A case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype

Seidahmed, Mohammed Zain; Shaheed, Meeralebbae M.; Abdulbasit, Omar Bashir; Dohami, Hessa Al; Babiker, Mirghani; Abdullah, Mohammed A.; Abomelha, Abdullah M.

doi:10.1002/bdra.20199

Cited by 29 publications

(27 citation statements)

References 25 publications

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“…There are several studies describing brain malformation induced by MTX in human and rabbits [2, 16, 35]. A report of Seidahmed et al [35] described that 2.5 mg of MTX 3 times a day for 7 days, for a total of 52.5 mg at 6 weeks of gestation, induced alobar holoprosencephaly, cerebellar hypoplasia and agenesis of the corpus callosum in human.…”

Section: Discussionmentioning

confidence: 99%

“…A report of Seidahmed et al [35] described that 2.5 mg of MTX 3 times a day for 7 days, for a total of 52.5 mg at 6 weeks of gestation, induced alobar holoprosencephaly, cerebellar hypoplasia and agenesis of the corpus callosum in human. Corona-Rivera et al.…”

Section: Discussionmentioning

confidence: 99%

“…Medical treatment protocols for MTX were established in the 1980s and have become a widely accepted primary treatment for unruptured ectopic pregnancy [25, 32, 33]. In humans, MTX embryopathy results from failed pregnancy termination with MTX or when mothers who are taking MTX for medical reasons become pregnant inadvertently [1, 2, 14, 35]. The anomalies of MTX embryopathy include nervous system anomalies, growth deficiency, craniofacial deformities and skeletal defects [14, 26].…”

mentioning

confidence: 99%

“…The anomalies of MTX embryopathy include nervous system anomalies, growth deficiency, craniofacial deformities and skeletal defects [14, 26]. As the central nervous system anomalies in MTX embryopathy, alobar/semilobar holoprosencephaly [2, 35], cerebellar hypoplasia [35], agenesis of the corpus callosum [35] and microcephaly [1, 8] have been reported. However, there are few reports to examine the brain anomalies in MTX embryopathy histopathologically, and their detailed histopathogical findings or their detailed pathogenesis remain unclear.…”

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confidence: 99%

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Effect of Methotrexate on Neuroepithelium in the Rat Fetal Brain

Sun

Sugiyama

Inoue

et al. 2014

The Journal of Veterinary Medical Science

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Pregnant rats were treated with 30 mg/kg of methotrexate (MTX) on gestation day 13, and fetal brains were examined histopathologically from 6 to 48 hr after the treatment. In the telencephalon of the control group, there were few pyknotic neuroepithelial cells throughout the experimental period. Six hr after MTX treatment, several pyknotic neuroepithelial cells scattered throughout the telencephalic wall. At 12–36 hr, pyknotic neuroepithelial cells increased significantly and were diffusely distributed throughout the telencephalic wall. Neuroepithelial cells were eliminated and showed sparse cell density at 36 hr in the telencephalon. Almost all fetuses died at 48 hr. Most of the pyknotic neuroepithelial cells were positively stained by the TUNEL method and positive for cleaved caspase-3. While mitotic and phospho-histone H3-positive neuroepithelial cells were located along the ventricular layer of telencephalon in the control group, they were rarely observed in the same region at 6–36 hr in the MTX-treated group. MTX induced few pyknotic changes to neuroepithelial cells in the metencephalon, compared to other parts of brain. The distribution of apoptotic neuroepithelial cells and the time-course changes of the indices of apoptotic and mitotic neuroepithelial cells were different from those of other DNA-damaging chemicals reported previously. The difference may reflect the disparity in mechanisms of apoptosis and the inhibition of cell proliferation in neuroepithelial cells induced by MTX. To our knowledge, this is the first report demonstrating histopathological findings of fetal brain damage induced by MTX.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Effect of Methotrexate on Neuroepithelium in the Rat Fetal Brain

Sun

Sugiyama

Inoue

et al. 2014

The Journal of Veterinary Medical Science

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“…The craniofacial anomalies are quite distinctive and include patent cranial sutures, craniosynostosis, unusual skull shape, dysmorphic facies, and other defects. Among the central nervous system (CNS) anomalies, hydrocephalus and holoprosencephaly and mental retardation have been documented in some adult patients [Bawle et al, 1998;Del Campo et al, 1999;Seidahmed et al, 2006]. Stenotic long bones, syndactyly, and talipes equinovarus are frequently reported.…”

Section: Discussionmentioning

confidence: 98%

Methotrexate and misoprostol teratogenicity: Further expansion of the clinical manifestations

Kozma

Ramasethu

2011

American J of Med Genetics Pt A

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We describe a boy who was exposed to misoprostol and methotrexate in the first trimester of gestation as a result of a failed medical abortion. He presented with severe growth retardation, skull defects, proptotic eyes, cleft palate, and severe micrognathia. There were bilateral defects of the upper and lower extremities, missing and hypoplastic ribs, and undescended testicles. He had clinical features of pulmonary hypoplasia with severe persistent pulmonary hypertension and remained ventilator-dependent until he expired. An autopsy revealed brain anomalies consistent with arrhinencephaly. Methotrexate is frequently used in conjunction with misoprostol to induce medical abortion, an off-label use as abortifacient. Both of these medications are well-established teratogens and have an X classification during pregnancy. Data from eight patients who were exposed to both medications in the first trimester indicate a significant teratogenic risk to the developing fetus. Reported anomalies include growth retardation, absence or hypoplasia of the frontal bones, craniosynostosis, large fontanelle, ocular hypertelorism, short palpebral fissures, wide nasal bridge, malformed and low-set ears, and micrognathia. Skeletal anomalies are frequent consisting of syndactyly, mesomelic shortening of the forearms, missing ribs, dislocated hips, and talipes equinovarus. The findings in our case are consistent with the pattern of abnormalities that have been reported in the literature. In addition, our patient had severe pulmonary hypoplasia and arrhinencephaly, anomalies that have not been described previously. This case adds to the documentation of the teratogenic effects of methotrexate and misoprostol on the developing fetus.

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Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome

Corona‐Rivera

Rea-Rosas

Santana-Ramírez

et al. 2010

American J of Med Genetics Pt A

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Prenatal exposure to methotrexate (MTX) in the first trimester may lead to fetal death, and surviving children have increased risks for cranial dysostosis, dysmorphic facies, skeletal malformations, limb defects, growth retardation, and, in some cases, developmental delay, a pattern of defects recognized as fetal MTX syndrome (FMS). We report on a male infant who, in addition to severe FMS, showed previously undescribed central nervous system (CNS) and genitourinary anomalies that contributed to the further delineation. The propositus was born to a G2, 20-year-old mother with an irregular menstrual history. The unplanned pregnancy was complicated by oral MTX treatment (5 mg/day) for suspected systemic lupus erythematosus for 14 days at the 5th week post-conception, as dated by the first trimester sonogram. In addition to the typical features of the FMS, our propositus exhibited congenital penile curvature, vesicoureteral reflux, hydronephrosis, and severe CNS anomalies including semilobar holoprosencephaly (HPE). A single previous report of lobar-type HPE in an infant with FMS led us to confirm that the HPE observed in the propositus is a feature attributable to MTX teratogenicity, although the exact mechanisms of the HPE production need to be further elucidated. Also, this case serves to highlight the presence of genitourinary anomalies in patients with FMS, a fact that requires intentional searches in future patients in order to confirm this as being characteristic of the entity.

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A case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype

Cited by 29 publications

References 25 publications

Effect of Methotrexate on Neuroepithelium in the Rat Fetal Brain

Effect of Methotrexate on Neuroepithelium in the Rat Fetal Brain

Methotrexate and misoprostol teratogenicity: Further expansion of the clinical manifestations

Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome

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