The portal for rare diseases and orphan drugs

Whilst the exact prevalence at birth is unknown, the incidence of caudal regression syndrome (CRS) is estimated between 1/20,000-100,000 pregnancies. Maternal diabetes is a major risk factor for developing CRS, and the disorder is up to 200 fold more frequent in this group of patients than in the general population.

The spectrum of anomalies affecting the caudal end of the trunk vary from isolated partial agenesis of the sacrococcygeal spine to more severe deformities. The caudal malformation can result in deformities of the pelvis (typically fusion of the iliac wings), anomalies of the lower extremities (i.e. flexion of the knees, varus position of the feet) and motor and neurological deficits of varying degrees of severity (i.e. spontaneous motor activity and impaired deep tendon reflexes of lower limbs). Additional complications of the genitourinary, gastrointestinal and respiratory systems may occur. Genitourinary anomalies can involve unilateral or bilateral renal agenesis, renal ectopia and fused ureters, and generally lead to urinary obstruction, neurogenic bladder, enuresis, or vesicoureteral reflux. Gastrointestinal anomalies can involve inability to control bowel movements (incontinence, encopresis) and an imperforate anus. Congenital heart anomalies are frequently observed. Cases with Chiari I malformation, holoprosencephaly, chronic hypertension and cleft lip and palate have also been reported.

The malformations are believed to result from impaired development of the mesoderm prior to 4 weeks gestation. However, vascular steal or hypoperfusion with fetal hypoxemia is also hypothesized due to a few descriptions of a single umbilical cord. Several etiologic factors have been suggested and include maternal diabetes, hypoperfusion, as well as a genetic predisposition (for example mutation in VANGL1 gene (1p13.1), CELSR1 (22q13.31) and, FUZ gene (19q13.33).

Diagnosis is based on antenatal ultrasound examination in the first trimester of pregnancy in the most severe cases. The severity of the disease is determined by examination of the newborn by means of postnatal ultrasonographic and nuclear magnetic resonance imaging (MRI) examination.

The main differential diagnosis is sirenomelia. CRS has also been associated with the VACTERL syndrome, and Currarino syndrome is a form of caudal regression syndrome characterized by the classic triad of presacral mass, sacral bone defect and anorectal malformation. Due to the similarity between sirenomelia, VACTERL and CRS, the distinction between these defects is debated.

In severe forms, diagnosis is easier in the first trimester and more difficult later in pregnancy due to oligohydramnios. Sacrococcygeal dysgenesis, abrupt termination of spinal cord, and other anomalies (cardiac, renal, gastrointestinal, lower limbs) can be diagnosed in the second or third trimester. Fetal MRI can be useful in difficult cases or to better define anomalies.

The most severe cases of CRS appear to be sporadic but the milder forms appear to be inherited in an autosomal dominant manner with variable phenotypes.

Treatment and management is supportive and requires a multidisciplinary approach by neurosurgeons, orthopedics, urologists, nephrologists, physical therapists, and psychologists. Neurogenic bladder is commonly described and clean intermittent catheterization and/or anticholinergic drug administration are generally required to treat urological disorders. Surgical interventions such as vesicoureteral reimplantation, cystostomy, Mitrofanoff are commonly performed in order to improve quality of life, urinary continence, and preserve renal function. Surgical reconstruction (Pena Procedure) can be required for imperforate anus, although colostomy may be required in some cases. Depending on the severity of the syndrome, orthopedic interventions may also be required.

Prognosis is poor and is mainly related to urological and cardiac malformations. Early neonatal death in the severe forms occurs from cardiac, renal and respiratory complications. Surviving infants usually have normal cognitive function.