Gray Matter Heterotopia: Histological Evidence of Intrauterine Radiation Exposure in a Nagasaki Atomic Bomb Survivor

Hiroshima and Nagasaki atomic bomb (A-bomb) survivors are a well-established cohort in which long-term outcomes of radiation exposure can be investigated. Although malignancies are the most recognized long-term outcome in this cohort, the effects of intrauterine exposure to ionizing radiation, including central nervous system abnormalities, also warrant consideration (1). Here, we report on a case of microcephaly in a Nagasaki A-bomb survivor. The patient was a 47-year-old male, whose mother was exposed to A-bomb radiation 2 km from the center of the explosion, at 12 weeks of pregnancy, outside without any cover. The mother’s estimated exposure dose was 0.13 Gy. The patient had presented an overall delay in physical and mental development throughout his life. He developed dilated cardiomyopathy and died from sepsis. Autopsy revealed that brain weight was 1,085 g, significantly lighter than that of the average healthy 47year-old Japanese male (1,429.8 6 109.3 g). Head circumference was 53.0 cm at the time of death, which is smaller than that of the average healthy 47-year-old Japanese male by two standard deviations (57.5 – 2 3 1.3 cm), thus meeting the criteria of microcephaly (2). In total, 47 regions throughout the brain were histologically evaluated. Low-power view of coronal sections with hematoxylin and eosin (H&E) stain demonstrated the presence of heterotopic gray matter inside the parahippocampal gyrus (Fig. 1A) and deep white matter of the frontal lobe. Tangential section through a sulcus was excluded by the evaluation of additional coronal sections. Histological analysis using Bodian staining showed optimal neuronal polarity in the true gray matter of the parahippocampal gyrus (Fig. 1B). In contrast, significant loss of polarity in neurons of the heterotopic gray matter inside the white matter of the parahippocampal gyrus was observed (Fig. 1C). Studies of A-bomb survivors in utero have demonstrated a high incidence of small head size and mental retardation. Otake and Schull reported that among 1,473 individuals prenatally exposed to A-bombing, 62 (4.2%) had microcephaly (head circumference in individuals smaller than the average circumference in a healthy age control, by twice the standard deviation) (3). Moreover, among 26 individuals with severe mental retardation, 15 (58%) had microcephaly (3). Intrauterine exposure resulting in microcephaly is thought to occur when the fetus is exposed to radiation during weeks 8–15 of pregnancy (3). Among the survivors prenatally exposed to A-bomb radiation during this critical pregnancy period, mental retardation rate is estimated to increase by 40% per 1 Gy exposure compared to the general population. During the pregnancy period, neuronal elements proliferate most rapidly and neuroblasts migrate to the cerebral cortex from the proliferative zones (4, 5). Heterotopic gray matter is likely to be a result of a neuronal migration defect induced by radiation, accompanied by an overall delay in growth and development of the brain, consistent with a published study of irradiated mice (6). Other clinical cases, illustrating the long-term effects of A-bomb radiation exposure in connection with epidemiological assessment, have been reported, including other cases of microcephaly. However, to our knowledge, this is the first case, reported in English, which describes intrauterine microcephaly with heterotopic gray matter as a feature of radiation exposure 1 Address for correspondence: Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan. , Address: 1-12-4, Sakamoto, Nagasaki, 8528523, Japan; email: moemoe@nagasaki-u.ac. jp.