Mutations in Long-Chain 3-Hydroxyacyl Coenzyme a Dehydrogenase are Associated with Placental Maternal Floor Infarction/Massive Perivillous Fibrin Deposition

Abstract

Maternal floor infarction/massive perivillous fibrin deposition (MFI/MPVFD) of the placenta has an unclear etiology. The placenta of an 8-month-old child diagnosed with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency reportedly showed MFI, but no further evidence of a direct association between MFI/MPVFD and LCHAD deficiency has been documented. Three cases of MFI/MPVFD were studied. Paraffin blocks of placental tissue were retrieved, tissue scrolls were harvested, and DNA was extracted. The alpha-subunit of the mitochondrial trifunctional protein containing the LCHAD coding region (HADHA) was subsequently amplified using specific primer sets and directly sequenced by the dideoxy chain termination method. All 3 placentas demonstrated heterozygous mutations in the HADHA gene. A sample from a 25-4/7 week gestation growth-restricted female infant revealed a heterozygous mutation in exon 11, 1072C>A (glutamine to lysine, Qln358Lys) with a heterozygous sequence difference in the intron following exon 6 (insertion of a T at position +9, +9insT). The 2nd sample from a 32-4/7 week gestation stillborn fetus revealed a heterozygous mutation (+3A>G after exon 3) and a clear homozygous sequence difference in exon 17. The 3rd sample from a 31 weeks gestation infant revealed heterozygosity for the+3A>G mutation after exon 3. All 3 placentas with MFI/MPVFD demonstrated heterozygous mutations in the HADHA gene, and 2 of the 3 placentas had 2 DNA changes. Given a background incidence of heterozygosity for LCHAD mutations of approximately 1 in 220, these findings lend support to the hypothesis that LCHAD mutations may be directly associated with and potentially causative of MFI/MPVFD.

Classification of placental lesions

“…58,59 Its pathogenesis remains obscure, but anecdotal evidence suggests that it may represent a reaction to diffuse trophoblast damage secondary to a variety of stressors including autoimmune disease, maternal thrombophilia, gestational hypertension, fetal long-chain 3-hydroxyacyl-CoA dehydrogenase mutations, and Coxsackie virus A16 infection. [60][61][62][63] A pathology report with this diagnosis should never be ignored.…”

Dichorionic Twins Discordant for Massive Perivillous Fibrinoid Deposition: Report of a Case and Review of the Literature

“…Thus, the accumulations in MFD/MFI likely represent a similar appearing pathological outcome of activations of converging pathways that have many triggers or exacerbating risk factors. 1,6 For example, maternal conditions such as heritable disorders of coagulation and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency 14 and mutations in the LCHAD gene 15 have been associated with MFD. Other maternal disorders such as hypertension/preeclampsia could be exacerbating conditions because they have been associated with imbalances in angiogenic and antiangiogenic factors.…”

Placental pathologic lesions with a significant recurrence risk – what not to miss!

“…MPFD/MFI is a rare lesion, reported in <1% of all pregnancies . Its clinical significance involves many fetal and neonatal morbidities including severe IUGR , preterm birth (PTB) , cystic renal dysplasia , hypercoiled umbilical cord with single umbilical artery , renal tubular dysplasia , fetal metabolic disease with reported mutations in the LCHAD (long‐chain 3‐hydroxyacyl‐CoA‐dehydrogenase) gene , and oligohydramnios . Neonatal morbidities include an association with neurocompromise .…”