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Craniosynostosis Associated with Prenatal Methotrexate Exposure
Christopher S. Zarella, MD1, Frank P. Albino, MD2, Chima O. Oluigbo, MD1, Suresh N. Magge, MD1, John S. Myseros, MD1, Robert F. Keating, MD1, Albert K. Oh, MD1, Gary F. Rogers, MD1.
1Children's National Medical Center, Washington, DC, USA, 2Georgetown University Medical Center, Washington, DC, USA.

Background: Methotrexate (MTX) is a folic acid antagonist that is a known teratogen and is used as an abortifacient. Newborns affected with MTX embryopathy demonstrate intrauterine growth retardation, and cardiac, craniofacial, and skeletal abnormalities. Four cases of MTX-associated, or MTX analog-associated craniosynostosis (CS) have been reported in the literature since 1956. We report an additional four patients with MTX-associated CS.
Methods: A retrospective, IRB approved chart review was performed. Characteristics of each patient were recorded as was pertinent medical and prenatal history.
Results: All patients were exposed to MTX early in the first trimester (< 9 weeks gestation) to induce abortion. In two instances, the mother did not finish the course of medication. All patients were born in the third trimester (33-40 weeks). Two patients had unilateral coronal synostosis, one had fusion of both coronal and the sagittal suture, and one had bilateral lambdoid and sagittal synostosis. All patients had upper limb anomalies, varying from mild to severe, including: clinodactyly of the small digits (n=3), absent distal phalanges of the index finger (n=2), thumb hypoplasia (n=1), radial hypoplasia (n=1), and humeral hypoplasia (n=1). Lower extremity anomalies included shortened femur, club foot, and oligodactly, (two patients having a single-toed foot bilaterally).
Discussion: MTX toxicity is associated with multiple developmental anomlaies, including craniosynostosis. This is the largest series of MTX-associated CS in the literature.

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