Role of Perimortem Testing and Autopsy in Children with Unexplained Illnesses

Introduction: Genetic disorders that result in death pose a difficult challenge, as the cause of death often remains unknown. The family is left with unanswered questions and other affected children or family members may be as risk. Case Presentation: An 8-year-old male experienced a series of unexplained illnesses over 2 year period prior to his death. During this time he had 6 episodes of acute illness requiring hospital care, each characterized by severe headache, emesis, and dehydration. During his last episode, rapid deterioration in his condition prompted transfer to the Cook Children’s Medical Center ICU. A head CT showed bilateral cerebral edema with herniation. His neurologic exam met established criteria for brain death and, after consultation with the family, artificial life-support was discontinued and the child expired. The parents consented to an autopsy. Generalized hyperpigmentation was noted at autopsy. Gross and anatomic examination of the autopsy specimens showed bilateral abnormalities of the adrenal glands, suggestive of adrenoleukodystrophy (ALD). Based upon the autopsy findings, the limited blood sample obtained prior to death was sent for targeted DNA mutation analysis. The study confirmed an ABCD1 variant previously reported in ALD. Discussion: ALD, a rare, X-linked disorder, is characterized by elevated levels of very long chain fatty acids (VLCFA) in the brain and adrenal cortex. Males are more often and more severely affected than females. Accumulation of VLCFA results in loss of myelin and progressive dysfunction of the adrenal gland. Primary adrenal insufficiency (AI) may manifest as nausea, vomiting, hyperkalemia, hyponatremia, and episodes of dehydration. AI can be the only symptom of ALD. ALD is typically debilitating or fatal within 2-5 years of onset. Other symptoms of ALD include deafness, blindness, muscle wasting, and dementia. As an X-linked disorder, establishing the correct diagnosis is critical for proper genetic counselling of potentially affected family members. Establishing the correct diagnosis can alleviate feelings of guilt and lack of closure often experienced by family members. Genetic testing avoids further misdiagnosis and allows discussions of treatment options of affected family members. In this case, the autopsy allowed family members to receive genetic testing. Autopsies are a source of clinically relevant information that help assess the accuracy of pre-mortem diagnosis. Nationally autopsy rates have been declining. The cause of decline is multifactorial, with age and cause of death being significant, although approximately one-third of autopsies lead to a new diagnosis. An informative autopsy can help determine the test most likely to provide a correct diagnosis, utilizing limited samples obtained prior to or shortly after death. This approach often avoids unnecessary testing and expense. Barriers to autopsy include physicians’ reluctance to request an autopsy and lack of information provided to family members. Conclusions: This case illustrates the important role of autopsy in helping direct additional postmortem testing to confirm the cause of death. A protocol utilizing autopsy data to help inform perimortem genetic testing can help avoid the consequences of an undiagnosed genetic disorder. Physicians should consider the use of autopsy in helping to determine an accurate cause of death, provide closure, and, as in this case, facilitate genetic counselling of family members.