Introduction

Caudal regression syndrome (CRS) is a rare congenital disorder that causes abnormal development of the lower (caudal) end of the spine and spinal cord.¹ During pregnancy, as the foetus is developing, growth abnormalities can occur and affect the lower end of the spine. This includes defects of the lumbar segment, sacrum, and coccyx parts of the lower spine. 

CRS has an incidence rate of 1 in 5 for every 100,000 newborns.² However, the exact prevalence of CRS remains unknown, as mild forms of abnormalities in CRS can be asymptomatic and escape detection by imaging techniques, thus leading to inaccurate measurements.³ 

Understanding the history of CRS is crucial as it allows us to not only understand the progression of the disease, but to also identify patterns and potential common risk factors to develop important prevention and treatment strategies. This article will provide key information regarding the history of caudal regression syndrome, and also the current development towards effective treatments.

Early observations and initial discovery

Within pre-modern medical literature, numerous references to caudal abnormalities exist, but these case descriptions lacked the scientific context necessary to identify them as one distinct syndrome at the time. The descriptions that referred to caudal abnormalities were only first observed in the mid-16^th century by Rocheus (1542) and Palfyn (1553).³

The first clinical cases that resembled CRS were described during the mid-19^th century by Geoffroy Saint-Hilaire, a French naturalist whose work contributed in evolutionary biology and anatomy, and Karl Hohl.² In the early 20^th century, patterns within similar cases of caudal abnormalities were identified. However, these cases were often blended with other conditions, such as Sirenomelia, often known as mermaid syndrome, or sacral agenesis.^3,4

In 1961, the term “caudal regression syndrome” was first coined by Bernard Duhamel. In his research paper, he described CRS as two different forms: the first was the “mermaid” form, with lower limbs being fused, and the second was the “anchipodal” type, which describes webbed lower limbs that are abducted and flexed.⁵

Medical advancements and identification

The mid-20^th century was an important milestone as it was the first time the term “caudal regression syndrome” was coined. In addition, it was also where important technological advancements were being developed. A particular highlight is the creation of X-ray machines, which allowed for more sophisticated, safer, and detailed examinations of spinal abnormalities in newborns, thus promoting accurate diagnoses.

This enabled consistent features to be discovered, such as sacral agenesis, which is the underdevelopment of the sacrum (a part of the lower spine). The “mermaid” form, as described in Duhamel’s paper, is known as sirenomelia. Although some researchers describe it as a severe form of CRS, many others consider it a distinct condition that has different effects, characteristics and underlying causes.³ Several alternative terms are associated with CRS and are used to describe the wide variety of abnormalities that can occur. This includes caudal dysplasia sequence, caudal dysgenesis syndrome, sacral regression syndrome, and lumbo-sacral agenesis.¹ 

Classification and diagnosis through the decades

With improved diagnosis tools, various classification systems for CRS could be established. Historically, diagnosis and classification systems were based on clinical signs/presentations and radiological findings.⁶ However, as other effects and cases were identified, functional assessments and neurological assessments were also being carried out. One well-known system is the Renshaw classification, produced in 1978, which divides CRS into four types depending on the severity of the abnormality.^3,7

As more medical advancements and imaging techniques (e.g., ultrasound, CT scanning and MRI scanning) were being made, advanced prenatal and postnatal diagnosis of CRS could occur for early syndrome detection.^7,8 However, many ethical debates arise around prenatal diagnosis and potential termination of pregnancies. Nevertheless, genetic testing and family genetic analysis can assess any predispositions to developing CRS which help people with their decision-making regarding pregnancy and family planning.

Understanding the aetiology

The cause and underlying mechanisms of CRS development are currently unknown. However, research shows that there are both genetic and environmental factors that can influence CRS development. Most often, cases occur randomly, suggesting the influence of environmental factors or new genetic changes (i.e., mutations). Potential environmental factors that have been suggested to contribute to CRS development include alcohol consumption, lack of oxygen (hypoxia) or an imbalance in amino acids during embryo development.

One important development that occurred was in the 1960s, when an association between maternal diabetes and CRS was established.⁹ CRS occurs more often (200-400 times more likely) in women with diabetes compared to the general population.^1,10 

Unfortunately, the underlying mechanism and cause for this association are unknown and require more research.

Modern embryological studies and research have provided researchers with more information on the timeline for CRS development. A disruption in embryo growth between the 3^rd and 7^th week affects the formation of the lower spine, resulting in caudal abnormalities.^3,4 Unfortunately, the exact reason why this disruption occurs is still unknown and under investigation. 

Treatment and management: historical to modern approaches

Early interventions were focused on managing symptoms and providing supportive care to those with CRS. Some orthopaedic interventions to improve mobility and stability were present, but surgical interventions were limited due to the limitations of technology at the time.

As medical technology and techniques advanced, not only has the understanding of the disorder improved, but more effective treatments for CRS have also been developed. Currently, many medical professionals of different backgrounds, including paediatricians, orthopaedic surgeons, neurologists, urologists, and physical therapists, collaborate to provide management strategies with CRS. 

Surgical options became more common as it aimed to correct the abnormalities of the spine, improve the function of the lower limbs and deal with any genitourinary issues that may be occurring.³ After-care, rehabilitation and assistive devices to help improve and maintain mobility are integral towards modern management strategies.^1,3 These not only provide physical benefits but also enhance your independence, mental health, and quality of life. 

Research and genetic insights in the 21st century

As improvements in genetic research continued into the 21^st century, several genetic syndromes were associated with caudal abnormalities. However, no single gene mutation has been identified as the genetic cause for all cases of CRS. For example, various genes such as the VANGL1 and HLXB9 gene have been linked to caudal abnormalities. This highlights the possibility of genetic predisposition in some cases. 

As mentioned previously, different risk factors can influence the development of CRS. However, there are currently debates around the classification and nomenclature of cases associated with CRS, or any of the other conditions, such as Sirenomelia and sacral agenesis. Henceforth, more research is required to not only accurately determine the different classifications of CRS, but to also identify the various genetic and environmental causes of this syndrome. 

Summary

The history of caudal regression syndrome mirrors the advancement and evolution of medicine itself. Before the 21^st century, limitations in technology and the knowledge of medicine at the time provided vague early descriptions with limited knowledge of classification, aetiology and treatment possibilities. Now in the 21^st century, with advanced medicine, technologies and genetic/molecular research, a deeper understanding of CRS is possible. As these advancements continue, our knowledge of CRS development and treatment strategies will also improve. Even though groundbreaking associations with CRS, such as those with maternal diabetes, have been identified, questions around the specific underlying causes remain.