non-compliance as a health offence, without prejudice to civil, administrative and criminal liability [34].

7.11. Real-world performance of the programmes

The existence of a programme is not equivalent to compliance with it. A utilisation study in three United States health insurance databases, covering 48,311 initiators of lenalidomide with a mean age of 59 years, 17,550 of thalidomide with a mean age of 65 years and 6560 of pomalidomide with a mean age of 65 years, of whom 45% were women, identified 1920 women of reproductive potential, corresponding to 3% of initiators, of whom 1004 were on thalidomide, 852 on lenalidomide and 64 on pomalidomide [67]. In that group, only 12% had a billing record of two pregnancy tests before starting, with 6% for thalidomide, 19% for lenalidomide and 17% for pomalidomide, and the proportions rose to 42%, 62% and 66% when only one test was required [67]. During the first month, only 9% of the 1359 women with at least thirty-three days of follow-up had a record of four tests, whereas 52% of those who received a prescription refill had a record of a test within the seven days before dispensing, with 41% for thalidomide, 61% for lenalidomide and 58% for pomalidomide [67]. The authors note that apparent adherence is about three times greater for the requirement whose non-fulfilment automatically prevents dispensing than for the weekly testing requirement, whose non-fulfilment does not block access, and acknowledge that billing data do not capture tests performed without a charge, which limits interpretation in absolute terms but does not nullify the pattern observed [67]. They further observed that persistence with treatment was lower in women of reproductive potential than in the overall cohort, with 25% versus 34% for thalidomide and 38% versus 44% for lenalidomide at 180 days, which may reflect the burden of the testing requirements [67]. Only 0.5% of thalidomide initiators had a diagnosis of leprosy, which shows that, in the United States, exposure occurs almost entirely in the oncological setting [67].

In Brazil, assessment of performance is indirect and comes from epidemiology. The generic is produced by a single official laboratory under Ministry of Health supervision and about four million tablets are distributed per year, mainly for erythema nodosum leprosum; until 2010 there was no information on the exact destination of those tablets, a gap the authors hold responsible for the occurrence of recent cases, and only from 2011 did the dispensing legislation with strict control of who receives the prescription come into force [25]. The fact that new cases were identified despite earlier restrictive legislation, and that the mothers denied exposure when questioned, shows that the weak point of the system lies not in the regulation but in informal sharing of the medicine, in self-medication and in coverage of the rural endemic areas [25, 39, 40].

7.12. Comparative regulatory table

7.13. Regulatory and scientific developments of the past twelve months

Three developments occurred in the twelve-month period before the date of this update, and their level of evidence differs.

The first is regulatory and is documented in a primary official source. The Food and Drug Administration approved, in 2026, the conversion of the thalidomide risk minimisation programme, originally approved on 3 August 2010 and modified on 27 April 2026, into a shared system designated Thalidomide REMS, with a change of designation, replacement of the brand by the generic name, transfer of ownership to the collective thalidomide applicants, removal of brand elements, a new electronic address and reformatting of the materials; the assessment plan requires the number of pregnancies per period and cumulatively, the outcome of each, follow-up of pending cases, root cause analysis of each notified pregnancy and linkage to the periodic safety report with worldwide information, the assessment schedule approved on 13 September 2015 being maintained [33]. In parallel, the same authority approved modifications to the shared lenalidomide programme, submitted on 30 October 2025, intended to harmonise it with the thalidomide and pomalidomide programmes, including elimination of the stand-alone emergency contraception leaflet, whose information moved to the prescriber and patient guides, clarification of the audit requirements and standardisation of pharmacy training; and approved, in the same cycle, modifications to the shared pomalidomide programme, submitted on 28 February 2026, whose shared version had been approved on 26 February 2025 [68, 69]. The practical consequence is the convergence of the three programmes into a common model, which simplifies certification of prescribers and pharmacies working with more than one of these drugs.

The second is the authorisation of a new cereblon modulator. Iberdomide received accelerated approval in the United States with an effective date of 13 August 2026, in combination with daratumumab and hyaluronidase-fihj and dexamethasone, for adult patients with multiple myeloma who have received at least one prior line of treatment including a proteasome inhibitor and an immunomodulatory agent; the approval is based on complete response without measurable residual disease at any time point and its maintenance may depend on verification of clinical benefit in a confirmatory trial [66]. The label classifies the drug as a cereblon-modulating protein degrader and includes a boxed warning of embryo-fetal toxicity and of venous and arterial thromboembolism, with contraindication in pregnancy, two negative pregnancy tests before starting, two effective forms of contraception or continuous abstinence during treatment and for the four weeks following the last dose, restricted distribution through a dedicated programme, and, for those who can father a pregnancy, effective contraception with a condom even after vasectomy and prohibition of sperm donation, for the same period; in rats and rabbits, administration during organogenesis produced adverse developmental outcomes, including embryo-fetal mortality [66]. From the point of view of this article, the significance is clear: the class of drugs acting through cereblon is expanding, and each new member brings with it teratogenic risk and the need for a prevention programme.

The third is scientific and preclinical. The development of analogues that retain the clinical benefit without the antiangiogenic action, and therefore without embryonic damage, has progressed, and analogues with neuroprotective actions without embryonic toxicity in animal models have been described; these compounds are not in clinical use and the available evidence is preclinical [31]. The same reasoning applies to knowledge of the neosubstrates: the identification of SALL4, p63 and PLZF opens the possibility of designing molecules that degrade the therapeutic targets without degrading the developmental targets, an aim explicitly stated by the authors of the respective studies, but not yet translated into an authorised drug [4–6].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk in a non-genetic condition

Counselling begins with a statement that relieves most of the anxieties of this population: there is no recurrence risk if the medicine is not used again during a pregnancy [55]. The risk is conditioned by exposure and not by genetic constitution, and for that reason prevention here replaces the calculation of Mendelian probabilities. For the woman who took thalidomide in one pregnancy and becomes pregnant again without exposure, the risk of malformation is that of the general population, estimated in the United States at 2% to 4% for major defects and 15% to 20% for clinically recognised miscarriage [8].

The counterpart is that the risk per exposure is very high and immediate: a single capsule taken within the critical window is enough to cause severe defects, so that preconception counselling of anyone treated with thalidomide or its analogues must be explicit about the need to stop the drug and to respect the safety intervals before attempting to conceive, which are at least four weeks in the two labels consulted [8, 26]. The Brazilian textbook advises the use of a condom and of contraception for the thirty days following discontinuation of the medicine, an interval coinciding with that of the national health regulation [34, 55].

8.2. The question of the second generation

The possibility that the defects might be transmitted to the children of affected people was the subject of intense public controversy and deserves a careful answer, because it remains a concern for survivors and their descendants. The most explicit analysis of the problem identified only two conceivable mechanisms: that the parent's defects, arising in embryonic life, might be transmitted to the next generation, a hypothesis that would require inheritance of acquired characteristics and is therefore excluded; or that thalidomide might be mutagenic as well as teratogenic, a hypothesis without scientific foundation [9]. The author concluded that congenital defects are no more frequent among the children of affected parents than in the general population and that affected adults should be firmly reassured in that regard [9]. The absence of mutagenic activity is documented in the assays reported in the label, and the reference review records that the defects are not heritable [8, 23].

The most solid empirical evidence is the Swedish study of 64 children, 29 girls and 35 boys aged between zero and eighteen years, born to 34 parents with the embryopathy, fourteen women and twenty men; five children had both parents affected, twenty-three the mother and thirty-six the father [10]. No malformations or functional anomalies of the type characteristic of the embryopathy were found [10]. There were one major malformation, a pulmonary stenosis in a girl, isolated cases of minor physical features and positional deformities, one boy with autism, four preterm births, all to affected mothers, one death within the first twenty-four hours and seven miscarriages, five of them in affected mothers [10]. The caesarean section rate was 39% in affected mothers versus 14% in unaffected mothers, partly because of pelvic and uterine malformations [10]. The reference review cites the same work as a demonstration that there was no evidence of damage in the offspring [23].

8.3. When the second generation indicates a genetic disorder

There is, however, a clinically decisive exception, and it is the reason why genetic testing forms part of counselling. Some cases historically presented as proof of transgenerational transmission of the embryopathy were, in fact, families with SALL4 variants. The publication that identified a novel variant of that gene in a family in which the father had been considered a victim of the embryopathy and the daughter had a similar phenotype concluded that some cases labelled as thalidomide embryopathy may result from SALL4 variants, with increased risk to offspring [13, 36]. The same group subsequently published the identification of SALL4 variants in a father and daughter with malformations previously attributed to mutagenesis by thalidomide [49]. The family described by McBride as evidence of the mutagenicity of the drug belongs to this group [48].

The practical consequence is a rule of conduct: in a person with a diagnosis of thalidomide embryopathy who has a child with similar radial ray malformations, with or without Duane anomaly and renal anomalies, molecular testing should be requested, and a SALL4 variant is more likely to be found than a TBX5 variant [11]. Once a dominant variant is confirmed, counselling changes radically: the risk for each child becomes 50% of inheriting the variant, with penetrance of about 95%, and about 40% to 50% of cases of SALL4-related disorder result from de novo variants, which explains the absence of a family history in many families [11].

8.4. Counselling people with the embryopathy who plan to have children

The content of counselling has four components. First, the information that the condition is not transmissible and that the risk of malformation in the offspring is that of the general population, supported by the Swedish data and by the analysis of the second-generation problem [9, 10]. Second, the offer of genetic testing when the phenotype is compatible with a phenocopy, especially if there is Duane anomaly, renal anomalies or a family history, not to contest the historical attribution, but because the answer alters the reproductive risk [11, 36]. Third, obstetric planning: the high frequency of caesarean section in affected women, associated with pelvic and uterine malformations, and the possibility of uterine and reproductive tract malformations described in the phenotype recommend gynaecological assessment before pregnancy [10, 23]. Fourth, functional assessment of the capacity to care for an infant with the limitations of the upper limb, which is resolved by adaptation and support and not by restriction, as illustrated by the follow-up data showing adults who are married, with children and in employment [31].

8.5. Contraceptive counselling of patients exposed to the drug

For women of childbearing age treated with thalidomide or its analogues, contraceptive counselling is part of treatment and not an adjunct. In the United States, women without an established method are required to be referred to a provider qualified in contraception, and the European rule provides for preferential referral to a professional with appropriate training to initiate the method [8, 26]. In the European Union, the choice should avoid combined oral contraceptives because of the thrombotic risk associated with myeloma, which in practice points towards progestogen-only methods, the levonorgestrel intrauterine device, the implant or the depot injectable [26]. In Brazil, the public system is formally responsible for supplying the methods throughout treatment and for the following thirty days, which transfers to the State the material responsibility for access [34].

Counselling must cover male patients, whose exposure is frequently undervalued. Thalidomide is present in semen, and both the United States and the European labels require a condom in any contact with a woman of reproductive potential, even after successful vasectomy, with prohibition of sperm donation [8, 26]. The Brazilian regulation frames the obligation as prescriber guidance on the use of a condom throughout treatment and for the following thirty days [34]. On the basis of findings in animals, male fertility may be impaired by treatment, information that should be given to young men before starting therapy [8].

8.6. Counselling of minors and social issues

The sources consulted do not specifically address the genetic counselling of minors in this entity, which is consistent with its non-heritable nature: there is no predictive test to offer and no carrier decision to make. What does exist, and is substantial, are social issues that counselling must recognise. Information about the exposure depends on maternal recall and may be hindered by fear of stigma for having used a medicine contraindicated in pregnancy, so that the approach must be explicitly non-accusatory, all the more so since, in the Brazilian context, the drug is frequently obtained through family sharing without knowledge of the risk [23, 25]. In countries with compensation schemes, the diagnostic attribution has financial and support access consequences, which adds a particular weight to the diagnostic decision and justifies the use of structured instruments for assessing causal probability [23, 27].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

The epidemiology of this entity must distinguish four quantities that the literature sometimes conflates: the historical number of people affected by the 1957 to 1962 exposure; the current prevalence of survivors; the birth prevalence rate of compatible phenotypes in populations with access to the drug; and the risk of malformation conditional on exposure within the critical window. This last quantity, discussed in the section on the clinical spectrum, is not a population measure and should not be presented as a prevalence [2, 23].

9.2. The historical exposure

The most frequently cited estimate is more than 10,000 children born with malformations between 1957 and 1962 worldwide, a figure that appears in the reference review and in the Brazilian descriptions [23, 25, 40]. A review from a regulatory perspective gives a higher estimate, above 12,000 children, and adds the hypothesis that about 40% of infants with drug-induced malformations in that era died in the neonatal period [24]. The two estimates are not contradictory: they depend on who is counted, identified survivors or total affected births, and neither includes the pregnancies lost, so that the true number will never be known [23].

The geographical distribution followed marketing in 46 countries [23, 25]. The country-level data available in the sources consulted refer to populations of survivors followed by compensation schemes, and not to birth denominators. In the United Kingdom, the national fund that administers the payments had 467 beneficiaries in 2015, of whom 351 responded to the health survey, and a later publication refers to 415 people resident in the country, with 392 participants, while the 2023 hand surgery review indicates approximately 450 survivors aged between 59 and 64 years [31, 35, 70]. In Germany, a cross-sectional survey recruited 202 people with the embryopathy in North Rhine-Westphalia alone, with a mean age of 50.6 years and 55.9% women, and another German study surveyed 206 affected people with a control group of 183 unaffected people, which gives an idea of the size of the remaining German population without allowing a national total [45, 71]. In Sweden, the study of offspring identified 34 affected parents [10]. In Japan, there are centres with experience in adults with the embryopathy that support clinical reviews and imaging studies [32]. None of the sources consulted gives a number of survivors in Portugal, nor a national registry, and Orphanet does not disaggregate its prevalence class by country [1].

9.3. Prevalence recorded by Orphanet

Orphanet assigns ORPHA:3312 a prevalence class of 1 to 9 per 1,000,000, with antenatal and neonatal onset, and indicates the inheritance category not applicable as the applicable one [1]. This class corresponds to the population of identified survivors and not to the risk of new cases, and should be read with the caveat that the entity has a very uneven distribution between countries, concentrated in those that marketed the drug in the 1950s and 1960s and in those that currently distribute it for leprosy [1, 23].

9.4. The contemporary epidemic in Brazil

Brazil is the country where the entity continues to occur, and its data are the only ones that allow birth rates to be estimated. Surveillance was based on the network of the Latin American Collaborative Study of Congenital Malformations, which has carried out quarterly surveillance of the embryopathy since 1982, with 56 Brazilian hospitals and 1,145,214 births examined, corresponding to 23.52% of the 4,868,490 births monitored by the network in nine Latin American countries [25].

In the baseline period, from 1982 to 1999, 152 newborns with the sentinel phenotype were identified in 793,177 births, corresponding to a birth prevalence rate of 1.92 per 10,000, with a 95% confidence interval of 1.60 to 2.20, without significant difference between regions: 1.41 per 10,000 in the North-East, with an interval of 0.90 to 2.10; 2.22 in the South-East, with an interval of 1.80 to 2.80; and 1.68 in the South, with an interval of 1.20 to 2.30 [25]. In the surveillance period, from 2000 to 2008, 109 cases were identified in 352,037 births, corresponding to 3.10 per 10,000, with an interval of 2.50 to 3.70, higher than in the baseline period; by region, 3.20 per 10,000 in the North-East, with an interval of 2.00 to 4.80, and 5.10 in the South-East, with an interval of 3.80 to 6.80, the South being the region with the lowest rate and without difference between the two periods [25].

Interpretation requires two qualifications that the authors themselves introduce. The first is that the regional distribution follows the distribution of leprosy in the country, which supports causal plausibility: where the disease is less prevalent, as in the South, the phenotype is also less frequent [25]. The second is that the increase may reflect a referral bias: excluding tertiary hospitals in both periods, the increase is not observed, with 1.59 per 10,000 in the baseline period, interval 1.30 to 1.87, versus 2.18 in the surveillance period, interval 1.64 to 2.71 [25]. Improved prenatal diagnosis and the channelling of fetuses with anomalies to specialised maternity units within the network would explain part of the effect [25]. The South-East showed the highest rate, possibly because of that same bias [25].

As to individually confirmed cases, the count is inevitably small and certainly incomplete. In the proactive surveillance from March 2007 to February 2008, 96 newborns with limb reduction defects were assessed in detail, of whom 16 were classified as having the sentinel phenotype; seven remained inconclusive for lack of information, seven were considered incompatible and two had a phenotype suggestive of exposure without another syndromic diagnosis, although the mothers denied taking the drug [25]. Before that, the Teratogen Information Service of Porto Alegre had recorded three cases born in Brazil since 2005, identified through a sequence of chance events and not through systematic surveillance, which led the authors to conclude that the real occurrence remained as frequent as that denounced ten years earlier; in Latin America there had been no reports of new cases since 1996 [39]. In 2013, two new cases identified in 2011 were described [40]. A structural limitation persists: the main endemic areas of leprosy lie in rural regions of the North and Central-West, where many births occur outside hospital and where the surveillance network has no coverage [25]. The authors proposed maintaining surveillance at population level through the official birth records, which include a mandatory description of congenital defects [25].

The sources consulted give no estimates of birth prevalence rates in Brazil after 2008, so it is not possible to state that the situation improved or worsened after the dispensing legislation of 2011 came into force [25, 34].

9.5. Background prevalence of phocomelia

To put the Brazilian rates in context it is useful to know the frequency of phocomelia in the absence of known exposure. A study of nineteen birth defect surveillance programmes belonging to the international clearinghouse for birth defects surveillance and research, with data covering periods between 1968 and 2006 and a total of 22,740,933 births, including live births, stillbirths and, in some programmes, terminations for fetal anomaly, identified 141 cases of true phocomelia after detailed review of the clinical data, corresponding to a total prevalence of 0.62 per 100,000 births, with a 95% confidence interval of 0.52 to 0.73; three programmes, the Australian programme of Victoria, the South American programme of the Latin American network and that of north-east Italy, gave significantly different estimates [20]. More than half the cases, 53.2%, had isolated phocomelia and 9.9% formed part of syndromes; among the non-syndromic cases, most were monomelic, at 55.9%, with an excess of left-sided and upper limb involvement, both at 64.9%, and 66.9% were live births [20]. These figures, from a 2011 analysis cited by the OMIM database, show that phocomelia is an extremely rare event in the absence of exposure and that the excess of left-sided and upper limb involvement is not exclusive to thalidomide embryopathy [20].

9.6. Context of exposure by country and by indication

The structure of exposure differs radically between high-income countries and countries with endemic leprosy, and this difference determines who is at risk. In the United States utilisation study, only 0.5% of thalidomide initiators had a diagnosis of leprosy, and the great majority had multiple myeloma, with 60% of thalidomide initiators, 81% of lenalidomide initiators and 98% of pomalidomide initiators; the mean ages, 59 to 65 years, place the population largely outside reproductive age, and women of reproductive potential made up only 3% of initiators [67]. In Brazil, by contrast, the dominant indication is erythema nodosum leprosum, a disease of young adults, and access occurs through public health programmes in regions of high prevalence, which places women of full childbearing age at risk [25]. The consequence is that the same drug has very different population teratogenic risk profiles depending on the country, and that prevention strategies are not transferable without adaptation [25, 67].

Outside these two contexts, thalidomide is used in dermatological and inflammatory diseases, including actinic prurigo, aphthous lesions, Behçet's disease, chronic graft-versus-host disease, Crohn's disease and erythema multiforme, besides haematological neoplasms, and it has further been proposed for complications of coronavirus infection, with no established role [31, 38]. In Brazil, the authorised indications have included, since the late 1990s, multiple myeloma, graft-versus-host disease, systemic lupus erythematosus and the ulcerations associated with acquired immunodeficiency syndrome, provided that the purpose of the prescription was documented [25].

9.7. Special populations

There are no data on differential susceptibility by ancestry: the sources consulted describe no variation in teratogenic risk between human populations, and the only well-documented axis of biological variation is between species, not between human groups [4, 41]. The study of genetic modifiers of susceptibility was conducted in a Brazilian population and produced no markers of clinical utility [42, 44].

The current paediatric population with this embryopathy is almost entirely Brazilian, and its needs are those of habilitation, not rehabilitation: these are children growing up with the malformations and benefiting from early intervention, unlike the European and Japanese survivors, who are ageing with disability acquired decades ago [23, 25]. The reference review notes precisely that the Brazilian tragedy, because it involves children and young adults, offers the possibility of studying the progression of the damage and the late-onset problems that in the historical cohort were observed only retrospectively [23].

9.8. Reference networks, registries and patient associations

There is no European reference network dedicated to this entity, which is consistent with its non-genetic nature. Orphanet links ORPHA:3312 to specialist centres, centre networks, diagnostic tests, patient organisations, research projects, biobanks and registries, without designating a single network [1]. In practice, follow-up is articulated with the reference structures for limb malformations and rare bone and joint diseases and with those for multiple congenital anomalies, according to each person's predominant manifestation [1].

Patient organisations have a greater role here than in many rare diseases, because they administer support and organise care. In the United Kingdom, the Thalidomide Trust maintains information on all beneficiaries of the payments, funded and took part in the design of the health surveys and offers support networks to patients and clinicians [31, 35]. In Germany, there are medical competence centres dedicated to people with the embryopathy, whose experience prompted the study on falls risk [71]. In Brazil, the Associação Brasileira dos Portadores da Síndrome da Talidomida took part in the identification and follow-up of the cases described by surveillance, together with the Movimento de Reintegração das Pessoas Atingidas pela Hanseníase, with the National Leprosy Programme of the Health Surveillance Secretariat and with the regulatory agency [25, 40]. In Europe, the national compensation foundations complement these structures, with coverage varying widely between countries [23].

10. Illustrative Clinical Case

10.1. A 63-year-old woman with stigmata of the embryopathy

The case published by Sara Malik and Philip Cohen in the journal Cureus in 2021 illustrates the typical presentation of a survivor of the historical exposure in adulthood, and has the interest of documenting that the diagnosis frequently arises in a clinical setting unrelated to the malformation [38].

The patient is a 63-year-old woman in the United States, who attended a dermatology clinic for a full skin examination and whose relevant medical history was the intrauterine exposure: her mother had been pregnant in 1957 and received thalidomide during the pregnancy [38]. The examination documented several stigmata of the embryopathy. In the face and head, strabismus, a high-arched palate and asymmetry of the auricles, the right auricle measuring 2.5 cm in length and the left 3 cm [38]. In the limbs, absence of the wrist bones, hands with only two digits each, feet without toes, shortened tibia and fibula, with a reduced distance between the knees and the ankles, and hypermobility of the hip joint; the patient had undergone multiple operations [38].

The reason for the consultation was resolved independently of the embryopathy. The skin examination revealed multiple black and brownish plaques on the back, two of which had changed in size and colour and were biopsied; microscopic examination showed thickening of the epidermis with acanthosis, horn cysts and abundant melanin deposits in the basal layer of the epithelium, with lymphocytic inflammation in the papillary dermis, and clinicopathological correlation established the diagnosis of benign irritated seborrhoeic keratosis in both lesions [38].

The images in the paper document the findings described and are available on the figure pages of the repository, specifically the palate at https://pmc.ncbi.nlm.nih.gov/articles/PMC8428198/figure/FIG1/, the auricular asymmetry at https://pmc.ncbi.nlm.nih.gov/articles/PMC8428198/figure/FIG2/, the upper and lower limb deformities at https://pmc.ncbi.nlm.nih.gov/articles/PMC8428198/figure/FIG3/ and the hands and feet in detail at https://pmc.ncbi.nlm.nih.gov/articles/PMC8428198/figure/FIG4/; the figure pages were not opened during the preparation of this article, because access was intercepted by an anti-robot check, so the descriptions presented here derive from the legends and the text of the paper and not from inspection of the images [38].

10.2. Critical reading of the case

The case is representative in three respects and atypical in one. It is representative of the association between a severe limb defect, asymmetrical auricular anomaly and ocular anomaly, which is the characteristic combination of the embryopathy; of the history of multiple operations in childhood, described in most affected adults; and of the fact that the diagnosis rests exclusively on documentation of the maternal exposure, without a confirmatory test [31, 38]. It is atypical in the marked asymmetry of the auricles, since the auricular anomalies of the embryopathy are usually described as symmetrical, which serves as a reminder that symmetry is a statistical tendency and not an absolute criterion [23].

The authors present, in the discussion, a chronology of the relationship between the timing of exposure and the type of damage, according to which external ear defects correspond to intake between days 20 and 24 after fertilisation, limb defects between days 24 and 30, hip dislocation between days 24 and 34 and lower limb defects between days 27 and 34 [38]. This chronology is cited by the authors from their own references and not from their own data, and is compatible with the general scheme of decreasing severity across the window described in the reference review, according to which earlier exposure produces more severe damage and exposure at the end of the window is confined to the digits, eyes and ears [23, 38].

A note of caution on applying the case to practice: the authors' description of the male contraception requirements does not fully match the current label, so that, for the purposes of prescribing and counselling, the reference should be the text of the label and not the paper [8, 38]. The management described in the case, namely biopsy of the altered skin lesions, corresponds to usual dermatological practice and not to any specific feature of the embryopathy [38].

10.3. Two Brazilian cases from active surveillance

The cases identified by Brazilian proactive surveillance complement the preceding one, by showing the contemporary neonatal presentation and the difficulty of documenting the exposure [25].

The first child, female, was born in July 2007 in the North-East of Brazil, weighing 2360 g, to a 29-year-old woman with no family history of malformations who denied any exposure during the pregnancy [25]. She had a bilateral intercalary defect of the upper limbs: absence of the left humerus with hypoplastic radius and ulna and a hypoplastic left hand with two rudimentary digits, and hypoplastic right radius and ulna with an equally hypoplastic hand and two rudimentary digits; the lower limbs were normal [25]. Besides the reduction defect, she had a unilateral cleft lip, and the electrocardiogram was normal [25].

The second case, male, was born in October 2007 in the same hospital, weighing 2405 g, the third child of a 34-year-old woman with no family history of malformations or genetic diseases, who likewise did not report exposure to thalidomide during the pregnancy [25]. He had amelia of all four limbs, bilateral microtia, an elongated nasal root, moderate retromicrognathia and left cryptorchidism, with a normal electrocardiogram [25].

In both cases, the phenotype was considered suggestive of thalidomide exposure and no other syndromic diagnosis was identified, but use of the drug was not confirmed by the mothers when specifically questioned [25]. The authors recall that, in three clinically characteristic cases recorded earlier in Brazil, the maternal interview was likewise negative, and attribute this to maternal recall, to fear of social stigma and to self-medication, a habitual behaviour in the population [25]. It should be noted that, in the first case, the association of cleft lip with a bilateral intercalary defect would require, under the criteria of the GeneReviews chapter on the ESCO2 spectrum, formal exclusion of that entity by karyotype with C banding and molecular testing, a step that the published description does not document [12, 25].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis in the neonatal period and in childhood

The immediate prognosis is determined by the internal malformations and not by the limb defects. About 40% of affected infants died at birth or shortly afterwards, a proportion concordant between the United States label, the Orphanet description and the reference review, attributed mainly to damage to internal organs, with small bowel atresia and cardiac and renal malformations cited as the most frequent causes in a regulatory analysis that presents that attribution as a hypothesis [1, 8, 23, 24]. The Brazilian textbook reports the same figure for infant mortality and describes the overall prognosis as guarded, because of early deterioration of the musculoskeletal structures, joint damage and reduced function of organs and tissues [2].

Among survivors, the functional prognosis of childhood and young adulthood is better than the appearance of the malformation suggests. Long-term follow-up of adults operated in childhood by wrist centralisation, most with pollicisation, documented overall good function and showed that many became well-adapted adults, married in their thirties and forties, had children and were in paid employment [31]. In Okihiro syndrome, by comparison, upper limb function is typically good because most do not have severe reduction defects, which illustrates the difference in severity between the phenocopy and the embryopathy [48].

11.2. Deterioration in adulthood: the concept of hidden defects

The organising observation of adult follow-up was formulated in 1977, in a series of children with the embryopathy, with the concept of hidden defects: differences not apparent at the initial clinical presentation that become manifest only with time, and with the explicit prediction that early osteoarthritis would occur [31]. The mechanics of that deterioration are now described. In the absence of the radius, forearm rotation is compromised and the elbow is frequently stiff; the young patient compensates with excessive and constant external rotation of the shoulder, but that compensation, maintained over decades, damages the glenohumeral joint and produces glenoid dysplasia with concave remodelling of the humeral head [31]. The overall effect of this remodelling is to displace the centre of rotation of the joint downwards and inwards, optimising the lever arm of the deltoid and, with it, stability and function, exactly the principle on which reverse shoulder arthroplasty is based, which is why this pattern has been termed the natural reverse shoulder prosthesis [31].

The incidence of these age-related changes is probably underestimated [31]. The prevalence of osteoarthritis is increased compared with the general population and affects about 93% of affected people at a mean age of 46 years, according to the two studies cited in the hand surgery review, and already in the fourth decade patient-reported outcomes were worse than population reference values; comparison between a study with a mean age of 46 years and another with a mean age above 60 shows significantly worse function in the older group, although there are no longitudinal studies with paired data [31].

11.3. Cohort data on the health of survivors

The 2015 British survey, with 351 respondents from 467 beneficiaries, a response rate of 75% and age around 55 years, provides the most detailed description [35]. Almost all, 93%, reported musculoskeletal problems, with pain or loss of mobility: spinal problems in 72%, shoulder in 60%, hands in 59%, arms and wrists in 56%, neck in 55%, knee in 48%, hip in 46% and ankles, feet and toes in 28%; in the general population aged 45 to 64, fewer than 20% report chronic musculoskeletal conditions [35]. Widespread pain was reported by 49%, severe or continuous in 26%, and neurological symptoms, such as tingling and numbness, by 66%; two fifths reported severe fatigue [35]. Half reported current or recent depression or anxiety, with 41% anxiety and 34% depression, against about 20% in the British population aged 50 to 54 and 19.5% in a sample of 7500 adults with physical disability, a value very close to the 47.7% found in German survivors by face-to-face psychiatric interview [35]. Deteriorating vision was a concern for 43% and hearing for 38%, including deterioration attributable to age [35]. Other frequent problems were weight control in 40%, bowel and digestive problems in 28%, bladder or continence problems in 20% and asthma or breathing difficulty in 15% [35]. Only 3% had no health problem at all and 46% reported between four and nine distinct problems, which contrasts with a Scottish multimorbidity cohort in which about one third of patients aged 55 to 59 had two or more morbidities and fewer than 10% had four or more [35].

The social consequences are proportionate. Two fifths, 41.4%, were unable to work because of disability or health problems, 15.4% worked full time and the probability of not working increased with the severity of the condition, from 35% in the least severe band to 75% in the most severe; economic inactivity reached 63% against 18% in the population aged 50 to 54 [35]. In health-related quality of life measured by the twelve-item questionnaire, the mean score of the physical domain was 26.7 against 50 in the reference population, with 59.7% of respondents below 30, that is, in a situation equal to or worse than the 2% of the general population with the worst physical health [35].

The German survey of 202 people, with 186 in the primary analysis, a mean age of 50.6 years and 55.9% women, compared them with the German population adjusted for age and chronic disease: the physical component of quality of life was 33.4 against 45.3, with p below 0.001, and in men the mental component was 45.0 against 50.0, with p equal to 0.005 [45]. Subgroup analysis showed a severity gradient: those with involvement of all four limbs had a physical component of 25.0 against 38.5 in those with hearing loss only; those with severe pain had 25.8 against 37.7 in mild pain for the physical component and 40.4 against 51.8 for the mental component; and those with depressive disorder had a mental component of 38.0 against 45.8, in every case with non-overlapping confidence intervals [45]. Those without mental disorder maintained a high mental component, 53.2, which identifies chronic pain and mental disorder as the two modifiable determinants of quality of life in this population [45].

The more recent British survey, with 392 of 415 residents in the United Kingdom, that is 94% participation, confirmed and updated this picture: fewer than 2%, five people, reported no comorbidities, 94% reported nervous system problems, including pain, paraesthesiae and numbness, and the total number of comorbidities, in particular musculoskeletal ones, was significantly higher than in an age-matched general population sample [70]. The Japanese narrative review, based on twenty-five studies and on clinical experience with Japanese patients, summarises the pattern of secondary disability: in the upper limb, neuropathy chiefly from carpal tunnel syndrome, digital pain from tenosynovitis and symptoms of osteoarthritis, mainly of the shoulders; in the trunk and spine, low back pain and neck pain; in the lower limbs, less frequently, pain from hip and knee osteoarthritis; and reduction of the physical domain of quality of life related to the musculoskeletal disabilities [32]. The same review notes that reports on rehabilitation approaches to these secondary disabilities, including physiotherapy, environmental modification and alternative medicine, are scarce [32].

A recent German study addressed falls risk specifically, comparing 206 people with the embryopathy and 183 controls through an online survey: limitations of hearing, balance, vision, sensation and strength were significantly more frequent in the affected group, which also reported significantly more frequent falls and injuries, with more severe injuries, which led the authors to recommend individual risk assessment and targeted preventive measures [71]. On the cardiovascular side, a 2025 review stresses that the subject has become more relevant than ever to vascular medicine and cardiology, because of the age-related increase in health service use, describing the cardiovascular anomalies of the embryopathy and discussing whether atherosclerotic disease and its complications are more frequent in these people than in the general population; the abstract consulted gives no numerical values for that comparison [72]. Brazilian data point in the same direction: in a study of 28 people assessed, born between 1959 and 2010, with a questionnaire applied to 23 adults aged 19 to 55 years, progressive deafness and tooth loss were reported, and comparison with the Brazilian population showed early onset of cardiovascular disease, with p equal to 0.009, and a higher frequency of psychological disorders, with p equal to 0.011, although the authors acknowledge that there is insufficient evidence that the exposure caused or aggravated those events [73].

One cross-cutting barrier deserves recording: up to 43% of survivors report difficulty in accessing health services, and survey data show that they perceive the lack of understanding of their complex care needs as a significant obstacle [31].

11.4. Surveillance table

The surveillance that follows derives from the clinical reviews and the cohorts cited and not from a formal guideline, because none of the sources consulted describes a clinical guideline dedicated to the follow-up of this embryopathy.

11.5. Transition and organisation of care

The transition from paediatric to adult care is, in this entity, a transition between two different problems: from the habilitation of a child with a malformation to the management of an acquired and progressive disability in an adult with multimorbidity. Managing upper limb problems in this adult population requires easier and more direct access to appropriate surgical expertise, and the authors of the hand surgery review anticipate that the number of referrals, still small, will increase as these people age and access to care widens [31]. The practical recommendation running through the cohort studies is organised long-term monitoring, so that support and rehabilitation services can keep pace with evolving needs, and the adoption of a holistic approach that helps these people maintain functional independence into their seventies [70].

For the Brazilian children with recently occurring embryopathy, the same logic applies in reverse: the opportunity lies in instituting early the structured follow-up that the historical cohort was offered only retrospectively, including surveillance of the complications now known to be expected decades later [23, 73].

12. Summary and Final Considerations

Thalidomide embryopathy is an acquired condition that behaves, clinically, as a multiple malformation syndrome, and that occupies a dual place in medical genetics: it is the mandatory differential diagnosis of any preaxial limb reduction defect and is, at the same time, the condition whose mechanistic investigation elucidated the function of human developmental transcription factors. The injury occurs within a window of seventeen days, between days 20 and 36 after fertilisation, and a single capsule taken in that period is enough to produce severe malformations, which makes prevention a matter of absolute control of access and not of dose reduction [8, 23].

The phenotype has a recognisable pattern. The reduction defects are typically bilateral and symmetrical, predominate in the upper limb and follow the order thumb, radius, humerus and ulna; they are associated with generally symmetrical auricular anomalies with hearing loss, ocular anomalies with microphthalmia, coloboma and a strabismus resembling Duane anomaly, transient midline facial capillary haemangioma, vertebral anomalies and cardiac, renal, digestive and genital malformations. Early mortality, of about 40%, arises from the internal malformations and not from the visible limb defects [1, 8, 23].

The diagnosis is clinical and history-based, and there is no aetiological test. This absence imposes two complementary disciplines. The first is rigorous documentation of the exposure, dated in days after fertilisation, in the knowledge that maternal denial is frequent and does not exclude the diagnosis, and that in countries with endemic leprosy exposure frequently occurs through informal sharing of the medicine. The second is formal exclusion of the genetic phenocopies: SALL4-related disorders, Holt-Oram syndrome and the ESCO2 spectrum produce overlapping phenotypes, have repeatedly been confused with the embryopathy and have entirely different reproductive implications, because they are heritable [12, 25, 27, 36].

The mechanism is now partly elucidated and explains both the pattern of the damage and the failure of the preclinical tests of the 1950s. Thalidomide binds cereblon and alters the substrate specificity of a ubiquitin ligase, inducing the degradation of proteins that were not targets, among them SALL4, the p63 isoforms and PLZF, all indispensable to the development of the limb, the ear or bone; rodents escape because their cereblon and their own SALL4 have sequence differences that prevent that degradation. To this mechanism are added the selective destruction of vessels undergoing active angiogenesis, the generation of reactive oxygen species and the induction of cell death, which probably operate in cascade and explain the time dependence and the variability of the damage [3–6, 23].

There is no targeted treatment. Care rests on rehabilitation, on functional surgery of the upper limb, whose techniques, developed in this population, remain in use in all congenital hand differences, and on treatment of the organ malformations. From the fourth decade a second clinical problem emerges, that of the hidden defects: biomechanical compensation maintained over decades produces glenoid dysplasia, early osteoarthritis, carpal tunnel syndrome and chronic pain, with an osteoarthritis prevalence of about 93% at 46 years, physical quality of life far below the reference population, half of survivors with depression or anxiety and two fifths unable to work. Added to this are an increased risk of falls with injury, early onset of cardiovascular disease described in a Brazilian cohort and difficulty in accessing care reported by a substantial part of this population [31, 35, 45, 70, 71, 73].

Family counselling rests on two firm messages and one exception. The condition is not transmissible, the drug is not mutagenic and the children of affected people are at no increased risk of malformation, as the Swedish study of 64 offspring demonstrated; and there is no recurrence risk if the medicine is not used again in a pregnancy. The exception is the family in which the phenotype recurs in the next generation: in that situation, molecular testing is mandatory, because the likely explanation is a dominant SALL4 variant, with a 50% risk per child [9, 10, 36, 55].

The entity is not historical. Thalidomide is a drug in use, with oncological and dermatological indications, and its class is expanding: lenalidomide, pomalidomide and, since August 2026, iberdomide share the same mechanism and the same embryo-fetal risk, and all require pregnancy prevention programmes. These programmes diverge between jurisdictions in the number of contraceptive methods, the frequency of testing and the duration of the male precautions, and their actual implementation, measured in United States administrative data, falls far short of the formal requirement. In Brazil, where the dominant indication is erythema nodosum leprosum in a population of childbearing age, the birth prevalence rate of compatible phenotypes rose from 1.92 to 3.10 per 10,000 births between the periods 1982 to 1999 and 2000 to 2008, with the methodological caveat that the increase is not observed when tertiary hospitals are excluded, and affected children continued to be born despite restrictive legislation [25, 34, 66, 67].

From this follows the practical conclusion of this article. The clinician assessing a newborn with a limb reduction defect should ask about thalidomide, date any exposure precisely, look for the auricular, ocular and facial signs that accompany the limb defect, request echocardiography and hearing, ophthalmological and renal assessment, and exclude the genetic phenocopies before establishing the diagnosis. The clinician who prescribes thalidomide or an analogue to a person of reproductive age should treat the prevention programme as an integral part of therapy, including the counselling of male patients. And the clinician who follows an adult with this embryopathy should anticipate pain, neuropathy, osteoarthritis, falls risk and psychological burden, rather than waiting for them to be brought as a complaint.

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