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Neuroradiology Case of the Week

Case 372

December 2008

Trushar Sarang, MD

Clinical Presentation: Patient is a 13-month-old female with a complex prenatal history including exposure to mycophenolate mofetil (MMF, trade name Cellcept), presenting at birth with multiple congenital anomalies. The mother of the child has a history of total transposition of the great vessels status post-heart transplant eight years prior to the patient's birth. The mother had three prior failed attempts at gestation and was on MMF immunosuppression during each of her attempted pregnancies. Her other medications included tacrolimus (Prograft), synthroid, propanolol, prilosec, aspirin, and citrucel. The mother was 35 years old at the time of gestation. Prenatal ultrasound demonstrated one umbilical artery, polydactyly, and severe polyhydramnios. The mother decided to proceed with the pregnancy and at 39 weeks gestation, labor was induced.
     The congenital anomalies of the patient at birth included total anomalous pulmonary venous return, ethmoid/frontal encephaloceole, cleft lip, micrognathia, bilateral congenital atresia of the external auditory canals, hypertelorism, multiple vertebral anomalies, bilateral lens dislocations, ocular colobomas, and microopthalmia.

Imaging Findings: Bilateral congenital colobomatous cysts, bilateral congenital lens dislocations, hypertelorism, and atresia of the external auditory canal.

Diagnosis: Bilateral congenital lens dislocations with colobomatous cysts after mycophenolate mofetil exposure in utero

Discussion: The use of mycophenolate mofetil (MMF) during pregnancy has been suggested to be linked to a number of congenital anomalies. MMF is a category C drug for pregnancy. Animal models have demonstrated developmental malformations, however, there is insufficient data to establish a clear link to humans. The drug manufacturer continues to stress the use of birth control during MMF treatment to avoid any potential teratogenic effects. There have been at least 7 case reports (as of 2/2008) describing a spectrum of congenital abnormalities, however an established phenotype has yet to be established. There is a striking resemblance of the constellation of findings in this patient with those previously described. Almost all of the prior literature involves mothers with renal transplants. This case illustrates a similar phenotype from a mother status post-heart transplantation.
     The most consistent phenotype illustrated in at least 6 of the 7 cases, includes cleft lip and palate, microtia with atresia of external auditory canal, micrognathia and hypertelorism. Other abnormalities seen which may be a part of this congenital spectrum include ocular anomalies, corpus callosum agenesis, heart defects, kidney malformations, and diaphragmatic hernias.
     Our patient demonstrates bilateral lens dislocations with bilateral ocular cysts, likely retinochoroidal colobomas. Colobomatous cysts are caused by a failure of closure of the parts of the eye during embryologic development. These malformations have been linked to many systemic syndromes, including oculocerebrocutaneous syndrome (Dellman's syndrome), focal dermal hypoplasia (Goltz's syndrome), brachio-oculofacial syndrome, CHARGE, VATER, and many others. Because of this patient's complex prenatal history and striking resemblance to recently described congenital phenotypes, we suggest that this patient may represent another case of MMF embryopathy.

References:

1. Perez-Aytes A, Ledo A, Boso V, et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A. 2008 Jan 1;146A(1):1-7. [PubMed]
2. Sifontis NM, Coscia LA, Constantinescu S, et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006 Dec 27;82(12):1698-702. [PubMed]
3. Som PM, Curtin HD. Head and Neck Imaging, 4th ed. St. Louis: Mosby, 2003: 463-65.