Traditionally, both the legal and medical communities determined death through the permanent end of certain bodily functions in clinical death, especially respiration and heartbeat. With the increasing ability of the medical community to resuscitate people with no respiration, heartbeat, or other external signs of life, the need for another definition of death occurred, raising questions of legal death. This gained greater urgency with the widespread use of life support equipment and the rising capabilities and demand for organ transplantation. Since the 1960s, laws governing the determination of death have been implemented in all countries that have active organ transplantation programs. The first European country to adopt brain death as a legal definition (or indicator) of death was Finland in 1971, while in the United States, the state of Kansas had enacted a similar law earlier.An ad hoc committee at Harvard Medical School published a pivotal 1968 report to define irreversible coma. The Harvard criteria gradually gained consensus toward what is now known as brain death. In the wake of the 1976 Karen Ann Quinlan case, state legislatures in the United States moved to accept brain death as an acceptable indication of death. In 1981, a presidential commission issued a landmark report entitled Defining Death: Medical, Legal, and Ethical Issues in the Determination of Death, which rejected the "higher-brain" approach to death in favor of a "whole-brain" definition. This report formed the basis for the Uniform Determination of Death Act, since enacted in 39 states.
Over a hundred ELANE mutations have been found in SCN1. This same gene is mutated in cyclic neutropenia. SCN2 is caused by heterozygous (autosomal dominant) mutation of the GFI1 gene on chromosome 1p22. GFI1 is a repressor of several transcriptional processes, including ELANE, as well as miR-21 and miR-196b micro-RNAs which influence myelopoiesis. SCN3 is the "classical", autosomal recessive form of Kostmann disease which arises from homozygous mutations in the HAX1 gene on chromosome 1p22.1. About one third of SCN3 individuals also have neurological changes including seizures, learning disabilities, or developmental delay. SCN4 is caused by autosomal recessive mutation of the G6PC3 gene on 17q21. SCN4 is associated with structural cardiac abnormalities, enlarged liver, intermittent thrombocytopenia and a prominent superficial venous pattern. A subset of SCN4 has severe primary pulmonary hypertension and respiratory failure. SCN5 arises from autosomal recessive Thr224Asn mutation in the VPS45 gene on chromosome 1q21.2. Unlike classical Kostmann disease, SCN5 also has defective platelet aggregation (thrombasthenia) and myelofibrosis. This type is refractory to granulocyte colony-stimulating factor. There is an absence of lysosomes in fibroblasts and depletion of alpha granules in platelets. Accelerated apoptosis occurs in the neutrophils and bone marrow. X-linked SCN (SCNX) is caused by mutation in the WASP gene on Xp11.SCN occasionally may arise from SBDS mutations. Usage
Severe congenital neutropenia (SCN) is used as the overarching term for all diseases that affect myelopoiesis most prominently. Kostmann syndrome can restrictively refer to Kostmann disease specifically, or can be used synonymously with SCN as an umbrella term.