Introduction

Caudal regression syndrome (CRS), or Caudal dysgenesis syndrome (CDS), is an unusual condition which results in incomplete development or growth of the lower half of the body, including the thighs, buttocks, lower back, and certain parts of the urinary and digestive systems. The cells that make up the limbs and organs here become shrunk, resulting in deformities that may range from mild to moderate to severe. Some children may have a torpedo-shaped spine, while in others, there may be absent lower limbs, or in some cases, there is poor control over urinary and faecal continence. The prevalence of CRS is quite low, ranging between 1 to 3 cases in every 100,000 live births.  

Why this happens is a reasonable question, but we still don't understand all of the risk factors associated with CRS. We do know that poorly controlled diabetes during pregnancy is known to have an added concern of CRS in newborns, with an estimated prevalence of 1 in 350 births. Increasing the awareness of such risk factors is important because it helps inform parents and healthcare providers to make better choices to help maintain optimal health during pregnancy.  This could reduce the CRS burden on healthcare providers and enable earlier CRS intervention.  

Genetic risk factors

Specific gene alterations  

In the case of Caudal Regression Syndrome, there is no single gene responsible for the condition. It is more likely that several genes associated with the regulation of the early stages of embryo development may play a role. Early investigations excluded the HLXB9 gene (also known as MNX1), which leads to the development of Currarino syndrome, from the typical CRS case range. The sample of 48 CRS cases without Currarino features showed no harmful HLXB9 variants.  

In fact, more recent studies propose that other genes such as CDX1 and CDX2, which play an important role in the development of the tail-end of the body, are relevant in the more rare variants of CRS.  Some rare detrimental mutations were found in a small pilot exome study, in genes such as SPTBN5, MORN1, ZNF330, CLTCL1, PDZD2, PTEN, GLTSCR2 and VANGL1 that are known to have CRS-related changes. Other genes involved in retinoic acid metabolism, such as CYP26A1, are known to cause CRS because of their role in embryo development. Additionally, in mouse and rat studies the PCSK5, Hoxa/Hoxd cluster, Wnt-3a, Mbtps1, and PLZF genes were associated with CRS-like changes. 

Patterns of inheritance

The most common cases of CRS are sporadic and appear to be random, with no family history. Some milder variants of CRS appear to be inherited, but the most common cause is diabetes during pregnancy. There are some reports of inheritance of dominant traits with variable penetrance, suggesting the presence of diabetes during pregnancy. This means that one copy of a mutated gene (autosomal dominant inheritance) may raise the risk, and the family may show varying severity in symptoms. 

Familial cases suggest that some PDZD2 or CLTCL1 genes identified through pilot exome sequencing exhibit autosomal recessive inheritance, where at least two gene copies with mutations are necessary. 

Abnormalities of the chromosomes

Chromosomal abnormalities are uncommon in Caudal Regression Syndrome (CRS), but when they do occur, it implies that there are minor variations or errors in an individual's chromosomes (the instruction books for the body) that could impact the development of the lower spine and surrounding organs.

These variations are at times traceable to issues with lower body growth and development, such as the spine, legs, or bladder.

Genetic factors  

CRS may be triggered by a combination of environmental and genetic factors.  In the case of maternal diabetes, if blood sugar levels are not well controlled during early pregnancy, the risk of CRS can increase by 200-400 times. Research suggests that mutations of the CYP26A1, PTEN, or VANGL1 genes may increase the risk of diabetes or vascular disease due to retinoic acid metabolism or embryonic signalling of those genes.

A collective model suggests CRS is both polygenic and environmental: between the fourth and the fifth week of pregnancy, certain underlying genetic factors may combine with high stress during pregnancy—like high blood sugar or low blood flow—to interfere with the early development of the baby's lower body.

Environmental risk factors

Caudal Regression Syndrome (CRS) is a rare congenital disorder that is classified under congenital malformations. Some of the possible reasons that cause CRS include the spinal cord, pelvis, and lower limbs of the body. Some genetic factors may cause it, although some genetic factors alone do not cause it; certain environmental factors do enhance the chances of this disorder greatly, especially within the sensitive early weeks of pregnancy.

Maternal diabetes

The most significant environmental risk for CRS is a diabetic mother. Both type 1 and type 2 diabetes can lead to CRS in a newborn. Studies have shown that mothers suffering from diabetes account for approximately 10% of CRS infants. The risk of a child born to a diabetic pregnant woman getting CRS is 1 in 350 when compared to the general population.

Some experimental animal studies have shown that excess glucose in the blood during pregnancy can lead to higher chances of teratogens, especially retinoic acid, which in turn can cause increased programmed cell death in the tailbud area and the underdevelopment of the tail through downregulating a significant gene called Wnt-3a, which is involved in caudal development failure.

Some additional molecular studies suggest that diabetes during pregnancy leads to higher chances of teratogenicity, which is the potential for congenital malformations due to the mesodermal structures, owing to the failure of the normal embryo’s homeostasis of vitamins and the normal homeostasis of vitamin A during pregnancy.

Exposure to harmful substances

Certain medications and harmful substances may potentially increase the risk of CRS in the first trimester of pregnancy. Retinoic acid, the active metabolite of vitamin A that is used in isotretinoin therapy, is one of the known teratogens. Unlike non-diabetic pregnancies, even small amounts of retinoic acid seem to be teratogenic in diabetic pregnancies.

Other examples of teratogens that disrupt retinoid metabolism, leading to an abnormal tail and spinal cord morphogenesis and overexpression of the tail-bud genes, are anticonvulsants valproic acid, antifungal fluconazole, and nicotine (and smoking).

Poor nutrition

It is accepted that insufficient amounts of folic acid may lead to the development of neural tube defects (NTDs) and other spinal anomalies, and is associated with CRS. Folic acid is needed for the metabolic processes of the DNA, as well as for the first stages of cell division in the embryo. While few studies of CRS and folate deficiency have been done, it is plausible that a combination of low folate, plus genetic risk factors, may increase the risk for some developmental disorders.

Interruption of vascular activity

Insufficient blood flow could impair the growth of caudal structures in the embryo. Imaging studies and case reports suggest some cases of CRS could stem from abnormal fetal vasculature, for instance, with the persistence of some vitelline vessels. Sirenomelia is often cited as a reference CRS is compared to, termed the vascular disruption hypothesis, which positions CRS as a type of sirenomelia where shared vascular disruption leads to limb fusion.  

Maternal infection or illness  

Infectious disease or a high fever during the early stages of pregnancy could result in oxidative stress or inflammation to embryonic tissues, caudal restriction and abnormal development. While CRS lacks dedicated primary research, the overarching concept is based on vertebral disruption hypothesised to result from hyperthermia and inflammatory mediators.  

Gene-environment interactions

Combined effects

Caudal Regression Syndrome (CRS) is essentially a multifactorial disease, arising from the intricate interaction between genetic susceptibility and environmental exposure. Neither environmental nor genetic factors alone are individually adequate in explaining the condition; individuals with increased genetic predisposition are at greater risk only when they are exposed to certain prenatal stressors, such as maternal metabolic or vascular abnormalities. 

Supporting evidence

• Diabetic milieu and teratogens: Experimental models have shown that embryos from 

diabetic mothers, when treated with teratogenic agents like retinoic acid, show a significantly increased frequency of caudal malformations over non-diabetic controls. This effect appears to be mediated by downregulation of the Wnt‑3a gene, responsible for normal caudal development.

• Genetic Heterogeneity in Animal and Human Investigations:
  • Pathogenic variants in genes such as CDX2, CDX1, PLZF, ID1, and others (SPTBN5, MORN1, ZNF330, CLTCL1, PDZD2) have been found in human CRS cases and murine models with caudal maldevelopment
  • Loss-of-function mutations in PLZF induce caudal agenesis-like phenotypes in rats and occur in a few rare human cases, recapitulating the animal phenotype
  • Conditional PCSK5 mutations in mice produce phenotypes overlapping with CRS, VACTERL, and Currarino syndrome; importantly, certain phenotypic expression was seen only with maternal diabetic or vascular modifiers

• Familial Clustering and Phenotypic Variability: Although the majority of cases of CRS are sporadic, familial cases have been reported with patterns of autosomal dominant, autosomal recessive, or X-linked inheritance, with variable penetrance and expressivity. This observation is in line with polygenic susceptibility and underscores the importance of gene–environment interaction.

Implications

• Risk Assessment: Clarifying such gene–environment interactions facilitates enhanced risk stratification, especially in diabetic or otherwise genetically predisposed pregnancies
• Targeted Prevention: Maximising maternal blood glucose control and the exclusion of proven teratogens (e.g., retinoic acid) at key times during embryogenesis (in particular at approximately day 28 after conception) may limit CRS occurrence
• Individualised Counselling: Genetic testing for CRS-predictive variants, particularly in those with a family history of the disorder or those presenting syndromically (e.g., Currarino or VACTERL overlap), can guide clinical monitoring, allow for earlier diagnosis, and improve patient counselling

Clinical and preventive considerations

Prenatal diagnosis and screening

• Ultrasound is the most common method used to detect pregnancies. The characteristic sonographic features are the abrupt separation of the spinal column from the level of the lumbosacral and the frog-like position of the lower limb. 22 weeks ahead of time, diagnosis can be skillfully reported, and a transvaginal 3D device can detect serious events even before.
• Fetal MRI is valuable in cases where ultrasound is restricted (e.g. Oligohydramnios). MRI clearly identifies vertebral, spinal cord, soft tissues, and related anomalies (genitourinary, Gastrointestinal), facilitating prognosis and perinatal monitoring.

Maternal health significance

• Maternal pregestational diabetes significantly increases CRS risk—up to 200-fold higher than environmental community rates. The risk of diabetic pregnancy is 1 per cent compared to 1:60,000 in the general population
• Optimal direct dwell of preconception guidance in the system to achieve euglycemia (e.g. fasting <110 mg/dL, post‑prandial <140 mg/dL) and oral hypoglycemics should be avoided, and alternatively, insulin therapy should be considered
• Folic acid supplementation and everyday prenatal thinking are particularly foreseeable to assist neural-mesodermal progress, although precise control tests within the limits of CRS are lacking. Teratogenic exposure should be reduced by a healthy lifestyle

Genetic counseling

• Most CRS examples are sporadic, but testimony indicates a multifactorial etiology, involving fusion of ancestral susceptibilities and sustainable exposure similar to maternal diabetes
• Genetics means a mutation in a gene containing CDX2, CDX1, CYP26A1, and possibly PLZF, ID1, and others, particularly in syndromic situations or familial cases (e.g., Currarino syndrome, VACTERL overlap)
• Genetic counselling is highly recommended for families with a record of CRS, sacral agenesis, anorectal deformity, or alternatively syndromic association to discuss recurrence issues, capability screening, and prenatal diagnostic options

FAQs

What Can be done and why does it matter?

For the prevention of CRS, prophylactic treatment is required: Strict blood sugar control greatly reduces the risk of CRS, with the exception of diabetes, covering pre, during, and post-pregnancy windows with tighter control, especially in the first trimester. While reducing the dose of known teratogens such as Valproic acid, isotretinoin, and some antifungals during pregnancy. Daily supplementation of 400–800 µg of folic acid, commencing pre-conception, assists in the prevention of neural tube and potentially caudal anomalies. Early treatment of fever and infections* and avoidance of high maternal core body temperature. Limiting smoke and environmental toxins, such as too much of a vitamin A supplement, industrial pollutants, etc.

Can caudal regression syndrome be prevented entirely?

While not all cases are preventable, the vast majority linked to maternal diabetes can be significantly reduced through tight blood sugar control before and during early pregnancy, along with avoiding known teratogens.

If I have no family history, is genetic testing necessary?

Usually not—sporadic cases tied to maternal metabolic issues don’t require genetic testing. Testing becomes more relevant if CRS occurs alongside other anomalies or if there’s a family history.

When should prenatal imaging begin if CRS is a concern?

High-resolution ultrasound and fetal MRI can be used as early as 12–14 weeks of gestation to evaluate sacral development in pregnancies at elevated risk.

Are there guidelines for diabetic women to reduce CRS risk?

Yes—international obstetric recommendations advise HbA1c levels below 6.5% before conception and close glucose monitoring in early gestation to reduce birth‑defect risk.

Is there any genetic counselling advice for future pregnancies after one CRS case?

Yes—if CRS was sporadic and linked to diabetes, the recurrence risk is low if future care is optimal. But if genetic or syndromic factors are suspected, counselling may include discussion of autosomal recessive risk or inherited mutations.

Summary

Caudal regression syndrome (CRS), a rare affliction which results in incomplete growth or expansion, alternatively cessation of growth in the lower half of the body inwards with variable engagement of the skeletal system, brain, intestine, and urinary organs. This area includes the lower body area, such as the thighs, buttocks, and lower back support, as well as certain parts of the urinary and bowel structures. 

Caudal Regression Syndrome (CRS) is caused by a combination of both genetic factors as well as environmental factors, with maternal diabetes being the most modifiable risk factor. As of today, little is known about the natural hazards associated with the development of caudal regression syndrome (CRS). This research suggests that exposure to ecological exhaustion and teratogenic vulnerability, together with family and worldwide exposure, may lead to Caudal Regression Syndrome. Preventive measures emphasise strict glycemic control prior to and during pregnancy and minimal teratogenic exposure. During sporadic cases, predominant, growing evidence indicates a heritable principle in select syndromic presentations. 

The lack of contemporary understanding highlights the urgent need for further analysis in order to clarify gene-environment interactions and improve the timely diagnostic and preventive approach. In order to reduce the incidence of CRS and improve perinatal outcomes, improved surveillance and guidance are important in at-risk groups.