Mycophenolate mofetil embryopathy (ORPHA:268249)
Mycophenolate mofetil (MMF) embryopathy is a malformative syndrome due to the teratogenic effect of MMF, an effective immunosuppressive agent widely used for the prevention of organ rejection after organ transplantation.
Epidemiology
To date, 25 cases have been reported, the majority being offspring of women who received a solid organ transplant.
Clinical description
Newborns or fetuses generally show external ear anomalies ranging from hypoplastic auricle (microtia) to complete absence of external ear (anotia) almost always associated with hypoplasia or atresia of the auditory canal (aural atresia) which can ultimately lead to deafness. Cleft lip-palate (see this term) with micrognathia is frequently observed. Aberrant orofacial cleft has been observed in one case. Ocular anomalies, such as microphthalmia and iris or chorioretinal coloboma, (see this term) are also frequent and can induce visual defects including severe visual impairment. Distal limbs anomalies (hypoplastic toe nails) as well as congenital malformations of the heart, kidneys and/or central nervous system may also be observed. Esophageal atresia, congenital diaphragmatic hernia (see these terms) and vertebral anomalies have been described in some cases. Intellectual deficit is usually absent, or only mild.
Etiology
MMF embryopathy is due to exposure to MMF during the intrauterine developmental period. MMF is an immunosuppressive agent that has been increasingly used in recent years in the prevention of organ transplant rejection and treatment of many autoimmune diseases because of its high efficacy and good tolerability. No dose-related effect has been demonstrated; however, exposure to low doses of MMF seems potentially teratogenic.
Diagnostic methods
Diagnosis is based on clinical examination (presence of the characteristic features in the fetus/newborn) and on maternal history of exposure to MMF during pregnancy.
Differential diagnosis
The differential diagnosis includes 18q deletion (distal), CHARGE syndrome and isotretinoin embryopathy (see these terms). 18q deletion is excluded by cytogenetic studies, CHARGE syndrome by CHD7 gene mutation scanning, and isotretinoin embryopathy by maternal interview.
Antenatal diagnosis
When relevant malformations are present (oro-facial clefts, heart defects, central nervous system malformations, diaphragmatic hernia), prenatal diagnosis by fetal ultrasonography is possible before 18 week gestation.
Management and treatment
In more than 90% of cases, internal ear anomalies require hearing-aids, and speech therapy is recommended during childhood. Oro-facial clefts and heart defects are treated surgically. To prevent the disease, it is recommended for women on MMF planning a pregnancy to replace MMF by an alternative immunosuppressive agent at least 6 weeks before stopping contraception.
Prognosis
Cases with severe cardiac malformations and/or diaphragmatic hernia may have a poor prognosis with early neonatal death. If no life-threatening malformations are present, patients may have a normal life expectancy.

                            Last update: 
                            September 2011


                            - Expert reviewer(s): 
                            Dr Antonio PÉREZ AYTÉS