Neuropathology of fetal stage Seckel syndrome: a case report providing a morphological correlate for the emerging molecular mechanisms.

Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Pathological descriptions of fetal stage Seckel syndrome are rare and pre-date the evolving understanding of the genetic and molecular mechanisms involved. The autopsy findings in a case of fetal Seckel syndrome at 30 weeks gestation are presented, with detailed description of the neuropathological findings. Severe neurological abnormalities in a male fetus were observed that included microencephaly, cortical neuronal migration disorder, white matter tract hypoplasia/aplasia, premature depletion of the germinal matrix with cystic transformation and patchy absence of the external granular cell layer of the cerebellum. The striking neuropathological finding in this case was evidence of failure of the developing brain's germinal elements, providing rare morphological insight into the abnormal development of the Seckel syndrome fetal brain. The selective failure of this proliferating cell population correlates with the emerging molecular evidence that Seckel syndrome is caused by defects in ATR-dependent DNA damage signaling with resultant premature death of proliferating cells.