Review · September 2026

What causes dysmelia?

Dr Loïc Rigal, for the DysNet documentation team · first published September 2026 · how this article was written · sources

Underlined words carry a plain-language definition: hover over one, tap it, or reach it with the keyboard.

It is the first question families ask, and the one research still cannot answer for most of them. A limb that formed differently is the visible end of a process that ran for about four weeks, early in pregnancy, and left almost no other trace. This review sets out what is established, what is probable and what is still only a hypothesis, in the order the evidence supports rather than the order the ideas are usually told in. It is written for families who want more than a leaflet and for clinicians who want the references. Nothing here is medical advice, and nothing here can diagnose a particular child.

Across large birth-defect cohortcohortA group followed forward in time, recording what happens to them. Slower and costlier than a case-control study, but less prone to error. NCI Dictionary of Cancer Terms →s, a cause is identified in roughly one case in five; for an isolated limb difference affecting a single limb, it is usually none.

Human limbs are built between roughly the fourth and the eighth week after conception. A bud of undifferentiated mesenchymemesenchymeThe soft, unspecialised tissue of the early embryo. It is the raw material from which bone, cartilage, muscle and blood vessels are later built. grows out of the body wall under the control of three signalling centres, each governing one axis. The apical ectodermal ridgeapical ectodermal ridgeA thin ridge of skin-forming tissue running along the tip of the growing limb bud. It tells the limb how far to grow, from shoulder to fingertip. Remove it in an animal embryo and the limb stops short., a thickened rim of ectoderm at the tip, drives outgrowth from shoulder to fingertip through fibroblast growth factorsfibroblast growth factorsA family of signalling proteins that tell cells to divide and keep growing. The ridge at the tip of the limb bud uses them to drive the limb outwards.. The zone of polarising activityzone of polarising activityA small patch of cells at the back edge of the limb bud that tells the hand which side is the thumb and which the little finger., at the posterior margin, sets the thumb-to-little-finger axis through sonic hedgehogsonic hedgehogA signalling protein, named after the video-game character, produced at the back edge of the limb bud. The amount of it a cell receives decides which finger that cell will help build. MedlinePlus Genetics →. The dorsal ectodermdorsal ectodermThe outer layer of cells covering the back of the developing limb. It is what makes the back of the hand different from the palm., through WNT7A, separates the back of the hand from the palm. The three are locked in feedback loops: remove one and the others fail in turn³.

Two consequences follow, and they shape everything below. First, timing decides the shape of the defect more than the cause does: the same insult a few days earlier or later produces a different limb, and very different insults striking at the same hour produce limbs that look alike^4,5. Second, by the time a pregnancy is confirmed, most of this window has already passed. A limb difference is therefore almost never the result of anything that happened after the mother knew she was pregnant.

The China Birth Cohort Study reviewed 2,123 birth defect cases and found an identifiable cause in 22.4% of them: 415 chromosomal anomalies, 31 monogenicmonogenicCaused by a change in a single gene. disorders, 23 environmental exposures and 6 attributable to twinning. Among live births the proportion fell to 13.4%¹. This is not a Chinese peculiarity; it is what every well-run cohort finds.

For limb differences specifically, the most useful study is a population-based series of 391 fetuses and children with limb reduction defects registered in the northern Netherlands between 1981 and 2017. An aetiological diagnosisaetiological diagnosisA diagnosis that names the cause, not just the condition. Saying a hand is affected describes it; saying which gene change produced it explains it. was made almost three times as often when several limbs were affected as when one was (relative riskrelative riskHow many times more likely an outcome is in one group than another. A relative risk of 1.14 means 14% more likely, which on a very rare condition still means very few extra cases. NCI Dictionary of Cancer Terms → 2.9, 95% CI95% CIThe confidence interval: the range within which the true figure most probably lies. A wide range, or one that includes 1, means the study cannot tell us much. NCI Dictionary of Cancer Terms → 2.2 to 3.8). No genetic disorder at all was identified among isolated defects of a single limb, whereas a genetic disorder was found in 16% of cases that had one affected limb alongside other anomalies². The practical reading is consistent with what geneticists advise: an isolated one-limb difference is usually sporadic, with a low recurrence risk; several limbs, or other organs involved, make genetic testing worthwhile.

Counting also depends on classification. Under the Oberg-Manske-Tonkin system, the 577 congenital upper-limb anomalies recorded in Stockholm over eleven years split into 429 malformations, 124 deformationsdeformationsA limb that formed normally and was then bent or squashed by outside forces. Distinct from a malformation, where the limb was built differently from the start., 10 dysplasias and 14 syndromes⁶. Malformations and deformations have entirely different causes, and mixing them is the commonest way to get the aetiology wrong.

Patterning genes. The HOX genesHOX genesA set of master genes that tell each part of the embryo what it should become, in the right order from head to tail and from shoulder to fingertip. NCI Dictionary of Genetics Terms → encode transcription factorstranscription factorsProteins whose job is to switch other genes on or off. NCI Dictionary of Genetics Terms → and act as the selectors of the body plan; HOXD13 is the one most often implicated in the hand. Changes inside and outside its homeodomainhomeodomainThe part of a HOX protein that grips DNA. A change here alters which genes the protein can switch on. NCI Dictionary of Genetics Terms → produce synpolydactylysynpolydactylyA hand or foot with both extra digits and digits joined together., in which digits are both extra and fused^7,8,9. Chromosomal breakpointsChromosomal breakpointsThe points at which a chromosome has broken and been rejoined in the wrong place. Genes near the break can end up cut off from the switches that control them. MedlinePlus Genetics → around the HOXD cluster, which do not touch the coding sequence at all, produce a whole range of limb malformations¹⁰, and the same is true of rearrangements affecting the distant control region of the HOXA cluster¹¹.

GLI3, which transducestransducesPasses a signal on: a message arriving at the cell is relayed inwards and changes what the cell does. NCI Dictionary of Genetics Terms → hedgehog signalling, illustrates how precisely genotypegenotypeThe genetic instructions a person carries, whether or not they show. NCI Dictionary of Genetics Terms → can predict phenotypephenotypeWhat can actually be observed in a person: the shape of the hand, the height, the results of a scan. The visible outcome, as opposed to the underlying genetic instructions. NCI Dictionary of Genetics Terms →. In 297 patients carrying 127 different variants, two distinct groups emerged: variants causing simple loss of one working copysimple loss of one working copyCalled haploinsufficiency: the person has one normal copy of the gene and one that does not work, and the half dose is not enough. NCI Dictionary of Genetics Terms → give anterior anomalies, while truncating variants inside the activator domain give posterior ones (postaxial polydactylypolydactylyBeing born with one or more extra fingers or toes. Preaxial means on the thumb or big-toe side, postaxial on the little-finger or little-toe side. Orphanet → of the hand, odds ratioodds ratioA way of comparing two groups. An odds ratio of 1 means no difference; 1.3 means roughly 30% higher odds in the exposed group; 12 means twelve times the odds. It is a comparison, not a personal risk. NCI Dictionary of Cancer Terms → 12.7; of the foot, 33.9) together with a raised risk of corpus callosumcorpus callosumThe thick bundle of fibres joining the two halves of the brain. anomalies (odds ratio 8.8)¹².

The switches, not the genes. Some of the clearest lessons of the last two decades concern DNA that codes for nothing. The ZRS is an enhancerenhancerA stretch of DNA that works as a switch: it does not describe a protein, it decides where and when a nearby gene is switched on. An enhancer can sit a long way from the gene it controls. NCI Dictionary of Genetics Terms → sitting about a megabase away from SHH, inside an intron of a neighbouring gene; single-letter changes and small insertions in it switch SHH on at the front of the limb bud, where it does not belong, creating a second polarising zone and a duplicated thumb or great toe^13,14,15. The number of enhancer copies can matter as much as their sequence¹⁶. A family can therefore carry a limb malformation with a completely normal coding genomecoding genomeThe parts of DNA that describe proteins. The rest, once called junk, contains the switches that control when and where genes work. MedlinePlus Genetics →, which is why standard gene panels miss some of them.

Signalling ligands and the severe end. Homozygous loss of WNT3 causes tetra-ameliatetra-ameliaThe absence of all four limbs. Amelia means the complete absence of a limb. Orphanet →, the absence of all four limbs¹⁷; homozygoushomozygousCarrying the same version of a gene on both copies, one inherited from each parent. Some conditions only appear when both copies are affected. NCI Dictionary of Genetics Terms → WNT7A variants do the same¹⁸. HeterozygousHeterozygousCarrying two different versions of a gene, one from each parent. For many conditions one affected copy is enough to cause them. NCI Dictionary of Genetics Terms → FGF8 variants are found in patients with VATER/VACTERLVATER/VACTERLA combination of malformations that occur together more often than chance allows: vertebrae, anus, heart, windpipe, oesophagus, kidneys and limbs. MedlinePlus Genetics → features¹⁹.

Where the genetic and the vascular meet. Roberts syndromeRoberts syndromeA rare inherited condition with severely shortened limbs and facial clefts. MedlinePlus Genetics → is caused by variants in ESCO2, a cohesion genecohesion geneA gene involved in holding the two copies of each chromosome together while a cell divides. When it fails, cells divide badly and die. with no obvious link to limb patterning. In a mouse model, the limb reduction turns out to be produced by p53-dependentp53-dependentDepending on p53, a protein that halts or destroys damaged cells. It protects us from cancer, but in an embryo it can also remove cells a limb still needed. NCI Dictionary of Genetics Terms → apoptosisapoptosisProgrammed cell death: the orderly self-destruction a cell undergoes when it is damaged or no longer needed. Too much of it in a limb bud removes tissue that should have been built. NCI Dictionary of Genetics Terms → together with disrupted blood-vessel formationblood-vessel formationThe growth of new blood vessels, called angiogenesis. A limb bud grows so fast that it needs new vessels continuously; losing them starves it. NCI Dictionary of Genetics Terms →²⁰. A genetic cause and a vascular mechanism are not alternatives; here they are the same story told at two levels.

Syndromes. TBX5 causes Holt-Oram syndromeHolt-Oram syndromeAn inherited condition combining a difference of the thumb or forearm with a heart defect. MedlinePlus Genetics →, the heart-hand condition, described across European registries²¹ and reviewed systematically for its cardiac spectrum²². SALL4 causes Duane-radial ray, IVIC and acro-renal-ocular syndromes, a group whose limb findings overlap closely with thalidomide embryopathyembryopathyThe pattern of damage caused to an embryo by a particular agent. Thalidomide embryopathy is the pattern left by that drug.^23,24; that overlap turns out not to be a coincidence, as section 04 explains.

ChromosomesChromosomesThe packages in which our DNA is stored. Humans normally have 46, in 23 pairs. MedlinePlus →. Trisomy 18Trisomy 18Also called Edwards syndrome: three copies of chromosome 18 instead of two, causing severe malformations including clenched hands with overlapping fingers. MedlinePlus Genetics → and trisomy 13trisomy 13Also called Patau syndrome: three copies of chromosome 13 instead of two, causing severe malformations of the brain, heart, face and limbs. MedlinePlus Genetics → have birth prevalenceprevalenceHow common something is in a population at a given time, here usually expressed as cases per 10,000 births. NCI Dictionary of Cancer Terms →s of 4.8 and 1.9 per 10,000 in Europe. Among live-born babies with trisomytrisomyHaving three copies of a chromosome instead of the usual two. NCI Dictionary of Genetics Terms → 13, 44% had polydactyly²⁵; limb deficiencies also occur, though less often²⁶. Smaller copy-number changes are found in a minority of patients with conditions usually called non-genetic, such as Poland syndromePoland syndromeThe absence or underdevelopment of the chest muscle on one side, usually with a smaller hand and shorter fingers on the same side. MedlinePlus Genetics →²⁷. In consanguineousconsanguineousDescribing parents who are blood relatives, most often first cousins. Their children are more likely to inherit the same rare gene change from both sides. NCI Dictionary of Genetics Terms → families, exome sequencingexome sequencingReading all the parts of a person's DNA that describe proteins, about 1-2% of the genome, in one test. It finds many causes, but not changes in switches outside those parts. NCI Dictionary of Genetics Terms → is the reasonable first test²⁸, and recessive variants in genes such as BHLHA9 account for syndactylysyndactylyFingers or toes joined together, by skin alone or by bone. Orphanet → forms that would otherwise look sporadic²⁹.

A teratogenteratogenAny substance, infection or physical agent that can disturb the development of an unborn child. NCI Dictionary of Cancer Terms → is any agent that can disturb the development of an unborn child. The list of those actually proved to cause limb differences in humans is far shorter than the internet suggests, and the strength of the evidence varies enormously from one entry to the next; the substances below are ordered accordingly, and those with a regulatory status are tracked in the teratogens register.

Thalidomide remains the reference case, and its mechanism has changed since most textbooks were written. The drug binds cerebloncereblonA protein inside our cells that selects which other proteins should be destroyed. Thalidomide sticks to it and changes that selection, which is how the drug is now thought to act on the embryo., the substrate receptor of a CRL4 ubiquitin ligaseubiquitin ligaseA cellular machine that tags unwanted proteins for destruction. Which proteins it tags depends on a receptor part that thalidomide is able to hijack. NCI Dictionary of Cancer Terms →, and reprograms what that ligase destroys. The proteins degraded include SALL4³⁰, PLZF/ZBTB16, degraded by thalidomide and by its metabolite 5-hydroxythalidomide³¹, and p63³². The SALL4 result is the most persuasive, because people with inherited SALL4 mutations are born with limbs that resemble thalidomide embryoembryoThe developing child during the first eight weeks after conception, the period in which the limbs are built. NCI Dictionary of Cancer Terms →pathy²³.

It is not the whole account. AntiangiogenicAntiangiogenicBlocking the growth of new blood vessels. NCI Dictionary of Genetics Terms → metabolites of thalidomide destroy the immature blood vessels of the early limb bud, upstream of any change in patterning gene expression³³, and current reviews treat loss of vasculature, targeted protein degradation and oxidative stress as mechanisms that act together^34,35,36,37. A 2025 re-evaluation goes further and argues that the usual human phenotype is a longitudinal, preaxial defect that becomes transverse only in its most severe form, with the arms affected before the legs and the left side before the right⁵. Saying simply that thalidomide "causes phocomeliaphocomeliaA limb in which the hand or foot is attached close to the body because the segments in between are absent or very short. Orphanet → by stopping blood vessels growing" is the short version of a question that is still open.

Why some exposed pregnancies produced an affected child and others did not is equally unresolved. Variation in CRBN³⁸, in ESCO2, SALL4 and TBX5³⁹ and in angiogenesis genes⁴⁰ has been examined in survivors, and screens continue in differentiating stem cells⁴¹, without a settled answer.

Misoprostol is the strongest post-thalidomide signal. First reported from Brazil, where it was used in unsuccessful attempts to end a pregnancy⁴², it was confirmed by a meta-analysismeta-analysisA study of studies: results from several separate studies are pooled statistically to get a single, more reliable figure. NCI Dictionary of Cancer Terms → of four case-control studcase-control studA study that starts from children who have the condition and compares their history with that of similar children who do not. Quick for rare conditions, but it relies on remembering past exposures correctly. NCI Dictionary of Cancer Terms →ies covering 4,899 cases: odds ratio 25.31 (95% CI 11.11 to 57.66) for Möbius sequenceMöbius sequenceA condition in which the nerves controlling the face and the eyes did not develop, so the face cannot show expression. It is often accompanied by limb differences. MedlinePlus Genetics → and 11.86 (4.86 to 28.90) for terminal transverse limb defects⁴³. The presumed mechanism is uterine contraction and a fall in blood flow to the embryo, which is why the defects are transverse rather than patterned^44,45.

Retinoids. Prenatal isotretinoin exposure has been associated with limb reduction defects⁴⁶, and retinoic acid produces limb malformations experimentally in a strictly stage-dependent way^47,48,49.

Antiseizure medicines need to be stated carefully, because the risk is real but is mostly not a limb risk. In EURAP, 10,121 prospectively followed monotherapy pregnancies gave major malformation rates of 9.9% for valproate, 6.3% for phenytoin, 6.2% for phenobarbital, 5.4% for carbamazepine, 4.9% for topiramate, 3.1% for lamotrigine, 2.9% for oxcarbazepine and 2.5% for levetiracetam, dose-dependent for the first three; as prescribing shifted away from valproate and carbamazepine, the overall malformation rate fell by 39%⁵⁰, a ranking the Cochrane review reproduces⁵¹. The limb findings in this group are typically hypoplastichypoplasticUnderdeveloped: present, but smaller or less complete than it should be. NCI Dictionary of Cancer Terms → distal phalanges and nails rather than dysmelia; postaxial defects after valproate⁵² and a hypoxic-ischaemic pattern after phenytoin⁵³ are described at the level of case reports. Nobody should stop an antiseizure medicine on the strength of this page; uncontrolled seizures carry their own risks.

Methotrexate produces a recognised embryopathy including limb anomalies when given in the sensitive window at sufficient dose^54,55.

Tobacco, alcohol and opioids. A meta-analysis of 37 studies puts maternal smoking at a pooled odds ratio of 1.27 (95% CI 1.18 to 1.38) for limb reduction defects; the same analysis found an association for polydactyly, syndactyly and adactyly taken as one group (1.32) that disappeared when polydactyly (1.06) and syndactyly (0.91) were analysed separately⁵⁶, which is a useful reminder of how fragile these signals are⁵⁷. PericonceptionalPericonceptionalIn the weeks just before and just after conception, the period when the limbs are formed. alcohol has been examined in the National Birth Defects Prevention Study without a consistent association⁵⁸. For prescription opioids, a population cohort found no excess of major malformations after first-trimester exposure (adjusted relative risk 1.40, 95% CI 0.84 to 2.34)⁵⁹. Recent surveillance of antipsychotics⁶⁰ and macrolides⁶¹ has likewise not produced a limb signal.

Air and workplace. The environmental literature is the weakest part of the field. In the National Birth Defects Prevention Study, adjusted odds ratios for limb deficiencies were near-null for particulates and ozone, and modestly raised for carbon monoxide (1.02 to 1.30)⁶². A 2026 cohort in Wuhan found a small association for sulphur dioxide in the first three months (1.033 to 1.043) and none for PM2.5, PM10, nitrogen dioxide, carbon monoxide or ozone⁶³. Occupational exposures in textile manufacturing⁶⁴ and parental pesticide exposure⁶⁵ have been reported, on small numbers. All of this rests on self-reported or modelled exposure, and the misclassification that follows can move an odds ratio in either direction⁶⁶.

A meta-analysis covering more than 80 million births found that pre-gestationgestationThe length of the pregnancy so far, counted in days or weeks. NCI Dictionary of Cancer Terms →al diabetes raises the risk of congenital anomaly overall (relative risk 1.99) far more than gestational diabetes does (1.18); for limb reduction defects specifically, gestational diabetes carried a relative risk of 1.14 (95% CI 1.06 to 1.23)⁶⁷. Caudal regressionCaudal regressionA failure of the lower end of the spine and the pelvis to form properly, strongly associated with diabetes in the mother. and femoral hypoplasia remain the signature patterns of diabetic embryopathy⁶⁸, and raised glucose alone is enough to produce limb defects in experimental embryos⁶⁹. Because the damage is done before most pregnancies are confirmed, glycaemic control before conception is where it is prevented, which is one of the few genuinely actionable findings in this whole article.

Maternal fever and hyperthermia have long been suspected, on an evidence base that is old and thin⁷⁰. Periconceptional supplements show a clearer effect for clubfoot than for limb deficiencies: in 63,969 singleton deliveries in Beijing, folic acid or multiple micronutrients were associated with a relative risk of 0.40 for clubfoot, while the reduction for limb defects overall did not reach significance (0.80, 95% CI 0.56 to 1.12)⁷¹. Younger maternal age is associated with vascular disruption anomalies as a group⁷², and maternal age also tracks with defects of unknown cause⁷³.

Infection deserves a proportionate statement. Congenital varicella syndrome, whose features include limb hypoplasia and scarring in a dermatomaldermatomalFollowing the strip of skin served by a single nerve root, which is why the scarring of congenital varicella appears in bands. pattern, is genuinely rare: in a prospective cohort of 347 pregnancies complicated by varicella, one definite case was identified (0.4%), and no case of limb hypoplasia was observed⁷⁴. The damage is attributed to viral injury to developing nerves rather than to the limb bud itself. Newer claims should be read cautiously: the report of Adams-Oliver syndrome after maternal COVID-19 is a single case, which is a hypothesis and not evidence of causation⁷⁵.

Vascular disruption is a different kind of cause. The limb is built correctly, and blood flow to it then fails, producing hypoxiahypoxiaA shortage of oxygen in a tissue. NCI Dictionary of Genetics Terms →, endothelialendothelialBelonging to the single layer of cells lining the inside of every blood vessel. damage, haemorrhage, tissue loss and repair. Of 7,020 infants with malformations at one American hospital over forty years, 105 had defects attributed to this process, including terminal transverse limb defects at three consistent levels⁴⁵; abnormal arterial anatomy is documented in limb deficiencies both clinically and experimentally⁷⁶. Across 26 EUROCAT registries, 5,220 vascular disruption anomalies were recorded, with a prevalence of 8.85 per 10,000 births in the United Kingdom against 5.44 elsewhere, though transverse limb reduction defects were equally common in both (2.16 and 2.14), which suggests they may not share the aetiology of the rest of the group⁷².

Poland syndrome is where this reasoning is most often applied and least often proved. The subclavian artery supply disruption sequence has been the leading hypothesis for decades and is supported by case-level evidence⁷⁷, but the published consensus recommendations describe the condition as a sequence of uncertain origin rather than a settled vascular diagnosis⁷⁸. Copy-number variantsCopy-number variantsStretches of DNA that are present in too many or too few copies. They can affect several genes at once, and are found by a different test from ordinary gene sequencing. NCI Dictionary of Genetics Terms → are found in a minority²⁷, a pair of affected monozygotic twinsmonozygotic twinsIdentical twins, formed when one fertilised egg splits. They share the same DNA, so a difference between them points to something other than inherited genes. NCI Dictionary of Genetics Terms → was found to share a de novode novoNew in the child: a genetic change that neither parent carries. It happened in the egg, the sperm or the earliest cell divisions, and it is nobody's fault. NCI Dictionary of Genetics Terms → chromosomal deletion⁷⁹, and classification remains under discussion⁸⁰. Honest practice is to present the vascular hypothesis as a hypothesis.

Amniotic band syndrome. Across 30 EUROCAT registries over forty years, 866 cases of amniotic bandamniotic bandA strand of the inner membrane of the amniotic sac, floating free after the membrane tears, which can wrap around a limb or a finger and constrict it. Orphanet → syndrome and 451 of limb body wall complexlimb body wall complexA severe pattern of malformation involving the limbs together with the wall of the abdomen or chest. Whether it shares a cause with amniotic bands is disputed. were recorded, a mean prevalence of 0.53 and 0.34 per 10,000 births, with twinning confirmed as a risk factor⁸¹. A Finnish case-control study of 106 limb deficiencies associated with bands found primiparity (adjusted odds ratio 2.42) and young maternal age (1.72) to raise the risk, together with first-trimester use of progestogens (3.79) and of beta-blockers, the latter on a very wide confidence interval that should be read with caution (24.2, 95% CI 2.57 to 228)⁸². Maternal vasoactive exposures have been linked to bands and terminal transverse defects together⁸³, and whether limb body wall complex and amniotic bands are one entity or two is still argued⁸⁴.

Crowding, and what it does not explain. Reduced amniotic fluidReduced amniotic fluidToo little of the fluid surrounding the baby, called oligohydramnios. The baby has less room to move, and pressure on the limbs can deform them. MedlinePlus →, uterine anomalies and twin pregnancies do restrict fetal movement and can deform a normally formed limb⁸⁵. But the common assumption that clubfoot and joint contractures are therefore mechanical is, in most cases, wrong. ArthrogryposisArthrogryposisBeing born with several joints fixed in one position. It is a description, not a cause: many different problems can produce it. and the fetal akinesiafetal akinesiaThe unborn baby moving too little. Movement is what shapes joints, so when it is reduced the joints stiffen, whatever the underlying reason. deformation sequence are usually intrinsic: more than 320 genes have been implicated, and neuromuscular or connective-tissue disease is a far more frequent explanation than crowding⁸⁶. The lack of movement produces the contractures; something else produces the lack of movement. This is exactly why the malformation-deformation distinction in the OMT classification matters⁶.

Chorionic villus samplingChorionic villus samplingA prenatal test in which a sample of the developing placenta is taken for genetic analysis. It is now performed after 11 weeks, which is why the limb risk seen in early studies has receded. NHS → performed before 70 days of gestation was shown, in a registry-based case-control study, to raise the risk of transverse limb defects and oromandibular-limb hypogenesis⁸⁷; maternal age was excluded as a confounder⁸⁸ and a distinctive effect on the fingers was described⁸⁹. Practice changed, and the procedure is now performed later. Fetoscopic laserFetoscopic laserKeyhole surgery inside the womb, using a camera and a laser to seal the shared blood vessels when identical twins share a placenta unequally. treatment for twin-twin transfusion syndrometwin-twin transfusion syndromeA complication of identical twins sharing one placenta, in which blood passes unevenly from one twin to the other. can produce a pseudoamniotic band sequence⁹⁰, with prevalence, risk factors and outcomes now quantified in dedicated series^91,92. Both are worth knowing precisely because they show what identifying a cause makes possible.

The division of this article into genetic and environmental sections is a convenience, not a claim about nature. Mice carrying one working copy of Shh or Gli2 develop limb defects after prenatal alcohol exposure that wild-type littermates do not⁹³, and a hedgehog pathway agonist given at the right hour produces preaxial polydactyly⁹⁴. Human candidate-gene studies have looked for the same interactions across limb development, angiogenesis and coagulation genes^95,96. For most children, the honest formulation is that susceptibility and exposure met, and that neither alone would have been enough.

In the Ain department of France, a regional registry reported an excess of isolated transverse upper-limb reduction defects and argued the cluster was real⁹⁷. A national, multidisciplinary investigation of three suspected clusters followed, examining exposures systematically, and concluded that no common cause could be identified⁹⁸. The episode is worth recording without taking a side: with defects this rare, small numbers make clusters both easy to see and hard to prove, and a registry designed for counting is not automatically a registry designed for causal investigation.

Three things keep this field where it is. Cases are rare and scattered across countries, so no single centre accumulates enough of them. Coding differs between registries, so the same limb is counted differently on either side of a border. And the phenotype is recorded far more often than the exposures, the family history and the genome that would make a cause findable. The result is the 22.4% with which this article opened.

That is the argument for an interoperable, consent-based registry owned by the community it describes, which families contribute to once and researchers can query across borders. It is what DysNet is building; see the registry and the plain-language two-minute guide. The evidence assembled here comes from the bibliography, and the substances named in section 04 are tracked, with their regulatory status, in the teratogens register. For what the individual conditions are called and how frequent they are, start with Understanding dysmelia.

Method

How this article was written.

Author. Dr Loïc Rigal, for the DysNet documentation team, September 2026.

Sources. The starting point was the DysNet bibliography, the register of peer-reviewed publications on our conditions, searched by theme for causes, genetics and epidemiology. Where the register had no coverage of a question that families ask (maternal diabetes, varicella, antiseizure medicines, misoprostol, fetal akinesia), the missing papers were found on PubMed and added to the register itself, so that every reference below is an entry of it. Every figure quoted is the figure the study itself reports, with its confidence interval where it gives one, checked against the published abstract or article rather than against a secondary source.

Drafting. The article was researched, drafted and fact-checked with the assistance of Claude Opus 5 (Anthropic), working directly against the bibliography register and the PubMed record. Every reference was resolved programmatically at build time, so that a citation on this page cannot drift from its entry in the register; the build fails if a citation cannot be resolved. Every glossary link was fetched and its page title verified. The judgements about what the evidence supports, and the responsibility for any error, are the author's.

Editorial stance. Where the evidence is a single case report, an animal model or a hypothesis, the text says so rather than rounding it up to a cause. Where a widely repeated claim is weaker than its reputation, such as the mechanism of thalidomide or the mechanical explanation of clubfoot, the text says that too.

Call for corrections

Researchers: tell us where we are wrong.

This page is a living document, and it is written by a patient network rather than by a specialist department of teratology or clinical genetics. If you work in this field and you find a statement that overstates the evidence, a figure that has been superseded, a reference that should be here and is not, or a mechanism described in terms the literature has moved beyond, we want to hear it and we will correct the page and credit the correction. Write to info@dysnet.org. Researchers are also welcome to add their team to the researchers register and their work to the bibliography. Families who spot something that reads as jargon, or a definition that does not help, should tell us as well: that is a correction too.

Sources

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2. Bergman JEH, Löhner K, van der Sluis CK, et al. Etiological diagnosis in limb reduction defects and the number of affected limbs: A population-based study in the Northern Netherlands. American journal of medical genetics. Part A. 2020;182:2909-2918. doi:10.1002/ajmg.a.61875
3. Lin GH, Zhang L. Apical ectodermal ridge regulates three principal axes of the developing limb. Journal of Zhejiang University. Science. B. 2020;21:757-766. doi:10.1631/jzus.B2000285
4. Ogino T. Clinical features and teratogenic mechanisms of congenital absence of digits. Development, growth & differentiation. 2007;49:523-31. doi:10.1111/j.1440-169X.2007.00939.x
5. Collins MD, Scott WJ. Thalidomide-induced limb malformations: an update and reevaluation. Archives of toxicology. 2025;99:1643-1747. doi:10.1007/s00204-024-03930-z
6. Ekblom AG, Laurell T, Arner M. Epidemiology of congenital upper limb anomalies in Stockholm, Sweden, 1997 to 2007: application of the Oberg, Manske, and Tonkin classification. The Journal of hand surgery. 2014;39:237-48. doi:10.1016/j.jhsa.2013.11.014
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