Case of the Week # 520

Case of the Week # 520

Javier Cortejoso
 on 03/04/2023
 on Saturday, March 4th, 2023
The ultrasound images demonstrate the following findings:
• Images 1-6, videos 1-3: bilateral cleft lip and palate, large ventricular septal defect, short long bones of the lower limb, and possible epispadias and micropenis.
• Images 7-16: 3D computed tomography images of the lower neonatal spine shows abnormal approximation of iliac bones and absence of the L5 and sacrum, creating the classic shield appearance. The femurs are held in an abducted position and the legs flexed, known as the “frog-leg” position.
• Images 17-31: Brain MRI images are not very striking, there could be a different pattern of neuronal migration in each hemisphere (this is doubtful). In the sagittal sections of the spine there is an interruption of its most distal part with a tethered cord and possibly an accumulation of cerebrospinal fluid or syringomyelia. Regarding the possibility of visceral abnormalities, I think there could be a horseshoe kidney and possibly an anorectal malformation
• Images 32 and 33: interruption of the spine from L5 and absent sacrum and coccyx.

Maternal diabetes is a well-known risk factor for congenital anomalies. Maternal hyperglycemia is teratogenic, imposing the same risk to pregnant women with type 1 or type 2 diabetes. Good metabolic control in the preconceptional period decreases the risk of malformations. In recent studies of pregnancies with pregestational diabetes, the risk of congenital anomalies has been estimated to be between 5 and 12% compared to 2 to 3% in the background population. There is a greater proportion of anomalies affecting the central nervous system including neural tube defects, the heart, and the kidneys. Caudal regression sequence, a rare malformation, has a strong association with maternal diabetes (odds ratio 26.40). However, only 17% of all caudal regression cases resulted from a pregnancy with pregestational diabetes. Other anomalies with significantly increased odds ratios in diabetic mothers are the VATER/VACTERL association and sirenomelia.

Caudal regression syndrome, also known as caudal regression sequence, caudal dysplasia, caudal dysgenesis, 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. Hohl first described agenesis of the lumbosacral spine in 1852. A century later, Duhamel coined the term “caudal regression syndrome” to describe a spectrum of congenital malformations ranging from malformations of the anal region to the most severe form, sirenomelia with fusion of the lower extremities. In fact, caudal regression syndrome is an inadequate term to describe sacral agenesis, since there is no regression of the sacrum, but rather an absence of its development. Although caudal regression syndrome is rare in the general population (frequency estimated 1.3 in 10,000 births), maternal hyperglycemia is thought to play an important role, and the malformation is 200 times more common in infants of diabetic mothers than in the general population. Other contributing factors may include genetic predisposition, vascular anomalies altering blood flow, drugs (minoxidil, trimethoprim-sulfamethoxazole, and tocilizumab) and other environmental exposures. The presence of caudal regression syndrome in one twin of a monozygotic twin pregnancy suggests that the etiology of this entity cannot be fully explained by an environmental influence alone.

Caudal regression syndrome is categorized into two types depending on the location and shape of the conus medullaris. Type 1 is characterized by distal cord hypoplasia that is wedge-shaped and terminates abruptly rostral to the first lumbar level. In contrast, Type 2 is characterized by a tapered and low-lying conus that ends caudal to the first lumbar segment. The elongated conus is often tethered by a thickened filum terminale, terminal myelocystocele, or transitional lipoma. In the case of excessive traction of the conus medullaris, syringomyelia can occur when the normal flow of cerebrospinal fluid is obstructed. Associated anomalies are common, often involving abnormalities of the genitourinary tract (ambiguous genitalia, hydronephrosis, dilated bladder, uni- or bilateral renal agenesis, horseshoe kidneys), hindgut (imperforate anus), cardiac (ventricular septal defect), and other systems (facial clefts, and neural tube defects).

Classic findings on prenatal ultrasound include abrupt termination of the spine at various levels (low thoracic, lumbar, or sacral levels), short femora, and abnormal “frog-leg” position of the lower limbs (also termed cross-legged tailor or Buddha pose). The sacrum has been described as “shield-shaped” with the iliac wings fused and decreased distance between the femoral heads. The lower extremities often show no or abnormal movement. First-trimester ultrasound findings suggestive of the diagnosis include short crown-rump length, protuberance of the lower spine, and increased nuchal translucency. 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.

Previously, it was thought that sirenomelia is the most severe form of caudal regression syndrome, but Twicker et al. reported in 1993 the differences in clinical presentation and etiologic factors for each syndrome. In contrast to caudal regression syndrome, sirenomelia exhibits more severe caudal dysgenesis, single umbilical artery, fused lower limbs and renal agenesis that leads to oligohydramnios, pulmonary hypoplasia, with a fatal progression. It is the result of a vascular steal phenomenon, which causes severe ischemia of the caudal portion of the fetus.

The VATER association is a nonrandom association of congenital malformations that include Vertebral anomalies, Anal atresia, TracheoEsophageal fistula, Renal and Radial limb anomalies. This definition has been expanded to include vascular defects as well, and some have renamed this association VACTERL, so that congenital Cardiovascular defects and Limb anomalies are represented in the name. Most authors consider the association of three or more of the VACTERL anomalies as mandatory for diagnosis, while others have made the diagnosis with only two of the associated anomalies. It seems to be a sporadic event in many cases (90%), although a significant association has been found with maternal diabetes. The coexistence of VACTERL association with caudal regression syndrome has been published.

In 1981, Currarino et al. described a triad that consists of partial sacral dysgenesis or hemisacrum, presacral mass (anterior meningocele, enteric cyst, or presacral teratoma) and anorectal malformation. Most cases are related to an autosomal-dominant inheritance, with nearly all the familial cases linked to a mutation of the HLXB9 homeobox gene located on chromosome 7q36. It exhibits variable expressivity and may be diagnosed on prenatal ultrasound.

Regarding the differential diagnosis, patterns of abnormalities that may be associated with caudal regression syndrome should be taken into account, such as VATER or OEIS associations. Sirenomelia, also known as the mermaid syndrome, involves a single fused lower extremity and is a lethal condition usually associated with renal agenesis. The position and decreased movements of the lower extremities found in caudal regression syndrome could make us think of a fetal akinesia deformation sequence, but in this pathology the spine is normal.

Suggested readings
1. Bashiri A, Sheizaf B, Burstein E, et al. Three dimensional ultrasound diagnosis of caudal regression syndrome at 14 gestational weeks. Arch Gynecol Obstet. 2009;280(3):505-507.
2. Bouchahda H, El Mhabrech H, Hamouda HB, et al. Prenatal diagnosis of caudal regression syndrome and omphalocele in a fetus of a diabetic mother. Pan Afr Med J. 2017 Jun 16;27:128.
3. Currarino G, Coln D, Votteler T. Triad of anorectal, sacral, and presacral anomalies. AJR Am J Roentgenol. 1981;137(2):395-398.
4. Duhamel B. From the Mermaid to Anal Imperforation: The Syndrome of Caudal Regression. Arch Dis Child. 1961;36(186):152-155.
5. Fadhlaoui A, Khrouf M, Gaigi S, et al. The sirenomelia sequence: a case history. Clin Med Insights Case Rep. 2010;3:41-49.
6. Fukada Y, Yasumizu T, Tsurugi Y, et al. Caudal regression syndrome detected in a fetus with increased nuchal translucency. Acta Obstet Gynecol Scand. 1999;78(7):655-656.
7. Garne E, Loane M, Dolk H, et al. Spectrum of congenital anomalies in pregnancies with pregestational diabetes. Birth Defects Res A Clin Mol Teratol. 2012;94(3):134-140.
8. Gedikbasi A, Yararbas K, Yildirim G, et al. Prenatal diagnosis of VACTERL syndrome and partial caudal regression syndrome: a previously unreported association. J Clin Ultrasound. 2009;37(8):464-466.
9. Heuser CC, Hulinsky RS, Jackson GM. Caudal Regression Syndrome. In: Copel JA, ed. Obstetric Imaging. Fetal diagnosis and care, 2nd ed. Elsevier, Philadelphia, PA, 2018; pg 291-294.e1
10. Mottet N, Chaussy Y, Auber F, et al. How to Explore Fetal Sacral Agenesis Without Open Dysraphism: Key Prenatal Imaging and Clinical Implications. J Ultrasound Med. 2018;37(7):1807-1820.
11. Negrete LM, Chung M, Carr SR, et al. In utero diagnosis of caudal regression syndrome. Radiol Case Rep. 2015; 10(1): 1049.
12. Palacios-Marqués A, Oliver C, Martín-Bayón T, et al. Prenatal diagnosis of caudal dysplasia sequence associated with undiagnosed type I diabetes. BMJ Case Rep. 2013;2013:bcr2013009043. Published 2013 Jun 3.
13. Twickler D, Budorick N, Pretorius D, et al. Caudal regression versus sirenomelia: sonographic clues. J Ultrasound Med. 1993;12(6):323-330.
14. Zaw W, Stone DG. Caudal Regression Syndrome in twin pregnancy with type II diabetes. J Perinatol. 2002;22(2):171-174.

You can be the first one to reply!

Sign In to Reply

Add bookmark Bookmarked