59  Caudal Regression Syndrome

291

SECTION THREE
Findings—Spinal Defects

59  Caudal Regression Syndrome

CARA C. HEUSER  |  REBECCA S. HULINSKY  |  G. MARC JACKSON

Introduction commonly in infants of diabetic mothers. Associated malforma-

Caudal regression syndrome (CRS), also known as caudal regres-
sion 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 patho-
genesis 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
tions are common, particularly those in the genitourinary tract.1
Disease
DEFINITION
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
292 PART 7  Skeletal Dysplasias: An Overview  •  SECTION THREE  Findings—Spinal Defects
Left leg
A B
Fig. 59.1  Left leg (A) and right leg (B) shows a frog-leg position in a 16-week fetus with caudal
regression.
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.2
PREVALENCE AND EPIDEMIOLOGY
The frequency is estimated to be 1.3 : 10,000 births.3 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.4
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.5
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.6 CRS has
also been associated with more subtle levels of glucose intolerance
even without overt diabetes.7 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.8,9 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,10,11
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.
Right leg
Manifestations of Disease
CLINICAL PRESENTATION
Characteristic features include short intergluteal cleft, flattened
buttocks, narrow hips, distal leg atrophy, and talipes deformities.
Urinary and bowel dysfunction are nearly universal. Motor
function is generally more affected than sensory function and
is correlated with the level of spinal aplasia. In very mild cases,
such as isolated coccygeal agenesis, patients may be
asymptomatic.1
Associated anomalies are common, often involving abnormali-
ties of the genitourinary tract, hindgut, cardiac, and respiratory
system. CRS has been associated with OEIS (omphalocele,
exstrophy, imperforate anus, and spinal defects)12 and VATER
(vertebral defects, imperforate anus, tracheoesophageal fistula,
radial and renal dysplasia) (Chapter 146) associations.13 Sireno-
melia is often associated with renal agenesis and pulmonary
hypoplasia and thus is fatal in such cases. Prognosis largely depends
on associated anomalies and the level of spinal involvement.
Intelligence and mental function generally are preserved.
IMAGING TECHNIQUE AND FINDINGS
Ultrasound
Classic findings on prenatal ultrasound (US) are sudden inter-
ruption of the spine with absence of vertebrae and frog-leg
position of the lower limbs (Fig. 59.1). The position of the lower
limbs has also been termed cross-legged tailor or Buddha pose.
First-trimester US findings suggestive of the diagnosis include
short crown-rump length, protuberance of the lower spine, and
increased nuchal translucency.14 The diagnosis has been suspected
at 13 weeks’ gestation but is usually not detected until the mid-
second trimester because the sacrum is not fully ossified until
approximately 18 weeks.15 High-resolution vaginal US may be
useful in the first trimester.
Findings described later in gestation include abrupt termina-
tion of the spine at various levels (low thoracic, lumbar, or sacral
levels), short femora, and abnormal lower extremity positioning.
Although CRS may be best visualized on sagittal imaging, axial
or coronal views of the fetal spine also show a lack of bony
ossification (Fig. 59.2). The sacrum has been described as “shield-
shaped” in CRS with the iliac wings fused and decreased distance
between the femoral heads (Fig. 59.3). Also, the femora may be
held in a fixed V shape (Fig. 59.4) and often show
 59  Caudal Regression Syndrome 293

Absence of ossific
Mid L Sp

Follow up

Fig. 59.2  Absent ossification of spine noted in a coronal view in a Fig. 59.5  Abrupt end of spine in a sagittal view in a 17-week fetus with
17-week fetus with caudal regression. caudal regression.

TABLE 59.1  Associated Anomalies

Gastrointestinal
Rectal agenesis or imperforate anus
Iliac crests Duodenal atresia
Inguinal hernia
Abdominal wall defects
Malrotation
Fistulas
Genitourinary
Ambiguous genitalia
Hydronephrosis/pyelectasis
Vesicoureteral reflux
Dilated bladder
Renal agenesis (unilateral or bilateral)
Fused or horseshoe kidney
Ectopic ureter(s)
Skeletal
Kyphoscoliosis
Equinovarus or other lower leg deformities
Fig. 59.3  Fused iliac wings in a 17-week fetus with caudal Flexion contractures
regression. Decreased number of ribs
Other
Facial clefts
Congenital heart disease
Neural tube defects with associated intracranial findings
Single umbilical artery

no or abnormal movement. Careful attention should be paid to

FL
Fig. 59.4  V-shaped femora in a 14-week fetus with caudal regression
(fetus did not move legs throughout examination).
the level at which the spine ends, and this may be best visualized
on sagittal imaging (Fig. 59.5). In some cases, the spine can
appear to “taper,” and this should not be misinterpreted as a
normal sacrum. On routine US, normal transverse views should
show spinal ossification centers at the level of the iliac wings.
Associated anomalies are common with CRS (Table 59.1),
and a detailed US examination including all fetal organ systems
is imperative. A formal fetal echocardiogram should be strongly
considered. Fetal growth and amniotic fluid should be serially
assessed in continuing pregnancies. Assessment of fetal position
before delivery is imperative because malpresentation is common.
Three-dimensional or four-dimensional US is useful in evaluating
the fetal spine for lack of continuity; multiplanar assessment is
ideal for this.
294 PART 7  Skeletal Dysplasias: An Overview  •  SECTION THREE  Findings—Spinal Defects
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) may be a useful adjunct to
US in certain cases of caudal regression.6 It may help delineate
the extent of the anatomic disruption or aid in further
characterization of associated anomalies. It can confirm the
absence or disorganization of ossification centers and may
illustrate cord termination with a wedge-shaped or tapered
termination of the cord. MRI may be particularly helpful in
obese patients or patients with oligohydramnios when US imaging
may be suboptimal.
CLASSIC SIGNS
Sudden interruption of the spine with abnormal positioning or
hypoplasia of lower extremities
Differential Diagnosis From
Imaging Findings
1. CRS may be associated with a pattern of anomalies such
VATER or OEIS association
2. Myelomeningocele
3. Arthrogryposis-akinesia (mimics mild CRS but the spine is
normal)
4. Sirenomelia
Sirenomelia involves a single fused lower extremity and is now
usually considered a separate entity from CRS. It is also known
as the mermaid syndrome. Sirenomelia is usually associated with
renal agenesis and is lethal (Fig. 59.6).
Synopsis of Treatment Options
PRENATAL
No intrauterine treatment is available for CRS. Prevention should
focus on identification of patients with diabetes and optimizing
Fig. 59.6  Fused lower extremity with a single femur in a 24-week fetus
with sirenomelia.
glycemic control. Early screening for patients at risk and aggressive
glucose management, especially in the periconception and
embryogenesis periods, is important in reducing the risk of
anomalies associated with maternal diabetes. After diagnosis,
subsequent management depends on gestational age, severity of
the primary lesion, and associated anomalies. Pregnancy termina-
tion should be discussed, and patients who elect to continue the
pregnancy should be referred to appropriate pediatric subspecial-
ists before delivery. Because growth restriction and abnormal
amniotic fluid volume are common, serial US examinations are
appropriate. Cesarean section should be reserved for the usual
obstetric indications.
POSTNATAL
Delivery should occur in a tertiary center to facilitate a multi-
disciplinary approach for management of complications. Individu-
als are usually managed primarily by pediatric, orthopedic, and
urologic specialists. Surgery may be required to correct or
ameliorate symptoms from associated anomalies. Treatment goals
include preservation of renal function, prevention of infection,
achievement of continence, and optimization of sensory and
motor neurologic function, including mobility.
WHAT THE REFERRING PHYSICIAN NEEDS TO KNOW
Patients with diabetes should have glucose control optimized before
conception and should be referred to an experienced center for
early US after pregnancy is diagnosed. Fetuses with suspected CRS
should be referred for US to a center with expertise in evaluating
the fetal skeleton.
KEY POINTS
• CRS represents a spectrum of anomalies involving the caudal
structures of the embryo.
• CRS is characterized by termination of the spine at various
levels and is commonly accompanied by abnormalities in
genitourinary and gastrointestinal system structure or function
or both.
• Associated anomalies are common.
• Maternal diabetes is the primary risk factor.
• Key imaging findings are sudden interruption of the spine and
abnormal lower extremity positioning.
• Prognosis depends on the level of spinal termination and
associated anomalies.
• No intrauterine treatment is available.
• Patients who choose to continue the pregnancy should have
consultation with the appropriate pediatric subspecialists.
SUGGESTED READING
Boulas MM. Recognition of caudal regression syndrome. Adv Neonatal Care.
2009;9(2):61-69, quiz 70-61.
Isik Kaygusuz E, Kurek Eken M, Sivrikoz ON, et al. Sirenomelia: a review of
embryogenic theories and discussion of the differences from caudal regression
syndrome. J Matern Fetal Neonatal Med. 2016;29(6):949-953.
All references are available online at
www.expertconsult.com.

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of embryogenic theories and discussion of the differences from caudal
regression syndrome. J Matern Fetal Neonatal Med. 2016;29(6):949-953.
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