Ultrasound Obstet Gynecol 2013; 42: 235–237 Published online 26 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12399
Congenital rubella with agenesis of the inferior cerebellar vermis and total anomalous pulmonary venous drainage C. CLUVER, R. MEYER, H. ODENDAAL and L. GEERTS University of Stellenbosch, Obstetrics and Gynaecology, Cape Town, Western Cape, South Africa
K E Y W O R D S: congenital rubella; inferior cerebellar vermis agenesis; TAPVD
ABSTRACT Congenital rubella infection has been associated with a number of abnormalities including cardiac, central nervous system and placental complications. We present a case with multiple fetal abnormalities detected on prenatal ultrasound, and confirmed postnatally, that included a single umbilical artery, severe tricuspid regurgitation, micrognathia and agenesis of the inferior cerebellar vermis. Postnatal echocardiography additionally revealed unobstructed total anomalous pulmonary venous drainage (TAPVD) into the coronary sinus. Placental examination showed signs of placentitis, and polymerase chain reaction on neonatal serum was positive for rubella. Following a multidisciplinary team review, it was decided to provide only supportive care, and the infant died at 6 months of age owing to a respiratory tract infection. To our knowledge, TAPVD and agenesis of the inferior cerebellar vermis have not been reported previously in association with congenital rubella infection. This case illustrates how congenital infection may present in atypical ways and stresses the importance of considering congenital infection in the differential diagnosis of fetal anomalies when multiple features are present. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORT A 16-year-old primigravida presented at our clinic for routine morphological ultrasound examination at 23 weeks’ gestation, and multiple fetal abnormalities, including agenesis of the inferior cerebellar vermis (Figures 1 and 2), micrognathia, single umbilical artery, short femur and mild tricuspid regurgitation with left cardiac axis deviation, were found. There was no record of
exposure to alcohol, nicotine or any medication. Analysis on amniocyte culture showed a normal karyotype (46,XY) and the patient elected to continue with the pregnancy. At 31 weeks, placentomegaly (width, 67 mm) and reduced amniotic fluid volume (amniotic fluid index, 6.6 cm) were noted. The fetus was small-for-gestational age, despite normal umbilical artery and middle cerebral artery Doppler results, and the tricuspid regurgitation had become severe (2.5 m/s). At this visit the patient revealed that she had been diagnosed with ‘measles’ at about 3 to 6 weeks’ gestation (diagnosis on clinical grounds only). The possibility of an underlying congenital infection was considered, but repeat invasive testing was not performed (the previous amniotic fluid sample was no longer available), as the mother wanted to continue with the pregnancy regardless of the outcome. A follow-up ultrasound examination at 35 weeks’ gestation showed new onset of mild ventriculomegaly (atrium width, 11.8 mm) and asymmetric growth. At 37 weeks the patient went into labor and delivered a male infant weighing 1670 g, with weight and height below the 3rd percentile and head circumference below the 5th percentile. The infant had hepatosplenomegaly and a ‘blueberry muffin’ skin rash, suggestive of extramedullary hematopoiesis. Dysmorphic features included micrognathia, low-set ears, a flat philtrum, a right-sided cataract, an abnormal head shape with a wide anterior fontanel, undescended testes and hypospadias. Detailed echocardiography revealed unobstructed total anomalous pulmonary venous drainage (TAPVD) into the coronary sinus, an atrial septal defect with unrestrictive right to left flow, dilatation of the right atrium and ventricle, severe tricuspid regurgitation (gradient, 45 mmHg), moderate pulmonary hypertension and a patent ductus arteriosus with bidirectional flow. Ophthalmological review and magnetic resonance imaging (MRI) confirmed
Correspondence to: Dr C. Cluver, University of Stellenbosch, Obstetrics and Gynaecology, PO Box 19063 Tygerberg, Cape Town, Western Cape 7505, South Africa (e-mail:
[email protected]) Accepted: 21 December 2012
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORT
Cluver et al.
236
Figure 1 Two-dimensional fetal brain ultrasound images at 23 weeks’ gestation. (a) Example of normal cerebellum showing cerebellar vermis (1,4) with two cerebellar hemispheres (2). (b) Described case showing absence of inferior cerebellar vermis (3) in association with early congenital rubella infection. A, anterior; L, left; P, posterior; R, right.
Figure 2 Three-dimensional fetal brain ultrasound images at 23 weeks’ gestation. (a) Example of normal cerebellum showing normal superior (1) and inferior (4) cerebellar vermis with two cerebellar hemispheres (2). (b) Described case showing absence of inferior cerebellar vermis (3) in association with early congenital rubella infection. A, anterior; L, left; P, posterior; R, right.
a significant right-sided cataract with bilateral microcornea and probable microphthalmos. Neonatal cranial ultrasound and MRI scans showed leukoencephalopathic changes, a thin corpus callosum, inferior cerebellar vermis agenesis, bilateral germinal matrix bleeds, periventricular punctate hemorrhages and ventricle size within normal limits. Blood results showed increased nucleated red blood cells, thrombocytopenia and leukopenia with increased activated and enlarged lymphocytes. Polymerase chain reaction on neonatal serum was positive for rubella. The placenta weighed 280 g and showed signs of placentitis with hypoplastic villi with vasculitis, focal mononuclear infiltration, mild edema with areas of hyalinization and vessels showing endothelial damage with fibrin thrombi. There was only one umbilical artery, with no remnant of a second artery found on multiple sections of the cord. After a multidisciplinary review the longterm prognosis was deemed poor and, after discussion with the parents, it was agreed that management would be limited to supportive care. Demise at 6 months occurred owing to a respiratory tract infection; postmortem examination was declined.
DISCUSSION
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Congenital rubella infection, first described in 1941, remains a problem1 . In developing countries vaccination programs are often lacking, while in developed countries immunization non-compliance occurs. Most of the literature dates from the rubella epidemic from 1963 to 1965 that spread across Western Europe and the USA and affected about 1% of pregnancies. It was discovered that earlier infection (i.e. before 8 weeks’ gestation) is associated with more severe abnormalities, including structural cardiac and eye defects, both of which were observed in our case2,3 . The rubella virus can be teratogenic via several mechanisms, including inhibition of cell growth, cytolysis, interference with blood supply, persistence of the virus and immunopathological mechanisms4,5 . Early embryos seem unable to clear the virus, as the normal cellular defense of apoptosis does not occur in proliferating embryonic cells6 . As the virus spreads through the vascular system of the embryo and placenta it causes extensive cytopathic damage to blood vessel walls (vasculitis and endothelial necrosis) as well as the cardiac lining7 . This is thought to be the main mechanism underlying the cardiovascular
Ultrasound Obstet Gynecol 2013; 42: 235–237.
Congenital rubella and associated anomalies and central nervous system anomalies. Further damage can be caused by secondary organ ischemia and organ infection. Direct cytopathic effects are responsible for cataract development7 . Cardiac anomalies in the fetus are commonly associated with rubella infection before 12 weeks’ gestation8 . The typical defects are patent ductus arteriosus, pulmonary stenosis and ventricular and atrial septal defects9 . TAPVD has, to our knowledge, not been associated with congenital rubella infection. We propose that vasculitis of the primordial pulmonary vein could have resulted in its obliteration, causing the venous splanchnic plexus circulation to remain and then drain into the anterior cardinal system, which ultimately becomes the coronary sinus. Typical lesions of congenital rubella in the brain show degenerative changes associated with destruction of blood vessels resulting in focal ischemic necrosis of tissue and retarded myelinization with replacement of normal tissue by deposits of amorphous granular material10 . Lesions are not necessarily restricted to the cerebrum, and in cultures of rat cerebellar tissue rubella virus had no effect on pure neuronal cell cultures but did have a cytopathic effect on glial cells, resulting in disaggregation of the neuronal processes11 . The cerebellar vermis originates from fusion of the rhombic lips from the dorsolateral portion of the alar plates, starting at 9 weeks and progressing from superior to inferior, with completion of the vermis by the 15th week. We postulate that inflammation with cellular damage resulted in incomplete inferior fusion, leading to agenesis of the inferior vermis. Inferior cerebellar vermis agenesis has, to our knowledge, not been reported previously in a case of congenital rubella infection. In conclusion, we report on a case of rubella infection occurring at 3–6 weeks’ gestation which was associated with multiple fetal anomalies, including TAPVD and agenesis of the inferior cerebellar vermis, observed on second-trimester ultrasound examination. To our knowledge, these anomalies have not previously been
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
237
reported with congenital rubella infection. This case illustrates how congenital infection may present in atypical ways and stresses the importance of considering congenital infection in the differential diagnosis of fetal anomalies when multiple features are present.
ACKNOWLEDGMENTS We thank Colleen Wright, Rebecca Folkerth, Stephanie Griffith-Richards and Lou Pistorius for their help and the Safe Passage Study for the images.
REFERENCES 1. Gregg NMA. Congenital cataract following German measles in mother. Trans Opthalmol Soc Aust 1941; 3: 35–46 2. Cooper LZ. The history and medical consequences of rubella. Rev Infect Dis 1985; 7 (Suppl): S2–S10. 3. Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982; 2: 781–784. 4. Rosenberg HS, Oppenheimer EH, Esterly JR. Congenital rubella syndrome: the late effects and their relation to early lesions. Perspect Pediatr Pathol 1981; 6: 183–202. 5. Dudgeon JA. Congenital rubella. J Pediatr 1975; 87: 1078–1086. 6. Adams JM, Heath HD, Imagawa DT, Jones MH, Shear HH. Viral infections in the embryo. AMA J Dis Child 1956; 92: 109–114. 7. Webster WS. Teratogen update: congenital rubella. Teratology 1998; 58: 13–23. 8. Sheridan MD. Final report of a prospective study of children whose mothers had rubella in early pregnancy. BMJ 1964; 2: 536–539. 9. Givens KT, Lee DA, Jones T, Ilstrup DM. Congenital rubella syndrome: ophthalmic manifestations and associated systemic disorders. Br J Ophthalmol 1993; 77: 358–363. 10. Rorke LB, Spiro AJ. Cerebral lesions in congenital rubella syndrome. J Pediatr 1967; 70: 243–255. 11. Natale VA, Caffrey JF, Sheahan BJ, Atkins GJ. Effect of infection with rubella virus on the development of rat cerebellar cells in culture. Neuropathol Appl Neurobiol 1993; 19: 530–534.
Ultrasound Obstet Gynecol 2013; 42: 235–237.
