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1. The result of segregation analysis is compatible with the hypothesis of a simple autosomal recessive mode of inheritance. 2. The number of sporadic cases is not greater than expected. 3. Among the affected siblings in the sibships analyzed, males are somewhat more frequent than females. However, this sex difference is also found among the unaffected siblings, and it is not statistically significant. 4. Contrary to assertions made in the literature, there is no clustering of affected in the sequence of siblings, no maternal age effect, and no preference of higher birth orders. 5. A high intrafamilial correlation for age at onset, and (very probably) number and severity of malformations points to genetic heterogeneity. Apart from the standard type, an especially mild type with late onset, few malformations, and a relatively benign course seems to exist. Its counterpart is possibly an especially severe type with early onset, many malformations, and a malignant course. However, definite conclusions on the special character of this heterogeneity will require application of additional methods.

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Spontaneous chromosomal breakage has been found in six inherited diseases: ataxia telangiectasia, Bloom’s syndrome, Fanconi’s anemia, glutathione reductase deficiency, Kostmann’s agranulocytosis and pernicious anemia. These diseases are not equally well researched and the cytogenetic data are by no means uniform. However, in each disease, the incidence of leukemia is increased. Chromosomal breakage has been investigated primarily in vitro. In order to connect this phenomenon with each syndrome and with the development of malignancy, the relationship between in vitro results and in vivo events must be established. This relationship may be clarified through the use of direct chromosome preparations from the bone marrow and bone marrow smears. A few such investigations have been carried out. Any evaluation of the results must consider the complexity of the bone marrow in general, as well as in each disease and in each individual case. An understanding of in vivo events in turn would allow an evaluation of factors specific to the in vitro condition, and their ability to enhance, provoke or diminish breakage. It is our opinion that contradictory results from in vitro investigations are not yet confirmed. The kind of studies necessary for such confirmation is fairly clear and, until they have been carried out, it is premature to subgroup the various diseases. A complete understanding of these diseases is possible only when the primary metabolic defect is known. Pernicious anemia is well understood although the genetics remain to be clarified. Biochemical investigations of the other five diseases are still at a preliminary stage. However, a comparison of the cytogenetic data, the clinical picture, as well as the course of the diseases may lead to a conceptualization of the unknown metabolic defect. Although the primary causes for each disease differ they manifest themselves at the cellular level in vitro and/or in vivo as spontaneous chromosomal breakage. As a consequence of this phenomenon a change in the genetic material itself may create, by chance, primary yet unknown conditions for malignant growth. This may partially explain the correlation between spontaneous chromosomal breakage and leukemia. Methodical research in this field requires that blood cultures, bone marrow smears and direct chromosome preparations from bone marrow smears and direct chromosome preparations from bone marrow be included in the close following of the diseases. It is also imperative that the designation of types of chromosome aberrations be standardized and published in detail. This, together with continuing biochemical research will finally elucidate the primary defects involved.