Caudal regression syndrome (CRS), also known as caudal regression sequence, caudal dysplasia, caudal aplasia, femoral hypoplasia, phocomelic diabetic embryopathy, or sacral agenesis , is a spectrum of anomalies involving the caudal end of the trunk. The pathogenesis involves abnormal differentiation of the developing spine, spinal cord, and caudal mesoderm. Although CRS is rare in the general population, maternal hyperglycemia is thought to play an important role, and the malformation is seen much more commonly in infants of diabetic mothers. Associated malformations are common, particularly those in the genitourinary tract.



CRS comprises various degrees of anomalous formation of the caudal trunk. The spectrum of disease can vary from isolated partial agenesis of the sacrococcygeal spine to complete absence of sacral, lumbar, or lower thoracic vertebrae. Although complete sirenomelia is considered by some authors to be part of the spectrum, many authors now consider complete sirenomelia to be a separate category.

Prevalence and Epidemiology

The frequency is estimated to be 1.3 : 10,000 births. No gender predominance has been reported. Although CRS is not limited to infants of diabetic mothers, it occurs 200 times more frequently in these infants than in the general population.

Etiology and Pathophysiology

The caudal eminence, or tailbud, is a mass of pluripotent tissue distinguished early in embryogenesis as a continuation of the primitive streak. It ultimately gives rise to all the tissues of the caudal embryo, including the primordia of the genitourinary system, the hindgut, the neural cord and crest cells, and somites. Various abnormalities that result to this structure through a combination of genetic and stochastic events, occurring before the fourth week of gestation, are thought to result in the spectrum of caudal regression.

The most common teratogen implicated in this process is hyperglycemia owing to maternal diabetes; poor glycemic control is a known risk factor. Some form of CRS has been estimated to occur in 1% of infants born to diabetic mothers. CRS has also been associated with more subtle levels of glucose intolerance even without overt diabetes. Other proposed contributing factors include genetic predisposition, vascular anomalies altering blood flow, and drugs or other environmental exposures. Cases have been reported after exposure to minoxidil, trimethoprim-sulfamethoxazole, and tocilizumab. CRS is likely caused by a combination of factors including genetic disposition combined with an epigenetic event. With rare exceptions, the fetal karyotype is normal.

Some investigators have described rare familial occurrences with suspected autosomal recessive inheritance. The HLXB9 gene has been implicated in some cases of autosomal dominant form of sacral agenesis, Currarino syndrome or Currarino triad, which is an association of partial sacral agenesis with intact first sacral vertebra (sickle-shaped sacrum), a presacral mass, and anorectal malformation, as well genitourinary abnormalities. There is variable penetrance of this disorder.

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