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2000-01-21-05 Answer of case of the week #17 © Giorlandino www.TheFetus.net

Answer to case #17

January 21-February 4, 2000

Submitted and discussed by Claudio Giorlandino, MD, Rome, Italy

These are images from a fetus whose mother is a 32-year-old diabetic woman (gravida 3, 1 term pregnancy and 1 miscarriage.)
This patient was referred after level I scan noted something abnormal with the feet. The legs were easy to image since the baby was not kicking during the exam.


Findings:

There were several findings in this case:

·        An abrupt interruption of the spine on image 1&2

·        Legs with little muscles (images 3-5)

·        Less obvious but still visible was the popliteal webbing on image 5, a sure sign that this leg is not bending. Note the inner curve in the popliteal fossa.

Finally there were 2 great big “clinical crutches”: the mother was diabetic and the baby’s legs were not moving during the examination

Diagnosis

As an unprecedented number of viewers had identified this combination of a foreshorten spine, immobile legs and wasted leg muscle are very typical of “Caudal regression syndrome”.

Differential diagnosis

Many suggested Arthrogryposis (and arthrogryposis-like conditions). This would certainly explain the immobility of the lower limbs, the abnormal positions, the hypotrophy of the leg muscles and the webbing. But the spine would be expected to be normal and the arms should also have been affected, which is not the case in the current case.

Caudal regression syndrome

Definition: Caudal regression syndrome (CRS) comprises developmental anomalies of the caudal vertebrae, neural tube, urogenital and digestive organs, and hind limbs, the precursors of all of which are derived from the caudal eminence. Although the syndrome is well recognized, the etiology and pathogenetic mechanisms are poorly understood.

Etiology: Maternal hyperglycemia has been proposed by most investigators as the primary teratogen factor, but hyperketonemia, hypoglycemia, somatomedin inhibitor excess, and excess free oxygen radicals have also been suggested1.

Impaired glycemic control and associated derangement in maternal metabolism appear to contribute to abnormal embryogenesis. The notion of excess glucose as the single teratogenic agent in diabetic pregnancy has thus been replaced with the view of a multifactorial etiology.

The congenital defect thought to be most characteristic of diabetic embryopathy is sacral agenesis or caudal dysplasia, an anomaly found 200 to 400 times more often in offspring of diabetic women. However, this defect is not pathognomonic for diabetes since it occurs in nondiabetic pregnancies. This defect can be found even in diabetic controlled subject.

To be a diabetic is not so necessary in order to be at risk to develop major anomalies in the children. In fact Schaefer et al3 found that in a large population of women without a diagnosis of diabetes before pregnancy, the maternal fasting serum glucose concentration at diagnosis was a useful predictor of the risk of major but not minor anomalies. The rate of major anomalies doubled with a fasting glucose level > 120 mg/dl. Thus a fasting glucose level below that of overt diabetes outside of pregnancy carries an important risk of major anomalies that must be considered in the counseling and management of these patients.

Several mechanisms have been proposed by which the above teratogenic factors produce malformations. Freinkel et al4 suggested that anomalies might arise from inhibition of glycolysis, the main energy-producing process during embryogenesis. When they inhibited glucolysis in rat embryo the result was a growth retardation and derangement of neural tube closure.

Goldman et al5 have suggested that the mechanism responsible for the increased incidence of neural tube defects in embryos cultured in a hyperglycemic medium may involve a functional deficiency of arachidonic acid, because supplementation with arachidonic acid reduce the frequency of neural tube defects in this experimental model.

Pinter and Reece, one year later6 have confirmed these studies and demonstrated that hyperglycemia-induced alterations in neural tube closure include disordered cells, decreased mitoses, and changes indicating premature maturation. These authors have further demonstrated that hyperglycemia during organogenesis has a primary deleterious effect on yolk sac function with resultant embryopathy. Altered oxidative metabolism from maternal diabetes may cause increased production of free oxygen radicals in the developing embryo, which are likely teratogenic.

Eriksson et al7 suggested that excess free oxygen radicals may have a direct effect on embryonic prostaglandin biosynthesis. Free oxygen radical excess may enhance lipid peroxidation, and in turn generated hydroperoxides might stimulate thromboxane biosynthesis and inhibit prostacyclin production, an imbalance that could have profound effects on embryonic development.

More recently Padmanabhan8 observed in animal model that use of retinoic acid can develops a caudal regression syndrome.

Personally, we think that different etiologies best explains the differences found in the histologic examination of among the subjects: hemorrhage, edema, cell death, vascular disruption, and tissue deficiency.

For example in the case presented we observed a very poor muscular tissue in the legs and this can be depending of the lack of muscle innervation secondary to the destroyed cauda equina nerves.

Differential diagnosis:

Recently the concept and even the existence of the caudal regression syndrome as independent entity in crisis. Cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs are now considered as defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in a lot of cases and makes such terms such as “caudal regression syndrome” or “axial mesodermal dysplasia spectrum” redundant10.

But, we still think that it is necessary to differentiate the typical malformation of the caudal end, from other conditions due to different etiologies with their different prognosis

Sirenomelia. Easy to distinguish. It was considered for many years to be the most severe form of caudal regression, but recent evidence suggests that these two conditions are separate entities9.

Amniotic band syndrome. Usually unilateral leg is involved. Destruction of a leg is asymmetrical and band can be searched.

Villus sampling limb defect. Have a story of chorionic villus sampling.

Associated anomalies

Klippel Feil syndrome.  In this case other congenital abnormalities are present such as: urinary incontinence, facial dysmorphia, short neck, arachnodactylia, lumbar kyphosis,  permanent flexion of the knee, talipes cavus, and at the level of the spine, a partial agenesis of the third and fourth lumbar vertebrae11. See also Klippel-Feil syndrome

Goldenhar syndrome. There are phenotypical and clinical features of the axial mesodermal dysplasia complex12. See also Goldenhar syndrome

References

See also: Caudal regression syndrome

1) Gabbe: Obstetrics - Normal and Problem Pregnancies, Third Edition,

2) Styrud J, Thunberg L, Nybacka O et al: Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats. Pediatr Res 37:343, 1995

3) Schaefer UM - Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy  Am J Obstet Gynecol - 1997 Nov; 177(5): 1165-71

4) Freinkel N, Lewis NJ et al: The honeybee syndrome: implication of the teratogenicity of mannose in rat-embryo culture. N Engl J Med 310:223, 1984

5) Goldman AS, Baker L et al: Hyperglycemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid. Proc Natl Acad Sci USA 82:8227, 1985

6) Pinter E, Reece EA: Arachidonic acid prevents hypreglycemia-associated yolk sac damange and embryopathy. Am J Obstet Gynecol 166:691, 1986

7) Eriksson NJ: Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia 34:325, 1991

8) Padmanabhan R -Retinoic acid-induced caudal regression syndrome in the mouse fetus Reprod Toxicol - 1998 Mar-Apr; 12(2): 139-51

9) Houfflin V.  Prenatal diagnosis of three caudal regression syndromes associated with maternal diabetes J Gynecol Obstet Biol Reprod (Paris) - 1996; 25(4): 389-95

10) Bohring A -Lewin SO; Reynolds JF; Voigtlander T; Rittinger O; Carey JC; Kopernik M; Smith R; Zackai EH; Leonard NJ; Gritter HL; Bamforth JS; Okun N; McLeod DR; Super M; Powell P; Mundlos S; Hennekam RC; van Langen IM; Viskochil DH; Wiedemann HR; Opitz JM Polytopic anomalies with agenesis of the lower vertebral column Am J Med Genet - 1999 Nov 19; 87(2): 99-114

11) Ly-Ba A - Caudal regression syndrome associated with Klippel-Feil syndrome Dakar Med - 1997; 42(2): 152-5

12) Bini R -Report of a new case of axial mesodermal dysplasia complex  Clin Genet - 1996 Nov; 50(5): 407-10

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