Acrania-exencephaly in a two-month-old newborn: genetic and epigenetic factors. A clinical case

Acrania-anencephaly is a neural tube defect believed to result from incomplete cranial neurulation between days 17 and 28 after fertilization, in which the cranial portion of the neural tube fails to close. Acrania-exencephaly is a rare and lethal malformation, occurring with an incidence of 1.0 to 10.0 per 10.000 live births. Although the exact mechanism of acrania is unknown, it is thought to result from a combination of genetic and epigenetic factors. Neural tube defects such as acrania may be associated with genetic abnormalities and disturbances in maternal folate metabolism.A case of a live birth of a neonate with acrania-anencephaly, who survived for 2 months and 22 days, is presented. To study the possible causes of the defect, genetic and biochemical testing of both mother and infant was performed. Chromosomal karyotyping of the infant revealed a normal female karyotype (46;XX), and comparative genomic hybridization (aCGH) did not reveal chromosomal imbalances. Genetic testing of the mother revealed carriage of the heterozygous MTHFR gene variant: 1298 A>C and the homozygous MTRR gene variant: 66A>G ((G/G)), while the infant was found to have the heterozygous MTRR variant: 66A>G. Biochemical tests revealed elevated levels of homocysteine in maternal plasma, combined with vitamin B12 and folate levels at the lower limits of normal. Similar findings were observed in the child, indicating a history of chronic hyperhomocysteinemia in utero.The uniqueness of this clinical observation lies in the rare opportunity to examine neonatal tissue samples. This case of acrania-exencephaly is likely associated with genetically determined disturbances in folate metabolism in the mother. Specifically, the identified genetic variants in the mother and newborn, as well as biochemical data, point to hyperhomocysteinemia as a potential factor contributing to the development of acrania-exencephaly. This identified factor is modifiable, as correction of hyperhomocysteinemia during the preconception period may contribute to the birth of a healthy child in this couple.