An additional patient with mycophenolate mofetil embryopathy: Cardiac and facial analyses

Abstract

We describe an infant male of Cambodian background who has typical craniofacial features of mycophenolate mofetil (MMF) embryopathy and a complex congenital heart defect (CHD) (double outlet right ventricle, mitral atresia, pulmonic stenosis, and total anomalous pulmonary venous return). Together with four case reports and the 20 patients included in two recent reviews, we report 24 (19 affected, five normal) patients with this pattern of anomalies. Eight (33%) have a CHD, most commonly, conotruncal or aortic arch defects (6/8, 75%). This would support the hypothesis that disturbance of cranial neural crest migration occurs in exposed infants, and may predict which additional anomalies will be observed in the future. We also attempted to score the severity of the facial anomalies in each MMF patient using a system created by plastic surgeons for patients with hemifacial microsomia. This classification had modest utility in comparing severity and correlating facial to extracranial defects. The findings are viewed with caution because of the preliminary methodology. Finally, since several exposed infants have been reported to be minimally affected, we remind clinicians to be sensitive to the potential mild expression of the effects of this teratogen. This awareness may influence clinical management of apparently normal MMF-exposed individuals.

ACG Clinical Guideline: Liver Disease and Pregnancy

“…Th e potential for impaired wound healing with everolimus and sirolimus must be considered if cesarean section is performed (193)(194)(195)(196). It is clear that mycophenolic acid should not be used during pregnancy owing to risk of congenital malformations and embryo-fetal toxicity (197)(198)(199)(200).…”

Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis

“…Despite inhibiting the ubiquitous process of GMP biosynthesis, some MPA-associated defects (e.g., cardiac defects, craniofacial defects, and coloboma) suggest that IMPDH inhibition disproportionately affects neural crest-derived cells (32). Interestingly, Drosophila IMPDH mutations (raspberry) cause mistargeting of photoreceptor axons (44), and MPA impairs cranial nerve development in rat embryos (45), demonstrating that defects in other neural cell types can be caused by abnormal purine metabolism.…”

“…MPA is teratogenic (31) in humans, and some MPA-associated malformations are plausibly due to defective neural crest-derived cell development (32). However, aganglionosis has not been described in MPA-exposed children or animals.…”

Esophageal atresia and prenatal exposure to mycophenolate

“…A specific pattern of anomalies has been described for mycophenolate embryopathy including microtia, atresia of external auditory canal, cleft lip and/or palate, congenital heart defects, diaphragmatic hernia, coloboma, and other eye anomalies [7,8,13]. To our knowledge, esophageal atresia has been described in five patients prenatally exposed to the drug, four of whom had also other frequently associated anomalies [8][9][10][11] (Table 1).…”

“…At present, information on the human teratogenic effect of mycophenolate includes at least 19 case reports with malformations observed after exposure in early pregnancy [7] and a prospective study that identified a 26% of malformations incidence and a rate of spontaneous abortion about twice as high than in low-risk pregnancies [8].…”