DOI: 10.1148/radiol.2301020942
(Radiology 2004;230:229-233.)
© RSNA, 2004
Case 66: Caudal Regression Syndrome in the Fetus of a Diabetic Mother1
Annemarie Stroustrup Smith, AB,
Ian Grable, MD and
Deborah Levine, MD
1 From the Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Boston, Mass (A.S.S.); and the Departments of Obstetrics and Gynecology (I.G., D.L.) and Radiology (D.L.), Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. Received August 1, 2002; revision requested September 16; revision received October 29; accepted November 11. Supported by the Carl J. Shapiro Institute for Education and Research Educational Innovation Fund; the Harvard Initiative in Patient-Associated Science: Training, Education, Understanding, and Research; and National Institutes of Health grant NS37945. Address correspondence to D.L. (e-mail: dlevine@caregroup.harvard.edu).
Index terms: Diabetes mellitus, complications • Diagnosis Please • Fetus, abnormalities • Infants, newborn • Pregnancy, abnormalities • Spinal cord, developmental defect, 32.141, 33.141 • Spine, developmental defect, 341.141, 351.141
 |
HISTORY
|
|---|
A 21-year-old pregnant woman with an 18-year history of type I diabetes mellitus was referred for a full fetal ultrasonographic (US) examination at 22 weeks gestation (Figs 1–4). Results of a prior US examination at 10 weeks gestation confirmed a single live intrauterine pregnancy; however, crown-rump length was found to be similar to that of a fetus 1 week 2 days younger than expected by last menstrual date. In addition, magnetic resonance (MR) imaging was performed to help assess fetal anatomy (Figs 5–7).
View larger version (142K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1a. Transabdominal US images of the head of the fetus at 22 weeks gestation. (a) The ventricles (V) and (b) the cerebellum (C) and cisterna magna (arrow) are of normal size and appearance. There is no Arnold-Chiari malformation.
|
|
View larger version (151K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1b. Transabdominal US images of the head of the fetus at 22 weeks gestation. (a) The ventricles (V) and (b) the cerebellum (C) and cisterna magna (arrow) are of normal size and appearance. There is no Arnold-Chiari malformation.
|
|
View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3. Transabdominal US image of the legs of the fetus at 22 weeks gestation. The orientation of the legs did not change during the examination. Soft tissue of the lower extremities is markedly decreased (arrows), which is consistent with severe atrophy. The right foot (f) is abnormally hyperextended and rotated, although it is not a classic club foot.
|
|
View larger version (159K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5. Sagittal half-Fourier single-shot RARE MR image (single-shot; effective echo time, 64 msec; field of view, 27 x 31 cm; matrix, 168 x 256; echo train length, 72; section thickness, 4 mm; one signal acquired) of a 22-week fetus. The lower portion of the body is small compared with the midbody and chest. The lower extremities (arrows) appear abnormally extended and atrophied. Structures above the level of L3 and intracranial anatomy appear normal.
|
|
View larger version (146K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6. Transverse half-Fourier single-shot RARE MR image (single-shot; effective echo time, 64 msec; field of view, 31 x 31 cm; matrix, 192 x 256; echo train length, 72; section thickness, 4 mm; one signal acquired) of a 22-week fetus. Two kidneys with a normal appearance (arrows) are present. Note the ossified spine (S) at the level of the midkidneys and the atrophic lower extremities (L).
|
|
View larger version (121K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 7. Transverse half-Fourier single-shot RARE MR image (single-shot; effective echo time, 64 msec; field of view, 31 x 31 cm; matrix, 192 x 256; echo train length, 72; section thickness, 4 mm; one signal acquired) of a 22-week fetus. A scrotum (S) and a small phallus (arrow) are present. No testicles are seen within the scrotum. The phallus is too small to be considered normal male genitalia.
|
|
|
IMAGING FINDINGS
|
|---|
US images of the fetal head demonstrated normal intracranial anatomy. In particular, the lateral ventricles and posterior fossa appeared normal (Fig 1), and biometric measurements of the head were normal for gestational age. The ossified elements of the spine were not depicted below the midlumbar region (Fig 2). The fetal legs were extended and clearly separate, and they exhibited reduced soft tissue and possessed a normal number of bones. The right foot had an abnormal orientation (Fig 3). Of note, the legs did not move during the course of the 30-minute examination, and the length of the femora was similar to that of a fetus 1 week younger than expected on the basis of other dating parameters. The left fibula was small. The pelvis was hypoplastic (Fig 4). The upper extremities appeared normal. The amniotic fluid volume was normal (Figs 1–4).
In this case, it was critical to conclusively identify intracranial, lower abdominal, and pelvic structures so that the severity of malformation could be assessed. To this end, a fetal MR imaging study was performed. Half-Fourier single-shot rapid acquisition with relaxation enhancement (RARE) MR images were obtained in the fetal coronal, transverse, and sagittal planes. These images showed normal-appearing structures above the waist, with a hypoplastic pelvis and markedly abnormal immobile legs with little soft tissue (Fig 5). Normal-appearing kidneys (Fig 6), rectum, and bladder and a small phallus (Fig 7) were seen.
|
DISCUSSION
|
|---|
Diagnostic considerations based on prenatal imaging included caudal regression syndrome (CRS), sirenomelia, and neural tube defect (NTD). CRS, also known as caudal dysplasia sequence, is characterized by a series of congenital abnormalities, including complete or partial agenesis of the sacrum and lumbar vertebrae associated with pelvic deformity. Femoral hypoplasia, clubbed feet, and flexion contractures of the lower extremities are also commonly seen. Additionally, CRS is often associated with anomalies of the gastrointestinal tract, genitourinary tract, and heart, as well as with NTD. A short crown-rump length in the first trimester, as was also seen in this fetus, is associated with CRS (1).
The majority of cases of CRS are sporadic, although at least partial genetic contribution to the development of this syndrome has been reported (2–4). CRS occurs in up to 1% of pregnancies of women with diabetes, and up to 22% of cases of CRS are associated with either type I or type II diabetes mellitus in the mother (5). Women with diabetes who are dependant on insulin are 200–400 times more likely to have a child with CRS than women without diabetes, making CRS the most characteristic fetal abnormality of diabetic embryopathy (6). Although the specific cause of CRS has not been fully elucidated, hyperglycemia is the most commonly recognized teratogen involved in this syndrome. In this case, the patient’s recent medical history was complicated by poorly controlled diabetes with glycosylated hemoglobin (hemoglobin A1C) levels of 13%–15% (0.13–0.15); normal levels are 4%–6% (0.04–0.06) (6).
CRS is thought to arise from a defect in induction of caudal elements of the embryo before the 7th week of gestation (7). To our knowledge, the exact process leading to the development of CRS has not been established, although it has been proposed that one or more processes of primitive streak migration, primary or secondary neurulation, or differentiation are compromised (2,5). The proximity and interdependency of developing caudal nervous, spinal, hindgut, and mesonephric elements result in the constellation of neural, distal vertebral, anorectal, renal, and genital abnormalities that make up CRS. Notably, structures that are developmentally separated from these caudal elements, such as the brain, proximal spine, and spinal cord, are generally spared by CRS. Prenatal diagnosis focuses on discerning the extent of caudal dysgenesis so that appropriate patient counseling can be provided and so that postnatal interventions to treat the congenital abnormalities of CRS, such as imperforate anus and fecal or urinary incontinence, can be planned.
It was previously thought that CRS and sirenomelia, also a syndrome of sacral agenesis in which the fused lower extremities cause the fetus to resemble a mermaid (siren), were manifestations of the same syndrome. In 1993, Twickler et al (8) described the differences between the two syndromes, which have different causes. Sirenomelia, rather than being a severe form of CRS, is now thought to result from a vascular steal phenomenon that causes severe ischemia of the caudal portion of the fetus (1,4,8). In sirenomelia, an aberrant vessel derived from the vitelline artery shunts blood from the high abdominal aorta directly through the umbilical cord to the placenta. This vessel, in effect, acts as an umbilical artery. The result is severe hypoperfusion of structures distal to the origin of the abnormal vessel, as this vessel "steals" blood from the caudal portion of the fetus.
Differences between CRS and sirenomelia are apparent at fetal US examination (Table). Fetuses with sirenomelia generally exhibit more severe caudal dysgenesis than those with CRS. Skeletal abnormalities seen in sirenomelia include sacral and lumbar agenesis and dysgenesis of the distal spine. The lower extremities are fused into a single limb or appear as fixed, side-by-side dysgenic legs. Often, there are fewer leg bones than normal. Unlike CRS, sirenomelia is most often fatal due to renal agenesis or severe dysgenesis and accompanying anhydramnios and pulmonary hypoplasia. Vascular anomalies, including the aberrant steal vessel, abnormally small abdominal aorta, and a two-vessel umbilical cord, are also seen with sirenomelia. The current case is distinguished from sirenomelia due to normal amniotic fluid volume, separate legs, normal number of lower extremity bones, and presence of normal-appearing kidneys.
In cases of NTD, there is splaying of the posterior spinal elements, typically with a posterior sac. In this fetus, such splaying is evident (Fig 3); however, with NTD the distal portion of the spine is present, whereas in this fetus the spine was not ossified distally. Additionally, severe lack of lower extremity musculature—which is present in this fetus—is not classically associated with NTD. Club feet can be present with either NTD or CRS. Finally, NTD is not associated with the pelvic dysgenesis seen in this fetus.
Typically, NTD is associated with Arnold-Chiari malformation, in which the tethered spinal cord causes the cerebellum and brainstem to herniate through the foramen magnum into the spinal canal. NTD cannot be excluded on the basis of a normal posterior fossa, however, as 1%–5% of NTDs occur in the absence of Arnold-Chiari malformation (4,5). In this case, there is no Arnold-Chiari malformation, which makes NTD less likely.
Patients with diabetes have a much higher risk of complications with pregnancy than patients without diabetes because of problems with glucose control. Preeclampsia, fetal growth abnormalities, and congenital anomalies are common. High blood glucose levels are thought to cause congenital abnormalities by inhibiting glycolysis, the primary process of energy production during embryogenesis (9). Dysgenesis prior to 7 weeks gestation leads to a variety of cardiac, renal, skeletal, and central nervous system malformations. Although CRS is the most characteristic defect associated with maternal diabetes, children of diabetic mothers have a 10-fold increased risk of having open spina bifida as well (6).
After extensive counseling, the patient decided to continue the pregnancy and delivered a baby boy by means of cesarean section at 38 weeks gestation (Fig 8). As predicted with antenatal imaging, the infant had CRS. There were multiple vertebral segmental anomalies extending from T6 through T9. Vertebral body L3 was dysplastic, and all vertebral bodies below L3 were absent. Additionally, the sacrum was absent. Iliac wings were present but hypoplastic. The left fifth and sixth ribs were dysplastic (Fig 9). The penis was small at 1.5 cm (normal size is 3.6 cm for 38-week gestational age [10]), with a normally placed urethra. The right testicle was in the scrotum, but the left testicle was undescended. The anus was high and posterior but patent (Fig 8b). Additionally, the infant had greater than 90th percentile body weight and greater than 90th percentile head circumference despite 25th percentile body length. Neurologic examination showed rigid lower extremities without movement, no response to stimuli of lower extremities, and absent deep tendon reflexes. The legs were flexed at the hips, and the knees were fully extended. There was a right club foot, and the left ankle was rigid in neutral position. There was no anal wink. There was good strength in the upper extremities but axial weakness at axillary suspension. The infant passed meconium spontaneously. The spinal cord termination was believed to be at the level of L1 or L2.
View larger version (137K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8a. Photographs of newborn infant with CRS. (a) The legs are extended, as was observed in utero. The right foot is inverted. (b) The anus is posterior and patent, as demonstrated by the presence of meconium.
|
|
View larger version (80K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8b. Photographs of newborn infant with CRS. (a) The legs are extended, as was observed in utero. The right foot is inverted. (b) The anus is posterior and patent, as demonstrated by the presence of meconium.
|
|
View larger version (99K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 9. Frontal radiograph of chest and abdomen of newborn infant with CRS. There are vertebral segmental anomalies from T6 through T9. Vertebral body L3 is dysplastic, and L4 and L5 are absent. The sacrum is absent. The left 5th and 6th ribs (arrows) are dysplastic.
|
|
In this fetus of a patient with diabetes, classic features of distal spine and sacral agenesis, iliac wing hypoplasia, separate legs, lower extremity contractures, and normal amniotic fluid levels and normal appearance of the kidney and brain led to the diagnosis of CRS.
|
FOOTNOTES
|
|---|
Part 1 of this case appeared 4 months previously and may contain larger images.
|
REFERENCES
|
|---|
- Benacerraf BR. Ultrasound of fetal syndromes Philadelphia, Pa: Churchill Livingstone, 1998; 250-254.
- Zaw W, Stone DG. Caudal regression syndrome in twin pregnancy with type II diabetes. J Perinatol 2002; 22:171-174.[CrossRef][Medline]
- Subtil D, Cosson M, Houfflin V, Vaast P, Valat A, Puech F. Early detection of caudal regression syndrome: specific interest and findings in three cases. Eur J Obstet Gynecol Reprod Biol 1998; 80:109-112.[CrossRef][Medline]
- Callen PW. Ultrasonography in obstetrics and gynecology 4th ed. Philadelphia, Pa: Saunders, 2000; 364-367.
- Twining P, McHugo J, Pilling D. Textbook of fetal abnormalities Philadelphia, Pa: Saunders, 2000; 158-160.
- Gabbe SG, Niebyl JR, Simpson JL. Obstetrics: normal and problem pregnancies 4th ed. New York, NY: Churchill Livingstone, 2002; 1090-1091.
- Sadler TW. Langman’s Medical Embryology 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2000; 61-110.
- Twickler D, Budorick N, Pretorius D, Grafe M, Currarino G. Caudal regression versus sirenomelia: sonographic clues. J Ultrasound Med 1993; 12:323-330.[Abstract]
- Freinkel N, Lewis NJ, Akazawa S, Roth SI, Gorman L. The honeybee syndrome: implication of the teratogenicity of mannose in rat-embryo culture. N Engl J Med 1984; 310:223-230.[Abstract]
- Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr 1975; 86:395-398.[CrossRef][Medline]
Congratulations to the 95 individuals who submitted the most likely diagnosis (caudal regression syndrome) for Diagnosis Please, Case 66. The names and locations of the individuals, as submitted, are as follows:
- Gholamali Afshang, MD, Tinley Park, Ill
- Dr Jorge Ahualli, Tucuman, Argentina
- Oguz Akin, MD, New York, NY
- Ahmed A. Al-Sinan, Dhahran, Saudi Arabia
- Ken Baliga, Rockford, Ill
- Aldo Benjamim R. Barbosa, Barretos, Brazil
- Ufuk Bayraktar, MD, Antalya, Turkey
- Lawrence N. Bennett, MD, Olympia, Wash
- Debra M. Berger, MD, New York, NY
- Jeffrey Boorstein, MD, PhD, Decatur, Ill
- Antonio Botero, MD, Bogotá, Colombia
- Michael P. Buetow, MD, Okemos, Mich
- Peter Buetow, MD, Bellingham, Wash
- Jim Cardoza, MD, Oakland, Calif
- Luisa Fernanda Cervantes, Miami, Fla
- Michael H. Childress, MD, Silver Spring, Md
- Bharath Chinta, Rochester Hills, Mich
- Timothy Clark, Greenville, NC
- James W. Cole, MD, Cincinnati, Ohio
- Wagner Diniz de Paula, MD, Brasilia, Brazil
- Jacques Demers, MD, La Pocatière, Québec, Canada
- Mustafa Kemal Demir, MD, Ataköy, Istanbul, Turkey
- Mark T. DiMarcangelo, DO, MS, FACR, Cherry Hill, NJ
- Elizabeth C. Dubovsky, MD, Alexandria, Va
- Juliet H. Fallah, MD, Chicago, Ill
- Gabriel C. Fernández Pérez, Vigo, Spain
- Ricardo B. Fonseca, MD, Nashville, Tenn
- Michael A. Foster, MD, Grove, Okla
- Arie Franco, MD, Livingston, NJ
- Akira Fujikawa, Tokyo, Japan
- Douglas Gardner, MD, Windsor, Ontario, Canada
- Ted A. Glass, MD, Jackson, Miss
- Mark Goldshein, MD, Andover, Mass
- Dr M. Grieten, Genk, Belgium
- D. Joseph Grunz, MD, Ladue, Mo
- Flavius Guglielmo, MD, Basking Ridge, NJ
- Howard T. Heller, MD, Garden City, NY
- François Humbert, Loire, France
- Alberto Iaia, MD, Wilmington, Del
- Rekha Jain, MD, Pontiac, Mich
- Vinay Jain, MD, Auburn Hills, Mich
- Sanjeeva Prasad Kalva, MD, Boston, Mass
- Koga Kaori, Tokyo, Japan
- Ercan Karaarslan, MD, Istanbul, Turkey
- Masako Kataoka, Cambridge, United Kingdom
- Pat Kiely, FFR(RCSI), Limerick, Ireland
- Eric Kinder, MD, Seattle, Wash
- Adem Kiris, MD, Elazig, Turkey
- Mitchell A. Klein, MD, Milwaukee, Wis
- E. Abelardo Lemus Rocha, MD, Juarez, Chih, Mexico
- Richard A. Levy, MD, Saginaw, Mich
- Donald R. Lewis, Jr, MD, Huntington, WVa
- John T. Lim, MD, Newport Coast, Calif
- N. B. S. Mani, MD, Nassau, Bahamas
- Frank McKowne, MD, Vancouver, Wash
- Luis Mendez-Uriburu, MD, Tucuman, Argentina
- Manabu Minami, MD, Tokyo, Japan
- Eduardo Mondello, MD, Buenos Aires, Argentina
- Albert Nizzero, MD, Sudbury, Ontario, Canada
- Mehmet Noyan Zenger, Izmir, Turkey
- Sanford M. Ornstein, MD, Phoenix, Ariz
- Harish Panicker, MD, Washington, DC
- Dr Roberto E. Perez Gautrin, Sonora, Mexico
- Sudhakar Pipavath, MD, Seattle, Wash
- Hilton W. Pittman, Pensacola, Fla
- Mario P. Pliego, MD, Bloomington, Minn
- John Plotke, Naperville, Ill
- Le-ping Pu, MD, Potomac, Md
- Nasrollah Rahbar, MD, Newport Beach, Calif
- Enrique Remartinez Escobar, MD, Melilla, Spain
- Pierre J. Sauvage, MD, Mâcon, France
- Abdelhafid Sbihi, Rabat, Morocco
- Janet Scheraga, Syracuse, NY
- Steven M. Schultz, MD, Fort Worth, Tex
- Mustafa Secil, MD, Izmir, Turkey
- Janet R. Shaefer, MD, Rapid City, SD
- S. Horatio Slawson, RPH, MD, Peoria, Ill
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- Dr John M. Stewart, Caribou, Me
- Lisa Suzuki, MD, São Paulo, Brazil
- Douglas L. Teich, MD, Brookline, Mass
- Antonio Terrones, MD, San Isidro City, Argentina
- Eugene Tong, MD, Austin, Tex
- Herminia Tyminski Al-Saffar, MD, Manama, Bahrain
- Hiroyuki Ueda, Kyoto, Japan
- Piet Vanhoenacker, MD, Aalst, Belgium
- Dra Elida Vazquez, Barcelona, Spain
- Zhen Jane Wang, MD, San Francisco, Calif
- Thomas A. Waslen, Saskatoon, Saskatchewan, Canada
- Howard C. Williams, MD, Garden City, NY
- Benjamin M. Yeh, MD, San Francisco, Calif
- Stanko Yovichevich, MD, Sydney, Australia
- Joe Yut, Olathe, Kan
- Jeffrey H. Zapolsky, Oshkosh, Wis
- Sérgio Zoriki, São Paulo, Brazil
TOP
HISTORY
IMAGING FINDINGS
